CA2119154C - Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof - Google Patents
Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereofInfo
- Publication number
- CA2119154C CA2119154C CA002119154A CA2119154A CA2119154C CA 2119154 C CA2119154 C CA 2119154C CA 002119154 A CA002119154 A CA 002119154A CA 2119154 A CA2119154 A CA 2119154A CA 2119154 C CA2119154 C CA 2119154C
- Authority
- CA
- Canada
- Prior art keywords
- cyclodextrin
- composition
- alkylene
- composition according
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
Abstract
Sulfoalkyl ether cyclodextrin derivatives and their use as solubilizing agents for water insoluble drugs for oral, intransal, or parenteral administration are disclosed.
Description
-- 211~1~i4 wos4~o2slR PCT/US93/06X80 TITLE OF T~E INVENTION
DERIVATIVES OF CYCLODEXTRINS ~l~ITING ENRANCED
AQUEOUS SOLUBILITY AND T~E USE T~EREOF
BACKGROUND OF THE lNv~llON
~: Field of the Invention:
.
The present invention relates to cyclodextrin derivatives and to their pharmaceutical application as clathrating agents.
Discussion of the 8ackground:
Cyclodextrins (CD) are a group of cyclic ho~ologous oligosaccharides that are obtained from the degradation of starch:by the action of the enzyme :cyclodextrin transglycosylasè elaborated by the bacterium Bacillus~macerans. ~ublished methods exist for-the production of~cyclodextrin transglycosylase as well~as making and isolating the ~yclodextrins.
Cyclodextrins are cyclic molecules containing six or more ~-D-glucopyranose units linked at the 1,4 positions by a linkagPs as in amylose. As a consequence of this cylic arrangement, the molecule is charscterized as having neither a reducing end group :nor a non-reducing end group.
.
.
211~1~4 wos4/o2sl8 PCT/US93/06X~0 The molecule is represented below by schematic ~ormula (l) where the hydroxyl groups are shown in the
DERIVATIVES OF CYCLODEXTRINS ~l~ITING ENRANCED
AQUEOUS SOLUBILITY AND T~E USE T~EREOF
BACKGROUND OF THE lNv~llON
~: Field of the Invention:
.
The present invention relates to cyclodextrin derivatives and to their pharmaceutical application as clathrating agents.
Discussion of the 8ackground:
Cyclodextrins (CD) are a group of cyclic ho~ologous oligosaccharides that are obtained from the degradation of starch:by the action of the enzyme :cyclodextrin transglycosylasè elaborated by the bacterium Bacillus~macerans. ~ublished methods exist for-the production of~cyclodextrin transglycosylase as well~as making and isolating the ~yclodextrins.
Cyclodextrins are cyclic molecules containing six or more ~-D-glucopyranose units linked at the 1,4 positions by a linkagPs as in amylose. As a consequence of this cylic arrangement, the molecule is charscterized as having neither a reducing end group :nor a non-reducing end group.
.
.
211~1~4 wos4/o2sl8 PCT/US93/06X~0 The molecule is represented below by schematic ~ormula (l) where the hydroxyl groups are shown in the
2, 3, and 6-positions of the glucopyranose units o :o o . ~ n Variable n~may~be~a~number from 4 to 6, or higher When n=4 the~molecule is commonly known as o-cyclodextrin or cy~lohpya~ qlose, when n=5 the molecule is~commonly known'~as~s-cyclodextrin or cy,c~oheptaamyIose~and ~hen n=6 the molecule is common;y kn~own~as~-cyclodextrin or cycloctaamylose When reference~is made~ here to cyclodextrin", it is intended,to include the foregoing forms o~ cyclodextrin as~well as~molecules~where n>6 It~ believéd that~a~ -~consequence of the cylic 'arrangement and the;-conformation of the ~-D-lu~o~anose,units,,~there is llmited free rotation about the glycosidic~bonds,~ and thé cyclodextrins exist as conical ~ ed~molecules with the primary hydroxyls situated at the~small end of the cone and the secondary hydroxyls situated at~the large o~ening to the cone The cavity is lined by hydrogen atoms from C3 and C5 ; .
~ along with the~glucosidic oxygen atoms resulting in a ~: :
2 1 ~
WO94/02518 _3_ PCT/US93~06880 relatively lipophilic cavity but hydrophilic outer surface.
As a result of the two separate polar regions and the changes in solvent structure that occur upon complexation, cyclodextrins have the ability to form complexes with a variety of organic and inorganic molecules. The formation of cyclodextrin inclusion complexes with molecules is referred to as the host-guest" phenomenon.
These unique properties of cyclodextrins have ' ~ resulted in their~commercial application in ~ ~ , a~riculture, water treatment, as surfactants and in drug delivery systems~. The application of cyclodextrins in the pharmaceutical fie}d has resulted in;time~r~leare micro~ ~CAr~ ation~ im~
stàbil$ty, and~incre4sed aqueous solubility of various drugs. ~
Cyclodextrins~ar~e known generally to improve t~e ,rQ~ntion rate~;;of drugs. The complexes formed are, hcue~er,; also~stable~in~ aqueous solution, 80 that the im~rovement in dissolution is accompanied by an increase in the saturation solubility of the drug.
Ynfortunately the very~B-cyclodextrin that forms the most stable complexes~with most drugs has the lowest water solubility,~so that drugs that are complexed with it rAnnot be brought into solution at theFapeutic ~ : ' :~ .
211!3 1 ~i 4 W094/02~18 PCT/US93/06880 concentrations. The reason for this appears to be due to the crystalline structure of B-cyclodextrin itself.
Chemical modification of cyclodextrins is known to modulate their properties. Electroneutral cyclodextrins have been described by Parmerter et al (U.S. Patent No. 3,~453,259), and Gramera et al (U.S.
Patent No. 3,459,731). These are obtained by the condensation reaction of cyclodextrins with various epoxides or organic halides.
Other derivatives include cycIodextrins with ~cationic properties (Parmerter (I); U.S. Patent No.
~ along with the~glucosidic oxygen atoms resulting in a ~: :
2 1 ~
WO94/02518 _3_ PCT/US93~06880 relatively lipophilic cavity but hydrophilic outer surface.
As a result of the two separate polar regions and the changes in solvent structure that occur upon complexation, cyclodextrins have the ability to form complexes with a variety of organic and inorganic molecules. The formation of cyclodextrin inclusion complexes with molecules is referred to as the host-guest" phenomenon.
These unique properties of cyclodextrins have ' ~ resulted in their~commercial application in ~ ~ , a~riculture, water treatment, as surfactants and in drug delivery systems~. The application of cyclodextrins in the pharmaceutical fie}d has resulted in;time~r~leare micro~ ~CAr~ ation~ im~
stàbil$ty, and~incre4sed aqueous solubility of various drugs. ~
Cyclodextrins~ar~e known generally to improve t~e ,rQ~ntion rate~;;of drugs. The complexes formed are, hcue~er,; also~stable~in~ aqueous solution, 80 that the im~rovement in dissolution is accompanied by an increase in the saturation solubility of the drug.
Ynfortunately the very~B-cyclodextrin that forms the most stable complexes~with most drugs has the lowest water solubility,~so that drugs that are complexed with it rAnnot be brought into solution at theFapeutic ~ : ' :~ .
211!3 1 ~i 4 W094/02~18 PCT/US93/06880 concentrations. The reason for this appears to be due to the crystalline structure of B-cyclodextrin itself.
Chemical modification of cyclodextrins is known to modulate their properties. Electroneutral cyclodextrins have been described by Parmerter et al (U.S. Patent No. 3,~453,259), and Gramera et al (U.S.
Patent No. 3,459,731). These are obtained by the condensation reaction of cyclodextrins with various epoxides or organic halides.
Other derivatives include cycIodextrins with ~cationic properties (Parmerter (I); U.S. Patent No.
3,453,257), inso1uble cros~linked cyclodextrins (Solms;
.~S. Patent No. 3~,420,788), and cyclodextrins with anionic properties~(Parmerter (II); U.S. Patent No.
3,42~6,011~. Among~the cyclodextrin deri~a~ives with anionic properties,~carboxylic~acids, phosphorus acids, p osphinous acids~, phosphonic acids, phosphoric acids, thiop~osr~oPi c ~ :acids, thior~h~ ~h;nic acids, and sulfonic acids (see~ Parmerter (II), fiupra)~ have been appended to the~parent~cycl~deYtrin.
, Cyclodextrins have~found applications in pharmaceutical delivery systems. As a ~host" for guest" drug molecules,~these inclusion (clathrate) complexes have shown increased aqueous solubility for pharm~ceuticals with intrinsically low aqueous .
solu~ility ~Jones;~U.S Patent 4,555,504).
:: ~
' 2119~ -~ 4 WO94/02~1X _5_ PCT/US93/06880 This solubilization results in the improved bioavailability for some drugs. As a clathrat~ complex some drugs have shown improved chemical stability in aqueous solution ~Harada et al; U.S. Patent No .
.~S. Patent No. 3~,420,788), and cyclodextrins with anionic properties~(Parmerter (II); U.S. Patent No.
3,42~6,011~. Among~the cyclodextrin deri~a~ives with anionic properties,~carboxylic~acids, phosphorus acids, p osphinous acids~, phosphonic acids, phosphoric acids, thiop~osr~oPi c ~ :acids, thior~h~ ~h;nic acids, and sulfonic acids (see~ Parmerter (II), fiupra)~ have been appended to the~parent~cycl~deYtrin.
, Cyclodextrins have~found applications in pharmaceutical delivery systems. As a ~host" for guest" drug molecules,~these inclusion (clathrate) complexes have shown increased aqueous solubility for pharm~ceuticals with intrinsically low aqueous .
solu~ility ~Jones;~U.S Patent 4,555,504).
:: ~
' 2119~ -~ 4 WO94/02~1X _5_ PCT/US93/06880 This solubilization results in the improved bioavailability for some drugs. As a clathrat~ complex some drugs have shown improved chemical stability in aqueous solution ~Harada et al; U.S. Patent No .
4,497,803 and Hayashi et al; U.S. Patent No.
~ .
3,816,394). In addition, cyclodextrins have proved effective in controlling the release oE highly water soluble pharmaceuticals (~riedman; U~S. Patent 4,774,329j. ; ~
Despite this~pharmaceutical utility, cyclodextrins are not without their limitations. The use of cyc1o~e~trins in~the clinical setting is limited to oral and t~riç~1 dosage forms as the cyclodextrins hi~hit nephrotoxicity upon:entering the body unmetabolized. Since~mammalian enzymes ~re specific ~or the deqradation of linear starch molecules, the cyc1~deYtrins~remain~largely unmetabolized and accumulate,~due~to~their recirculation and r~a~rQrption,~;in~ the proximal tubule cells.
Cyc1oA~Ytrins~-nd their derivatives are mostly crystalline solids~and co~rentration in the renal : ~ :
tissue is followed~by crystal formation causing ' necrotic damage to~the~cells. Despite forming water soluble c}athrate complexes, the crystalline :
cyclodextrin drug complexes have been limited in their utility to sublingual administration.
:
W094/0~51X PCT/US93/06880 Efforts have been made to inhibit crystal :: formation in cyclodextrin drug complexes by derivatizing parent cyclodextrins in a non-specific manner to obtain amorphous m}xtures containing many cyclodextrin derivative components (cf. Pitha; U.S.
Patent No. 4,596~,795 and 4,727,064). These mixtures prevent the crystallization processes seen with single compounds, pro~iding a~lowering of toxicity.
: SUMt4,sRY 0~ T~E lNVI r.llON
The present invention provides purified oyc~lodextrin derivatives present both as single derivatives and~as mixtures of derivatives. These are obtained~by heating~a cyclodextrin starting material with~s; reagent~(s~)~ which~intro~ s a specific anionic-type~substituent,~ i.e., a (C2_6 alkylene)-S03 anionic substituent, onto the~cyr~o~xtrin molecule. These have~;been discovered;to possess notably ~h~ced aqyeous solu~lllty~and~an advantageou~ly low de~.ee of toxicity. The more~highly substituted cyclodextrin derivatives have~further been found to advantageously c~ essentially no membrane disruption. ~hese derivatized cyc7~AP~trins are useful as clathrating agents in parenteral pharmaceutical formulations and other related uses.
211.91S~
WO g4/112~il8 _7_ PCr/US93/068~0 BRIE:F DESCRIPTION OF T~E FIGURES
A more complete appreciation of this invention and ; many of its attendan~ advantages will be readily obtained as the same becomes better understood by the ~: reference to the following detailed description when considered in connection with the accomr~nying ~igures, wherein:
. .
FIGURE 1 sets out cumulative urinary cyclodextrin excretion in mice for underivatized cyclodextrin, hydroxy propyl-derivatized cyclodextrin, and two sulEoalkyl cyclQdextrin derivatives of the present invention;
FI~u~S 2 and 3 provide data showing that the more highly substituted alkylsulfonic acids of the present nvention cause less membrane disruption, as determined by~red blood cell hemolysis ~tudies, as compared to the mono-substituted~alkylsulfonic acid derivatives, with the~:underivatized~cyclodextrin causi~g the most membrane;dis~uption,:and that the mono~substituted alkylsulfonic acid~derivatives of the present invention cause abo~t the same~amount of membrane disruption as , ~
does the bydroxypropyl cyclodextrin derivative, as also determined by red b~ood cell hemolysis study;
: FI~R~S 4, 5 and 6 show that the association onstants for the equilibrium between the sulfoalkyl cyclodextrin derivatives of the present inventlon and 211.~154 WO94~0~518 PCT/US~3/06880 digoxin or progesterone are considerably larger than the association constant for the equili~rium between a hydroxypropyl cycIodextrin derivative and digoxin or progesterone, respectively; and FI~uK~ 7, 8, 9 and lO similarly show that with phenytoin and testosterone the ~ulfoalkyl cyclodextrin derivatives of the present invention poC~ecs notably ~reater ~-oçiation:constants as compared to the :
hyd~oxy~ropyl cyclodextrin derivative.
FIGURES ll,~ 12:and 13 show the results of so1ubillty studies of testosterone, prs~ erone and nap~.. with sulfoalkylether cyclodextrin derivatives : of;~ e ~ ent i~ .Lion;.
DETPTTF~ F''~TPTION OF T~E PREF~ Fn EM~ODIME~3TS
Thus~this:invention provides cyclodextrin :; derivatives suitable for pharmaceutical use. These derivatives are:sùitable for:use as clathrating agents :with~drugs to provide clathrate complexes which are useSul in parenteral and other pharmaceutical ~:~' formulations. Procedures for making and isolating the cyclodextrin derivatives are also provided.
: : . The cyclodextrin derivatives of the present invention are functi~ z~ed with (C2_6alkylene)-SO3 ; groups, and are thus charged species. The fact that WO94J02Sl~ S ~ PCT/VS93/06880 _g _ these compounds have been discovered to possess a very low level of toxicity is surprising in light of the ~: prior art ' s belief that cyclodextrin deri~tives must retain electroneutrality to sustain lack o~ toxicity tcf. Pitha, "Amorphous Water-Soluble" "Third Int'l Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, Utah, Feb. 23-27, 1987).
:: The high a~ueous solubility of the cyclodextrin : ~ derîvatives of the present invention, and their :~ resulting lowered nephrotoxicity, is further surprising in light of US 4,727,064's disclosure that to maintain a high level of solubility for cyclodextrin derivatives, a mixture of derivatives should be used.
: The aqueous solubility exhibited by the present sulfoalkyl cyclodextrin derivatives appears to be ,. ~
obtained throu~h~solvation of the sulfonic acid ~oieties. Thus heterogeneous mixture of the present cyclodextrin~derivatives is not a requirement for the : observed e~h~nred solvation to occur. Although a ~: : : : -: mixture of sulfoalkyl ether derivatives can be used in accordance with the present in~ention, such a mixture ~ I .
is not required for e~h~nced solubility.
In a preferred embodiment (1), the cyclodex~rin derivatives of this invention have structuxes represented by formula ~2).
Wos4/o2sl8 PCT/US93/06880 0~0~o~ ' -n ; ~ wherein:
n is 4, 5 or 6;:
Rl, R2, R3 ~ R4 ~ R5 ~ R6 ~ R7 ~ R8 and Rg are each, independently,:~O~ or a O-(C2_6 alkylene)-SO3- group, wherein at least one of Rl and R2 is independently a ~-(CZ-6 alkylenc)-SO3 group,~ preferably a O-~CH2)-mSO3 roup, wherein m:is:~.Z~ to:;6,~ preferably 2 to 4, (e.g.
;ocHzcHzcHzso3 ~~r;OC~2CUzcHzc z 3 Sl, Sz, S3~ S4~;S5~ S6~ S~ S8 and Sg are each, indepen~ently, a;phàrmaceutic~lly acceptable cation which~includes,~;for~example, H+, alkali metals (e.g.
Li~ Na+,~;K~ al~Aline~earth~metals (e.g., Ca+2, M~ 2~, ammonium~lons~ànd~amines cations such as the cations~Cl_6~alkylaminés,~piperidine, pyrazine, Cl_6 ; ~ kanolamine and~C4_8~cyclo-1k~nolamine.
In~a~nothe;r~preferred embodiment (2):
;is a:O-(~C2_6~alkylene)-5O3~ group, preferably a ;~~(C~2)~mS~3 ~o~ e~g.;ocH2cH2cH2so3- or )~t R2:to Rg are O ,~
S1 to Sg are as~deSined in embodiment (1) supra.
In another preferred~embodiment t3~:
211~ 4 WO94/0~518 PCT/~IS93/06880 Rl, R2 and R3 are each, independently, a O-(C2_6-alkylene~-S03~ group, preferably a 0-(CH2)mS03- group, (e.g. ocH2cH2cH2so3 or 0CH2C~2C~2C~2S~3 ) R4 to Rg are O ; and Sl to Sg are as defined in embodiment ~1) supra In another preferred embodiment (~):
Rl to R3 are as defined in embodiments (2) or ~3);
:::: . ~supra;
at least~one of~ R4,~R6 and R8 is a 0-C2_6-alkylene)-S03~ group, preferably a 0-(C~21m-S03- group e-g- ~cH2cH2~H2so3 or ocH2cH2cH2cH2so3-)-R5~ R7 and Rg~are~O~;;~and 51 to Sg;are as defined in embodiment (1) supra.
In another~preferred embodiment (6):
Rl, R2, R3,~R4, R6 and R8 are each, independently, a~o~ c2-6-alkylene)-so3- grou~, prefera~ly a ~-~tc~2)-mso3- group~(eg- ocH2cH2c~2so3 or OCH ~ 2C~2C~2S~3 ~
~"
R5, R7 and Rg~are O~;~and Sl;to~Sg àre as~defined in e~bodiment ~1) supra.
he terms~nalk~ylene~ and "alkyl" in this text e.g., in the O-(C2_6-alkylene)S03 group or in the alkylamines) include~both linear and branched, saturated and unsaturated (i~e., containing one double bond) divalent;alkylene groups an~ monovalent alkyl ~, ~;~ groups, respectively. The term "alkanol" in this text wos4/o2s18 PCT/US93/06880 ewise includes both linear and branched, saturated and unsaturated alkyl components of the alkanol groups, in which the hydroxyl~groups may be situated at any position on the alkyl~moiety. The term "cycloalkanol"
incIudes unsubstituted or substituted (e.g., by methyl or ethyl) cyclic alcohols.
The present~invention provides compositions containing a mixture of cyclodextrin derivatives havin~
the structure set~out~ n;formula (2), where the composition overall contains on the average at least l and up to~3n~+~ 6 alkyl~sulfonic acid moieties p*r cy~1o~?Ytrin~molecule. ~he present invention also provides~compositions contA i ni~9 essentially only one single~type of cyclodextrin derivative.
The present~ cy~l o~eYtrin derivatives are either substituted at;least~at one of the primary hydroxyl group~ti.e.,~ at~least~one of Rl to R3 is a subst;ituent),~or~they are~substituted at both the pr~imary hydroxyl~;group and at the 3-position hydroxyl group (i.e.,~both~at least one of Rl to R3 and at least one of R4, R6~and~R8~are a substituent). Substitution at the 2-position~hydroxyl group, while theoretically possible, on the basi~s of the inventors' studies, does not ~r~Ar to appear~to be substantial in the products of the in~ent~on. ~
i ~
:~ :
WO94/0251X 2119 I 5 4;
-13- PCT/USg3~06880 The cyclodextrin derivatives of the present invention are obtained (as discussed below) as purified compositions, preferably as compositions containing at least 95 wt. S of cyclodextrin derivative(s) with the substitution occuring at least on the primary hydroxyl group of the cyclodextrin molecule (i.e. Rl, R2 or R3 of formula (2)), aa determined by 300 MHz lH NMR). In a preferred embodiment, purified compositions contjining at:least~98 wt.% cyclodextrin derivative(s) ~:
~ can be obtained. :
~
This is:to be~contrasted with the US 3,426,011 disclosure which reports obtaining only reaction products of~ the~reaction of a cyclodextrin with a sultone reactant~. These reaction products contain considerable~quantities of unsubstituted cyclodextrin ;starting material~
; In these~pre~ferred compositions of the i-l~e.-lion unreacted cyclodextrin has been substantially removed, :with:the rem~ D~impurities (i.e., < 5 wt.~ of composition)~being;~inconsequential to the performance of the cyclodexeriA~derivative-containing composition.
The more highly 8ubstituted alkyl sulfonic acid :cyclodextrin deriva~tives of~the present invention have been discover*d~:to~possess, in addition to notably enhanced solubility characteristics and low toxicity, the advantageous property of causing less membrane disruption. In red blood cell hemolysis studies, the more highly substituted cyclodextrin derivatives demonstrated negligible membrane disruption. The mono-substituted cyclodextrin derivatives caused about the same amount of membrane disruption as the hydroxy propyl derivative.
These improved characteristics are achieved by the purified composition of the invention which contain <5%, preferably less than 2%, of unreacted .beta.-cyclodextrin, and are particularly important for compositions to be administered to a patient by parenteral administration. The present inventors, however, have found that compositions containing somewhat higher amounts of unreacted .beta.-cyclodextrin, while not suitable for parenteral administration, are still useful for oral administration.
The administration of a drug included into a cyclodextrin preparation by an intravenous route must not contain .beta.-cyclodextrin due to its inherent nephrotoxicity. An IV administered dose gains access to the kidneys via the route of blood circulation.
2 11 ~
W094/025l~ PCT/US93/06880 Once ~-cyclodextrin is filtered by the kidney cells it appears to cause nephrotoxicity due to disruption of cellular membranes caused by removal of cholesterol from the cell membranes. Conse~uently, there is little tolerance for a derivatized cyclodextrin cont~ining residual ~-cyclodextrin if that product is to be used , :
in a parenteral formulation.
In contrast, the allowance for residual ~-cyclodextrin would be broader;for a sulfoalkylether cyclodextrin preparation used in an oral formulation.
The~ oral absorption~of~ Q clodextsin is limited (if it o~ at all) and;~the elimination of ~-cyclodextrin in the feces would preclude any~nephrotoxicity. Howeves, the level of ~-cyclodextriD which might be tolerated in an~oral formulation would still be dependent upon other characteristics of the materiaI particularly on its lntrinsic agueous~-olubility.
As a~ ~J~~lt,~the sulfoalkylether derivatives of the~ ent i~ ..Lion~ay be~used for oral formulations,~even~if unreacted ~-cyclodextrin is contained in an~amount of up to about 50%, although preferably the amount~is limited to less than 40%, and most preferably~less than about 25%.
::::
~ ~ , 2 1 1 !) 1 r~ 4 ~094/0~SIX -16- PCT/US93/06880 Preparation o~ the Cyclodextrin (CD) Derivatives:
The cyclodextrin derivatives described may be generally prepared by dissolving the cyclodextrin in aqueous base at~an appropriate temperature, e.g., 70~
to 80~C, at the highest concentration possible. For example, to prepare the cyclodextrin derivatives of embodiment ~4), an amount of an~appropriate alkyl sultone, corresponding to the number of moles of primary CD~hydroxyl~group present, is added with vigorous stirring to ensure maximal contact of the h~te:~Gy~n~o~s phase~
To~prepare the cycl~ extrin derivatives of the embodiment (2) a molar~amount o~ the alkyl sultone, corr~s,~ ing to;~the;~nuDber~of~moles of CD used, is used.~ As would~be readily determinable by one of skill 1n this~art,~ to~prepare~cyclo~eYtrin derivatives of embo~diment ;~ w~ich~ encompasses both cyclodextrin der~ivatives embo iments~ 4) and ~2~, an amount of alkyl sultone~beL~ n~that~stated~a~ove is used. Other cyrl~oA~Ytrin derivatives~provided by the present invention are;prepared~Mutatis Mutandis.
; The mixtures are allowed to react until one phase results which is;~ddicative of depletion of the alkyl sultone. The reaction mixture is diluted with an equal volume of water and~neutralized with an acid such as hydrochloric acid.~ The solution is then dialyzed to WO94/02518 2~ IS4 PCI/1'S93/06880 remove impurities followed by concentration of the solution by ultrafiltration.
The concentrated solution is then subjected to ion-exchange chromatography to remove unreacted ~: cyclodextrin, and then freeze-dried to yield the :
desired product.
The CD used~in this invention may be any CD
obtained by known me~thods, e.g., by the action of ~ cyclodextrin-glucanotransferase (CGTase, E.C., :~: 2.4.I.l9.) upon starch.: Thus CD herein means ~-CD in which six glucose;units are linked together : through~Q-1,4 bond~,~s-CD in which seven glucose units are~linked together, or ~-CD in:which eight glucose un;i~ts~are linked~together, or a mixture thereof. Of these, use of B~-CD is~most preferred for production of partia~ly derivatized~products~of broad utility.
As~noted~above~and depending on the cyclodextrin derivative sought,.~the~amount of alkyl sultone used as the~derivatizing~agent~ be:not~more than about one~molar eguivalent~ based on the number of primary hydroxyl groups~presPnt~in~the CD, although the optimum amount may be somewhat dependent on the reactant ;concentration.~:Lithium~:hydroxide, sodium hydroxide ànd ; potassium hydroxide may be used as the accelerator. of these,~sodium hydroxide is preferable because of the : its low cost. ~ts:amount must be more than about 30 :~ :
: ~
21191~i 1 .
WO 94/02~18 -18- PCI/US93/06880 molar equivalents, and should preferably be in the range of 80 to 200 molar e~uivalents, with the reactant concentration being set at a level higher than 10%
~ (wt/wt), preferably in the range of 40 to 60% (wt/wt).
; Any solvent which is substantially inert to the :
partial alkylation may be used as reaction medium.
~ypical examples are~water, DMF, DMSO, and mixtures thereof, but use of water alone is most preferred for ease of after-treatment.
The type and concentration of alkylsultone and al kAl i are not critical to the reaction. However, the reaceion is norma~ly~carr~ied out with stirring at 10 to~-~80~C for one hour,;preferably at 20~ to 50~C ~or 5 to 20 hours. ~
e~hniques~ com~only used in this fi-ld may be employed to isolate~and~purify the objective compounds Erom reaction~mixtures.~ These include extraction with organic solvents,~dialysis, adsorption chromatography wlth~activàted~charcoal, silica gel, al~mina and other adsorbents, chromatography using, as carrier, crosslinked dextrin,~styrene/divinylbenzene copolymers and other cross~linked po}ymers, and combinations thereof.
