CA1297016C - Sustained release pharmaceutical preparations - Google Patents
Sustained release pharmaceutical preparationsInfo
- Publication number
- CA1297016C CA1297016C CA000539906A CA539906A CA1297016C CA 1297016 C CA1297016 C CA 1297016C CA 000539906 A CA000539906 A CA 000539906A CA 539906 A CA539906 A CA 539906A CA 1297016 C CA1297016 C CA 1297016C
- Authority
- CA
- Canada
- Prior art keywords
- particulate material
- polymer
- group
- neutral
- ion
- 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 - Fee Related
Links
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B33/00—After-treatment of single crystals or homogeneous polycrystalline material with defined structure
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Abstract of the Disclosure Sustained release solid dosage forms--i.e., tablets, pellets, granules, and powders--can be made using a com-bination of polymeric and ionic particulate materials to modify release profiles, permeability and processability.
0043D/a
0043D/a
Description
The trea~ment or coating of active substance~, ~uch as drug~, ~itamin~, mineral~, and the lik:e, has re6ulted in a varie~y of orally-adminis~rable do~age form~. One principal goal in the foemula~ion of 6uch do6a~e fo~ms i&
oftan the ~low and su~ai~ed rel~ase o~ the ac~.ive i~-gredi~nt ov~r a relati~ely long p~eriod of ti~e, e.g., several hours. Such ~u~tain~d relea~e profila~ genecally a~20rd ~uch bene~it6 a~ maxlmum aosagQ delivery wit~
minimal compliance problem~ ~ince!, in the ca6e of drug~, the patie~ need not ta~e repeated do~age6 in orde~ to en~ure long-term drug relea~e.
The Inyention It ha~ been di~co~ered that solid preparatio~ ~or tha ad~ini6tration of pharmaceuticals and otAer active ~ub6ta~ce~ can be pro~uced having 6ustained release properties when the drug or other active ingredien~ i~
treated in accordance with a proce~ which comprises:
(1~ co~tacting at l~ast one active ~ubstance wit~
at least one ionically neutral poly~er and at lea~t one ionic par~iculate ~aterial or ad~rbe~t~
(2~ producing a co~posite o~ particulate ~aterial and active sub~ance in which ion pair~ bond the activ~
substance to the ~articulate ~aterial, or the active i8 ad30rbsd on th~ parti~ulate material and neu~ral polymer~
form binder ;
~3) coati~g the co~po~it~ produc~d witb a ~eu~ral polym~r; a~d S4~ recovering the produc~ of ~tep t3)-The composite produc~ made in ac~ordance with the process of the in~ention i~ believed ~o be ~he result of adsorptio~ a~d~o~ ionic bonding betwee~ the ~urfaces of the acti~e substance, e.g., drug, and the particulate ionic ~aterialO The bonding i~ balie~ad to be ~ore electroseatic than ~hemical i~ nature ~i~ce the ch~mical natur~ o~ ~one of the compone~ts ha6 been ~hown to be altered.
Advanta~es The proc~s of the inveneion has ~everal advantages S over prior ar2 me~hods of treating ac~ive 6ubs~ances.
Pirst, the product~ hava ben~icial release pro~ile6.
That i~, drug~ or other ac~iYe ingredient~ are ~eleaæed into the ~ystem o~ the patient/consumer gradu~lly oYer a period of up to several hour~ at a con~tant rate.
In addition, the permeability CharactQri6tic~ of the poly~er~containing me~br~nes can be modified by 6uitable adjustment of the ratio o the coating level~ o~ the neutral polymer.
Oth~r advantage~ and aspects o~ the invention will b~ made appar~ne by the following description.
Description o~ ~he Invention The invention comprises the proce6s as sum~arized above. In general, it can be sai~ to re6ide in a method which call~ for:
~O (1) cont~cting one or more drugs or othsr active sub~tances with a particulate ~aterial ~hich ha~ ionic and/o~ adsorbent character, (2~ ~roduciQg a co~po~its of t~ese three i~gre-ient~, which composite comprise~:
a) the product of the interaction, presum-ably the elecero-chemical bonding, between the ~ur~a~es sf the particulat2 material a~d the active compone~t;
b~ a neu~ral polymer that acts as a binder, and .. 30 c) a neutral polymer which form~ the membrane that partially con~rol~ ~he eate of relea~e of the actiYe component afger inge~tio~; and (3~ recov~ring t~e product o~ ~Sep t2~.
Drug relea~e i~ believed to be eontrolled by desorption fron the ad~orbent or di6as~0ciation of the ion pair and the enca~ing me~brane (i.e. th~
coati~g).