Preparation of the Clathrate Complexes:
:
211~
WO94/0?51~ PCT/US93/06880 The clathrate complexes of the invention may be prepared by any method known in the art for the preparation of complexes of cyclodextrins~
or example, to prepare the clathrate complexes, a cyclodextrin derivative dissolved in water or in an organic solvent miscible with water may be added to a physiologically active compound (dru~) dissolved in an organic solvent which is miscible with water. After the mixture i8 hea~ted, the desired product is obtained by concentrating~the mixture under reduced pressure or leaving it to be~cooled. In this case, the mixing ratio of organic 801vent with water may be suitably varied according to;the solubilities of the starting ;materials and ~products.
Ex~ ples of~drugs which may be complexed with tbe cyclodeYtrin~derivatives~include diphenyl ~ydantoin, adiphenine,~allobarbital, ~mi~~J~en~oic acid a~obarbital,~#mpi~ , ~nethole, aspirin, azoprop#z~one,~azulene barbituric acid, beclome~ one, beclome~h~rone di~v~l~o.late,~bencyclane, ~n7~1dehyde, benzocaine, benzoA;a7~rines, benzothiazide, betamethasone,~betame~h~one 17-valerate, brnmo~?n~ic acid, bromoisovaIerylurea, butyl-p-amino~~n~oate~
chloral~ e,~chlor~bucil, chloramphenicol, chlorobenzoic acid, ;chlo~yI~mazine, cinn~miC acid, clofibrate, coen7yme ~A, cortisone, cortisone acetate, 21191rj 1 WO94~02518 Pcr/us93/o688o cyclo~arbital, cyclohexyl anthranilate, deoxycholic acid, dexamethasone, dexamethasone acetate, diazepam, digitoxon, digoxin, estradiol, flufenamic acid, ; fluocinolone acetonide, 5-fluorouracil, flurbiprofen, griseofulvin, guaiazulene, hydrocortisone, hydrocortisone acetate! ibuprofen, indican, .
indomethacin, iodine, ketoprofen, lankacidin-group antibiotics, mefanamic acid, menadione, mephorbarbital, methbarbital, methici~llin, metronidazole, mitomycin, nitrazepam' nitroqlycerin~ nitrosureas, paramethasone, penecillin, pentobarbital, phenobarbital, phe~cb~r~itone, phenyl-butyric acid, phenyl-valeric acid, phenytoin,::prednisolone, prednisolone acetate, progesterone, propylparaben, proscillaridin, prostaglan~in;A series~:pros~tsglAn~in B series, ~r~J~agta~~ E ~erie6, prostagl~nA~in F series, quinolone anti~icrobials~, reserpine, ~pironolactone, ~ ~ .
r~ fA-retamide~odium,~sulphona~ide, testo~terone, tbalidomide,~thiamine~dilauryl~-~lr~-te, thiamphenicol-palmitate, thiopontal, triamcinoione, ~itamin A, vitamin D3, vita~in:~E, vitamin K3, and *arfar~n.
The drug~may be~ dissolved in water or an organic solvent (eithe~ miscible or immiscible with water~.
Convenient solvents:~include for example diethylether, tetrahydrofuran, diox~ne, acetone, dimethylsulfoxide, :~ dimethylformamide and lower aliphatic alcohols.
~ ~ .
? "'; 2 i 1 3 1 ~
W094/02~18 -21- PCT/US93fO688Q
Preferably the drug is dissolved in either water or a mixture of water and a water-miscible solvent such as methanol or ethanol. The drug may also be suspended in water.
After equilibrium is reached, the complex may be isolated by any suitable technique for example lyophilization, evaporation of the solvent, precipitation, low temQerature crystallization, or spray-drying.~ Cyclodextrin inclusion complexes may ~; also be produced~:by:physicially grinding or kneading the cyclodextrin and~the guest molecule with or without a small:amount: of solvent.
The ratio:of:~cyclodextrin derivative to drug use~
to~prepare th~e:~clathrste~complexes of the invention may be any~convenient~ratio~but conveniently the cyclodextrin:derivative is used in a molar excess.
The~benefits~;dèrived from the invention may be obtained by hav~ng~the molar ratio of cyclodextrin derivative to drug~in~;the range of 10:1 to 1:10 .prefersbly~2:1 to~S~:l for example 3:1 and by using the : ::methods and ratios:~descr~ibed:~above Complexes are conveniently obtained: containing up to 2096 w/w of the drug. ~owever~in~view of the low doses of the drug normally administered a~d the difficulty of preparing homogenous mixtures~of active ingredient and excipients :: ::
~ it may be desirable to prepare the complex with an 21191~4 WO94/02518 PCT/~lS93/06880 excess of the cyclodextrin derivative present, for example complexes containing in the order of O.l to 10%
by weight of the drug, particularly in the range 0.5 to 0.2~ by weight.
The clathrate complexes of the invention provide a more convenient way of administering the drugs, the cyclodextrin acting merely as a solubilizing agent without altering the therapeutic behavior of the drug in any way.
Composition Containinq the Clathrate Complexes of the Invention:
The invention thus also provides an inclusion complex as defined ~erein for use in human or veterinary medicine. The complex, for use as a pharmaceutical,~may presented as a pharmaceutical formulation.
:
The invention therefore provides in a further sspect a pharmaceuti~cal formulation comprising an ~: : : :: ~ : :
~ inalusion complex of a drug with a cyclodextrin :: ~
derivative together with a pharmaceutically acceptable carrier therefor and optionally other therapeutic and/or prophylactic ingredients. The carriers must be ~acceptable" in the sense of bei~g c~rAtible with the ~ other ingredients of the formula and nQt deleterious to :: . the recipient thereof. Suitably the pharmaceutical ~ formulation will be in unit dosage form~ Each unit 211~ 1 ' '4 ~WO94/02518 PCT/US93/06880 dose will conveniently contain that amount of drugnormally incorporated into a unit dose of such drug in the absence of a cyclodextrin.
The pharmaceutical formulations may be any formulation in which the inclusion complexes may be :: :
administered and include those suitable for oral, intr~n~l, intraoccular or paren~eral (including intramuscular and~intravenous) administration. The ormulations may,~where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods;well known in the art of pharmacy~.~ All~methods~inclùde the s~ep of bringing Y~ into ~ociation the~active compound with liquid carriers or fi~nely~divided solid carriers or both, and then, if necess~ry,~shaping the product into the desired~f~ormulaCion.~;~
Pharmaceùtical~formulations suitable for oral adminlstration~w~ere~D~the carrier is a solid are most preferably~-presented~as~unit aose formulations such as boiuses, capsules,~ c~h~ts or~tablets ea~h containing a predetermined amount~of the active ingredient. A
tablet may be made by;compression or molding, optio~ y~with~one or~more~accessory ingredients.
Compressed tablets~may be prepared by compressing in a suita~le machine~the;~active compound in a free-flowing form such as a powder or granules optionally mixed with ~: r ~11!31~4 WO94~02518 a binder, lubricant, inert diluent, lubricating, ~urface active or dispersing agent. Molded tablets may be made by molding an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored. Capsules may be prepared by ~illing the active compound, either alone or in admixture with one or more accessory ingredients, into : ':
the capsule cases a~nd then sealing them in the usual manner~ Cachets;are analogous to capsules wherein the active ingredient together-with any accessory ingredient(s) is sealed in a rice paper envelope.
~ ~ .
Tablets contain~the~active ingredient in admixture with~non-toxic~ pharmaceutically~acceptable excipients which~are suitable for manufacture of tablets~ These ;excipients may be,~~or example, inert diluents, such as calcium carbonate,~sodium carbonate, lactose, calcium phosph~ate or sodium pbospbate;~gran~ ting and disintegrating agents, for~example maize starch, or alginic acid; binding~agents, for example starch, gélatin or acsci~a,~and~ lubricating agents, for example magnesium stearate,~steariC acid or talc- The tablets may be ~~n~o~ted or they may be coated by known techniques to delay disintegration and absorption in the gastrointestina~l tract and thereby provide a ; sustained action over~ a longer period. For example, a ~ time delay material such as glyceryl monostearate or : ~: : :: :
:: : :
21191 5~1 WO94~0251X -25- PCT/US93/06880 glyceryl distearate alone or with a wax may be employed.
; The present invention also provides the complexes of the present invention in pharmaceutical formulations èxhibiting sustained release of a drug. Pharmaceutical formuIations exhibiting sustained release of a drug are generally known. ~Such~formulations include devices made of inert polymers or biodegradable poly-acids in which the active ingredient (the present complex) is ; either dispersed, covalently linked via labile bonds, or ~stored as~a~reservoir between polymer membranes.
Sustained release~is;achieved through diffusîon of the active ingredient~through the polymer matrix or hydrolysis of any covalent linkages present.
Sustained;~release~may also be presented by délivery~of~the;active ingredient via osmotic pumps.
Osmotic~pu ps~consist~of a~reservoir of solution or suspension~of active~ingredient (i.e., the present complex) surrounded~by~a semipermeable membrane containing a drug~portal. As water penetrates through the~ semipermeabi~e membrane~ into the comrleX reservoir, the complex solution is r~ShP~ through the portal and released.
; The cyclodextrin derivatives of the invention act as drug solubilizing~agents in these systems. The present cycloAeYtrin derivatives can also act as :::
:: ~
211~31S4 WO94/02518 PCT/US93~06880 osmotic driving aqents providing potential for the influx of water in such systems.
Pharmaceutical formulations suitable for oral administration wherein the carrier is liquid may conveniently be presented as a solution in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulslon. Pharmaceutical formulations suitable for parenteral administration are con~veniently presented:in unit dose or multi-dose containers which are sealed a~ter introduction of the formulation unit~required for use.
ormulations~for:oral use:may also be presented as hard gelatin capsules wherein the active ingredient is mixed:with an inert~solid diluent, ~or example calcium carbonate, calcium ~hos~l~ate or kaolin, or as soft gelatin capsules:wher~ein:the active ingredient is mixed with~water~or:an~oil~medium, ~for example arachis oil, peanut oll, liquid p raffin or olive oil.
; It;should~be~understood that in addition to the aforementioned~carrier: ingredients,the pharmaceutical : :formulations described~:above m~y include, as appropriate, one or more additional carrier ingredients such as diluents,~buffers,~flavoring agents, binders, surface active:agents,~:thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering .
21191~4 the formulation isotonic with the blood of the intended ; recipient.
For these purposes the compounds of the present invention may be administered orally, t~pically, ~:~ intranasa~ly, intraoccularly, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pbarmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections~, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-~looded animals such as~mice, rats,~horses~, dogs~, cats, etc., the comrou~
of the invention~are:~effective in the treatment of humans.
Aqueous~suspensions~ contain the active materials in~admixture~with:excipi~ents:suitable for the nufacture of~aqu~ous 8uspensions. Such excipients ;are~suspending~agents,~for example sodium carboxymethy}cellulose,:methylcellulose, :-hydroxypropylmethylcellulose~,: sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wett~ing~agents may be a naturally occuring phosph8~tide, for~example, lecithin, or condensation products of an alkylene oxide with fatty ' :~
~ acids, for example of polyoxyethylene stearate, or : ~ :
~ .
211~15~.
WO94/02Sl~ -28- PCT/US93/06880 condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol~anhydrides, for example polyoxyethylene sorbitan mono-oleate. The aqueous suspensions may a1so contain one or more preservatives, for example, ethyl or n-propyl p-hydroxy benzoate, one or~more coloring agents,~ one or more flavoring agents and one or more~sweetening agents, such as sucrose or saccharin. ~
~ , Oi~ly s~srensi~ons may be formulated by suspenAing the~active~ingredient in a vegetable oîl, for example arachIs~oil, olive oil,~sesame oil or rororl)t oil, or in;a~mineral oil~such~?s liquid paraffin. The oil ;; ~nsr~nsions may~contain a ~hickening agent, for example beeswax,~hard~paraffin or cetyl alcohol. Sweetening agents, such as~those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by ;the addition~of an~antioxidant such as ascorbic acid.
Dispersible powders and granules suitable ~or preparation of an agueous suspension by the addition of : :
: ~ :
211~154 ,, . ~ , WO94/0~518 PCT/US93/06880 water provide the active ingredient in admixture with a dispersing or wettînq agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspendinq agents are exemplified by those already mentioned~above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. ;
The pharmaceutical compositions of the invention may~also be in the form~of oil-in-water emulsions.
The oily phase may~be~a vegetable oil, for example olive oil or arachis oils, or a mineral oil~ for example liquid paraf~fin or mixtu;es of these. Suitable emulsifying agen~ts~may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides,~for~example soya bean lecithin, and èsters or~part~ial esters deri~ed from ~atty acids ;and~hexitol anhydrides, for example sorbitan mono-oleate, and co~den~-tion products of the said partial esters~with ethylene~oYide, for example polyo~yethylene sorbitan m~l~o oleate.; The emulsions may also contain '~ ~ sweetening and flavoring agents.
Sy-u~s and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and colorinq agents. The pharmaceutical composîtions may be in the 211~15 ll WO94/0~18 _30_ PCT/US93/06880 ' form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspe'nding agents which have been mentioned above. The sterile ~; inje~table preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or~ solvent.
Among the acceptable vehicles and solvents that may be employed are water, Ringer's~solution and isotonic sodium chloride , solution. In addition, sterile, fixed oils are conveotionAlly employ~d as a solvent or suspending f,~ medium. ~or this~purpose any bland fixed oil may be employed including~synthetic mono- or diglyc'erides. In addltlon,~ fatty~acids~such as oleic acid find use in the~preparation~'~of~injectables-The~compounds~of this invention may also be admlnistered~in~ hé form of su~positories for rectal administration of the drug. These compositions can be prepared by mixing~the~drug with a suitable non-irritating excipient which is solid at ordinary ' temperatures~but liquid~at the rectal temperature and will therefore melt~ in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
, ~' 2il91'~
-3l- PC~US93/06880 ~ or topical use, creams, oin~ments, jellies, solutions or suspensions, etc. containing the active :: ingredient are employed.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary~depending upon the host treated and the particular mode of administration. ~or example, a formulation intended for the oral administration~of humans may contain from 1.0 to 750 mg. of active agent compounded with an appropriate and c~ enient amount of carrier material which may vary vary~from about 5~to about 95 weight percent of the total~compos~ition. Unit dosage forms will generally contain between from~abou:t 1 to about 500 mg. of active ingredient.
Administration:;of::the~Clathrate Complexes to a Patient:
It will be understood:that the specifi~ dose level for~any~particular:patient will depend upon a variety of factors including~the activity of the specific compound employed,~ the age, body weightrgeneral health, .
ex, diet, time o~ administration, route of : : administration, rate of excretion, drug combination and the severity of the~particular disease undergoing therapy.
~:~
2119t~4 WO94/02~18 -32- PCT/US93/06880 Pharmaceutical formulations containin~ inclusion complexes may ~e administered at dosage levels and dosage intervals required to achieve the desired pharmacologic response normally associated with the drug and the disease state in absence of the cycIodextrin.
The other features of the invention will ~ecome apparent in the course~of the following descriptions of exemplary embodiments which are given for illustration ;of the invention and:~are not intended to be limiting thereof. ~ ~ :
:ExamDles The hydroxypropyl cyclodextrin derivative used i~
the:experiments~repor~ted below was purchased from Pharmatec, Inc.,::Alachua, Fl.
Preparation of the~cyclodextrin derivative of the invention~
Example 1:' Mono-sulfobutyl ether of B-cyclodextrin In a:lOO~mL:round-bottom flask, lO
grams~B-cyclodextrin~8~8l x lO 3 mole) was added with stirring to an aqueous solution composed of 30 mL water and 5.0 grams sodium~hydroxide maintained at 70~C. ~o this solution::1.8:mL~(2.40 gm, l.76 x lO 2 mole) butane : ~ .
sultone was slowly added with vigorous stirring to insure maximal~contact;of the heterogenous phases.
: , :
~: , WO 94/02518 2 ~ 4 PCI/US93/06880 Af ter a sin~7le phase was observed indicating depletion of the alkyl sultone, the solution was cooled to room temperature and di~ uted with 20 mL water . The resulting solution was neutralized with 1 N
;~; hydrochloric acid and dialyzed against 3 x 700 mL water ::
to remove-salts and hydroxyalkyl sufonic acids formed as side products.
The diasylste~was concentrated by ultrafiltration and placed on an ion-eYch~nge column composed of 50 grams A-25 DEAE-Sephadex packed in a 1~25 înch i.d.
glass column. Unreacted B-cyclodextr}n was removed by elution with distilled water. The mono-substituted s~ulfobutyl ether;of ~-cyclodextrin was isolated by elution with O.l;N~sodium hydroxide. The effluent fraction containing~the~mono 3ubstituted derivative was ultrafiltered to~remove any residual salts. ' The pH of the~retentate;was~adjusted to neutrality and ized-to obtain~2.~17 grams of the monosubstituted ulfobutyl ether~of~B-cyclo~eYtrin as a whîte amorphous solid. Elemental~analysis of the product showed a carbon to sulfur~ratio;~of 13.7 which corresponds to Ca.
, ~ 1.2 substitutions per molecule.
Example 2: Nono-sul~opropyl ether of B-cyclodextrin The proce~ces of Example 1 were repeated substituting 1.54~mL (2.15 grams, 1.76 x 10-2 mole) ' :
~: :
2 1 1 ~
propane sultone for butane sultone to yield 1.97 grams mono-sulfo~utyl e~her of B-cyclodextrin as a white amorphous solid. Elemental analysis of the product showed a carbon to sulfur ratio of 12.1 which corresponds to Ca. 1.4 substitutions per molecule.
:, Example 3: Sulfobutyl ethers of ~-cyclodextrin , ~
In a ~0 mL round-bottom flask, ~ grams ~-cyclodextrin (4:.41 x 10-3 mole) was added with stirring to an:aqueous solution composed of 10 mL water and 2.0 grams sodium hydroxide maintained at 70~C. ~o this solution 4.5 mL (6.0 gm, 4.41 x 1o~2 mole) butane sultone was~slowly added with vigorous stirring to insùre maximal contact~of the heterogenous phases.
After~a:single: phase was observed indicating depletion ,o'f~the:alkyl sultone,~the solution was cooled to room te~persture~and~diluted~ with 20 mL water. The :resulting solution:was neutralized with 1 N
hydrochlor~ic acid~and~di~alyzed against 3 x 700 mL water to remove salts~and hydroxyalkyl sulfonic acids formed as side products.:;:The diasylate was concentrated by :
ultrafiltration and the pH of the retentate was adjusted to'neutrality and lyophilized to obtain the sulfobutyl ether of B-cyclodextrin as a white amorphous solid. Elemental analysis of the product showed a ~ c'arbon to sulfur ratlo of 3.73 vhich corresponds to Ca.
:: :
211 91 ~ ~ ' WO94/02518 _35- PCT/US93/068X0 ; 7 substitutions per molecule. Thin-layer chromatography of the product (2-butanone:methanol:water, 4:4:2) shows the absence of unreacted ~-cyclodextrin.
:
.
: Example 4: Additional sulfoalkylethers of cyclodextrin The processes of Example 3 were varied with regard to reactants and~molar ratios to obtain cyclodextrin derivatives with varying degrees of substitution.
~:: Representative results ~foIlow:
:
~ Cy~lo~e~trin Mbles Sultone Moles Carbon/Sulfur Ratio~Substitutions :: ~
B-~..... .4.41x10~~:propane... .4.4xlO~C 3.28................. 7.2 B~ ..... 4.41X1O 3:~lop~al~e.. .2.2xlO~2 5.53.... ~............ 3.6 B~ .4.4lxlO-3:~butane~ 2~2xto-2 4.83................. 4.7 ...... 1.54xlO-3 ~.op~r,e..... 7.71xlO~3 ........ ~............ 3.5 .. :.... 1.54xlO~3~butane....... 7.71xlO~3 .................... 3.2 : Substitution determined by peak areas from 1H-NMR spectra~
::: :
~: :
,: ~: ' ~: ~
21191 r~
WO94~02~1X -36- PCT/US93~06880 .
Cumulative Urinary Cyclodextrin Excretion:
The data provided in tbe group set out in Figure 1 indicates that although the sulfoalkyl cyclodextrin derivatives of the invention as well as the hydroYypropyl derivative are excreted faster and to a greater extent~ in mice than the parent comr~ d~ the p.~-~nt derivatives a~e excreted fastest. Figure l provides data for the underivatized cyclodextrin col pound, the~ ~.y~ y~ropyl: derivative, the sulf-Jl.~l~l derivative of the imention, and the ~;ulfopropyl derivative~ of~:the~ invention.
Acote ~Par-nter-l Toxic~ty:
The ~sulfoslky1~ ~cyclodextrin derivatives of the invention :eyhi~bited' nQ~observable toxic eff~cts in male micé~over: a 30:~day~peri~following intraperi~o~e~l of
~ .
3,816,394). In addition, cyclodextrins have proved effective in controlling the release oE highly water soluble pharmaceuticals (~riedman; U~S. Patent 4,774,329j. ; ~
Despite this~pharmaceutical utility, cyclodextrins are not without their limitations. The use of cyc1o~e~trins in~the clinical setting is limited to oral and t~riç~1 dosage forms as the cyclodextrins hi~hit nephrotoxicity upon:entering the body unmetabolized. Since~mammalian enzymes ~re specific ~or the deqradation of linear starch molecules, the cyc1~deYtrins~remain~largely unmetabolized and accumulate,~due~to~their recirculation and r~a~rQrption,~;in~ the proximal tubule cells.
Cyc1oA~Ytrins~-nd their derivatives are mostly crystalline solids~and co~rentration in the renal : ~ :
tissue is followed~by crystal formation causing ' necrotic damage to~the~cells. Despite forming water soluble c}athrate complexes, the crystalline :
cyclodextrin drug complexes have been limited in their utility to sublingual administration.
:
W094/0~51X PCT/US93/06880 Efforts have been made to inhibit crystal :: formation in cyclodextrin drug complexes by derivatizing parent cyclodextrins in a non-specific manner to obtain amorphous m}xtures containing many cyclodextrin derivative components (cf. Pitha; U.S.
Patent No. 4,596~,795 and 4,727,064). These mixtures prevent the crystallization processes seen with single compounds, pro~iding a~lowering of toxicity.
: SUMt4,sRY 0~ T~E lNVI r.llON
The present invention provides purified oyc~lodextrin derivatives present both as single derivatives and~as mixtures of derivatives. These are obtained~by heating~a cyclodextrin starting material with~s; reagent~(s~)~ which~intro~ s a specific anionic-type~substituent,~ i.e., a (C2_6 alkylene)-S03 anionic substituent, onto the~cyr~o~xtrin molecule. These have~;been discovered;to possess notably ~h~ced aqyeous solu~lllty~and~an advantageou~ly low de~.ee of toxicity. The more~highly substituted cyclodextrin derivatives have~further been found to advantageously c~ essentially no membrane disruption. ~hese derivatized cyc7~AP~trins are useful as clathrating agents in parenteral pharmaceutical formulations and other related uses.
211.91S~
WO g4/112~il8 _7_ PCr/US93/068~0 BRIE:F DESCRIPTION OF T~E FIGURES
A more complete appreciation of this invention and ; many of its attendan~ advantages will be readily obtained as the same becomes better understood by the ~: reference to the following detailed description when considered in connection with the accomr~nying ~igures, wherein:
. .
FIGURE 1 sets out cumulative urinary cyclodextrin excretion in mice for underivatized cyclodextrin, hydroxy propyl-derivatized cyclodextrin, and two sulEoalkyl cyclQdextrin derivatives of the present invention;
FI~u~S 2 and 3 provide data showing that the more highly substituted alkylsulfonic acids of the present nvention cause less membrane disruption, as determined by~red blood cell hemolysis ~tudies, as compared to the mono-substituted~alkylsulfonic acid derivatives, with the~:underivatized~cyclodextrin causi~g the most membrane;dis~uption,:and that the mono~substituted alkylsulfonic acid~derivatives of the present invention cause abo~t the same~amount of membrane disruption as , ~
does the bydroxypropyl cyclodextrin derivative, as also determined by red b~ood cell hemolysis study;
: FI~R~S 4, 5 and 6 show that the association onstants for the equilibrium between the sulfoalkyl cyclodextrin derivatives of the present inventlon and 211.~154 WO94~0~518 PCT/US~3/06880 digoxin or progesterone are considerably larger than the association constant for the equili~rium between a hydroxypropyl cycIodextrin derivative and digoxin or progesterone, respectively; and FI~uK~ 7, 8, 9 and lO similarly show that with phenytoin and testosterone the ~ulfoalkyl cyclodextrin derivatives of the present invention poC~ecs notably ~reater ~-oçiation:constants as compared to the :
hyd~oxy~ropyl cyclodextrin derivative.
FIGURES ll,~ 12:and 13 show the results of so1ubillty studies of testosterone, prs~ erone and nap~.. with sulfoalkylether cyclodextrin derivatives : of;~ e ~ ent i~ .Lion;.
DETPTTF~ F''~TPTION OF T~E PREF~ Fn EM~ODIME~3TS
Thus~this:invention provides cyclodextrin :; derivatives suitable for pharmaceutical use. These derivatives are:sùitable for:use as clathrating agents :with~drugs to provide clathrate complexes which are useSul in parenteral and other pharmaceutical ~:~' formulations. Procedures for making and isolating the cyclodextrin derivatives are also provided.
: : . The cyclodextrin derivatives of the present invention are functi~ z~ed with (C2_6alkylene)-SO3 ; groups, and are thus charged species. The fact that WO94J02Sl~ S ~ PCT/VS93/06880 _g _ these compounds have been discovered to possess a very low level of toxicity is surprising in light of the ~: prior art ' s belief that cyclodextrin deri~tives must retain electroneutrality to sustain lack o~ toxicity tcf. Pitha, "Amorphous Water-Soluble" "Third Int'l Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, Utah, Feb. 23-27, 1987).
:: The high a~ueous solubility of the cyclodextrin : ~ derîvatives of the present invention, and their :~ resulting lowered nephrotoxicity, is further surprising in light of US 4,727,064's disclosure that to maintain a high level of solubility for cyclodextrin derivatives, a mixture of derivatives should be used.
: The aqueous solubility exhibited by the present sulfoalkyl cyclodextrin derivatives appears to be ,. ~
obtained throu~h~solvation of the sulfonic acid ~oieties. Thus heterogeneous mixture of the present cyclodextrin~derivatives is not a requirement for the : observed e~h~nred solvation to occur. Although a ~: : : : -: mixture of sulfoalkyl ether derivatives can be used in accordance with the present in~ention, such a mixture ~ I .
is not required for e~h~nced solubility.
In a preferred embodiment (1), the cyclodex~rin derivatives of this invention have structuxes represented by formula ~2).
Wos4/o2sl8 PCT/US93/06880 0~0~o~ ' -n ; ~ wherein:
n is 4, 5 or 6;:
Rl, R2, R3 ~ R4 ~ R5 ~ R6 ~ R7 ~ R8 and Rg are each, independently,:~O~ or a O-(C2_6 alkylene)-SO3- group, wherein at least one of Rl and R2 is independently a ~-(CZ-6 alkylenc)-SO3 group,~ preferably a O-~CH2)-mSO3 roup, wherein m:is:~.Z~ to:;6,~ preferably 2 to 4, (e.g.
;ocHzcHzcHzso3 ~~r;OC~2CUzcHzc z 3 Sl, Sz, S3~ S4~;S5~ S6~ S~ S8 and Sg are each, indepen~ently, a;phàrmaceutic~lly acceptable cation which~includes,~;for~example, H+, alkali metals (e.g.
Li~ Na+,~;K~ al~Aline~earth~metals (e.g., Ca+2, M~ 2~, ammonium~lons~ànd~amines cations such as the cations~Cl_6~alkylaminés,~piperidine, pyrazine, Cl_6 ; ~ kanolamine and~C4_8~cyclo-1k~nolamine.
In~a~nothe;r~preferred embodiment (2):
;is a:O-(~C2_6~alkylene)-5O3~ group, preferably a ;~~(C~2)~mS~3 ~o~ e~g.;ocH2cH2cH2so3- or )~t R2:to Rg are O ,~
S1 to Sg are as~deSined in embodiment (1) supra.
In another preferred~embodiment t3~:
211~ 4 WO94/0~518 PCT/~IS93/06880 Rl, R2 and R3 are each, independently, a O-(C2_6-alkylene~-S03~ group, preferably a 0-(CH2)mS03- group, (e.g. ocH2cH2cH2so3 or 0CH2C~2C~2C~2S~3 ) R4 to Rg are O ; and Sl to Sg are as defined in embodiment ~1) supra In another preferred embodiment (~):
Rl to R3 are as defined in embodiments (2) or ~3);
:::: . ~supra;
at least~one of~ R4,~R6 and R8 is a 0-C2_6-alkylene)-S03~ group, preferably a 0-(C~21m-S03- group e-g- ~cH2cH2~H2so3 or ocH2cH2cH2cH2so3-)-R5~ R7 and Rg~are~O~;;~and 51 to Sg;are as defined in embodiment (1) supra.
In another~preferred embodiment (6):
Rl, R2, R3,~R4, R6 and R8 are each, independently, a~o~ c2-6-alkylene)-so3- grou~, prefera~ly a ~-~tc~2)-mso3- group~(eg- ocH2cH2c~2so3 or OCH ~ 2C~2C~2S~3 ~
~"
R5, R7 and Rg~are O~;~and Sl;to~Sg àre as~defined in e~bodiment ~1) supra.
he terms~nalk~ylene~ and "alkyl" in this text e.g., in the O-(C2_6-alkylene)S03 group or in the alkylamines) include~both linear and branched, saturated and unsaturated (i~e., containing one double bond) divalent;alkylene groups an~ monovalent alkyl ~, ~;~ groups, respectively. The term "alkanol" in this text wos4/o2s18 PCT/US93/06880 ewise includes both linear and branched, saturated and unsaturated alkyl components of the alkanol groups, in which the hydroxyl~groups may be situated at any position on the alkyl~moiety. The term "cycloalkanol"
incIudes unsubstituted or substituted (e.g., by methyl or ethyl) cyclic alcohols.
The present~invention provides compositions containing a mixture of cyclodextrin derivatives havin~
the structure set~out~ n;formula (2), where the composition overall contains on the average at least l and up to~3n~+~ 6 alkyl~sulfonic acid moieties p*r cy~1o~?Ytrin~molecule. ~he present invention also provides~compositions contA i ni~9 essentially only one single~type of cyclodextrin derivative.
The present~ cy~l o~eYtrin derivatives are either substituted at;least~at one of the primary hydroxyl group~ti.e.,~ at~least~one of Rl to R3 is a subst;ituent),~or~they are~substituted at both the pr~imary hydroxyl~;group and at the 3-position hydroxyl group (i.e.,~both~at least one of Rl to R3 and at least one of R4, R6~and~R8~are a substituent). Substitution at the 2-position~hydroxyl group, while theoretically possible, on the basi~s of the inventors' studies, does not ~r~Ar to appear~to be substantial in the products of the in~ent~on. ~
i ~
:~ :
WO94/0251X 2119 I 5 4;
-13- PCT/USg3~06880 The cyclodextrin derivatives of the present invention are obtained (as discussed below) as purified compositions, preferably as compositions containing at least 95 wt. S of cyclodextrin derivative(s) with the substitution occuring at least on the primary hydroxyl group of the cyclodextrin molecule (i.e. Rl, R2 or R3 of formula (2)), aa determined by 300 MHz lH NMR). In a preferred embodiment, purified compositions contjining at:least~98 wt.% cyclodextrin derivative(s) ~:
~ can be obtained. :
~
This is:to be~contrasted with the US 3,426,011 disclosure which reports obtaining only reaction products of~ the~reaction of a cyclodextrin with a sultone reactant~. These reaction products contain considerable~quantities of unsubstituted cyclodextrin ;starting material~
; In these~pre~ferred compositions of the i-l~e.-lion unreacted cyclodextrin has been substantially removed, :with:the rem~ D~impurities (i.e., < 5 wt.~ of composition)~being;~inconsequential to the performance of the cyclodexeriA~derivative-containing composition.
The more highly 8ubstituted alkyl sulfonic acid :cyclodextrin deriva~tives of~the present invention have been discover*d~:to~possess, in addition to notably enhanced solubility characteristics and low toxicity, the advantageous property of causing less membrane disruption. In red blood cell hemolysis studies, the more highly substituted cyclodextrin derivatives demonstrated negligible membrane disruption. The mono-substituted cyclodextrin derivatives caused about the same amount of membrane disruption as the hydroxy propyl derivative.
These improved characteristics are achieved by the purified composition of the invention which contain <5%, preferably less than 2%, of unreacted .beta.-cyclodextrin, and are particularly important for compositions to be administered to a patient by parenteral administration. The present inventors, however, have found that compositions containing somewhat higher amounts of unreacted .beta.-cyclodextrin, while not suitable for parenteral administration, are still useful for oral administration.
The administration of a drug included into a cyclodextrin preparation by an intravenous route must not contain .beta.-cyclodextrin due to its inherent nephrotoxicity. An IV administered dose gains access to the kidneys via the route of blood circulation.
2 11 ~
W094/025l~ PCT/US93/06880 Once ~-cyclodextrin is filtered by the kidney cells it appears to cause nephrotoxicity due to disruption of cellular membranes caused by removal of cholesterol from the cell membranes. Conse~uently, there is little tolerance for a derivatized cyclodextrin cont~ining residual ~-cyclodextrin if that product is to be used , :
in a parenteral formulation.
In contrast, the allowance for residual ~-cyclodextrin would be broader;for a sulfoalkylether cyclodextrin preparation used in an oral formulation.
The~ oral absorption~of~ Q clodextsin is limited (if it o~ at all) and;~the elimination of ~-cyclodextrin in the feces would preclude any~nephrotoxicity. Howeves, the level of ~-cyclodextriD which might be tolerated in an~oral formulation would still be dependent upon other characteristics of the materiaI particularly on its lntrinsic agueous~-olubility.
As a~ ~J~~lt,~the sulfoalkylether derivatives of the~ ent i~ ..Lion~ay be~used for oral formulations,~even~if unreacted ~-cyclodextrin is contained in an~amount of up to about 50%, although preferably the amount~is limited to less than 40%, and most preferably~less than about 25%.
::::
~ ~ , 2 1 1 !) 1 r~ 4 ~094/0~SIX -16- PCT/US93/06880 Preparation o~ the Cyclodextrin (CD) Derivatives:
The cyclodextrin derivatives described may be generally prepared by dissolving the cyclodextrin in aqueous base at~an appropriate temperature, e.g., 70~
to 80~C, at the highest concentration possible. For example, to prepare the cyclodextrin derivatives of embodiment ~4), an amount of an~appropriate alkyl sultone, corresponding to the number of moles of primary CD~hydroxyl~group present, is added with vigorous stirring to ensure maximal contact of the h~te:~Gy~n~o~s phase~
To~prepare the cycl~ extrin derivatives of the embodiment (2) a molar~amount o~ the alkyl sultone, corr~s,~ ing to;~the;~nuDber~of~moles of CD used, is used.~ As would~be readily determinable by one of skill 1n this~art,~ to~prepare~cyclo~eYtrin derivatives of embo~diment ;~ w~ich~ encompasses both cyclodextrin der~ivatives embo iments~ 4) and ~2~, an amount of alkyl sultone~beL~ n~that~stated~a~ove is used. Other cyrl~oA~Ytrin derivatives~provided by the present invention are;prepared~Mutatis Mutandis.
; The mixtures are allowed to react until one phase results which is;~ddicative of depletion of the alkyl sultone. The reaction mixture is diluted with an equal volume of water and~neutralized with an acid such as hydrochloric acid.~ The solution is then dialyzed to WO94/02518 2~ IS4 PCI/1'S93/06880 remove impurities followed by concentration of the solution by ultrafiltration.
The concentrated solution is then subjected to ion-exchange chromatography to remove unreacted ~: cyclodextrin, and then freeze-dried to yield the :
desired product.
The CD used~in this invention may be any CD
obtained by known me~thods, e.g., by the action of ~ cyclodextrin-glucanotransferase (CGTase, E.C., :~: 2.4.I.l9.) upon starch.: Thus CD herein means ~-CD in which six glucose;units are linked together : through~Q-1,4 bond~,~s-CD in which seven glucose units are~linked together, or ~-CD in:which eight glucose un;i~ts~are linked~together, or a mixture thereof. Of these, use of B~-CD is~most preferred for production of partia~ly derivatized~products~of broad utility.
As~noted~above~and depending on the cyclodextrin derivative sought,.~the~amount of alkyl sultone used as the~derivatizing~agent~ be:not~more than about one~molar eguivalent~ based on the number of primary hydroxyl groups~presPnt~in~the CD, although the optimum amount may be somewhat dependent on the reactant ;concentration.~:Lithium~:hydroxide, sodium hydroxide ànd ; potassium hydroxide may be used as the accelerator. of these,~sodium hydroxide is preferable because of the : its low cost. ~ts:amount must be more than about 30 :~ :
: ~
21191~i 1 .
WO 94/02~18 -18- PCI/US93/06880 molar equivalents, and should preferably be in the range of 80 to 200 molar e~uivalents, with the reactant concentration being set at a level higher than 10%
~ (wt/wt), preferably in the range of 40 to 60% (wt/wt).
; Any solvent which is substantially inert to the :
partial alkylation may be used as reaction medium.
~ypical examples are~water, DMF, DMSO, and mixtures thereof, but use of water alone is most preferred for ease of after-treatment.
The type and concentration of alkylsultone and al kAl i are not critical to the reaction. However, the reaceion is norma~ly~carr~ied out with stirring at 10 to~-~80~C for one hour,;preferably at 20~ to 50~C ~or 5 to 20 hours. ~
e~hniques~ com~only used in this fi-ld may be employed to isolate~and~purify the objective compounds Erom reaction~mixtures.~ These include extraction with organic solvents,~dialysis, adsorption chromatography wlth~activàted~charcoal, silica gel, al~mina and other adsorbents, chromatography using, as carrier, crosslinked dextrin,~styrene/divinylbenzene copolymers and other cross~linked po}ymers, and combinations thereof.
Preparation of the Clathrate Complexes:
:
211~
WO94/0?51~ PCT/US93/06880 The clathrate complexes of the invention may be prepared by any method known in the art for the preparation of complexes of cyclodextrins~
or example, to prepare the clathrate complexes, a cyclodextrin derivative dissolved in water or in an organic solvent miscible with water may be added to a physiologically active compound (dru~) dissolved in an organic solvent which is miscible with water. After the mixture i8 hea~ted, the desired product is obtained by concentrating~the mixture under reduced pressure or leaving it to be~cooled. In this case, the mixing ratio of organic 801vent with water may be suitably varied according to;the solubilities of the starting ;materials and ~products.
Ex~ ples of~drugs which may be complexed with tbe cyclodeYtrin~derivatives~include diphenyl ~ydantoin, adiphenine,~allobarbital, ~mi~~J~en~oic acid a~obarbital,~#mpi~ , ~nethole, aspirin, azoprop#z~one,~azulene barbituric acid, beclome~ one, beclome~h~rone di~v~l~o.late,~bencyclane, ~n7~1dehyde, benzocaine, benzoA;a7~rines, benzothiazide, betamethasone,~betame~h~one 17-valerate, brnmo~?n~ic acid, bromoisovaIerylurea, butyl-p-amino~~n~oate~
chloral~ e,~chlor~bucil, chloramphenicol, chlorobenzoic acid, ;chlo~yI~mazine, cinn~miC acid, clofibrate, coen7yme ~A, cortisone, cortisone acetate, 21191rj 1 WO94~02518 Pcr/us93/o688o cyclo~arbital, cyclohexyl anthranilate, deoxycholic acid, dexamethasone, dexamethasone acetate, diazepam, digitoxon, digoxin, estradiol, flufenamic acid, ; fluocinolone acetonide, 5-fluorouracil, flurbiprofen, griseofulvin, guaiazulene, hydrocortisone, hydrocortisone acetate! ibuprofen, indican, .
indomethacin, iodine, ketoprofen, lankacidin-group antibiotics, mefanamic acid, menadione, mephorbarbital, methbarbital, methici~llin, metronidazole, mitomycin, nitrazepam' nitroqlycerin~ nitrosureas, paramethasone, penecillin, pentobarbital, phenobarbital, phe~cb~r~itone, phenyl-butyric acid, phenyl-valeric acid, phenytoin,::prednisolone, prednisolone acetate, progesterone, propylparaben, proscillaridin, prostaglan~in;A series~:pros~tsglAn~in B series, ~r~J~agta~~ E ~erie6, prostagl~nA~in F series, quinolone anti~icrobials~, reserpine, ~pironolactone, ~ ~ .
r~ fA-retamide~odium,~sulphona~ide, testo~terone, tbalidomide,~thiamine~dilauryl~-~lr~-te, thiamphenicol-palmitate, thiopontal, triamcinoione, ~itamin A, vitamin D3, vita~in:~E, vitamin K3, and *arfar~n.
The drug~may be~ dissolved in water or an organic solvent (eithe~ miscible or immiscible with water~.
Convenient solvents:~include for example diethylether, tetrahydrofuran, diox~ne, acetone, dimethylsulfoxide, :~ dimethylformamide and lower aliphatic alcohols.
~ ~ .
? "'; 2 i 1 3 1 ~
W094/02~18 -21- PCT/US93fO688Q
Preferably the drug is dissolved in either water or a mixture of water and a water-miscible solvent such as methanol or ethanol. The drug may also be suspended in water.
After equilibrium is reached, the complex may be isolated by any suitable technique for example lyophilization, evaporation of the solvent, precipitation, low temQerature crystallization, or spray-drying.~ Cyclodextrin inclusion complexes may ~; also be produced~:by:physicially grinding or kneading the cyclodextrin and~the guest molecule with or without a small:amount: of solvent.
The ratio:of:~cyclodextrin derivative to drug use~
to~prepare th~e:~clathrste~complexes of the invention may be any~convenient~ratio~but conveniently the cyclodextrin:derivative is used in a molar excess.
The~benefits~;dèrived from the invention may be obtained by hav~ng~the molar ratio of cyclodextrin derivative to drug~in~;the range of 10:1 to 1:10 .prefersbly~2:1 to~S~:l for example 3:1 and by using the : ::methods and ratios:~descr~ibed:~above Complexes are conveniently obtained: containing up to 2096 w/w of the drug. ~owever~in~view of the low doses of the drug normally administered a~d the difficulty of preparing homogenous mixtures~of active ingredient and excipients :: ::
~ it may be desirable to prepare the complex with an 21191~4 WO94/02518 PCT/~lS93/06880 excess of the cyclodextrin derivative present, for example complexes containing in the order of O.l to 10%
by weight of the drug, particularly in the range 0.5 to 0.2~ by weight.
The clathrate complexes of the invention provide a more convenient way of administering the drugs, the cyclodextrin acting merely as a solubilizing agent without altering the therapeutic behavior of the drug in any way.
Composition Containinq the Clathrate Complexes of the Invention:
The invention thus also provides an inclusion complex as defined ~erein for use in human or veterinary medicine. The complex, for use as a pharmaceutical,~may presented as a pharmaceutical formulation.
:
The invention therefore provides in a further sspect a pharmaceuti~cal formulation comprising an ~: : : :: ~ : :
~ inalusion complex of a drug with a cyclodextrin :: ~
derivative together with a pharmaceutically acceptable carrier therefor and optionally other therapeutic and/or prophylactic ingredients. The carriers must be ~acceptable" in the sense of bei~g c~rAtible with the ~ other ingredients of the formula and nQt deleterious to :: . the recipient thereof. Suitably the pharmaceutical ~ formulation will be in unit dosage form~ Each unit 211~ 1 ' '4 ~WO94/02518 PCT/US93/06880 dose will conveniently contain that amount of drugnormally incorporated into a unit dose of such drug in the absence of a cyclodextrin.
The pharmaceutical formulations may be any formulation in which the inclusion complexes may be :: :
administered and include those suitable for oral, intr~n~l, intraoccular or paren~eral (including intramuscular and~intravenous) administration. The ormulations may,~where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods;well known in the art of pharmacy~.~ All~methods~inclùde the s~ep of bringing Y~ into ~ociation the~active compound with liquid carriers or fi~nely~divided solid carriers or both, and then, if necess~ry,~shaping the product into the desired~f~ormulaCion.~;~
Pharmaceùtical~formulations suitable for oral adminlstration~w~ere~D~the carrier is a solid are most preferably~-presented~as~unit aose formulations such as boiuses, capsules,~ c~h~ts or~tablets ea~h containing a predetermined amount~of the active ingredient. A
tablet may be made by;compression or molding, optio~ y~with~one or~more~accessory ingredients.
Compressed tablets~may be prepared by compressing in a suita~le machine~the;~active compound in a free-flowing form such as a powder or granules optionally mixed with ~: r ~11!31~4 WO94~02518 a binder, lubricant, inert diluent, lubricating, ~urface active or dispersing agent. Molded tablets may be made by molding an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored. Capsules may be prepared by ~illing the active compound, either alone or in admixture with one or more accessory ingredients, into : ':
the capsule cases a~nd then sealing them in the usual manner~ Cachets;are analogous to capsules wherein the active ingredient together-with any accessory ingredient(s) is sealed in a rice paper envelope.
~ ~ .
Tablets contain~the~active ingredient in admixture with~non-toxic~ pharmaceutically~acceptable excipients which~are suitable for manufacture of tablets~ These ;excipients may be,~~or example, inert diluents, such as calcium carbonate,~sodium carbonate, lactose, calcium phosph~ate or sodium pbospbate;~gran~ ting and disintegrating agents, for~example maize starch, or alginic acid; binding~agents, for example starch, gélatin or acsci~a,~and~ lubricating agents, for example magnesium stearate,~steariC acid or talc- The tablets may be ~~n~o~ted or they may be coated by known techniques to delay disintegration and absorption in the gastrointestina~l tract and thereby provide a ; sustained action over~ a longer period. For example, a ~ time delay material such as glyceryl monostearate or : ~: : :: :
:: : :
21191 5~1 WO94~0251X -25- PCT/US93/06880 glyceryl distearate alone or with a wax may be employed.
; The present invention also provides the complexes of the present invention in pharmaceutical formulations èxhibiting sustained release of a drug. Pharmaceutical formuIations exhibiting sustained release of a drug are generally known. ~Such~formulations include devices made of inert polymers or biodegradable poly-acids in which the active ingredient (the present complex) is ; either dispersed, covalently linked via labile bonds, or ~stored as~a~reservoir between polymer membranes.
Sustained release~is;achieved through diffusîon of the active ingredient~through the polymer matrix or hydrolysis of any covalent linkages present.
Sustained;~release~may also be presented by délivery~of~the;active ingredient via osmotic pumps.
Osmotic~pu ps~consist~of a~reservoir of solution or suspension~of active~ingredient (i.e., the present complex) surrounded~by~a semipermeable membrane containing a drug~portal. As water penetrates through the~ semipermeabi~e membrane~ into the comrleX reservoir, the complex solution is r~ShP~ through the portal and released.
; The cyclodextrin derivatives of the invention act as drug solubilizing~agents in these systems. The present cycloAeYtrin derivatives can also act as :::
:: ~
211~31S4 WO94/02518 PCT/US93~06880 osmotic driving aqents providing potential for the influx of water in such systems.
Pharmaceutical formulations suitable for oral administration wherein the carrier is liquid may conveniently be presented as a solution in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulslon. Pharmaceutical formulations suitable for parenteral administration are con~veniently presented:in unit dose or multi-dose containers which are sealed a~ter introduction of the formulation unit~required for use.
ormulations~for:oral use:may also be presented as hard gelatin capsules wherein the active ingredient is mixed:with an inert~solid diluent, ~or example calcium carbonate, calcium ~hos~l~ate or kaolin, or as soft gelatin capsules:wher~ein:the active ingredient is mixed with~water~or:an~oil~medium, ~for example arachis oil, peanut oll, liquid p raffin or olive oil.
; It;should~be~understood that in addition to the aforementioned~carrier: ingredients,the pharmaceutical : :formulations described~:above m~y include, as appropriate, one or more additional carrier ingredients such as diluents,~buffers,~flavoring agents, binders, surface active:agents,~:thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering .
21191~4 the formulation isotonic with the blood of the intended ; recipient.
For these purposes the compounds of the present invention may be administered orally, t~pically, ~:~ intranasa~ly, intraoccularly, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pbarmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections~, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-~looded animals such as~mice, rats,~horses~, dogs~, cats, etc., the comrou~
of the invention~are:~effective in the treatment of humans.
Aqueous~suspensions~ contain the active materials in~admixture~with:excipi~ents:suitable for the nufacture of~aqu~ous 8uspensions. Such excipients ;are~suspending~agents,~for example sodium carboxymethy}cellulose,:methylcellulose, :-hydroxypropylmethylcellulose~,: sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wett~ing~agents may be a naturally occuring phosph8~tide, for~example, lecithin, or condensation products of an alkylene oxide with fatty ' :~
~ acids, for example of polyoxyethylene stearate, or : ~ :
~ .
211~15~.
WO94/02Sl~ -28- PCT/US93/06880 condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol~anhydrides, for example polyoxyethylene sorbitan mono-oleate. The aqueous suspensions may a1so contain one or more preservatives, for example, ethyl or n-propyl p-hydroxy benzoate, one or~more coloring agents,~ one or more flavoring agents and one or more~sweetening agents, such as sucrose or saccharin. ~
~ , Oi~ly s~srensi~ons may be formulated by suspenAing the~active~ingredient in a vegetable oîl, for example arachIs~oil, olive oil,~sesame oil or rororl)t oil, or in;a~mineral oil~such~?s liquid paraffin. The oil ;; ~nsr~nsions may~contain a ~hickening agent, for example beeswax,~hard~paraffin or cetyl alcohol. Sweetening agents, such as~those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by ;the addition~of an~antioxidant such as ascorbic acid.
Dispersible powders and granules suitable ~or preparation of an agueous suspension by the addition of : :
: ~ :
211~154 ,, . ~ , WO94/0~518 PCT/US93/06880 water provide the active ingredient in admixture with a dispersing or wettînq agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspendinq agents are exemplified by those already mentioned~above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. ;
The pharmaceutical compositions of the invention may~also be in the form~of oil-in-water emulsions.
The oily phase may~be~a vegetable oil, for example olive oil or arachis oils, or a mineral oil~ for example liquid paraf~fin or mixtu;es of these. Suitable emulsifying agen~ts~may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides,~for~example soya bean lecithin, and èsters or~part~ial esters deri~ed from ~atty acids ;and~hexitol anhydrides, for example sorbitan mono-oleate, and co~den~-tion products of the said partial esters~with ethylene~oYide, for example polyo~yethylene sorbitan m~l~o oleate.; The emulsions may also contain '~ ~ sweetening and flavoring agents.
Sy-u~s and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and colorinq agents. The pharmaceutical composîtions may be in the 211~15 ll WO94/0~18 _30_ PCT/US93/06880 ' form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspe'nding agents which have been mentioned above. The sterile ~; inje~table preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or~ solvent.
Among the acceptable vehicles and solvents that may be employed are water, Ringer's~solution and isotonic sodium chloride , solution. In addition, sterile, fixed oils are conveotionAlly employ~d as a solvent or suspending f,~ medium. ~or this~purpose any bland fixed oil may be employed including~synthetic mono- or diglyc'erides. In addltlon,~ fatty~acids~such as oleic acid find use in the~preparation~'~of~injectables-The~compounds~of this invention may also be admlnistered~in~ hé form of su~positories for rectal administration of the drug. These compositions can be prepared by mixing~the~drug with a suitable non-irritating excipient which is solid at ordinary ' temperatures~but liquid~at the rectal temperature and will therefore melt~ in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
, ~' 2il91'~
-3l- PC~US93/06880 ~ or topical use, creams, oin~ments, jellies, solutions or suspensions, etc. containing the active :: ingredient are employed.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary~depending upon the host treated and the particular mode of administration. ~or example, a formulation intended for the oral administration~of humans may contain from 1.0 to 750 mg. of active agent compounded with an appropriate and c~ enient amount of carrier material which may vary vary~from about 5~to about 95 weight percent of the total~compos~ition. Unit dosage forms will generally contain between from~abou:t 1 to about 500 mg. of active ingredient.
Administration:;of::the~Clathrate Complexes to a Patient:
It will be understood:that the specifi~ dose level for~any~particular:patient will depend upon a variety of factors including~the activity of the specific compound employed,~ the age, body weightrgeneral health, .
ex, diet, time o~ administration, route of : : administration, rate of excretion, drug combination and the severity of the~particular disease undergoing therapy.
~:~
2119t~4 WO94/02~18 -32- PCT/US93/06880 Pharmaceutical formulations containin~ inclusion complexes may ~e administered at dosage levels and dosage intervals required to achieve the desired pharmacologic response normally associated with the drug and the disease state in absence of the cycIodextrin.
The other features of the invention will ~ecome apparent in the course~of the following descriptions of exemplary embodiments which are given for illustration ;of the invention and:~are not intended to be limiting thereof. ~ ~ :
:ExamDles The hydroxypropyl cyclodextrin derivative used i~
the:experiments~repor~ted below was purchased from Pharmatec, Inc.,::Alachua, Fl.
Preparation of the~cyclodextrin derivative of the invention~
Example 1:' Mono-sulfobutyl ether of B-cyclodextrin In a:lOO~mL:round-bottom flask, lO
grams~B-cyclodextrin~8~8l x lO 3 mole) was added with stirring to an aqueous solution composed of 30 mL water and 5.0 grams sodium~hydroxide maintained at 70~C. ~o this solution::1.8:mL~(2.40 gm, l.76 x lO 2 mole) butane : ~ .
sultone was slowly added with vigorous stirring to insure maximal~contact;of the heterogenous phases.
: , :
~: , WO 94/02518 2 ~ 4 PCI/US93/06880 Af ter a sin~7le phase was observed indicating depletion of the alkyl sultone, the solution was cooled to room temperature and di~ uted with 20 mL water . The resulting solution was neutralized with 1 N
;~; hydrochloric acid and dialyzed against 3 x 700 mL water ::
to remove-salts and hydroxyalkyl sufonic acids formed as side products.
The diasylste~was concentrated by ultrafiltration and placed on an ion-eYch~nge column composed of 50 grams A-25 DEAE-Sephadex packed in a 1~25 înch i.d.
glass column. Unreacted B-cyclodextr}n was removed by elution with distilled water. The mono-substituted s~ulfobutyl ether;of ~-cyclodextrin was isolated by elution with O.l;N~sodium hydroxide. The effluent fraction containing~the~mono 3ubstituted derivative was ultrafiltered to~remove any residual salts. ' The pH of the~retentate;was~adjusted to neutrality and ized-to obtain~2.~17 grams of the monosubstituted ulfobutyl ether~of~B-cyclo~eYtrin as a whîte amorphous solid. Elemental~analysis of the product showed a carbon to sulfur~ratio;~of 13.7 which corresponds to Ca.
, ~ 1.2 substitutions per molecule.