~25~
Ac~ive SubstancQs The activ0 co~ponent or lngredient to be treated in accorda~ce with ~he invention is a biologically active sub~tance. A wide variety of active ~aterials ar~ conte~-5 pl~ed. Chi~f among them are drugs Of pharmaceuticals,vi~amins, ~ineral~ and other ~sycholo.gical sub~tances which have beneficial biologieal ef~cts a~ter in~e~tion.
The ~ollowins i~ ~82~1y a sampling of the type~ o~
acti~e ~ub0tance~ whi~h can be employed. Su~h ub~ta~c~s include ac~tylcholine, noradr~nalin, ~ero~onin, calli~
cretin, gastri~, secretin, adren.alin, i~ulin. glucagon, ACTH, growth hormone, genadotropi~ hor~one, oxytocin, vasopre~sin, thyroxinf tQsticular hor~on~ (te6to~erone), ovarian hormone (es~radiol~ corpus luteum ~or~one, luteal hormo~e (progesterone), adrenocor~ical hormone, pro6ta-gladin, various antihi~aminic agen~s, antihyp~rten~ive~, va~odilators, va~oprotector6, ~tomachics and digestive6, anti-diarrheals and inte~tinal ab~orbers, con~acepti~e~, ant~phlogi6tic, acetysalicylic acid, ibuprof~n, phenacetin, mefenamic acid, maproxen, tiaramide, indo-~athaci~, vita~ins, variou6 enzyme~, a~titu~or agents (bleomyci~, sarco~y~in, actinomycin D, cyclophosphamide, nit~ogen ~u~ta~d. tr~ethylene thiophos~horamid2, mercap~o-- purine, metho- treYale, thorou-acil, mitomyci~ C, car~ino-philin, chromomyci~ 2(2-t~cahydro-~uryl)-5 fluorouracil et~), radio~ha~maceuticals, antibiotic~
(~trepto~ycins, chloramphenicols, te~racycline~, erythLo-mycins, trichomycin~, bacitracin6, coli~tins, polymixins, gra~icidin~, penicillin6, g~i6eofulvin~, etc.), 6ul-- 30 fanilamide and it~ derivatives, anti~uberculosi6 drug~
(TB prepara~ions), anti~yphili~ic , antilep, various biological preparatio~ (vaccines, anti6erum~ toxin~ and a~titoxin~, etc.~ a~bicides, a~thelmintics, ata~axocs, (anti~ataract agents, a~tiglaucoma agent.s, etc.), variou~
fi~h drugs, agricultural drug~, interfe-onO auxin, gibberelline, cytoki~in, ab~inthic acid, o~her phy~o-hormone~, ~ex pheromone, aggrega~ien pheromone, alarm _ .
~h~ro~one, trall pheromone. ca~t pharo~on~, other ~hero~ones, and the like. l~ixtures can be used.
The active ingredie~ will generally comprise about 0.001 to about 50 ~c %, preferably about 0.001 ~o abou~
5 40 wt t, of ~ch* final dc~age for~, based on total weight.
N~y~
The bindec Of matrl:~ portio~l of the co~posite ~ade in accorda~ce wit:h 'ctle instant pS'OC~l~B ia a polymeric material having no ionizable group~ i~ it~ backbone or 10 elsewhers in it~ structure. By "ionizable gro~ps" i~
rleane group~ which, when pr3~ent in appropr iate vehicle~3, dis~ociate to ~ufnish positively and negative cha~ged specie~. One typical ionically..neutral polymer is hydr~propyl cellulo~e.
.. _ . _ _ _ ... . ..
The coating poly~er6 are derived from acrylic ester~, cellulosics and polyvinyl e~ter~ and ether~ and/or other functionally equivalent monom~r~ . While Che f inal polyiners are es~entially neu~-ral, the pre~ence of acid, salt or other moieties which do no~c ~ignif ican~ly e~ect 20 'che ionic r~eu~rali'cy of tlle polymers is p@rmis~ible.
U~eful coating polymer~ are u6ually 6upplied as aqueou~ ti~per6ions. ~hey can also be solvent-based coat-ing system~. The presenc~ o~ one or Dlore co-diluents i~
contemplated. E~os~ver, disper6ions con~aining water as 25 the only ~ilue~t are pr~ferred ~or ~afe~y rea~on~.
I~ th~ ~inal do~age îorm, the poly~eric material will co~prise about 10 to about 50 wt ~, preferably about 10 to about 40 wt ~6, based o~l to~al weight.
The Par~ ulate Ionic ~qaterial U6eful particulate material~ are tho6e who~e ionic character make ths~ candidate6 for participation i~l ~he ion pai~ bondZ; or ad60rption to be ~ormed between the surf2ee of the acti~e ~ubstance and the ~ur~ace of the ionic particulate.
~ahile particle ~ize ig ~lOt criti~alt it i~ generally advisable to employ particle6 who~e rheological proper-ties isl combinatioll with 'che aqueous polymeric bi~