Example 2: Nono-sul~opropyl ether of B-cyclodextrin The proce~ces of Example 1 were repeated substituting 1.54~mL (2.15 grams, 1.76 x 10-2 mole) ' :
~: :
2 1 1 ~
propane sultone for butane sultone to yield 1.97 grams mono-sulfo~utyl e~her of B-cyclodextrin as a white amorphous solid. Elemental analysis of the product showed a carbon to sulfur ratio of 12.1 which corresponds to Ca. 1.4 substitutions per molecule.
:, Example 3: Sulfobutyl ethers of ~-cyclodextrin , ~
In a ~0 mL round-bottom flask, ~ grams ~-cyclodextrin (4:.41 x 10-3 mole) was added with stirring to an:aqueous solution composed of 10 mL water and 2.0 grams sodium hydroxide maintained at 70~C. ~o this solution 4.5 mL (6.0 gm, 4.41 x 1o~2 mole) butane sultone was~slowly added with vigorous stirring to insùre maximal contact~of the heterogenous phases.
After~a:single: phase was observed indicating depletion ,o'f~the:alkyl sultone,~the solution was cooled to room te~persture~and~diluted~ with 20 mL water. The :resulting solution:was neutralized with 1 N
hydrochlor~ic acid~and~di~alyzed against 3 x 700 mL water to remove salts~and hydroxyalkyl sulfonic acids formed as side products.:;:The diasylate was concentrated by :
ultrafiltration and the pH of the retentate was adjusted to'neutrality and lyophilized to obtain the sulfobutyl ether of B-cyclodextrin as a white amorphous solid. Elemental analysis of the product showed a ~ c'arbon to sulfur ratlo of 3.73 vhich corresponds to Ca.
:: :
211 91 ~ ~ ' WO94/02518 _35- PCT/US93/068X0 ; 7 substitutions per molecule. Thin-layer chromatography of the product (2-butanone:methanol:water, 4:4:2) shows the absence of unreacted ~-cyclodextrin.
:
.
: Example 4: Additional sulfoalkylethers of cyclodextrin The processes of Example 3 were varied with regard to reactants and~molar ratios to obtain cyclodextrin derivatives with varying degrees of substitution.
~:: Representative results ~foIlow:
:
~ Cy~lo~e~trin Mbles Sultone Moles Carbon/Sulfur Ratio~Substitutions :: ~
B-~..... .4.41x10~~:propane... .4.4xlO~C 3.28................. 7.2 B~ ..... 4.41X1O 3:~lop~al~e.. .2.2xlO~2 5.53.... ~............ 3.6 B~ .4.4lxlO-3:~butane~ 2~2xto-2 4.83................. 4.7 ...... 1.54xlO-3 ~.op~r,e..... 7.71xlO~3 ........ ~............ 3.5 .. :.... 1.54xlO~3~butane....... 7.71xlO~3 .................... 3.2 : Substitution determined by peak areas from 1H-NMR spectra~
::: :
~: :
,: ~: ' ~: ~
21191 r~
WO94~02~1X -36- PCT/US93~06880 .
Cumulative Urinary Cyclodextrin Excretion:
The data provided in tbe group set out in Figure 1 indicates that although the sulfoalkyl cyclodextrin derivatives of the invention as well as the hydroYypropyl derivative are excreted faster and to a greater extent~ in mice than the parent comr~ d~ the p.~-~nt derivatives a~e excreted fastest. Figure l provides data for the underivatized cyclodextrin col pound, the~ ~.y~ y~ropyl: derivative, the sulf-Jl.~l~l derivative of the imention, and the ~;ulfopropyl derivative~ of~:the~ invention.
Acote ~Par-nter-l Toxic~ty:
The ~sulfoslky1~ ~cyclodextrin derivatives of the invention :eyhi~bited' nQ~observable toxic eff~cts in male micé~over: a 30:~day~peri~following intraperi~o~e~l of
5.49~s~1~0-3 ~ol/Kg.~
This~dose~is eguivalent to 7.1 gm~Kg for the : monosulfoalky}:~derivatives,~ I2.3 gm/Kg for the ., ~, , i sulfobutyl derivative w/7 degrees of substitution, and 11.8 gmtKg for ~the ~sulfopropyl derivative w/7 degrees :: of ;substitution. ~ ~
.
t S ~
W094/02~18 37 PCT/US93/06880 Plasma Urea Nitro~en:
Plasma urea nitrogen levels are an indicator of : kidney function with higher levels indicating renal damage. The data in Table 1 indicates that the sulfoalkyl cyclodextrin derivatives of the invention do not cause increased plasma urea nitrogen levels in mice as compared to the underivatized paren~ compound control). There~is however no statistical difference ~ : , between our derivatives and the hydroxypropyl derivative. ::
~ : ~
. , ;
, .~
': : ~: : :
: :
~ .
:::
211~1~A
w o 94/a~51~ -38- PCT/VS93/06880 ;~'~
T~ble 1 : Plasma Urea Nitro~en(1) ~ .
SamD1e time (hrs) PUN~S.D. (m~/dl-)(2) Control (normal saline) 24 1~.88+1.21 ~, . :
Cyclodextrin 24 160.10+26.16 MoIecusolTM;(hydroxylpropyl derivative) 24 15.43~1.50 :: -~:~ Sulfop.op~l ether of B-Cyclodextrin 24 15.27l0.7 (3~.6 substitution~per~CD~olecule) Sulfo~utyl ether of B-Cyclodex rin 24 14.42~0.46 4~7 substitution per~CD molecule) :: ; ~ : ~
. : :
)SIGMA Urea Ni~-og~ F~-oce~ur~ No. 64a-A
emolysis of Red Blood Cells:
; : As can bé seen~from the data in Figures 2 and 3 :: the ~ore highly~substituted alkylsulfonic acid ~: : :
derivatives of the inYention caused less membrane : disruption as indicated by the percent hemolysis than '. 2119t~4 . -39-the mono substituted derivatives. The mono substituted derivatives caused about the same amount of membrane disruption as~the hydroxypropyl derivative.
: ~ :
: Phase SolubilitY Behavior:
As can be seen~from Table 2 below and the data provided in Figures 4a:and 4b the association constants for the equilibrium between the~sulfobutyl derivatives ~ . ~
o f: the~invention~:and:~Digoxin are S times larger than that of the hydlo~y~ropyl derivative.
::: :: : : : :
' ;~ :
21191 S~ ~
WO 94~02518 40 PCl/US93/06880 Table 2 DIGOXIN ASSOCIATION CONSTANTS
~::: - K1 1(M-1) B-Cyclodextrin 2.82 x 104 Molecusol (h~ C ) 4.90 x 103 Sulfobutyl ether of B-cyclodextrin (1 sub)(1) 2.76 x tO4 (4.8 subs) 1.71 x 104 ( 7 subs ) 6 . 88 X 103 Sul~p.opyl ether of B-cyclodextrin ( 1 sub) 2.74 x to4 (3.6 subs) 1.41 x 104 : (7 subs) ~ ~.29 x 103 ) No. of subst;ituents per CD molecule Table 3 cy~1 o~e~trin . . , Molecusol (~ .o~yy~o~yl ~-CD) 1.12 x 104 Sulfobu'cyl ether~ B-c!,rclodextrin ~1 sub) (1) 1.72 x 104 ~: ~4.7 su~s) 1.57 x ~Q4 (7 subs) 1.83 x 104 ~ .
~ .
21191 S l W O 94/0~ 41- P ~ /VS93/06880 : Sulfopropvl ether ~-cvclodextrin (1 sub) 1.66 x 104 (3.6 subs) 1.19 x to4 ~7 subs~ 7.68 x 103 (1) No. of substituents per CD molecule .: :
It should be noted tha~t the x axis for the graphs of FigD~s 4a and 4b have a maximum of 1.8% w/w ~,, ~ : cyclodextrin. ~f the~relative solubilizing ability of :::
the present derivatives is considered relative to that for the hydroxypropyl:;~derivative (at 50% solutions as is;done in US:4,727,~064, Table l) the apparent solubility of::digoxin is -216 mg/mL for the present sulfobutyl de~rivatives~as compared to 80 mg/mL for the hydroxypropyl der~ivative.: The value of 45.0 mg/mL
reported in as 4:,727,~064 was for a hydroxypropyl derivative~with~a dif ferent degree of substitution than the~h ~ roAy~Lopy}:~derivative used herein for comparison.
Similar:r~esults~can be~seen for progesterone (see Table 3 and Figurés 5 and 6), phenytoin (see Table 4 and Figures 7 and ~8), and testosterone tsee Table 5 and~Figùres 9 and 103.
21191~
WO 94tO2518 -4 2- PCr/US93/06880 Table 5 TESTOSTERONE ASSOCIATIQN CONSTANTS
~: ' K 1 1 ( M 1 : B-cyclodextrin 1.78 x 104 Molecusol (hydroxypropyl ~-CD) 1.16 x 104 1 sub)(~ 1.64 x lOq Sulfobutyl ether ~-cyclodextrin :: (4.7 subs) ~ 1.82 x 104 ~ (7 ~ subs) :~ 2.25 x 104 :~ Sulfopropyl ether~B-cyclodextrin '1 sub) 1.87 x 104 3.6 subs) ~ : 1.43 x 10 7~ subs) ~ 9.63 x 103 Ro~ of substituen;ts per CD molecule , .
:: ~: :: :
~ W O 94/02~l8 2 1 1 ~ PCT/~IS93/06880 Table 4 PHENYTOIN ASSOCIATION CONSTANTS
K (M-1) : B-cyclodextrin 1.51 x 103 : Molecusol (t~drGxy~l~op~l B-CD~ 1.07 X 103 ; (1 :sub)(l) 1.22 x 103 Sulfobutyl ether B-cyclodextrin :(4.7 subs) :~ ~: 1.26 x 103 (7 ~:subs): ~ 7:.56 x 102 1.03 X 103 lfop op~l ether~B-cyclodextrin (3.:6:subs) ~ : 1.31 x 103 : :(7: s~bs): ~ 8.24 x lOZ
.~:or substltuents per:CD molecule ;:Studies on Oral~ arations As~ above, oral~for~ulations ean tolerate h~er~ a~oUnts~of~ eyel dextrin:withou~t eompromising :toxie ~ eoneerns.~ Useful tolerated levels of ~-eyelodex*rin, ho~ver,~still derenA~upon a ~lG~er balaneing of other:eharacteris~ies, ineluding :partieularly intrinsie aqueous solubility.
211~1~ 4 The maximum water solubility o~ any modified cyclodextrin dictates the limits of its usefulness in solubilizing drug substances. The greater the aqueous solubility the greater the potential for use of the cyclodextrin at high enough ronGentrations to solubilize all of the drug substance by formation of an inclusion complex. Table 6 shows the results of a co~parison of the water solubility of various sulfoalkylether derivatives generated by the present invention which have been~doped to contain <0.7 to 25%
by weight residual ~-cyolodextrin ver~us the water 801nhil-ty of the derivative6 generated by the method d~escribed in U.S.~Patent 3,426,01~ to Parmerter which ~' , contain from 69-82% by weight residual ~-cyclodextrin.
: me ,~ ts~in Table 6 show that as the conc~.L,ation o~~the;residual ~-cyclodextrin content in¢re~re~ from <1 weight ~e.c~ up to 25 weight pe,~,L the aqueous solubllity decrea~~ Ic-r_~er, even at a content of 25% (wt/wt) res~
~ ~:
cyclodextrin, the~mixLuLa~of~*he sulfoalkyl ether derivatives eYhi~its water ~olubilit~e~ of 84 and 94 mg/mL for the sulfopropyl and ~ulfobutyl ether :
:
:~:
:
~-' 211~t~i~
WO ~4/02~18 PCl /~lS93tO6~80 derivatives respectively. This means that the preparation according to the present invention containing as much as 25~ by weight ~-cyclodextrin would still eYhihit a water solubility which was - 1.5-2 timés that of the~co~res~o-.ding Parmerter ~: preparations.
~: :
;; ~ :
, .
21 1915~ ' W~94~0~518 PCT/US93/06880 Table 6 Effect of ~-CD content on Water Solubility Comparison o~ Various Cycl~odextrin Preparations ~-CD Content Water - (wt/wt) Solubility CYCLODEXTRIN (CZE)* (mg/mL) beta-Cyclodextrin (~-CD) A~aizo, ~-CD - 100 19 Sulfopropyl Ether Derivatives Parmerter Present Invention DAD-6-40 + ~-CD** 25 84 DAD-6-39-F*** 7 >700 DAD-6-40-F*** 8 >700 : DAD-6-39-12**** <0.7 >700 Sulfobuty} Ether Derivatives Parmerter Present Invention : : ~
:DAD-6-17 ~ ~-CD** 25: 94 :: DAD-1-127 <2 ~800 DAD-6-12 <2 ~800 :DAD-6-17 ~ <2 >800 - * : Capillary Zone~Ele~Ll~horesis *:* : Rajewski/Stella~Preparation ~ore~ with beta-CycIodextrin *** Xajewski/Stella Preparation prior to chromatographic step **** Rajewski/Stella Preparation after chro~ato~raphic step ~ .
. .
~ 094/0251X 2 1 1 9 :t ~ ~ PCT/US93/~6880 Figures 11-13 graphically show the solu~ility characteristics of several drugs with the derivatives of the present invention containing varying amounts of ,B-cyclodextrin. ~igures 11 and 12 show the results of solubility studies with two different drugs, testosterone and p, G~esterone, respectively . In both f i~U~e6~ solubility~characteristics are plotted for the sulfol~uLyl ether and sulfopropyl ether derivatives of the ~ ..rt invention containing various amounts of ,~1-cyclodextrin and ~ also ~ plotted are the sulfopropyl ethér and sulfobutyl ether derivatives of Parmerter. The r~ ts in both studies show that the derivatives of the ~r.~r~nt i~l~e..~ion ~rh~hit much higher solu~ility ~s compa~red to the:Parmerter:derivatives. Even the ;composition con~ g the~sulfoblltyl ether ~erivative of the p~ nt imention with 5~ cyclodextrin still showed~much h~hr-~solub'ility as comp~red to the Par~erter~compositions.~:The results also indicate, howe~er, a~rather:~dr~ma~ic decrease in ~801ubility after the~a~ount of ~-cyclodextrin b:ecomes greater than 50%.
~: .
.
.
2i191S~
WO94/02518 PCT/US93/06~80 :
Figure 13 reports the results of solubility characteristics ~or naproxen for compositions of the sulfobutyl ether derivatives of the invention with various amounts of ~-cyclodextrin. This study surprisingly showed that the solubility of naproxen was not as high as testosterone and progesterone at low levels of ~-cyclodextrin, but also the solubility of the drug did not appear to significantly decrease with increasing amount of ~-cyclodextrin. Nevertheless, the lts in ~igures~11 and 12 show that the solubility of some drugs does decrease with increasing amounts of cyclodextrin. For those drugs, compositions of the ~ulfoalkyl ether cyclodextrin derivatives of the present invention provide eYcellent drug solubility, :
;even with up to 40-S0% of ~-cyclodextrin.
Obviously, numerous modifications and variations of the present invention are possible in light of the above~teachi~c. It is therefore to be understood that ~:
within the scope of~;the ~lell~1 claims, the invention may be practiced otherwise than as specifically described herein.
: : :
; , :
.
.
This~dose~is eguivalent to 7.1 gm~Kg for the : monosulfoalky}:~derivatives,~ I2.3 gm/Kg for the ., ~, , i sulfobutyl derivative w/7 degrees of substitution, and 11.8 gmtKg for ~the ~sulfopropyl derivative w/7 degrees :: of ;substitution. ~ ~
.
t S ~
W094/02~18 37 PCT/US93/06880 Plasma Urea Nitro~en:
Plasma urea nitrogen levels are an indicator of : kidney function with higher levels indicating renal damage. The data in Table 1 indicates that the sulfoalkyl cyclodextrin derivatives of the invention do not cause increased plasma urea nitrogen levels in mice as compared to the underivatized paren~ compound control). There~is however no statistical difference ~ : , between our derivatives and the hydroxypropyl derivative. ::
~ : ~
. , ;
, .~
': : ~: : :
: :
~ .
:::
211~1~A
w o 94/a~51~ -38- PCT/VS93/06880 ;~'~
T~ble 1 : Plasma Urea Nitro~en(1) ~ .
SamD1e time (hrs) PUN~S.D. (m~/dl-)(2) Control (normal saline) 24 1~.88+1.21 ~, . :
Cyclodextrin 24 160.10+26.16 MoIecusolTM;(hydroxylpropyl derivative) 24 15.43~1.50 :: -~:~ Sulfop.op~l ether of B-Cyclodextrin 24 15.27l0.7 (3~.6 substitution~per~CD~olecule) Sulfo~utyl ether of B-Cyclodex rin 24 14.42~0.46 4~7 substitution per~CD molecule) :: ; ~ : ~
. : :
)SIGMA Urea Ni~-og~ F~-oce~ur~ No. 64a-A
emolysis of Red Blood Cells:
; : As can bé seen~from the data in Figures 2 and 3 :: the ~ore highly~substituted alkylsulfonic acid ~: : :
derivatives of the inYention caused less membrane : disruption as indicated by the percent hemolysis than '. 2119t~4 . -39-the mono substituted derivatives. The mono substituted derivatives caused about the same amount of membrane disruption as~the hydroxypropyl derivative.
: ~ :
: Phase SolubilitY Behavior:
As can be seen~from Table 2 below and the data provided in Figures 4a:and 4b the association constants for the equilibrium between the~sulfobutyl derivatives ~ . ~
o f: the~invention~:and:~Digoxin are S times larger than that of the hydlo~y~ropyl derivative.
::: :: : : : :
' ;~ :
21191 S~ ~
WO 94~02518 40 PCl/US93/06880 Table 2 DIGOXIN ASSOCIATION CONSTANTS
~::: - K1 1(M-1) B-Cyclodextrin 2.82 x 104 Molecusol (h~ C ) 4.90 x 103 Sulfobutyl ether of B-cyclodextrin (1 sub)(1) 2.76 x tO4 (4.8 subs) 1.71 x 104 ( 7 subs ) 6 . 88 X 103 Sul~p.opyl ether of B-cyclodextrin ( 1 sub) 2.74 x to4 (3.6 subs) 1.41 x 104 : (7 subs) ~ ~.29 x 103 ) No. of subst;ituents per CD molecule Table 3 cy~1 o~e~trin . . , Molecusol (~ .o~yy~o~yl ~-CD) 1.12 x 104 Sulfobu'cyl ether~ B-c!,rclodextrin ~1 sub) (1) 1.72 x 104 ~: ~4.7 su~s) 1.57 x ~Q4 (7 subs) 1.83 x 104 ~ .
~ .
21191 S l W O 94/0~ 41- P ~ /VS93/06880 : Sulfopropvl ether ~-cvclodextrin (1 sub) 1.66 x 104 (3.6 subs) 1.19 x to4 ~7 subs~ 7.68 x 103 (1) No. of substituents per CD molecule .: :
It should be noted tha~t the x axis for the graphs of FigD~s 4a and 4b have a maximum of 1.8% w/w ~,, ~ : cyclodextrin. ~f the~relative solubilizing ability of :::
the present derivatives is considered relative to that for the hydroxypropyl:;~derivative (at 50% solutions as is;done in US:4,727,~064, Table l) the apparent solubility of::digoxin is -216 mg/mL for the present sulfobutyl de~rivatives~as compared to 80 mg/mL for the hydroxypropyl der~ivative.: The value of 45.0 mg/mL
reported in as 4:,727,~064 was for a hydroxypropyl derivative~with~a dif ferent degree of substitution than the~h ~ roAy~Lopy}:~derivative used herein for comparison.
Similar:r~esults~can be~seen for progesterone (see Table 3 and Figurés 5 and 6), phenytoin (see Table 4 and Figures 7 and ~8), and testosterone tsee Table 5 and~Figùres 9 and 103.
21191~
WO 94tO2518 -4 2- PCr/US93/06880 Table 5 TESTOSTERONE ASSOCIATIQN CONSTANTS
~: ' K 1 1 ( M 1 : B-cyclodextrin 1.78 x 104 Molecusol (hydroxypropyl ~-CD) 1.16 x 104 1 sub)(~ 1.64 x lOq Sulfobutyl ether ~-cyclodextrin :: (4.7 subs) ~ 1.82 x 104 ~ (7 ~ subs) :~ 2.25 x 104 :~ Sulfopropyl ether~B-cyclodextrin '1 sub) 1.87 x 104 3.6 subs) ~ : 1.43 x 10 7~ subs) ~ 9.63 x 103 Ro~ of substituen;ts per CD molecule , .
:: ~: :: :
~ W O 94/02~l8 2 1 1 ~ PCT/~IS93/06880 Table 4 PHENYTOIN ASSOCIATION CONSTANTS
K (M-1) : B-cyclodextrin 1.51 x 103 : Molecusol (t~drGxy~l~op~l B-CD~ 1.07 X 103 ; (1 :sub)(l) 1.22 x 103 Sulfobutyl ether B-cyclodextrin :(4.7 subs) :~ ~: 1.26 x 103 (7 ~:subs): ~ 7:.56 x 102 1.03 X 103 lfop op~l ether~B-cyclodextrin (3.:6:subs) ~ : 1.31 x 103 : :(7: s~bs): ~ 8.24 x lOZ
.~:or substltuents per:CD molecule ;:Studies on Oral~ arations As~ above, oral~for~ulations ean tolerate h~er~ a~oUnts~of~ eyel dextrin:withou~t eompromising :toxie ~ eoneerns.~ Useful tolerated levels of ~-eyelodex*rin, ho~ver,~still derenA~upon a ~lG~er balaneing of other:eharacteris~ies, ineluding :partieularly intrinsie aqueous solubility.
211~1~ 4 The maximum water solubility o~ any modified cyclodextrin dictates the limits of its usefulness in solubilizing drug substances. The greater the aqueous solubility the greater the potential for use of the cyclodextrin at high enough ronGentrations to solubilize all of the drug substance by formation of an inclusion complex. Table 6 shows the results of a co~parison of the water solubility of various sulfoalkylether derivatives generated by the present invention which have been~doped to contain <0.7 to 25%
by weight residual ~-cyolodextrin ver~us the water 801nhil-ty of the derivative6 generated by the method d~escribed in U.S.~Patent 3,426,01~ to Parmerter which ~' , contain from 69-82% by weight residual ~-cyclodextrin.
: me ,~ ts~in Table 6 show that as the conc~.L,ation o~~the;residual ~-cyclodextrin content in¢re~re~ from <1 weight ~e.c~ up to 25 weight pe,~,L the aqueous solubllity decrea~~ Ic-r_~er, even at a content of 25% (wt/wt) res~
~ ~:
cyclodextrin, the~mixLuLa~of~*he sulfoalkyl ether derivatives eYhi~its water ~olubilit~e~ of 84 and 94 mg/mL for the sulfopropyl and ~ulfobutyl ether :
:
:~:
:
~-' 211~t~i~
WO ~4/02~18 PCl /~lS93tO6~80 derivatives respectively. This means that the preparation according to the present invention containing as much as 25~ by weight ~-cyclodextrin would still eYhihit a water solubility which was - 1.5-2 timés that of the~co~res~o-.ding Parmerter ~: preparations.
~: :
;; ~ :
, .
21 1915~ ' W~94~0~518 PCT/US93/06880 Table 6 Effect of ~-CD content on Water Solubility Comparison o~ Various Cycl~odextrin Preparations ~-CD Content Water - (wt/wt) Solubility CYCLODEXTRIN (CZE)* (mg/mL) beta-Cyclodextrin (~-CD) A~aizo, ~-CD - 100 19 Sulfopropyl Ether Derivatives Parmerter Present Invention DAD-6-40 + ~-CD** 25 84 DAD-6-39-F*** 7 >700 DAD-6-40-F*** 8 >700 : DAD-6-39-12**** <0.7 >700 Sulfobuty} Ether Derivatives Parmerter Present Invention : : ~
:DAD-6-17 ~ ~-CD** 25: 94 :: DAD-1-127 <2 ~800 DAD-6-12 <2 ~800 :DAD-6-17 ~ <2 >800 - * : Capillary Zone~Ele~Ll~horesis *:* : Rajewski/Stella~Preparation ~ore~ with beta-CycIodextrin *** Xajewski/Stella Preparation prior to chromatographic step **** Rajewski/Stella Preparation after chro~ato~raphic step ~ .
. .
~ 094/0251X 2 1 1 9 :t ~ ~ PCT/US93/~6880 Figures 11-13 graphically show the solu~ility characteristics of several drugs with the derivatives of the present invention containing varying amounts of ,B-cyclodextrin. ~igures 11 and 12 show the results of solubility studies with two different drugs, testosterone and p, G~esterone, respectively . In both f i~U~e6~ solubility~characteristics are plotted for the sulfol~uLyl ether and sulfopropyl ether derivatives of the ~ ..rt invention containing various amounts of ,~1-cyclodextrin and ~ also ~ plotted are the sulfopropyl ethér and sulfobutyl ether derivatives of Parmerter. The r~ ts in both studies show that the derivatives of the ~r.~r~nt i~l~e..~ion ~rh~hit much higher solu~ility ~s compa~red to the:Parmerter:derivatives. Even the ;composition con~ g the~sulfoblltyl ether ~erivative of the p~ nt imention with 5~ cyclodextrin still showed~much h~hr-~solub'ility as comp~red to the Par~erter~compositions.~:The results also indicate, howe~er, a~rather:~dr~ma~ic decrease in ~801ubility after the~a~ount of ~-cyclodextrin b:ecomes greater than 50%.
~: .
.
.
2i191S~
WO94/02518 PCT/US93/06~80 :
Figure 13 reports the results of solubility characteristics ~or naproxen for compositions of the sulfobutyl ether derivatives of the invention with various amounts of ~-cyclodextrin. This study surprisingly showed that the solubility of naproxen was not as high as testosterone and progesterone at low levels of ~-cyclodextrin, but also the solubility of the drug did not appear to significantly decrease with increasing amount of ~-cyclodextrin. Nevertheless, the lts in ~igures~11 and 12 show that the solubility of some drugs does decrease with increasing amounts of cyclodextrin. For those drugs, compositions of the ~ulfoalkyl ether cyclodextrin derivatives of the present invention provide eYcellent drug solubility, :
;even with up to 40-S0% of ~-cyclodextrin.
Obviously, numerous modifications and variations of the present invention are possible in light of the above~teachi~c. It is therefore to be understood that ~:
within the scope of~;the ~lell~1 claims, the invention may be practiced otherwise than as specifically described herein.
: : :
; , :
.
.
Claims (48)
1. A cyclodextrin derivative composition which comprises a cyclodextrin derivative of formula wherein:
n is 4, 5 or 6;
R1, R2, R3, R4, R4, R5, R6, R7, R8 and R9 are each, independently, 0- or a 0-(C2-6 alkylene)-SO3- group, and at least one of R1 and R2 is, independently, said 0-(C2-6 alkylene) -SO3- group; and S1, S2, S3, S4, S5, S6, S7, S8 and S9 are each, independently, a pharmaceutically acceptable cation, and wherein said composition contains less than about 50% of underivatized cyclodextrin.
n is 4, 5 or 6;
R1, R2, R3, R4, R4, R5, R6, R7, R8 and R9 are each, independently, 0- or a 0-(C2-6 alkylene)-SO3- group, and at least one of R1 and R2 is, independently, said 0-(C2-6 alkylene) -SO3- group; and S1, S2, S3, S4, S5, S6, S7, S8 and S9 are each, independently, a pharmaceutically acceptable cation, and wherein said composition contains less than about 50% of underivatized cyclodextrin.
2. The composition of Claim 1, wherein R1, R2 and R3 are each, independently, said 0-(C2-6 alkylene) -SO3-group.
3. The composition of Claim 1, wherein at least one of R1, R2 and R3 is, independently a 0-(CH2)m-SO3-group, wherein m is 2, 3, 4, 5 or 6.
4. The composition of Claim 1, wherein R1, R2 and R3 are each, independently a 0-(CH2)m-SO3 group, wherein m is 3 or 4.
5. The composition of Claim 1, wherein:
at least one of R4, R6 and R6 is, independently, said 0-(C2-6 alkylene)-SO3- group; and R5, R7, and R9 are all O-.
at least one of R4, R6 and R6 is, independently, said 0-(C2-6 alkylene)-SO3- group; and R5, R7, and R9 are all O-.
6. The composition of Claim 2, wherein:
at least one of R4, R6 and R8 is, independently, said 0-(C2-6- alkylene)-SO3- group; and R5, R7, and R9 are all O-.
at least one of R4, R6 and R8 is, independently, said 0-(C2-6- alkylene)-SO3- group; and R5, R7, and R9 are all O-.
7. The composition of Claim 2, wherein:
R4, R6 and R8 are each a 0-(C2-6 alkylene)-SO3- group;
and R5, R7, and R9 are all O-.
R4, R6 and R8 are each a 0-(C2-6 alkylene)-SO3- group;
and R5, R7, and R9 are all O-.
8. The composition according to claim 1, wherein n is 5.
9. The composition according to claim 8, wherein said C2-6 alkylene is a C3 alkylene.
10. The composition according to claim 8, wherein said C2-6 is a C4 alkylene.
11. The composition according to claim 9, wherein said cyclodextrin derivatives in said co position contain an average of about one 0-(C2-C6 alkylene)-SO3- group per cyclodextrin molecule.
12. The composition according to claim 9, wherein said cyclodextrin derivatives in said composition contain an average of about 3.6 0-(C2-C6 alkylene) -SO3- group per cyclodextrin molecule.
13. The composition according to claim 9, wherein said cyclodextrin derivatives in said composition contain an average of about 7 0-(C2-C6 alkylene) -SO3- group per cyclodextrin molecule.
14. The composition according to claim 10, wherein said cyclodextrin derivatives in said composition contain an average of about one 0-(C2-C6 alkylene)-SO3- group per cyclodextrin molecule.
15. The composition according to claim 10, wherein said cyclodextrin derivatives in aid composition contain an average of about 4.7 0-(C2-C6 alkylene)-SO3- group per cyclodextrin molecule.
16. The composition according to claim 10, wherein said cyclodextrin derivatives in said composition contain an average of about 7 0-(C2-C6 alkylene)-SO3- group per cyclodextrin molecule.
17. The composition according to claim 1, wherein said composition contains less than 40% underivatized cyclodextrin.
18. The composition according to claim 8, wherein said composition contains less than 40% underivatized cyclodextrin.
19. The composition according to claim 9, wherein said composition contains less than 40% .beta.-cyclodextrin.
20. The composition according to claim 10, wherein said composition contains less than 40% .beta.-cyclodextrin.
21. The composition according to claim 1, wherein said composition contains less than 25% .beta.-cyclodextrin.
22. The composition according to claim 8, wherein said composition contains less than 25% underivatized cyclodextrin.
23. The composition according to claim 9, wherein said composition contains less than 25% underivatized cyclodextrin.
24. The composition according to claim 10, wherein said composition contains less than 25% .beta.-cyclodextrin.
2S. A composition comprising a drug complexed to a cyclodextrin derivative of formula (2):
wherein:
n is 4, 5 or 6;
R1, R2, R3, R4, R5, R6, R7, R8 and R9 are each independently 0 or a 0-(C2-6alkylene)-SO3 group, and at least one of R1 and R2 is, independently, said 0-(C2-6 alkylene)-SO3 group; and S1 to S9 are each, independently, a pharmaceutically acceptable cation;
wherein said composition contains not more than about 50 wt.% of underivatized cyclodextrin.
wherein:
n is 4, 5 or 6;
R1, R2, R3, R4, R5, R6, R7, R8 and R9 are each independently 0 or a 0-(C2-6alkylene)-SO3 group, and at least one of R1 and R2 is, independently, said 0-(C2-6 alkylene)-SO3 group; and S1 to S9 are each, independently, a pharmaceutically acceptable cation;
wherein said composition contains not more than about 50 wt.% of underivatized cyclodextrin.
26. The composition of Claim 25, wherein R1, R2 and R3 are each, independently, said 0-(C2-6 alkylene)-SO3 group.
27. The composition of Claim 25, wherein:
at least one of R4, R6 and R8 is, independently, said 0-(C2-6- alkylene) -SO3- group; and R5, R7, and R9 are all O.
at least one of R4, R6 and R8 is, independently, said 0-(C2-6- alkylene) -SO3- group; and R5, R7, and R9 are all O.
28. The composition of Claim 25, wherein:
at least one of R4, R6 and R8 is, independently, said 0-(C2-6- alkylene)-SO3 group; and R5, R7, and R9 are all O.
at least one of R4, R6 and R8 is, independently, said 0-(C2-6- alkylene)-SO3 group; and R5, R7, and R9 are all O.
29. The composition of Claim 28, wherein R4, R6 and R8 are each, independently, said 0-(C2-6 alkylene)-SO3 group.
30. The composition of Claim 25, wherein said drug is one member selected from the group consisting of but not limited to amobarbital,ampicillin aspirin, beclomethasone, benzocaine, benzodiazepines, betamethasone, chlorambucil, chloramphenicol, chlorpromazine, clofibrate, coenzyme A, cortisone, cortisone acetate, cyclobarbital, dexamethasone, dexamethasone acetate, diazepam digitoxon, digoxin, estradiol, 5-fluorouracil, flurbiprofen, griseofulvin, hydrocortisone, hydrocortisone acetate, ibuprofen, indomethanin, ketoprofen, methicillin, metronidazole, mitomycin, nitrazepam, nitroglycerin, penecillin, pentobarbital, phenopbarbital, phenobarbitone, phenyltoin, prednisolone, predisolone acetate, progesterone, prostaglandin A series, prostaglanin B
series, prostaglandin E series, prostaglandin F series, reserpine, sulfaceatamide sodium, testosterone, vitamin A, vitamin D3, vitamin E, vitamin K3, and warfarin.
series, prostaglandin E series, prostaglandin F series, reserpine, sulfaceatamide sodium, testosterone, vitamin A, vitamin D3, vitamin E, vitamin K3, and warfarin.
31. The composition according to claim 25, wherein n is 5.
32. The composition according to claim 31, wherein said C2-6 alkylene is a C3 alkylene.
33. The composition according to claim 31, wherein said C2-6 is a C4 alkylene.
34. The composition according to claim 32, wherein said cyclodextrin derivatives in said composition contain an average of about 1, 3.6 or 7 0-(C2-C6 alkylene)-SO3-groups per cyclodextrin molecule.
35. The composition according to claim 33, wherein said cyclodextrin derivatives in said composition contain an average of about 1, 4.7 or 7 0-(C2-C6 alkylene)-SO3 groups per cyclodextrin molecule.
36. The composition according to claim 25, wherein said composition contains less than 40% .beta.-cyclodextrin.
37. The composition according to claim 31, wherein said composition contains less than 40% .beta.-cyclodextrin.
38. The composition according to claim 32, wherein said composition contains less than 40% .beta.-cyclodextrin.
39. The composition according to claim 33, wherein said composition contains less than 40% .beta.-cyclodextrin.
40. The composition according to claim 34, wherein said composition contains less than 40% .beta.-cyclodextrin.
41. The composition according to claim 35, wherein said composition contains less than 40% .beta.-cyclodextrin.
42. The composition according to claim 25, wherein said composition contains less than 25% .beta.-cyclodextrin.
43. The composition according to claim 31, wherein said composition contains less than 25% .beta.-cyclodextrin.
44. The composition according to claim 32, wherein said composition contains less than 25% .beta.-cyclodextrin.
45. The composition according to claim 33, wherein said composition contains less than 25% .beta.-cyclodextrin.
46. The composition according to claim 34, wherein said composition contains less than 25% .beta.-cyclodextrin.
47. The composition according to claim 35 wherein said composition contains less than 25% .beta.-cyalodextrin.
48. A pharmaceutical composition for oral administration comprising a pharmaceutically, orally suitable carrier and a clathrate complex comprising a drug complexed to a cyclodextrin derivative of formula (2):
wherein:
n is 4,5 or 6;
R1, R2, R3, R4, R5, R6, R7, R8 and R9 are each independently 0 or a 0-(C2-6 alkylene)-SO3 group, and at least one of R1 and R2 is, independently, said 0-(C2-6 alkylene)-SO3 group; and S1 to S9 are each, independently, a pharmaceutically acceptable cation;
wherein said composition contains not more than 50 wt. % of underivatized cyclodextrin.
wherein:
n is 4,5 or 6;
R1, R2, R3, R4, R5, R6, R7, R8 and R9 are each independently 0 or a 0-(C2-6 alkylene)-SO3 group, and at least one of R1 and R2 is, independently, said 0-(C2-6 alkylene)-SO3 group; and S1 to S9 are each, independently, a pharmaceutically acceptable cation;
wherein said composition contains not more than 50 wt. % of underivatized cyclodextrin.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/918,702 | 1992-07-27 | ||
US07/918,702 US5376645A (en) | 1990-01-23 | 1992-07-27 | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2119154A1 CA2119154A1 (en) | 1994-02-03 |
CA2119154C true CA2119154C (en) | 1998-06-16 |
Family
ID=25440795
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002119154A Expired - Lifetime CA2119154C (en) | 1992-07-27 | 1993-07-26 | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
Country Status (16)
Country | Link |
---|---|
US (1) | US5376645A (en) |
EP (1) | EP0620828B2 (en) |
JP (1) | JP3393253B2 (en) |
KR (1) | KR100279111B1 (en) |
AT (1) | ATE217325T1 (en) |
AU (1) | AU672814B2 (en) |
CA (1) | CA2119154C (en) |
DE (1) | DE69331900T3 (en) |
DK (1) | DK0620828T4 (en) |
ES (1) | ES2176206T5 (en) |
GE (1) | GEP19991649B (en) |
MD (1) | MD1813C2 (en) |
PT (1) | PT620828E (en) |
RU (1) | RU2113442C1 (en) |
TJ (1) | TJ275B (en) |
WO (1) | WO1994002518A1 (en) |
Families Citing this family (570)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0709099A3 (en) * | 1994-09-28 | 1996-07-24 | Senju Pharma Co | An aqueous nasal suspension comprising cyclodextrin |
ZA959469B (en) * | 1994-11-15 | 1996-05-15 | South African Druggists Ltd | Pharmaceutical composition |
US5468502A (en) * | 1994-12-20 | 1995-11-21 | American Home Products Corporation | Ibuprofen enhancing solvent system |
AU5774796A (en) * | 1995-06-13 | 1997-01-09 | Dyer, Alison Margaret | Pharmaceutical compositions containing lornoxicam and cyclod extrin |
DE69733664T3 (en) | 1996-04-19 | 2011-04-14 | Grifols Inc. (n.d. Ges.d.Staates Delaware), Los Angeles | Method of inactivating viruses and lyophilizing blood proteins |
UA57734C2 (en) | 1996-05-07 | 2003-07-15 | Пфайзер Інк. | Arylheterocyclic inclusion complexes |
US5906981A (en) * | 1996-06-04 | 1999-05-25 | Troy Corporation | Halopropargyl inclusion complexes |
EP0877600B1 (en) * | 1996-08-09 | 2003-10-22 | Alcon Manufacturing Ltd. | Preservative systems for pharmaceutical compositions containing cyclodextrins |
DE19716120A1 (en) * | 1997-04-17 | 1998-10-22 | Europ Lab Molekularbiolog | Use of cholesterol-lowering agents |
US6046177A (en) * | 1997-05-05 | 2000-04-04 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations |
US5874418A (en) * | 1997-05-05 | 1999-02-23 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use |
JP4439596B2 (en) * | 1997-06-13 | 2010-03-24 | サイデクス ファーマシューティカルズ、 インク. | Pharmaceutical composition containing polar drug or polar prodrug having long shelf life, and method for producing the same |
GB9713149D0 (en) * | 1997-06-21 | 1997-08-27 | Pfizer Ltd | Pharmaceutical formulations |
DK0889056T3 (en) * | 1997-07-01 | 2006-07-17 | Pfizer Prod Inc | Process for making a cyclodextrin |
EP1029872A4 (en) * | 1997-11-07 | 2001-05-02 | Daiichi Seiyaku Co | Piperazine-cyclodextrin complexes |
US6699849B1 (en) * | 1998-02-23 | 2004-03-02 | Cyclops, Ehf. | Cyclodextrin complexes of benzodiazepines |
AU759280C (en) * | 1998-02-23 | 2004-01-22 | Cyclops, Ehf | High-energy cyclodextrin complexes |
AU757896B2 (en) * | 1998-09-02 | 2003-03-13 | Allergan, Inc. | Preserved cyclodextrin-containing compositions |
FR2784584B1 (en) * | 1998-10-14 | 2002-09-20 | Adir | PROCESS FOR THE PREPARATION OF A NASAL SPRAY SOLUTION CONTAINING ONE OR MORE SEXUAL HORMONES AND A CYCLODEXTRIN |
EP1133318B1 (en) * | 1998-12-04 | 2007-03-14 | California Institute of Technology | Supramolecular complexes containing therapeutic agents |
US7375096B1 (en) | 1998-12-04 | 2008-05-20 | California Institute Of Technology | Method of preparing a supramolecular complex containing a therapeutic agent and a multi-dimensional polymer network |
EP1143796A4 (en) | 1999-01-21 | 2002-03-20 | Bristol Myers Squibb Co | Complex of ras-farnesyltransferase inhibitor and sulfobutylether-7-beta-cyclodextrin or 2-hydroxypropyl-beta-cyclodextrin and method |
GB9913932D0 (en) | 1999-06-15 | 1999-08-18 | Pfizer Ltd | Purine derivatives |
GB9915231D0 (en) * | 1999-06-29 | 1999-09-01 | Pfizer Ltd | Pharmaceutical complex |
CA2315614C (en) | 1999-07-29 | 2004-11-02 | Pfizer Inc. | Pyrazoles |
GB9924361D0 (en) | 1999-10-14 | 1999-12-15 | Pfizer Ltd | Purine derivatives |
GB9924363D0 (en) | 1999-10-14 | 1999-12-15 | Pfizer Central Res | Purine derivatives |
WO2001030391A2 (en) * | 1999-10-27 | 2001-05-03 | Farmarc Nederland Bv | Pharmaceutical composition containing midazolam |
US20030113367A1 (en) * | 2000-03-28 | 2003-06-19 | Penkler Lawrence John | Alprazolam inclusion complexes and pharmaceutical compositions thereof |
SI1278549T1 (en) | 2000-05-02 | 2009-04-30 | Theravance Inc | Composition containing a cyclodextrin and a glycopeptide antibiotic |
US6667314B2 (en) | 2000-05-26 | 2003-12-23 | Pfizer, Inc. | Tropane derivatives useful in therapy |
ES2215129T3 (en) | 2000-05-26 | 2004-10-01 | Pfizer Inc. | DERIVATIVES OF TRIAZOLIL TROPANO AS MODULAR OF CCR5. |
US6753322B2 (en) | 2000-06-06 | 2004-06-22 | Pfizer Inc | 2-aminocarbonyl-9H-purine derivatives |
US6921753B2 (en) | 2000-06-27 | 2005-07-26 | Pfizer Inc | Purine derivatives |
US6468989B1 (en) | 2000-07-13 | 2002-10-22 | Dow Pharmaceutical Sciences | Gel compositions containing metronidazole |
US6420557B1 (en) | 2000-07-28 | 2002-07-16 | Pfizer Inc. | Crystalline therapeutic agent |
US7198801B2 (en) | 2000-08-03 | 2007-04-03 | Antares Pharma Ipl Ag | Formulations for transdermal or transmucosal application |
US8980290B2 (en) | 2000-08-03 | 2015-03-17 | Antares Pharma Ipl Ag | Transdermal compositions for anticholinergic agents |
WO2002011768A1 (en) * | 2000-08-03 | 2002-02-14 | Antares Pharma Ipl Ag | Novel composition for transdermal and/or transmucosal administration of active compounds that ensures adequate therapeutic levels |
PE20020300A1 (en) * | 2000-08-22 | 2002-05-10 | Pharmacia Corp | COMPOSITION OF SOLUTION OF AN ANTIBIOTIC DRUG BASED ON OXAZOLIDINONE WITH IMPROVEMENT OF DRUG LOAD |
GB0022695D0 (en) | 2000-09-15 | 2000-11-01 | Pfizer Ltd | Purine Derivatives |
AR031135A1 (en) | 2000-10-10 | 2003-09-10 | Upjohn Co | TOPIC ANTIBIOTIC COMPOSITIONS FOR THE TREATMENT OF OCULAR INFECTIONS |
US6548508B2 (en) | 2000-10-20 | 2003-04-15 | Pfizer, Inc. | Use of PDE V inhibitors for improved fecundity in mammals |
US6566556B2 (en) * | 2000-12-19 | 2003-05-20 | Nippon Shokubai Co., Ltd. | Method for production of alkanolamine and apparatus therefor |
JP2005503446A (en) | 2001-01-11 | 2005-02-03 | イーストマン ケミカル カンパニー | Cyclodextrin sulfonate, guest inclusion complex, production method thereof and related substances |
US20020146409A1 (en) * | 2001-01-30 | 2002-10-10 | Herring Steven W. | Methods for stabilizing lyophilized blood proteins |
IL141647A0 (en) * | 2001-02-26 | 2002-03-10 | Yeda Res & Dev | Synthetic human peptides and pharmaceutical compositions comprising them for the treatment of systemic lupus erythematosus |
US6579898B2 (en) | 2001-03-01 | 2003-06-17 | Pfizer Inc. | Compositions having improved bioavailability |
US7034013B2 (en) * | 2001-03-20 | 2006-04-25 | Cydex, Inc. | Formulations containing propofol and a sulfoalkyl ether cyclodextrin |
EA007184B1 (en) * | 2001-04-10 | 2006-08-25 | Пфайзер Инк. | Pyrazole derivatives for treating hiv |
CZ20032959A3 (en) * | 2001-05-01 | 2004-01-14 | Pfizer Products Inc. | Process for preparing a pharmaceutical composition with low dosage of a medicament and having uniform distribution and efficiency of the medicament |
US7595378B2 (en) | 2001-06-13 | 2009-09-29 | Genmab A/S | Human monoclonal antibodies to epidermal growth factor receptor (EGFR) |
EP1269994A3 (en) * | 2001-06-22 | 2003-02-12 | Pfizer Products Inc. | Pharmaceutical compositions comprising drug and concentration-enhancing polymers |
US7008934B2 (en) * | 2001-06-28 | 2006-03-07 | Baxter International Inc. | Composition and method for reducing adverse interactions between phenothiazine derivatives and plasma using cyclodextrins |
JP2004522803A (en) * | 2001-06-29 | 2004-07-29 | マキシゲン・エイピーエス | Interferon preparation |
GB0116453D0 (en) | 2001-07-05 | 2001-08-29 | Imp College Innovations Ltd | Method |
WO2003013498A2 (en) * | 2001-07-20 | 2003-02-20 | Dynamit Nobel Gmbh | Nitrate ester-cyclodextrin complexes for treating diseases, particularly coronary diseases |
US6653339B2 (en) | 2001-08-15 | 2003-11-25 | Pfizer Inc. | Method of treating irritable bowel syndrome |
US7141540B2 (en) * | 2001-11-30 | 2006-11-28 | Genta Salus Llc | Cyclodextrin grafted biocompatible amphilphilic polymer and methods of preparation and use thereof |
GB0129273D0 (en) | 2001-12-06 | 2002-01-23 | Pfizer Ltd | Crystalline drug form |
US6881726B2 (en) | 2001-12-24 | 2005-04-19 | Dow Pharmaceutical Sciences | Aqueous compositions containing metronidazole |
IL162870A0 (en) | 2002-02-01 | 2005-11-20 | Pfizer Prod Inc | Controlled release pharmaceutical dosage forms of a cholesteryl estertransfer protein inhibitor |
CA2475712C (en) | 2002-02-11 | 2009-11-24 | Simon Bailey | Nicotinamide derivatives useful as pde4 inhibitors |
US6756392B2 (en) | 2002-02-11 | 2004-06-29 | Pfizer Inc | Nicotinamide derivatives useful as PDE4 inhibitors |
CA2477044A1 (en) * | 2002-02-22 | 2003-09-04 | Pharmacia Corporation | Ophthalmic formulation with gum system |
MXPA04008173A (en) * | 2002-02-22 | 2004-11-26 | Pharmacia Corp | Ophthalmic antibiotic drug formulations containing a cyclodextrin compound and cetyl pyridinium chloride. |
GB0207104D0 (en) | 2002-03-26 | 2002-05-08 | Pfizer Ltd | Stable hydrate of a muscarinic receptor antagonist |
US6855724B2 (en) | 2002-04-08 | 2005-02-15 | Agouron Pharmaceuticals, Inc. | Tropane derivatives useful in therapy |
GB0209022D0 (en) | 2002-04-19 | 2002-05-29 | Imp College Innovations Ltd | Compounds |
US6869939B2 (en) * | 2002-05-04 | 2005-03-22 | Cydex, Inc. | Formulations containing amiodarone and sulfoalkyl ether cyclodextrin |
US6818662B2 (en) | 2002-05-28 | 2004-11-16 | Taisho Pharmaceutical Co., Ltd. | Pharmaceutical composition |
GB0212749D0 (en) * | 2002-06-01 | 2002-07-10 | Boots Co Plc | Personal care compositions |
TWI307626B (en) * | 2002-08-20 | 2009-03-21 | Bristol Myers Squibb Co | Aripiprazole complex formulation and method |
GB0219961D0 (en) | 2002-08-28 | 2002-10-02 | Pfizer Ltd | Oxytocin inhibitors |
KR20120104412A (en) | 2002-09-06 | 2012-09-20 | 인설트 테라페틱스, 인코퍼레이티드 | Cyclodextrin-based polymers for delivering the therapeutic agents covalently bound thereto |
GB0221169D0 (en) | 2002-09-12 | 2002-10-23 | Univ Bath | Crystal |
AU2003275329B2 (en) * | 2002-09-13 | 2008-04-03 | Cydex Pharmaceuticals, Inc. | Capsules containing aqueous fill compositions stabilized with derivatized cyclodextrin |
US20040058895A1 (en) * | 2002-09-18 | 2004-03-25 | Bone Care International, Inc. | Multi-use vessels for vitamin D formulations |
US7148211B2 (en) * | 2002-09-18 | 2006-12-12 | Genzyme Corporation | Formulation for lipophilic agents |
US7230025B2 (en) | 2002-09-26 | 2007-06-12 | Pfizer, Inc. | Pyrazole derivatives |
US6933312B2 (en) | 2002-10-07 | 2005-08-23 | Agouron Pharmaceuticals, Inc. | Pyrazole derivatives |
IL152575A (en) * | 2002-10-31 | 2008-12-29 | Transpharma Medical Ltd | Transdermal delivery system for water insoluble drugs |
IL152573A (en) * | 2002-10-31 | 2009-11-18 | Transpharma Medical Ltd | Transdermal delivery system for anti-emetic medication |
US7323462B2 (en) | 2002-12-10 | 2008-01-29 | Pfizer Inc. | Morpholine dopamine agonists |
KR20050085563A (en) | 2002-12-13 | 2005-08-29 | 워너-램버트 캄파니 엘엘씨 | Alpha-2-delta ligand to treat lower urinary tract symptoms |
CA2451267A1 (en) | 2002-12-13 | 2004-06-13 | Warner-Lambert Company Llc | Pharmaceutical uses for alpha2delta ligands |
CN1761477A (en) | 2003-01-14 | 2006-04-19 | 特瓦制药工业有限公司 | Parenteral formulations of a peptide for the treatment of systemic lupus erythematosus |
EA009123B1 (en) * | 2003-01-14 | 2007-10-26 | Тева Фармасьютикал Индастриз, Лтд. | Parenteral formulations of peptides for the treatment of systemic lupus erythematosus |
EP1460064A1 (en) | 2003-03-14 | 2004-09-22 | Pfizer Limited | Indole-2-carboxamide derivatives useful as beta-2 agonists |
EP1621199B8 (en) * | 2003-04-18 | 2011-01-19 | Advanced Medicine Research Institute | Remedies for diseases to be applied to eye |
CL2004000826A1 (en) | 2003-04-25 | 2005-03-04 | Pfizer | USE OF AN AGONIST FOR THE 5-HT2C RECEPTOR TO PREPARE A USEFUL MEDICINAL PRODUCT IN THE TREATMENT OF URINARY INCONTINENCE CAUSED BY STRESS, WITH THE CONDITION THAT THE AGONIST IS NOT 1- [6-CHLORINE-5- (TRIFLUOROMETIL) -2- PIRIDINIL] PIPERAZINA (ORG-129 |
US7157446B2 (en) * | 2003-05-02 | 2007-01-02 | Bristol Myers Squibb Company | Complex of ras-farnesyltransferase inhibitor, a cyclodextrin, and ethanol |
US7268147B2 (en) | 2003-05-15 | 2007-09-11 | Pfizer Inc | Compounds useful for the treatment of diseases |
BRPI0414105B8 (en) | 2003-09-03 | 2021-05-25 | Askat Inc | benzimidazolone compounds with 5-ht4 receptor agonist activity |
US7875630B2 (en) | 2003-09-03 | 2011-01-25 | Glaxo Group Limited | Process salts compositions and use |
US7220772B2 (en) | 2003-09-05 | 2007-05-22 | Pfizer, Inc. | Pyrazole derivatives |
US6960300B2 (en) * | 2003-09-08 | 2005-11-01 | Sami Labs Limited | Process for preparing water soluble diterpenes and their applications |
BRPI0414343A (en) | 2003-09-12 | 2006-11-07 | Pfizer | combinations comprising alpha-2-delta ligands and serotonin / norepinephrine reuptake inhibitors |
ATE380813T1 (en) | 2003-10-03 | 2007-12-15 | Pfizer | IMIDAZOPYRIDINE-SUBSTITUTED TROPANE DERIVATIVES WITH CCR5 RECEPTOR ANTAGONISTIC EFFECTS FOR THE TREATMENT OF HIV AND INFLAMMATION |
AU2004283431B2 (en) | 2003-10-10 | 2009-09-10 | Antares Pharma Ipl Ag | Transdermal pharmaceutical formulation for minimizing skin residues |
TW200517114A (en) | 2003-10-15 | 2005-06-01 | Combinatorx Inc | Methods and reagents for the treatment of immunoinflammatory disorders |
US7129042B2 (en) * | 2003-11-03 | 2006-10-31 | Diagnostic Hybrids, Inc. | Compositions and methods for detecting severe acute respiratory syndrome coronavirus |
SG148198A1 (en) | 2003-11-21 | 2008-12-31 | Combinatorx Inc | Methods and reagents for the treatment of inflammatory disorders |
US20070020196A1 (en) * | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid prepared from a unit dose suspension |
AU2004312096A1 (en) * | 2003-12-31 | 2005-07-21 | Cydex Pharmaceuticals, Inc. | Inhalant formulation containing sulfoalkyl ether gamma-cyclodextrin and corticosteroid |
US20070020299A1 (en) * | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid |
CA2553293C (en) | 2004-01-22 | 2010-12-14 | Pfizer Inc. | Sulfonamide derivatives for the treatment of diseases |
AU2005214153B2 (en) | 2004-01-22 | 2008-09-18 | Pfizer Inc. | Sulfonamide derivatives for the treatment of diseases |
US7629358B2 (en) | 2004-03-17 | 2009-12-08 | Pfizer Inc | Compounds useful for the treatment of diseases |
AU2005223483B2 (en) | 2004-03-18 | 2009-04-23 | Zoetis Llc | N-(1-arylpyrazol-4l)sulfonamides and their use as parasiticides |
US7538141B2 (en) | 2004-03-23 | 2009-05-26 | Alan Daniel Brown | Compounds for the treatment of diseases |
PL1730103T3 (en) | 2004-03-23 | 2010-10-29 | Pfizer | Formamide derivatives useful as adrenoceptor |
US20050234018A1 (en) * | 2004-04-15 | 2005-10-20 | Allergan, Inc. | Drug delivery to the back of the eye |
CN102174076A (en) | 2004-04-15 | 2011-09-07 | 普罗特奥里克斯公司 | Compounds for proteasome enzyme inhibition |
US8198270B2 (en) * | 2004-04-15 | 2012-06-12 | Onyx Therapeutics, Inc. | Compounds for proteasome enzyme inhibition |
CN101098678A (en) * | 2004-04-23 | 2008-01-02 | 锡德克斯公司 | Dpi formulation containing sulfoalkyl ether cyclodextrin |
EP1745029A1 (en) | 2004-04-30 | 2007-01-24 | Warner-Lambert Company LLC | Substituted morpholine compounds for the treatment of central nervous system disorders |
CN1980574A (en) * | 2004-05-06 | 2007-06-13 | 锡德克斯公司 | Taste-masked formulations containing sertraline and sulfoalkyl ether cyclodextrin |
US7456164B2 (en) | 2004-05-07 | 2008-11-25 | Pfizer, Inc | 3- or 4-monosubtituted phenol and thiophenol derivatives useful as H3 ligands |
PL2030981T3 (en) * | 2004-05-10 | 2014-12-31 | Onyx Therapeutics Inc | Compounds for proteasome enzyme inhibition |
EP1595881A1 (en) | 2004-05-12 | 2005-11-16 | Pfizer Limited | Tetrahydronaphthyridine derivates useful as histamine H3 receptor ligands |
EP1758891A2 (en) | 2004-06-15 | 2007-03-07 | Pfizer Japan Inc. | Benzimidazolone carboxylic acid derivatives |
US7737163B2 (en) | 2004-06-15 | 2010-06-15 | Pfizer Inc. | Benzimidazolone carboxylic acid derivatives |
AU2005273612B2 (en) | 2004-08-12 | 2010-10-14 | Pfizer Inc. | Triazolopyridinylsulfanyl derivatives as p38 map kinase inhibitors |
ATE463486T1 (en) | 2004-08-26 | 2010-04-15 | Pfizer | ENANTIOMER PURE AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS |
ITMI20041763A1 (en) * | 2004-09-16 | 2004-12-16 | Altergon Sa | NEW INJECTABLE FORMULATIONS CONTAINING PROGESTERONE |
MX2007005290A (en) | 2004-11-02 | 2007-07-09 | Pfizer | Sulfonyl benzimidazole derivatives. |
US9120774B2 (en) | 2004-11-03 | 2015-09-01 | University Of Kansas | Novobiocin analogues having modified sugar moieties |
GT200500317A (en) * | 2004-11-05 | 2006-10-27 | PROCESS TO PREPARE QUINOLINE COMPOUNDS AND PRODUCTS OBTAINED FROM THEM | |
WO2006052922A2 (en) * | 2004-11-08 | 2006-05-18 | Eastman Chemical Company | Pharmaceutical formulations of cyclodextrins and selective estrogen receptor modulator compounds |
WO2006052921A2 (en) * | 2004-11-08 | 2006-05-18 | Eastman Chemical Company | Cyclodextrin solubilizers for liquid and semi-solid formulations |
CA2589921C (en) * | 2004-12-07 | 2016-01-26 | Proteolix, Inc. | Composition comprising a cyclodextrin and a proteasome inhibitor |
EP1674098A1 (en) | 2004-12-23 | 2006-06-28 | Schering Aktiengesellschaft | Stable and tolerable parental formulations of highly reactive organic drug substances with low or no solubility in water |
CA2614223A1 (en) | 2005-02-24 | 2006-08-31 | Dr Pharma Nova, Llc | A registry method and control system for dea schedule ii-v medicines |
BRPI0608436A2 (en) | 2005-03-17 | 2009-12-29 | Pfizer | n- (n-sulfonylaminomethyl) cyclopropanecarboxamide derivatives usable for the treatment of pain |
ATE412648T1 (en) | 2005-03-21 | 2008-11-15 | Pfizer Ltd | SUBSTITUTED TRIAZOLE DERIVATIVES AS OXYTOCIN ANTAGONISTS |
CA2851079A1 (en) * | 2005-04-15 | 2006-10-26 | Albert Einstein College Of Medicine Of Yeshiva University | Vitamin k for prevention and treatment of skin rash secondary to anti-egfr therapy |
CA2602022C (en) | 2005-04-19 | 2016-03-22 | Gabriel Stavros Panayi | Binding immunoglobulin protein (bip) for prevention or treatment of bone conditions or diseases |
WO2007124250A2 (en) | 2006-04-21 | 2007-11-01 | Antares Pharma Ipl Ag | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
CA2606064A1 (en) * | 2005-04-24 | 2006-11-02 | Wyeth | Methods for modulating bladder function |
JP2008540396A (en) | 2005-05-04 | 2008-11-20 | ファイザー・リミテッド | 2-Amido-6-amino-8-oxopurine derivatives as toll-like receptor modulators for treating viral infections such as cancer and hepatitis C |
US8940764B2 (en) | 2005-05-26 | 2015-01-27 | Aldexa Therapeutics, Inc. | Compositions and methods of treating retinal disease |
WO2006125642A1 (en) | 2005-05-27 | 2006-11-30 | Antares Pharma Ipl Ag | Methods and apparatus for transdermal or transmucosal application of testosterone |
CA2611917A1 (en) * | 2005-06-13 | 2006-12-21 | Takeda Pharmaceutical Company Limited | Injection |
ES2338699T3 (en) | 2005-06-15 | 2010-05-11 | Pfizer Limited | SUBSTITUTED ARILPIRAZOLES FOR USE AGAINST PARASITES. |
US20080176865A1 (en) * | 2005-06-15 | 2008-07-24 | Pfizer Limited | Substituted arylpyrazoles |
US20080146643A1 (en) * | 2005-06-15 | 2008-06-19 | Pfizer Limited | Combination |
US7645786B2 (en) | 2005-06-15 | 2010-01-12 | Pfizer Inc. | Substituted arylpyrazoles |
AR054849A1 (en) * | 2005-07-26 | 2007-07-18 | Wyeth Corp | DIAZEPINOQUINOLINAS, SYNTHESIS OF THE SAME, AND INTERMEDIARIES TO OBTAIN THEM |
US20070191306A1 (en) * | 2005-08-17 | 2007-08-16 | Bristol-Myers Squibb Company | FACTOR Xa INHIBITOR FORMULATION AND METHOD |
DE102005041860A1 (en) * | 2005-09-02 | 2007-03-08 | Schering Ag | Nano-particle embedded- and charged-complex, useful for the production of a pharmaceutical composition, comprises two complex partners, where the complex partner is an embedded anionic and a cationic active substance |
EP1928464B1 (en) | 2005-09-30 | 2014-05-14 | Lundbeck Inc. | Novel parenteral carbamazepine formulation |
US20100204178A1 (en) * | 2006-10-02 | 2010-08-12 | James Cloyd | Novel parenteral carbamazepine formulation |
EP2581078B1 (en) | 2005-10-26 | 2014-12-10 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof |
US7629331B2 (en) | 2005-10-26 | 2009-12-08 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof |
PT1948678E (en) | 2005-11-09 | 2013-07-16 | Onyx Therapeutics Inc | Compounds for enzyme inhibition |
EA017290B1 (en) | 2005-11-28 | 2012-11-30 | Домейн Раша Инвестментс Лимитед | Ganaxolone-based formulations |
US20070135586A1 (en) * | 2005-12-09 | 2007-06-14 | Shreyas Chakravarti | Polyamide blend compositions formed article and process thereof |
NL2000323C2 (en) | 2005-12-20 | 2007-11-20 | Pfizer Ltd | Pyrimidine derivatives. |
US20070185066A1 (en) * | 2005-12-20 | 2007-08-09 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids |
US20070178049A1 (en) * | 2005-12-20 | 2007-08-02 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids having an enhanced pharmacokinetic profile |
US20070249572A1 (en) * | 2005-12-20 | 2007-10-25 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids |
EP1971346A2 (en) * | 2005-12-20 | 2008-09-24 | Tika Läkemedel AB | Systems and methods for the delivery of corticosteroids |
US20070197486A1 (en) * | 2005-12-20 | 2007-08-23 | Verus Pharmaceuticals, Inc. | Methods and systems for the delivery of corticosteroids |
US20070160542A1 (en) * | 2005-12-20 | 2007-07-12 | Verus Pharmaceuticals, Inc. | Methods and systems for the delivery of corticosteroids having an enhanced pharmacokinetic profile |
US20070141684A1 (en) | 2005-12-21 | 2007-06-21 | Pfizer Inc | Preparation of gamma-amino acids having affinity for the alpha-2-delta protein |
GB0600406D0 (en) | 2006-01-10 | 2006-02-15 | Univ Bath | Crystal |
TW200734334A (en) * | 2006-01-13 | 2007-09-16 | Wyeth Corp | Treatment of substance abuse |
GB0600928D0 (en) | 2006-01-17 | 2006-02-22 | Novacta Biosystems Ltd | Improvements relating to lantibiotics |
JP2009526860A (en) * | 2006-02-15 | 2009-07-23 | ティカ レーケメデル アーベー | Stable corticosteroid mixture |
CL2007000773A1 (en) * | 2006-03-24 | 2008-01-25 | Wyeth Corp | Use of compounds derived from condensed diazepine for the treatment of a cognitive disorder such as add or adhd; or its use to treat spm or pmdd. |
TW200806298A (en) * | 2006-03-24 | 2008-02-01 | Wyeth Corp | Methods for modulating bladder function |
BRPI0709163A2 (en) * | 2006-03-24 | 2011-06-28 | Wyeth Corp | pain treatment |
MX2008012212A (en) * | 2006-03-24 | 2008-10-02 | Wyeth Corp | Methods for treating cognitive and other disorders. |
JP2009531435A (en) * | 2006-03-24 | 2009-09-03 | ワイス | Novel therapeutic combinations for the treatment of depression |
US20070238789A1 (en) * | 2006-03-31 | 2007-10-11 | Chin-Ming Chang | Prednisolone acetate compositions |
KR20090037388A (en) | 2006-04-18 | 2009-04-15 | 이케이알 테라퓨틱스, 인코포레이티드 | Pre-mixed, ready-to-use iv bolus compositions and methods of use |
CN100374468C (en) * | 2006-05-25 | 2008-03-12 | 重庆通量精细化工有限公司 | Synthetic process for water soluble sulfoalkyl ether-beta-cyclic dextrine |
US7691852B2 (en) * | 2006-06-19 | 2010-04-06 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
WO2008003317A1 (en) * | 2006-07-03 | 2008-01-10 | Genmab A/S | Prevention of rash in patients undergoing anti-egfr therapy |
AR061889A1 (en) | 2006-07-13 | 2008-10-01 | Medichem Sa | IMPROVED PROCESS FOR THE PREPARATION OF VORICONAZOL |
WO2008012538A2 (en) | 2006-07-25 | 2008-01-31 | The Secretary Of State For Defence | Live vaccine strains of francisella |
US20100022481A1 (en) * | 2006-08-02 | 2010-01-28 | Dong Wang | Drug Carriers, Their Synthesis, and Methods of Use Thereof |
EP2061459B1 (en) | 2006-08-23 | 2012-12-26 | Intellect Neurosciences Inc. | 3-(3-indolyl) propionic acid calcium salt and method of making 3-(3-indolyl) propionic acid free acid therefrom |
US20090239942A1 (en) * | 2006-09-15 | 2009-09-24 | Cloyd James C | Topiramate Compositions and Methods of Making and Using the Same |
EP2380566A3 (en) | 2006-09-15 | 2012-04-11 | Stevia APS | Treatment of insulin resistance or diseases associated with insulin resistance using steviol or isosteviol |
EP2061458B1 (en) * | 2006-09-15 | 2014-12-10 | Regents of the University of Minnesota | Topiramate compositions and methods for their use |
ATE512969T1 (en) | 2006-09-21 | 2011-07-15 | Raqualia Pharma Inc | BENZIMIDAZOLE DERIVATIVES AS SELECTIVE ACID PUMP INHIBITORS |
EP2076287A2 (en) | 2006-10-12 | 2009-07-08 | Wyeth | Methods and compositions with reduced opalescence |
DK2076508T3 (en) | 2006-10-18 | 2011-02-21 | Pfizer Prod Inc | The biaryl ether urea compounds |
KR20110098009A (en) | 2006-10-20 | 2011-08-31 | 이코스 코포레이션 | Compositions of chk1 inhibitors and cyclodextrin |
JP2010512305A (en) | 2006-10-23 | 2010-04-22 | ファイザー株式会社 | Substituted phenylmethylbicyclocarboxamide compounds |
US8158609B1 (en) * | 2006-11-02 | 2012-04-17 | Novartis Ag | Use of cyclodextrins as an active ingredient for treating dry AMD and solubilizing drusen |
MX2009004519A (en) | 2006-11-03 | 2009-05-12 | Wyeth Corp | Glycolysis-inhibiting substances in cell culture. |
KR100822133B1 (en) * | 2006-11-06 | 2008-04-15 | 한미약품 주식회사 | Complex formulation for preventing or treating osteoporosis which comprises solid dispersion of vitamin d or its derivative and bisphosphonate |
KR20090087079A (en) * | 2006-11-21 | 2009-08-14 | 노파르티스 아게 | Stable parenteral formulation containing a rsv inhibitor of a benzodiazepine structure |
JP2010516625A (en) | 2007-01-24 | 2010-05-20 | インサート セラピューティクス, インコーポレイテッド | Polymer-drug conjugates with tether groups for controlled drug delivery |
ES2373867T3 (en) * | 2007-03-02 | 2012-02-09 | The University Of Wollongong | COMPOSITIONS AND PROCEDURES FOR THE SUPPLY OF ANTI-TARGET AGENTS. |
KR20090127326A (en) | 2007-03-02 | 2009-12-10 | 와이어쓰 | Use of copper and glutamate in cell culture for production of polypeptides |
DK2152078T3 (en) | 2007-04-27 | 2021-02-08 | Cydex Pharmaceuticals Inc | FORMULATIONS CONTAINING CLOPIDOGREL AND SULFOALKYLETHERCYCLODEXTRINE AND USE PROCEDURES |
AU2015255164B2 (en) * | 2007-04-27 | 2017-06-08 | Cydex Pharmaceuticals, Inc. | Formulations containing clopidogrel and sulfoalkyl ether cyclodextrin and methods of use |
US7960353B2 (en) * | 2007-05-10 | 2011-06-14 | University Of Kansas | Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders |
EP2160381A2 (en) * | 2007-05-24 | 2010-03-10 | Pfizer Limited | Spirocyclic quinazoline derivatives and their use as pde7 inhibitors |
TWI364290B (en) | 2007-05-25 | 2012-05-21 | Ipsen Pharma Sas | Melanocortin receptor ligands modifled with hydantoin |
ES2493641T3 (en) * | 2007-06-28 | 2014-09-12 | Cydex Pharmaceuticals, Inc. | Nasal administration of aqueous corticosteroid solutions |
TWI428132B (en) * | 2007-07-02 | 2014-03-01 | Lilly Co Eli | Potentiation of cancer chemotherapy |
GB0714029D0 (en) | 2007-07-18 | 2007-08-29 | Novacta Biosystems Ltd | Lantibiotic-based compounds having antimicrobial activity |
GB0714030D0 (en) | 2007-07-18 | 2007-08-29 | Novacta Biosystems Ltd | The use of type-B lantibiotic-based compounds having antimicrobial activity |
CA2697495C (en) | 2007-09-05 | 2013-02-05 | Pfizer Limited | Xinafoate salt of n4-[(2,2-difluoro-4h-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-n2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine |
KR100929920B1 (en) | 2007-09-05 | 2009-12-04 | 주식회사 마크로케어 | Method for preparing clathrate containing hydrophobic physiologically active ingredient in cyclodextrin and derivatives thereof and use of clathrate prepared thereby |
CL2008002777A1 (en) * | 2007-09-21 | 2010-01-22 | Wyeth Corp | Method of preparing chiral diazepinoquinoline compounds by recrystallization in a ternary solvent system. |
KR20170040374A (en) * | 2007-10-04 | 2017-04-12 | 오닉스 세라퓨틱스, 인크. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
EP2057982A1 (en) | 2007-11-09 | 2009-05-13 | Archimedes Development Limited | Intranasal compositions |
US8040246B2 (en) * | 2007-12-04 | 2011-10-18 | Avaya Inc. | Systems and methods for facilitating a first response mission at an incident scene |
US8192721B2 (en) * | 2007-12-13 | 2012-06-05 | Verrow Pharmaceuticals, Inc. | Compositions useful for reducing toxicity associated with gadolinium-based contrast agents |
US8815953B2 (en) * | 2008-03-13 | 2014-08-26 | Spectrum Pharmaceuticals, Inc. | Formulations of vitamin K analogs for topical use |
GB2458473A (en) | 2008-03-17 | 2009-09-23 | Imuthes Ltd | 3'-O-allyl- and 3'-O-carboxymethyl- 2'-aminosaccharide derivatives, & amides thereof with peptides, as adjuvants |
US7635773B2 (en) | 2008-04-28 | 2009-12-22 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
WO2009137611A2 (en) * | 2008-05-06 | 2009-11-12 | Board Of Regents, The University Of Texas System | Treatment of pulmonary fungal infection with voriconazole via inhalation |
EP2303229A1 (en) * | 2008-06-16 | 2011-04-06 | Debiopharm S.A. | Concentrated oxaliplatin solution and its method of preparation |
US20100022635A1 (en) * | 2008-07-28 | 2010-01-28 | University Of Kansas | Heat shock protein 90 inhibitor dosing methods |
US8518952B2 (en) | 2008-08-06 | 2013-08-27 | Pfizer Inc. | 6 substituted 2-heterocyclylamino pyrazine compounds as CHK-1 inhibitors |
EP2163253B1 (en) | 2008-09-15 | 2013-07-17 | ULLRICH, Oliver | Extracts from the plant Hornstedtia scyphifera and immunosuppressive effects thereof |
US20100093872A1 (en) * | 2008-10-15 | 2010-04-15 | Erimos Pharmaceuticals Llc | Stable aqueous formulations of water insoluble or poorly soluble drugs |
MX2011004225A (en) | 2008-10-21 | 2011-06-21 | Onyx Therapeutics Inc | Combination therapy with peptide epoxyketones. |
US10463677B2 (en) | 2008-11-07 | 2019-11-05 | Cydex Pharmaceuticals, Inc. | Composition containing sulfoalkyl ether cyclodextrin and latanoprost |
CA2743419C (en) | 2008-11-15 | 2017-02-14 | Rib-X Pharmaceuticals, Inc. | Antimicrobial compositions |
RU2528406C2 (en) | 2008-11-21 | 2014-09-20 | Раквалиа Фарма Инк. | New pyrazole-3-carboxamide derivative possessing antagonist activity on 5-нт2в receptor |
KR20110101212A (en) | 2008-12-17 | 2011-09-15 | 제넨테크, 인크. | Hepatitis c virus combination therapy |
DK2385938T3 (en) | 2009-01-12 | 2015-04-27 | Pfizer Ltd | Sulfonamidderivater |
GB0900599D0 (en) | 2009-01-14 | 2009-02-18 | Novacta Biosystems Ltd | Treatment |
EP2387580B1 (en) | 2009-01-14 | 2014-08-13 | Novacta Biosystems Limited | Deoxyactagardine derivatives |
JP5731407B2 (en) | 2009-02-04 | 2015-06-10 | ノヴァクタ バイオシステムズ リミティッド | Actagardine derivatives |
EP2406281B1 (en) | 2009-03-12 | 2016-02-17 | Haase Investments UG | Bone morphogenetic protein 2 (bmp2) variants with reduced bmp antagonist sensitivity |
TWI504598B (en) | 2009-03-20 | 2015-10-21 | Onyx Therapeutics Inc | Crystalline tripeptide epoxy ketone protease inhibitors |
EP2233502A1 (en) | 2009-03-27 | 2010-09-29 | Deutsches Rheuma-Forschungszentrum Berlin | Sialylated antigen-specific antibodies for treatment or prophylaxis of unwanted inflammatory immune reactions and methods of producing them |
WO2010116270A1 (en) | 2009-04-10 | 2010-10-14 | Pfizer Inc. | Ep2/4 agonists |
GB0906234D0 (en) | 2009-04-14 | 2009-05-20 | Secr Defence | Vaccine |
DK3100728T3 (en) | 2009-05-13 | 2020-02-17 | Cydex Pharmaceuticals Inc | PHARMACEUTICAL COMPOSITIONS COMPREHENSIVE PRASUGREL AND CYCLODEXTRIN DERIVATIVES AND METHODS FOR PREPARING AND USING SAME |
CN102458114A (en) | 2009-05-29 | 2012-05-16 | 锡德克斯药物公司 | Injectable melphalan compositions comprising a cyclodextrin derivative and methods of making and using the same |
KR20120018813A (en) | 2009-05-29 | 2012-03-05 | 화이자 리미티드 | Novel glucocorticoid receptor agonists |
US11020363B2 (en) | 2009-05-29 | 2021-06-01 | Cydex Pharmaceuticals, Inc. | Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same |
US8492538B1 (en) | 2009-06-04 | 2013-07-23 | Jose R. Matos | Cyclodextrin derivative salts |
EP2266563A1 (en) | 2009-06-11 | 2010-12-29 | Charité-Universitätsmedizin Berlin (Charité) | Use of opioid receptor antagonists for acute treatment of paraphilic arousal states |
AU2010260208B2 (en) | 2009-06-16 | 2014-11-13 | Bristol-Myers Squibb Holdings Ireland Unlimited Company | Dosage forms of apixaban |
WO2011004276A1 (en) | 2009-07-06 | 2011-01-13 | Pfizer Limited | Hepatitis c virus inhibitors |
DE102009034368A1 (en) | 2009-07-20 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-acyloxyalkylenephenyl derivatives, process for their preparation and their use for the treatment of diseases |
WO2011041593A1 (en) * | 2009-09-30 | 2011-04-07 | University Of Kansas | Novobiocin analogues and treatment of polycystic kidney disease |
WO2011060179A1 (en) | 2009-11-13 | 2011-05-19 | Onyx Therapeutics, Inc | Use of peptide epoxyketones for metastasis suppression |
WO2011077313A1 (en) | 2009-12-22 | 2011-06-30 | Pfizer Inc. | Piperidinecarboxamides as mpges - 1 inhibitors |
ME02186B (en) | 2009-12-23 | 2016-02-20 | Takeda Pharmaceuticals Co | Fused heteroaromatic pyrrolidinones as syk inhibitors |
WO2011083387A1 (en) | 2010-01-07 | 2011-07-14 | Pfizer Limited | Hydrochloride salt of biphenyl-2-yl-carbamic acid 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl}-piperidin-4-yl ester |
ES2646829T3 (en) | 2010-01-21 | 2017-12-18 | Drawbridge Pharmaceuticals Pty Ltd. | Anesthetic formulation |
GB201001688D0 (en) | 2010-02-02 | 2010-03-17 | Novacta Biosystems Ltd | Compounds |
EP2531519A1 (en) | 2010-02-02 | 2012-12-12 | Novacta Biosystems Limited | Lantibiotic salts |
CA2789606A1 (en) | 2010-02-25 | 2011-09-01 | Pfizer Limited | Peptide analogues as opioid receptor agonists |
MA34133B1 (en) | 2010-03-01 | 2013-04-03 | Onyx Therapeutics Inc | COMPOUNDS FOR INHIBITORS OF IMMUNOPROTEASOME |
CA2792733C (en) * | 2010-03-13 | 2015-06-02 | Eastpond Laboratories Limited | Fat-binding compositions comprising .alpha.- or .beta.-cyclodextrin |
US8697646B2 (en) | 2010-04-07 | 2014-04-15 | Onyx Therapeutics, Inc. | Crystalline peptide epoxyketone immunoproteasome inhibitor |
WO2011138751A2 (en) | 2010-05-04 | 2011-11-10 | Pfizer Inc. | Heterocyclic derivatives as alk inhibitors |
NZ604498A (en) | 2010-05-26 | 2014-10-31 | Neurophyxia B V | 2-iminobiotin formulations and uses thereof |
WO2011154871A1 (en) | 2010-06-10 | 2011-12-15 | Pfizer Limited | Hepatitis c virus inhibitors |
WO2011156481A2 (en) * | 2010-06-11 | 2011-12-15 | Baxter International Inc. | Formulations including amiodarone and salts thereof and methods of their manufacture and use |
US9145407B2 (en) | 2010-07-09 | 2015-09-29 | Pfizer Limited | Sulfonamide compounds |
JP5830534B2 (en) | 2010-07-09 | 2015-12-09 | ファイザー・リミテッドPfizer Limited | Compound |
ES2526675T3 (en) | 2010-07-09 | 2015-01-14 | Pfizer Limited | N-sulfonylbenzamides as voltage dependent sodium channel inhibitors |
ES2526541T3 (en) | 2010-07-12 | 2015-01-13 | Pfizer Limited | N-sulfonylbenzamides as voltage dependent sodium channel inhibitors |
JP2013536165A (en) | 2010-07-12 | 2013-09-19 | ファイザー・リミテッド | Sulfonamide derivatives as NAV 1.7 inhibitors for the treatment of pain |
CA2801032A1 (en) | 2010-07-12 | 2012-01-19 | Pfizer Limited | N-sulfonylbenzamide derivatives useful as voltage gated sodium channel inhibitors |
CA2804716A1 (en) | 2010-07-12 | 2012-01-19 | Pfizer Limited | Chemical compounds |
EP2593431B1 (en) | 2010-07-12 | 2014-11-19 | Pfizer Limited | N-sulfonylbenzamides as inhibitors of voltage-gated sodium channels |
GB201013507D0 (en) | 2010-08-11 | 2010-09-22 | Novacta Biosystems Ltd | Compounds |
GB201013513D0 (en) | 2010-08-11 | 2010-09-22 | Novacta Biosystems Ltd | Formulations |
GB201013508D0 (en) | 2010-08-11 | 2010-09-22 | Novacta Biosystems Ltd | Compounds |
GB201013509D0 (en) | 2010-08-11 | 2010-09-22 | Novacta Biosystems Ltd | Compounds |
AU2011294888B2 (en) | 2010-08-24 | 2015-06-18 | Imperial Innovations Limited | Glycodendrimers of polypropyletherimine |
WO2012042421A1 (en) | 2010-09-29 | 2012-04-05 | Pfizer Inc. | Method of treating abnormal cell growth |
EP2635121B1 (en) | 2010-11-01 | 2020-01-08 | MEI Pharma, Inc. | Isoflavonoid compounds and methods for the treatment of cancer |
CA2817896A1 (en) | 2010-11-15 | 2012-05-24 | Viiv Healthcare Uk Limited | Inhibitors of hiv replication |
WO2012095781A1 (en) | 2011-01-13 | 2012-07-19 | Pfizer Limited | Indazole derivatives as sodium channel inhibitors |
CN103415292A (en) | 2011-01-26 | 2013-11-27 | 阿勒根公司 | Androgen composition for treating an opthalmic condition |
WO2012148548A1 (en) | 2011-02-25 | 2012-11-01 | Takeda Pharmaceutical Company Limited | N-substituted oxazinopteridines and oxazinopteridinones |
WO2012120398A1 (en) | 2011-03-04 | 2012-09-13 | Pfizer Limited | Aryl substituted carboxamide derivatives as trpm8 modulators |
MX2013011612A (en) | 2011-04-05 | 2013-10-17 | Pfizer Ltd | Pyrrolo [2, 3 -d] pyrimidine derivatives as inhibitors of tropomyosin- related kinases. |
RU2616978C2 (en) | 2011-05-18 | 2017-04-19 | Раквалиа Фарма Инк. | Polymorph form of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}-tetrahydro-2h-pyran-4-carboxylic acid |
TWI544922B (en) | 2011-05-19 | 2016-08-11 | 愛爾康研究有限公司 | High concentration olopatadine ophthalmic composition |
EP2720723B1 (en) | 2011-06-15 | 2018-04-11 | Synthon BV | Stabilized voriconazole composition |
EP2723739B1 (en) | 2011-06-22 | 2016-08-24 | Takeda Pharmaceutical Company Limited | Substituted 6-aza-isoindolin-1-one derivatives |
ES2564366T3 (en) | 2011-07-13 | 2016-03-22 | Pfizer Limited | Encephalin analogues |
US8575336B2 (en) | 2011-07-27 | 2013-11-05 | Pfizer Limited | Indazoles |
RU2014102935A (en) | 2011-08-02 | 2015-09-10 | Пфайзер Инк. | CRYZOTINIB FOR USE IN CANCER TREATMENT |
EP2739274A1 (en) | 2011-08-02 | 2014-06-11 | Pensieve Biosciences Cyprus Limited | Treatment of cognitive impairment |
LT2753632T (en) | 2011-09-08 | 2023-07-10 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
LT2758052T (en) | 2011-09-18 | 2018-04-10 | Euro-Celtique S.A. | Pharmaceutical composition comprising an HDAC inhibitor and a cyclopolysaccharide |
WO2013054185A1 (en) | 2011-10-13 | 2013-04-18 | Pfizer, Inc. | Pyrimidine and pyridine derivatives useful in therapy |
ES2738526T3 (en) | 2011-10-14 | 2020-01-23 | Sage Therapeutics Inc | Compounds 19-norpregnano 3,3-disubstituted, compositions and uses thereof |
JP5363636B2 (en) | 2011-10-21 | 2013-12-11 | ファイザー・リミテッド | New salts and medical uses |
AU2012328034B2 (en) | 2011-10-26 | 2015-04-23 | Pfizer Limited | (4-phenylimidazol-2-yl) ethylamine derivatives useful as sodium channel modulators |
ES2648901T3 (en) | 2011-10-28 | 2018-01-08 | Inhibitaxin Limited | Pyridazine derivatives useful in therapy |
JP6058023B2 (en) | 2011-12-15 | 2017-01-11 | ファイザー・リミテッドPfizer Limited | Sulfonamide derivatives |
WO2013093688A1 (en) | 2011-12-19 | 2013-06-27 | Pfizer Limited | Sulfonamide derivatives and use thereof as vgsc inhibitors |
TW201332572A (en) | 2011-12-28 | 2013-08-16 | Otsuka Pharma Co Ltd | Pharmaceutical preparation comprising substituted β -cyclodextrin |
US20150291514A1 (en) | 2012-01-04 | 2015-10-15 | Pfizer Limted | N-Aminosulfonyl Benzamides |
GB201201332D0 (en) | 2012-01-26 | 2012-03-14 | Imp Innovations Ltd | Method |
AR092790A1 (en) | 2012-02-01 | 2015-05-06 | Euro Celtique Sa | BENCIMIDAZOLIC DERIVATIVES OF HYDROXAMIC ACID |
ES2548228T3 (en) | 2012-02-03 | 2015-10-15 | Pfizer Inc | Benzimidazole and imidazopyridine derivatives as sodium channel modulators |
TW201336527A (en) | 2012-02-10 | 2013-09-16 | Alcon Res Ltd | Aqueous pharmaceutical composition with enhanced stability |
PT2814849T (en) | 2012-02-15 | 2020-03-04 | Cydex Pharmaceuticals Inc | Manufacturing process for cyclodextrin derivatives |
JP2015508846A (en) | 2012-02-28 | 2015-03-23 | サイデックス・ファーマシューティカルズ・インコーポレイテッド | Alkylated cyclodextrin compositions and methods for their preparation and use |
ES2621220T3 (en) | 2012-03-06 | 2017-07-03 | Pfizer Inc. | Macrocyclic derivatives for the treatment of proliferative diseases |
US9365566B2 (en) | 2012-03-27 | 2016-06-14 | Takeda Pharmaceutical Company Limited | Cinnoline derivatives |
EP2831122B1 (en) | 2012-03-30 | 2016-02-03 | SapioTec GmbH | Anthocyanidin complex |
US9309283B2 (en) | 2012-07-09 | 2016-04-12 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
TW201414734A (en) | 2012-07-10 | 2014-04-16 | Takeda Pharmaceutical | Azaindole derivatives |
WO2014022841A1 (en) | 2012-08-03 | 2014-02-06 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Cyclodextrin for the treatment of lysosomal storage diseases |
EP2909212B1 (en) | 2012-09-07 | 2017-02-22 | Takeda Pharmaceutical Company Limited | Substituted 1,4-dihydropyrazolo[4,3-b]indoles |
US9533989B2 (en) | 2012-09-18 | 2017-01-03 | Ziarco Pharma Ltd. | Substituted pyrimidine-5-carboxamides as spleen tyrosine kinase inhibitors |
JP6254169B2 (en) | 2012-09-28 | 2017-12-27 | ファイザー・インク | Benzamide and heterobenzamide compounds |
WO2014055493A1 (en) | 2012-10-02 | 2014-04-10 | Cerulean Pharma Inc. | Methods and systems for polymer precipitation and generation of particles |
EP2903989A1 (en) | 2012-10-04 | 2015-08-12 | Pfizer Limited | Pyrrolo[2,3-d]pyrimidine tropomyosin-related kinase inhibitors |
JP2015531395A (en) | 2012-10-04 | 2015-11-02 | ファイザー・リミテッドPfizer Limited | Pyrrolo [3,2-C] pyridine tropomyosin-related kinase inhibitor |
JP2015531393A (en) | 2012-10-04 | 2015-11-02 | ファイザー・リミテッドPfizer Limited | Tropomyosin-related kinase inhibitor |
KR20150070303A (en) * | 2012-10-17 | 2015-06-24 | 자피오텍 게엠베하 | Anthocyanidin complex for the treatment of multiple myeloma |
WO2014066274A1 (en) | 2012-10-22 | 2014-05-01 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
US20150291625A1 (en) | 2012-11-08 | 2015-10-15 | Pfizer Inc. | Heteroaromatic Compounds and their Use as Dopamine D1 Ligands |
CN104837839A (en) | 2012-11-08 | 2015-08-12 | 辉瑞公司 | Heteroaromatic compounds as dopamine D1 ligands |
JP6235603B2 (en) * | 2012-11-15 | 2017-11-22 | ザピオテック・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングSAPIOTEC GmbH | Delphinidin complex as anti-inflammatory and / or immunosuppressive active ingredient |
CN104837836B (en) | 2012-11-21 | 2018-07-03 | 拉夸里亚创药株式会社 | Polymorph |
JP6039100B2 (en) | 2012-12-03 | 2016-12-07 | ファイザー・インク | Novel selective androgen receptor modulator |
EP2931287B1 (en) * | 2012-12-11 | 2017-10-04 | Sapiotec GmbH | Delphinidin for combating melanoma cells |
UA112028C2 (en) | 2012-12-14 | 2016-07-11 | Пфайзер Лімітед | IMIDAZOPYRIDASINE DERIVATIVES AS HAMBA-RECEPTOR MODULATORS |
UA111305C2 (en) | 2012-12-21 | 2016-04-11 | Пфайзер Інк. | Condensed with lactams of aryl and heteroaryl |
CN111135171B (en) | 2013-01-23 | 2023-09-08 | 奥尔德拉医疗公司 | Diseases and treatments associated with toxic aldehydes |
PL3431475T3 (en) | 2013-02-21 | 2021-09-13 | Pfizer Inc. | Solid forms of a selective cdk4/6 inhibitor |
JO3377B1 (en) | 2013-03-11 | 2019-03-13 | Takeda Pharmaceuticals Co | Pyridinyl and fused pyridinyl triazolone derivatives |
US20160022701A1 (en) | 2013-03-13 | 2016-01-28 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
ES2699445T3 (en) | 2013-03-13 | 2019-02-11 | Sage Therapeutics Inc | Neuroactive steroids and methods of using them |
EP2784083A1 (en) | 2013-03-28 | 2014-10-01 | Charité - Universitätsmedizin Berlin | Bone Morphogenetic Protein (BMP) variants with highly reduced antagonist sensitivity and enhanced specific biological activity |
CA2909546C (en) | 2013-04-17 | 2019-01-22 | Sage Therapeutics, Inc. | 19-nor neuroactive steroids and methods of use thereof |
EP3498725B1 (en) | 2013-04-17 | 2021-06-09 | Sage Therapeutics, Inc. | 19-nor c3,3-disubstituted c21-n-pyrazolyl steroid for use in therapy |
EP2792360A1 (en) | 2013-04-18 | 2014-10-22 | IP Gesellschaft für Management mbH | (1aR,12bS)-8-cyclohexyl-11-fluoro-N-((1-methylcyclopropyl)sulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,2b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide for use in treating HCV |
TW201512171A (en) | 2013-04-19 | 2015-04-01 | Pfizer Ltd | Chemical compounds |
TW201443025A (en) | 2013-04-19 | 2014-11-16 | Pfizer Ltd | Chemical compounds |
WO2014181213A1 (en) | 2013-05-10 | 2014-11-13 | Pfizer Inc. | Crystalline form of (sa)-(-)-3-(3-bromo-4-((2,4-difluorobenzyl)oxy)-6-methyl-2-oxopyridin-1 (2h)-yl)-n,4-dimethylbenzamide |
MD20150122A2 (en) | 2013-06-27 | 2016-05-31 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
CA2916033C (en) | 2013-07-08 | 2022-08-23 | Abbvie Inc. | Stabilized pharmaceutical dosage forms comprising atrasentan |
GB201312737D0 (en) | 2013-07-17 | 2013-08-28 | Univ Greenwich | Cyclodextrin |
CN105555277B (en) | 2013-07-19 | 2022-01-11 | 萨奇治疗股份有限公司 | Neuroactive steroid compounds, compositions and uses thereof |
AU2014308621C1 (en) | 2013-08-23 | 2022-01-06 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
US8962675B1 (en) | 2013-09-12 | 2015-02-24 | Abbvie Inc. | Atrasentan mandelate salts |
CN104513253A (en) | 2013-10-01 | 2015-04-15 | 南京波尔泰药业科技有限公司 | Macrocyclic compounds for the treatment of proliferative diseases |
RU2572334C2 (en) * | 2013-12-06 | 2016-01-10 | Общество С Ограниченной Ответственностью "Луфатен" | Clathrate complex of arabinogalactan or arabic gum with 20-hydroxyecdysones, method for producing it (versions), pharmaceutical composition and medicinal product |
WO2015092610A1 (en) | 2013-12-20 | 2015-06-25 | Pfizer Limited | N-acylpiperidine ether tropomyosin-related kinase inhibitors |
WO2015106012A1 (en) | 2014-01-09 | 2015-07-16 | Takeda Pharmaceutical Company Limited | Azaindole derivatives |
WO2015106014A1 (en) | 2014-01-09 | 2015-07-16 | Takeda Pharmaceutical Company Limited | Azaindole derivatives |
CN104971355B (en) * | 2014-04-02 | 2018-04-24 | 上海现代药物制剂工程研究中心有限公司 | Composition containing razaxaban and preparation method thereof |
EP3131891A1 (en) | 2014-04-15 | 2017-02-22 | Pfizer Inc. | Tropomyosin-related kinase inhibitors containing both a 1h-pyrazole and a pyrimidine moiety |
US9868744B2 (en) | 2014-04-25 | 2018-01-16 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
WO2015162516A1 (en) | 2014-04-25 | 2015-10-29 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine d1 ligands |
KR20160142401A (en) | 2014-04-25 | 2016-12-12 | 화이자 인코포레이티드 | Heteroaromatic compounds and their use as dopamine d1 ligands |
CA2946990A1 (en) | 2014-04-28 | 2015-11-05 | Pfizer Inc. | Heterocyclic compounds and their use as dopamine d1 ligands |
US9856263B2 (en) | 2014-04-28 | 2018-01-02 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine D1 ligands |
EP3140298A1 (en) | 2014-05-07 | 2017-03-15 | Pfizer Inc. | Tropomyosin-related kinase inhibitors |
CN106459048A (en) | 2014-05-14 | 2017-02-22 | 辉瑞公司 | Pyrazolopyridines and pyrazolopyrimidines |
EP3143019B1 (en) | 2014-05-15 | 2020-12-16 | Pfizer Inc | Crystalline form of 6-[(4r)-4-methyl-1,2-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile |
KR102471082B1 (en) | 2014-05-20 | 2022-11-25 | 라퀄리아 파마 인코포레이티드 | Benzisoxazole derivative salt |
GB201409471D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
GB201409485D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
GB201409488D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
CN114369135A (en) | 2014-05-29 | 2022-04-19 | 萨奇治疗股份有限公司 | Neuroactive steroids, compositions, and uses thereof |
JP2017516803A (en) | 2014-05-30 | 2017-06-22 | ファイザー・インク | Benzenesulfonamides useful as sodium channel inhibitors |
CN106572997A (en) | 2014-05-30 | 2017-04-19 | 辉瑞公司 | Carbonitrile derivatives as selective androgen receptor modulators |
ES2664810T3 (en) | 2014-06-12 | 2018-04-23 | Pfizer Limited | Imidazopyridazine derivatives as modulators of GABAA receptor activity |
WO2015193768A1 (en) | 2014-06-17 | 2015-12-23 | Pfizer Inc. | Aryl fused lactams as ezh2 modulators |
CR20160574A (en) | 2014-06-17 | 2017-02-23 | Pfizer | DIHYDROISOQUINOLINONA SUBSTITUTED COMPOUNDS |
US10259840B2 (en) | 2014-06-18 | 2019-04-16 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
WO2015195448A1 (en) | 2014-06-18 | 2015-12-23 | Eli Lilly And Company | Transdermal formulations of pergolide and uses thereof |
WO2016009296A1 (en) | 2014-07-16 | 2016-01-21 | Pfizer Inc. | N-acylpiperidine ether tropomyosin-related kinase inhibitors |
WO2016009303A1 (en) | 2014-07-17 | 2016-01-21 | Pfizer Inc. | Pharmaceutical combinations comprising gabapentin or pregabalin with nav1.7 inhibitors |
WO2016009297A1 (en) | 2014-07-18 | 2016-01-21 | Pfizer Inc. | Pyridine derivatives as muscarinic m1 receptor positive allosteric modulators |
WO2016020784A1 (en) | 2014-08-05 | 2016-02-11 | Pfizer Inc. | N-acylpyrrolidine ether tropomyosin-related kinase inhibitors |
HUE063851T2 (en) | 2014-08-22 | 2024-02-28 | Cydex Pharmaceuticals Inc | Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same |
WO2016034971A1 (en) | 2014-09-04 | 2016-03-10 | Pfizer Limited | Sulfonamides derivatives as urat1 inhibitors |
JOP20200195A1 (en) | 2014-09-08 | 2017-06-16 | Sage Therapeutics Inc | Neuroactive steroids, compositions, and uses thereof |
WO2016044433A2 (en) | 2014-09-16 | 2016-03-24 | Biopharma Works | Metformin derivatives |
GB201417163D0 (en) | 2014-09-29 | 2014-11-12 | Provost Fellows & Scholars College Of The Holy Undivided Trinity Of Queen Elizabeth Near Dublin | Substituted pyrimidine derivatives useful in the treatment of autoimmune diseases |
GB201417165D0 (en) | 2014-09-29 | 2014-11-12 | Provost Fellows & Scholars College Of The Holy Undivided Trinity Of Queen Elizabeth Near Dublin | Treatments for Autoimmune Disease |
KR20170065637A (en) | 2014-10-07 | 2017-06-13 | 세이지 테라퓨틱스, 인크. | Neuroactive compounds and methods of use thereof |
ES2808855T3 (en) | 2014-10-16 | 2021-03-02 | Sage Therapeutics Inc | Compositions and methods for treating CNS disorders |
CN117024502A (en) | 2014-10-16 | 2023-11-10 | 萨奇治疗股份有限公司 | Compositions and methods for targeting CNS disorders |
WO2016067143A1 (en) | 2014-10-28 | 2016-05-06 | Pfizer Inc. | N-(2-alkyleneimino-3-phenylpropyl)acetamide compounds and their use against pain and pruritus via inhibition of trpa1 channels |
SI3224269T1 (en) | 2014-11-27 | 2020-10-30 | Sage Therapeutics, Inc. | Compositions and methods for treating cns disorders |
ES2746839T3 (en) | 2014-12-18 | 2020-03-09 | Pfizer | Pyrimidine and triazine derivatives and their use as AXL inhibitors |
TW201636342A (en) | 2014-12-19 | 2016-10-16 | 武田藥品工業有限公司 | Fumagillol derivatives |
EP3556376A1 (en) | 2015-01-22 | 2019-10-23 | Phytoplant Research S.L. | Methods of purifying cannabinoids, compositions and kits thereof |
DK3050574T3 (en) | 2015-01-28 | 2020-01-20 | Univ Bordeaux | Use of plerixafor for the treatment and / or prevention of acute exacerbations of chronic obstructive pulmonary disease |
PL3253208T3 (en) | 2015-02-02 | 2021-11-08 | Mei Pharma, Inc. | Combination therapies for use in the treatment of breast cancer |
IL252848B1 (en) | 2015-02-06 | 2024-03-01 | Marinus Pharmaceuticals Inc | Intravenous ganaxolone formulations and their use in treating status epilepticus and other seizure disorders |
JP6875996B2 (en) | 2015-02-20 | 2021-05-26 | セージ セラピューティクス, インコーポレイテッド | Neurostimulatory steroids, compositions, and their use |
TN2017000357A1 (en) | 2015-02-24 | 2019-01-16 | Pfizer | Substituted nucleoside derivatives useful as anticancer agents |
CA2979527A1 (en) | 2015-03-13 | 2016-09-22 | Endocyte, Inc. | Conjugates of pyrrolobenzodiazepine (pbd) prodrugs for treating disease |
CA2980170A1 (en) | 2015-03-19 | 2016-09-22 | Cydex Pharmaceuticals, Inc. | Compositions containing silymarin and sulfoalkyl ether cyclodextrin and methods of using the same |
EP3280420B1 (en) | 2015-04-10 | 2024-03-27 | Sage Therapeutics, Inc. | Compositions and methods for treating cns disorders |
BR112017026287A2 (en) | 2015-06-10 | 2018-09-18 | Vtesse Inc | hydroxypropyl beta-cyclodextrin compositions and methods |
IL256710B2 (en) | 2015-07-06 | 2024-01-01 | Sage Therapeutics Inc | Oxysterols and methods of use thereof |
MX2020010690A (en) | 2015-07-06 | 2022-02-25 | Sage Therapeutics Inc | Oxysterols and methods of use thereof. |
CA2991311A1 (en) | 2015-07-06 | 2017-01-12 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
WO2017007805A1 (en) | 2015-07-09 | 2017-01-12 | Gilead Sciences, Inc. | Intravenous formulations of a late sodium current inhibitor |
BR112018000041A2 (en) | 2015-07-31 | 2018-09-04 | Pfizer Inc. | 1,1,1-TRIFLUORO-3-HYDROXYPROPAN-2-ILA CARBAMATE DERIVATIVES AND 1,1,1-TRIFLUORO-4-HYDROXYBUTAN-2-ILA CARBAMATE DERIVATIVES AS MAGL INHIBITORS |
WO2017035077A1 (en) | 2015-08-21 | 2017-03-02 | Aldeyra Therapeutics, Inc. | Deuterated compounds and uses thereof |
US10538523B2 (en) | 2015-12-10 | 2020-01-21 | Pfizer Limited | 4-(biphen-3-yl)-1H-pyrazolo[3,4-c]pyridazine derivatives of formula (I) as GABA receptor modulators for use in the treatment of epilepsy and pain |
SG11201805331QA (en) | 2015-12-24 | 2018-07-30 | Takeda Pharmaceuticals Co | Cocrystal, production method thereof, and medicament containing cocrystal |
EP3399968B8 (en) | 2016-01-07 | 2021-12-01 | Xuanzhu Biopharmaceutical Co., Ltd. | Selective inhibitors of clinically important mutants of the egfr tyrosine kinase |
WO2017119732A1 (en) | 2016-01-08 | 2017-07-13 | Samsung Electronics Co., Ltd. | Electronic device and operating method thereof |
SG11201805202VA (en) | 2016-01-15 | 2018-07-30 | Pfizer | 6,7,8,9-TETRAHYDRO-5H-PYRIDO[2,3-d]AZEPINE DOPAMINE D3 LIGANDS |
JP2019512538A (en) | 2016-02-18 | 2019-05-16 | メリンタ セラピューティクス、 インコーポレイテッドMelinta Therapeutics, Inc. | Oritavancin formulation |
CA3016759A1 (en) | 2016-02-28 | 2017-08-31 | Aldeyra Therapeutics, Inc. | Treatment of allergic eye conditions with cyclodextrins |
CN108884445A (en) | 2016-03-09 | 2018-11-23 | 北京智康博药肿瘤医学研究有限公司 | Tumour cell suspension culture and correlation technique |
AU2017240609B2 (en) * | 2016-03-31 | 2021-07-15 | Takeda Pharmaceutical Company Limited | Isoquinolinyl triazolone complexes |
PL3436022T3 (en) | 2016-04-01 | 2022-08-08 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US10752653B2 (en) | 2016-05-06 | 2020-08-25 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
CA3022665A1 (en) | 2016-05-09 | 2017-11-16 | Aldeyra Therapeutics, Inc. | Combination treatment of ocular inflammatory disorders and diseases |
US20190030170A1 (en) * | 2016-05-10 | 2019-01-31 | Vireo Health LLC | Cannabinoid formulations with improved solubility |
CA2969295A1 (en) | 2016-06-06 | 2017-12-06 | Pfizer Inc. | Substituted carbonucleoside derivatives, and use thereof as a prmt5 inhibitor |
SI3481846T1 (en) | 2016-07-07 | 2021-11-30 | Sage Therapeutics, Inc. | 11-substituted 24-hydroxysterols for use in the treatment of nmda related conditions |
JP7049313B2 (en) | 2016-07-11 | 2022-04-06 | セージ セラピューティクス, インコーポレイテッド | C17, C20, and C21 substitution neurostimulatory steroids and how to use them |
MA45600A (en) | 2016-07-11 | 2019-05-15 | Sage Therapeutics Inc | NEUROACTIVE STEROIDS SUBSTITUTED IN C7, C12 AND C16 AND ASSOCIATED METHODS OF USE |
EP3491005A1 (en) | 2016-07-29 | 2019-06-05 | Pfizer Inc | Cyclic peptides as c5 a receptor antagonists |
JP2019524816A (en) | 2016-08-11 | 2019-09-05 | オービッド・セラピューティクス・インコーポレイテッドOvid Therapeutics, Inc. | Methods and compositions for the treatment of epileptic disorders |
GEP20217234B (en) | 2016-08-15 | 2021-03-25 | Pfizer | Pyridopyrimdinone cdk2/4/6 inhibitors |
US10391105B2 (en) | 2016-09-09 | 2019-08-27 | Marinus Pharmaceuticals Inc. | Methods of treating certain depressive disorders and delirium tremens |
ES2935057T3 (en) | 2016-09-30 | 2023-03-01 | Sage Therapeutics Inc | C7 substituted oxysterols and these compounds for use as NMDA modulators |
CA3040155C (en) | 2016-10-11 | 2024-01-16 | Euro-Celtique S.A. | Compound for use in the treatment of hodgkin lymphoma |
CA3234484A1 (en) | 2016-10-18 | 2018-04-26 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
RU2019115112A (en) | 2016-10-18 | 2020-11-24 | Сейдж Терапьютикс, Инк. | OXYSTEROLES AND METHODS OF THEIR APPLICATION |
TW201828938A (en) | 2016-11-18 | 2018-08-16 | 德商艾庫里斯抗感染治療有限公司 | Novel formulations of amidine substituted beta-lactam compounds on the basis of modified cyclodextrins and acidifying agents, their preparation and use as antimicrobial pharmaceutical compositions |
US10316021B2 (en) | 2016-11-28 | 2019-06-11 | Pfizer Inc. | Heteroarylphenoxy benzamide kappa opioid ligands |
WO2018118791A2 (en) | 2016-12-20 | 2018-06-28 | Oligomerix, Inc. | Novel quinazolinones that inhibit the formation of tau oligomers and their method of use |
US11091462B2 (en) | 2017-01-20 | 2021-08-17 | Shenzhen Targetrx, Inc. | (Hetero)arylamide compound for inhibiting protein kinase activity |
EP3571191A1 (en) | 2017-01-20 | 2019-11-27 | Pfizer Inc | 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives as magl inhibitors |
CN108699039B (en) | 2017-01-20 | 2019-12-20 | 深圳市塔吉瑞生物医药有限公司 | (hetero) aryl amides for inhibiting protein kinase activity |
EP3571202B1 (en) | 2017-01-23 | 2021-06-30 | Pfizer Inc. | Heterocyclic spiro compounds as magl inhibitors |
US11274164B2 (en) | 2017-02-07 | 2022-03-15 | Biophore India Pharmaceuticals Pvt. Ltd. | Method for the preparation of sulfobutylether beta cyclodextrin sodium |
CA3054811A1 (en) | 2017-03-16 | 2018-09-20 | Aldeyra Therapeutics, Inc. | Polymorphic compounds and uses thereof |
MX2019011286A (en) | 2017-03-26 | 2019-12-19 | Takeda Pharmaceuticals Co | Piperidinyl- and piperazinyl-substituted heteroaromatic carboxamides as modulators of gpr6. |
CN114213421A (en) | 2017-04-01 | 2022-03-22 | 晟科药业(江苏)有限公司 | 1H-imidazole [4,5-H ] quinazoline compound as protein kinase inhibitor |
US20180318249A1 (en) | 2017-05-03 | 2018-11-08 | Cydex Pharmaceuticals, Inc. | Composition containing cyclodextrin and busulfan |
GB201709402D0 (en) | 2017-06-13 | 2017-07-26 | Euro Celtique Sa | Compounds for treating t-pll |
GB201709405D0 (en) | 2017-06-13 | 2017-07-26 | Euro Celtique Sa | Compounds for treating ovarian cancer |
GB201709406D0 (en) | 2017-06-13 | 2017-07-26 | Euro-Cletique S A | Compounds for treating TNBC |
GB201709403D0 (en) | 2017-06-13 | 2017-07-26 | Euro Celtique Sa | Compounds for treating sarcoma |
JOP20180057A1 (en) | 2017-06-15 | 2019-01-30 | Takeda Pharmaceuticals Co | Tetrahydropyridopyrazine modulators of gpr6 |
SG11201912397RA (en) | 2017-06-22 | 2020-01-30 | Curadev Pharma Ltd | Small molecule modulators of human sting |
US11718611B2 (en) | 2017-06-26 | 2023-08-08 | Shenzhen Targetrx, Inc. | Benzenesulfonylbenazamide compound for inhibiting BCL-2 protein and composition and use thereof |
CN108623576B (en) | 2017-06-26 | 2021-01-08 | 深圳市塔吉瑞生物医药有限公司 | Indazole compound for inhibiting kinase activity and composition and application thereof |
US10675296B2 (en) | 2017-07-11 | 2020-06-09 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
KR102464677B1 (en) | 2017-08-11 | 2022-11-10 | 셍커 파마슈티컬스 (지앙수) 엘티디. | 1H-pyrazolo[4,3-H]quinazoline compound serving as protein kinase inhibitor |
EP3692048A4 (en) | 2017-08-30 | 2021-10-20 | Beijing Xuanyi Pharmasciences Co., Ltd. | Cyclic di-nucleotides as stimulator of interferon genes modulators |
US11267810B2 (en) | 2017-08-30 | 2022-03-08 | Shenzhen Targetrx, Inc. | Aminopyrimidine compound and composition comprising same and use thereof |
KR20200083448A (en) | 2017-09-05 | 2020-07-08 | 바이오아르디스 엘엘씨 | Aromatic derivatives, methods for their preparation and medical applications thereof |
EP3681879A1 (en) | 2017-09-11 | 2020-07-22 | Krouzon Pharmaceuticals, Inc. | Octahydrocyclopenta[c]pyrrole allosteric inhibitors of shp2 |
TW201920108A (en) | 2017-09-25 | 2019-06-01 | 日商武田藥品工業有限公司 | N-(cyano-substituted benzyl or pyridinylmethyl)-3-hydroxypicolinamide derivatives |
CN111356451A (en) | 2017-10-10 | 2020-06-30 | 奥尔德拉医疗公司 | Treatment of inflammatory disorders |
WO2019075362A1 (en) | 2017-10-12 | 2019-04-18 | Sage Therapeutics, Inc. | Method of treating cns disorders with neurosteroids and gabaergic compounds |
KR20200096596A (en) | 2017-12-08 | 2020-08-12 | 세이지 테라퓨틱스, 인크. | Deuterated 21-[4-cyano-pyrazole-1-yl]-19-nor-pregan-3 for the treatment of CNS disorders. Alpha-ol-20-one derivative |
EP3730503A4 (en) | 2017-12-21 | 2021-05-05 | Shenzhen TargetRx, Inc. | Antiviral nucleoside reverse transcriptase inhibitor |
WO2019120071A1 (en) | 2017-12-21 | 2019-06-27 | 深圳市塔吉瑞生物医药有限公司 | Novel antiviral nucleoside reverse transcriptase inhibitor |
CN109627263B (en) | 2017-12-21 | 2022-05-20 | 深圳市塔吉瑞生物医药有限公司 | Diphenylaminopyrimidine compounds for inhibiting kinase activity |
CN109369721A (en) | 2017-12-21 | 2019-02-22 | 深圳市塔吉瑞生物医药有限公司 | For inhibiting the aryl phosphorous oxides of kinase activity |
AU2018392093B2 (en) | 2017-12-22 | 2024-02-01 | Sage Therapeutics, Inc. | Compositions and methods for treating CNS disorders |
IL310454A (en) | 2017-12-22 | 2024-03-01 | Sage Therapeutics Inc | Compositions and methods for treating cns disorders |
TW201930269A (en) | 2018-01-12 | 2019-08-01 | 美商賽吉醫療公司 | Compositions and methods for treating CNS disorders |
CN111788171A (en) | 2018-01-29 | 2020-10-16 | 菲拓普兰特研究公司 | Use solution: method for purifying cannabinoids by liquid chromatography |
TW201942115A (en) | 2018-02-01 | 2019-11-01 | 美商輝瑞股份有限公司 | Substituted quinazoline and pyridopyrimidine derivatives useful as anticancer agents |
TW201942116A (en) | 2018-02-09 | 2019-11-01 | 美商輝瑞股份有限公司 | Tetrahydroquinazoline derivatives useful as anticancer agents |
SG11202008398XA (en) | 2018-03-01 | 2020-09-29 | Takeda Pharmaceuticals Co | Piperidinyl-3-(aryloxy)propanamides and propanoates |
US10538542B2 (en) | 2018-03-15 | 2020-01-21 | Pfizer Inc. | Cyclopentane-based modulators of STING (stimulator of interferon genes) |
JP7092405B2 (en) | 2018-04-16 | 2022-06-28 | 深▲チェン▼市塔吉瑞生物医薬有限公司 | Di (hetero) aryl macrocycle to inhibit kinase activity |
CN109970745B (en) | 2018-04-16 | 2020-12-08 | 深圳市塔吉瑞生物医药有限公司 | Substituted pyrrolotriazine compound, pharmaceutical composition and application thereof |
UA126177C2 (en) | 2018-04-26 | 2022-08-25 | Пфайзер Інк. | 2-amino-pyridine or 2-amino-pyrimidine derivatives as cyclin dependent kinase inhibitors |
CN112218627B (en) | 2018-05-30 | 2024-04-16 | 康维尔特制药有限公司 | Prodrugs and their medical use |
EP4241563A3 (en) | 2018-06-01 | 2023-11-15 | Bayer CropScience LP | Stabilized fungicidal composition comprising cyclodextrin |
WO2019243823A1 (en) | 2018-06-21 | 2019-12-26 | Curadev Pharma Limited | Azaheterocyclic small molecule modulators of human sting |
WO2020007234A1 (en) | 2018-07-02 | 2020-01-09 | 深圳市塔吉瑞生物医药有限公司 | Alkynyl(hetero)aromatic compound for inhibiting protein kinase activity |
US20210283132A1 (en) | 2018-07-12 | 2021-09-16 | Shenzhen Targetrx, Inc. | Diarylpyrazole compound, composition comprising same, and use thereof |
US11746110B2 (en) | 2018-07-17 | 2023-09-05 | Shenzhen Targetrx, Inc. | Alkynyl (hetero) aromatic ring compounds used for inhibiting protein kinase activity |
CA3106510A1 (en) | 2018-07-19 | 2020-01-23 | Pfizer Inc. | Heterocyclic spiro compounds as magl inhibitors |
CN112714762A (en) | 2018-08-06 | 2021-04-27 | 奥尔德拉医疗公司 | Polymorphic compounds and uses thereof |
US11197821B2 (en) | 2018-09-25 | 2021-12-14 | Aldeyra Therapeutics, Inc. | Formulations for treatment of dry eye disease |
WO2020076728A1 (en) | 2018-10-08 | 2020-04-16 | Takeda Pharmaceutical Company Limited | SUBSTITUTED OXAZINOPTERIDINONES AS INHIBITORS OF mTOR |
US20210386737A1 (en) | 2018-10-10 | 2021-12-16 | Shenzhen Targetrx, Inc. | Dihydroimidazopyrazinone compound, composition including same, and use thereof |
AU2019357040A1 (en) | 2018-10-12 | 2021-05-20 | Sage Therapeutics, Inc. | Neuroactive steroids substituted in position 10 with a cyclic group for use in the treatment of CNS disorders |
CA3116892A1 (en) | 2018-10-19 | 2020-04-23 | Sage Therapeutics, Inc. | 9(11)-unsaturated neuroactive steroids and their methods of use |
US11142525B2 (en) | 2018-11-15 | 2021-10-12 | Pfizer Inc. | Azalactam compounds as HPK1 inhibitors |
MX2021006095A (en) | 2018-11-29 | 2021-07-06 | Pfizer | Pyrazoles as modulators of hemoglobin. |
TW202039528A (en) | 2018-12-05 | 2020-11-01 | 美商賽吉醫療公司 | Neuroactive steroids and their methods of use |
WO2020114388A1 (en) | 2018-12-06 | 2020-06-11 | 深圳市塔吉瑞生物医药有限公司 | Substituted pyrazolo[1,5-a]pyridine compound, composition containing the same and use thereof |
WO2020118142A1 (en) | 2018-12-07 | 2020-06-11 | Marinus Pharmaceuticals, Inc. | Ganaxolone for use in prophylaxis and treatment of pospartum depression |
WO2020125391A1 (en) | 2018-12-21 | 2020-06-25 | 深圳市塔吉瑞生物医药有限公司 | Aminopyrimidine compound used for inhibiting activity of protein kinase |
CN113195512A (en) | 2018-12-21 | 2021-07-30 | 萨奇治疗股份有限公司 | 3. Alpha-hydroxy-17 beta-amide neuroactive steroids and compositions thereof |
US11246851B2 (en) | 2019-01-04 | 2022-02-15 | Sq Innovation Ag | Pharmaceutical compositions of furosemide and uses thereof |
CA3124703C (en) | 2019-01-14 | 2023-10-17 | Beijing Xuanyi Pharmasciences Co., Ltd. | Tetrazolone substituted steroids and use thereof |
EP3914597A1 (en) | 2019-01-23 | 2021-12-01 | Pfizer Inc. | Polymorph form of a monophosphate hydrate salt of a known tetrahydroisoquinoline derivative |
JP7094456B2 (en) | 2019-01-31 | 2022-07-01 | ファイザー・インク | CDK2 inhibitor |
US20220098204A1 (en) | 2019-02-18 | 2022-03-31 | Shenzhen Targetrx, Inc. | Substituted fused aromatic ring derivative, composition and use thereof |
WO2020173457A1 (en) | 2019-02-27 | 2020-09-03 | 深圳市塔吉瑞生物医药有限公司 | Substituted pyrazole compounds, compositions containing same, and use thereof |
WO2020198053A1 (en) | 2019-03-22 | 2020-10-01 | Takeda Pharmaceutical Company Limited | 2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-6-yl)-4-methylbenzamide derivatives and similar compounds as ripk2 inhibitors for treating e.g. autoimmune diseases |
US11786518B2 (en) | 2019-03-26 | 2023-10-17 | Aldeyra Therapeutics, Inc. | Ophthalmic formulations and uses thereof |
EP3946606A1 (en) | 2019-03-27 | 2022-02-09 | Insilico Medicine IP Limited | Bicyclic jak inhibitors and uses thereof |
CA3137584A1 (en) | 2019-04-29 | 2020-11-05 | Solent Therapeutics, Llc | 3-amino-4h-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as inhibitors of mrgx2 |
JOP20210293A1 (en) | 2019-05-31 | 2023-01-30 | Sage Therapeutics Inc | Neuroactive steroids and compositions thereof |
CN112047938B (en) | 2019-06-06 | 2022-11-22 | 北京泰德制药股份有限公司 | 2,4, 6-trisubstituted pyrimidine compounds as ATR kinase inhibitors |
KR20220038681A (en) | 2019-06-27 | 2022-03-29 | 세이지 테라퓨틱스, 인크. | Compositions and methods for treating CNS disorders |
CA3143545A1 (en) | 2019-06-27 | 2020-12-30 | Sage Therapeutics, Inc. | Compounds for treating cns disorders |
AU2020302748A1 (en) | 2019-06-27 | 2022-01-06 | Sage Therapeutics, Inc. | Compositions and methods for treating CNS disorders |
US11339159B2 (en) | 2019-07-17 | 2022-05-24 | Pfizer Inc. | Toll-like receptor agonists |
JP2022542144A (en) | 2019-07-25 | 2022-09-29 | キュラデブ ファーマ ピーブイティー. リミテッド | Small molecule inhibitors of acetyl coenzyme A synthetase short chain 2 (ACSS2) |
WO2021026124A1 (en) | 2019-08-05 | 2021-02-11 | Marinus Pharmaceuticals, Inc. | Ganaxolone for use in treatment of status epilepticus |
US20230000997A1 (en) | 2019-08-06 | 2023-01-05 | L.E.A.F. Holdings Group Llc | Processes of preparing polyglutamated antifolates and uses of their compositions |
JP2022546375A (en) | 2019-08-23 | 2022-11-04 | 北京泰徳製薬股▲フン▼有限公司 | Compounds that inhibit EGFR and ALK to inhibit their degradation |
MX2022003177A (en) | 2019-09-16 | 2022-04-06 | Takeda Pharmaceuticals Co | Azole-fused pyridazin-3(2h)-one derivatives. |
BR112022005463A2 (en) | 2019-09-25 | 2022-06-14 | Pfizer | Polyheterocyclic sting modulators (interferon gene stimulator) |
AU2020355359B2 (en) | 2019-09-26 | 2023-08-24 | Shenzhen Targetrx, Inc. | Substituted aromatic fused ring derivative and composition comprising same, and use thereof |
AU2020374041B2 (en) | 2019-11-01 | 2024-02-08 | Jing Medicine Technology (Shanghai) Ltd. | EED inhibitor, and preparation method therefor and use thereof |
KR20220134529A (en) | 2019-12-06 | 2022-10-05 | 마리누스 파마슈티컬스 인코포레이티드 | Ganaxolone for use in the treatment of complex tuberous sclerosis |
KR20220114615A (en) | 2019-12-16 | 2022-08-17 | 베이징 타이드 파마슈티컬 코퍼레이션 리미티드 | Compounds that inhibit and induce degradation of EGFR kinase |
KR20220157363A (en) | 2020-01-17 | 2022-11-29 | 셍커 파마슈티컬스 (지앙수) 엘티디. | Novel compounds as inhibitors of PCSK9 |
CA3166358A1 (en) | 2020-02-12 | 2021-08-19 | Monali BANERJEE | Small molecule sting antagonists |
JP2023518411A (en) | 2020-03-18 | 2023-05-01 | セージ セラピューティクス, インコーポレイテッド | Neuroactive steroids and methods of use thereof |
AR121683A1 (en) | 2020-03-31 | 2022-06-29 | Takeda Pharmaceuticals Co | N-HETEROARYLALKYL-2-(HETEROCYCLIL AND HETEROCYCLILMETHYL)ACETAMIDE DERIVATIVES AS SSTR4 AGONISTS |
AR121682A1 (en) | 2020-03-31 | 2022-06-29 | Takeda Pharmaceuticals Co | N-(HETEROCYCLIL AND HETEROCYCLILALKYL)-3-BENZYLPYRIDIN-2-AMINE DERIVATIVES AS SSTR4 AGONISTS |
JP2021167301A (en) | 2020-04-08 | 2021-10-21 | ファイザー・インク | Co-treatment with cdk4/6 and cdk2 inhibitors to suppress tumor adaptation to cdk2 inhibitors |
PE20230323A1 (en) | 2020-05-01 | 2023-02-22 | Pfizer | AZALACTAM COMPOUNDS AS HPK1 INHIBITORS |
PE20231375A1 (en) | 2020-05-04 | 2023-09-07 | Takeda Pharmaceuticals Co | N-(PIPERIDIN-4-IL)BENZAMIDE DERIVATIVES OF LUMINAL ACTION |
WO2021224818A1 (en) | 2020-05-08 | 2021-11-11 | Pfizer Inc. | Isoindolone compounds as hpk1 inhibitors |
WO2021233376A1 (en) | 2020-05-20 | 2021-11-25 | 北京泰德制药股份有限公司 | 2,4,6-tri-substituted pyrimidine compounds as atr kinase inhibitors |
US20230250129A1 (en) | 2020-06-24 | 2023-08-10 | Sage Therapeutics, Inc. | Neuroactive steroids and compositions thereof |
TW202214641A (en) | 2020-06-30 | 2022-04-16 | 美商艾瑞生藥股份有限公司 | Her2 mutation inhibitors |
KR20230039675A (en) | 2020-07-13 | 2023-03-21 | 베이징 타이드 파마슈티컬 코퍼레이션 리미티드 | Pyrazolopyrimidine compounds used as ATR kinase inhibitors |
WO2022013692A1 (en) | 2020-07-15 | 2022-01-20 | Pfizer Inc. | Polymorphs of (1s,2s,3s,5r)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7h-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol mono-hydrochloride |
WO2022013691A1 (en) | 2020-07-15 | 2022-01-20 | Pfizer Inc. | Polymorph of (1s,2s,3s,5r)-3-((6-(difluoromethyl)-5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-5-(4-methyl-7h-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol |
WO2022018667A1 (en) | 2020-07-24 | 2022-01-27 | Pfizer Inc. | Combination therapies using cdk2 and cdc25a inhibitors |
GB202011812D0 (en) | 2020-07-29 | 2020-09-09 | Provost Fellows Found Scholars And The Other Members Of Board Of The College Of The Holy And Undivid | Compounds |
GB202011811D0 (en) | 2020-07-29 | 2020-09-09 | Provost Fellows Found Scholars And The Other Members Of Board Of The College Of The Holy And Undivid | Compounds |
CN116096721A (en) | 2020-08-27 | 2023-05-09 | 晟科药业(江苏)有限公司 | 1H-imidazo [4,5-H ] quinazoline compounds as novel selective FLT3 inhibitors |
TW202229239A (en) | 2020-09-23 | 2022-08-01 | 日商武田藥品工業股份有限公司 | 3-(6-aminopyridin-3-yl)benzamide derivatives as ripk2 inhibitors |
EP4251634A1 (en) | 2020-11-25 | 2023-10-04 | Sage Therapeutics, Inc. | Compositions and methods for treating cns disorders |
US11964978B2 (en) | 2021-03-18 | 2024-04-23 | Pfizer Inc. | Modulators of STING (stimulator of interferon genes) |
GB202104609D0 (en) | 2021-03-31 | 2021-05-12 | Sevenless Therapeutics Ltd | New Treatments for Pain |
AU2022250712A1 (en) | 2021-03-31 | 2023-10-05 | Sevenless Therapeutics Limited | Sos1 inhibitors and ras inhibitors for use in the treatment of pain |
EP4320121A2 (en) | 2021-04-07 | 2024-02-14 | LifeArc | 2,4-diaminopyrimidine derivatives as ulk1/2 inhibitors and their use thereof |
US11649299B2 (en) | 2021-06-10 | 2023-05-16 | Cyclolab Cyclodextrin Research And Development Laboratory Ltd. | Purification of sulfobutylated cyclodextrins with specific ion exchange resins |
EP4359082A1 (en) | 2021-06-26 | 2024-05-01 | Array BioPharma Inc. | Her2 mutation inhibitors |
WO2023009584A1 (en) | 2021-07-28 | 2023-02-02 | Sage Therapeutics, Inc. | Crystalline forms of a neuroactive steroid |
TW202321231A (en) | 2021-08-11 | 2023-06-01 | 印度商裘拉德製藥私人有限公司 | Small molecule urea derivatives as sting antagonists |
AU2022325543A1 (en) | 2021-08-11 | 2024-02-15 | Curadev Pharma Pvt. Ltd. | Small molecule sting antagonists |
WO2023049295A1 (en) | 2021-09-22 | 2023-03-30 | Sage Therapeutics, Inc. | Deuterated positive nmda-modulating compounds and methods of use thereof |
WO2023099072A1 (en) | 2021-12-01 | 2023-06-08 | Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) | Compounds |
WO2023144692A1 (en) * | 2022-01-25 | 2023-08-03 | Leiutis Pharmaceuticals Llp | Novel naproxen sodium preparations for parenteral |
WO2023156966A1 (en) | 2022-02-18 | 2023-08-24 | Beren Therapeutics P.B.C. | Compositions of hydroxypropyl-beta-cyclodextrin and methods of purifying the same |
WO2023187677A1 (en) | 2022-03-30 | 2023-10-05 | Takeda Pharmaceutical Company Limited | N-(pyrrolidin-3-yl or piperidin-4-yl)acetamide derivatives |
TW202345838A (en) | 2022-04-07 | 2023-12-01 | 日商武田藥品工業股份有限公司 | Fused pyridazine derivatives |
WO2023205165A1 (en) * | 2022-04-22 | 2023-10-26 | Brii Biosciences Offshore Limited | A polymyxin composition and methods for producing the same |
CN116969851A (en) | 2022-04-29 | 2023-10-31 | 北京剂泰医药科技有限公司 | Ionizable lipid compounds |
EP4332087A1 (en) | 2022-04-29 | 2024-03-06 | Beijing Jitai Pharmaceutical Technology Co., Ltd. | Lipid nanoparticles |
WO2024026337A1 (en) | 2022-07-27 | 2024-02-01 | Sage Therapeutics, Inc. | Crystalline forms of a neuroactive steroid |
US20240109915A1 (en) | 2022-07-29 | 2024-04-04 | Pfizer Inc. | Novel acc inhibitors |
WO2024033845A1 (en) | 2022-08-10 | 2024-02-15 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
WO2024059608A1 (en) | 2022-09-15 | 2024-03-21 | Sage Therapeutics, Inc. | Deuterated neuroactive steroids |
WO2024074827A1 (en) | 2022-10-05 | 2024-04-11 | Sevenless Therapeutics Limited | New treatments for pain |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3426011A (en) * | 1967-02-13 | 1969-02-04 | Corn Products Co | Cyclodextrins with anionic properties |
JPS503362B1 (en) * | 1970-06-10 | 1975-02-04 | ||
EP0056995B1 (en) * | 1981-01-23 | 1986-03-26 | The Wellcome Foundation Limited | Chemical complex |
JPS58177949A (en) * | 1982-04-12 | 1983-10-18 | Takeda Chem Ind Ltd | Clathrate compound of lankacidin-group antibiotic substance |
HU191101B (en) * | 1983-02-14 | 1987-01-28 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt,Hu | Process for preparing water-soluble cyclodextrin polymers substituted with ionic groups |
DE3477929D1 (en) * | 1983-12-17 | 1989-06-01 | Hoechst Ag | Beta-cyclodextrin and process for its preparation |
EP0146841A3 (en) * | 1983-12-17 | 1986-11-20 | Consortium für elektrochemische Industrie GmbH | Water soluble mixed ether of beta-cyclodextrin, and process for its preparation |
US4727064A (en) * | 1984-04-25 | 1988-02-23 | The United States Of America As Represented By The Department Of Health And Human Services | Pharmaceutical preparations containing cyclodextrin derivatives |
US4596795A (en) * | 1984-04-25 | 1986-06-24 | The United States Of America As Represented By The Secretary, Dept. Of Health & Human Services | Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives |
JPH0651725B2 (en) * | 1985-02-28 | 1994-07-06 | メルシャン株式会社 | Partially methylated cyclodextrin and method for producing the same |
GB8506792D0 (en) * | 1985-03-15 | 1985-04-17 | Janssen Pharmaceutica Nv | Derivatives of y-cyclodextrin |
US4808232A (en) * | 1986-12-08 | 1989-02-28 | American Maize-Products Company | Separation and purification of cyclodextrins |
JPH0819004B2 (en) * | 1986-12-26 | 1996-02-28 | 日清製粉株式会社 | Sustained-release pharmaceutical preparation |
US4774329A (en) * | 1987-08-04 | 1988-09-27 | American Maize-Products Company | Controlled release agent for cetylpyridinium chloride |
KR0166088B1 (en) * | 1990-01-23 | 1999-01-15 | . | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
WO1991013100A1 (en) * | 1990-03-02 | 1991-09-05 | Australian Commercial Research & Development Limited | Cyclodextrin compositions and methods for pharmaceutical and industrial applications |
-
1992
- 1992-07-27 US US07/918,702 patent/US5376645A/en not_active Expired - Lifetime
-
1993
- 1993-07-26 MD MD96-0306A patent/MD1813C2/en not_active IP Right Cessation
- 1993-07-26 KR KR1019940700951A patent/KR100279111B1/en not_active IP Right Cessation
- 1993-07-26 TJ TJ96000377A patent/TJ275B/en unknown
- 1993-07-26 DE DE69331900T patent/DE69331900T3/en not_active Expired - Lifetime
- 1993-07-26 PT PT93918302T patent/PT620828E/en unknown
- 1993-07-26 EP EP93918302A patent/EP0620828B2/en not_active Expired - Lifetime
- 1993-07-26 DK DK93918302T patent/DK0620828T4/en active
- 1993-07-26 AU AU47799/93A patent/AU672814B2/en not_active Ceased
- 1993-07-26 CA CA002119154A patent/CA2119154C/en not_active Expired - Lifetime
- 1993-07-26 GE GEAP19932498A patent/GEP19991649B/en unknown
- 1993-07-26 RU RU94028890A patent/RU2113442C1/en not_active IP Right Cessation
- 1993-07-26 ES ES93918302T patent/ES2176206T5/en not_active Expired - Lifetime
- 1993-07-26 JP JP50467894A patent/JP3393253B2/en not_active Expired - Fee Related
- 1993-07-26 AT AT93918302T patent/ATE217325T1/en active
- 1993-07-26 WO PCT/US1993/006880 patent/WO1994002518A1/en active IP Right Grant
Also Published As
Publication number | Publication date |
---|---|
JP3393253B2 (en) | 2003-04-07 |
CA2119154A1 (en) | 1994-02-03 |
DK0620828T4 (en) | 2008-11-03 |
RU2113442C1 (en) | 1998-06-20 |
GEP19991649B (en) | 1999-06-14 |
DE69331900T3 (en) | 2009-03-26 |
EP0620828A4 (en) | 1996-05-15 |
MD1813C2 (en) | 2002-08-31 |
AU672814B2 (en) | 1996-10-17 |
ES2176206T3 (en) | 2002-12-01 |
EP0620828A1 (en) | 1994-10-26 |
MD1813B2 (en) | 2001-12-31 |
AU4779993A (en) | 1994-02-14 |
EP0620828B2 (en) | 2008-07-09 |
US5376645A (en) | 1994-12-27 |
DK0620828T3 (en) | 2002-08-26 |
DE69331900T2 (en) | 2003-01-16 |
TJ275B (en) | 2000-10-05 |
KR100279111B1 (en) | 2001-03-02 |
WO1994002518A1 (en) | 1994-02-03 |
PT620828E (en) | 2002-10-31 |
DE69331900D1 (en) | 2002-06-13 |
ATE217325T1 (en) | 2002-05-15 |
EP0620828B1 (en) | 2002-05-08 |
ES2176206T5 (en) | 2008-12-01 |
JPH06511513A (en) | 1994-12-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2119154C (en) | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof | |
US5134127A (en) | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof | |
WO1994002518A9 (en) | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof | |
AU750207B2 (en) | Polar drug or prodrug compositions with extended shelf-life storage and a method of making thereof | |
EP0056995B1 (en) | Chemical complex | |
US7786095B2 (en) | Amphiphilic macrocyclic derivatives and their analogues | |
Szejtli | The properties and potential uses of cyclodextrin derivatives | |
CA2137319A1 (en) | Composition containing a water-insoluble or slightly water-soluble compound with enhanced water-solubility | |
Inaba et al. | Prostaglandins and their cyclodextrin complexes | |
EP1594515A2 (en) | Drug formulation and delivery using crystalline methylated cyclodextrins | |
AU687966B2 (en) | Use of mono-3,6-anhydro-cyclodextrins for solubilising a hydrophobic compound and monitoring the purity of an enantiomer, and method for preparing said cyclodextrins | |
KUM et al. | THE CYCLODEXTRINS: A REVIEW | |
KR20030068034A (en) | Amphiphilic macrocyclic derivatives and their analogues |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |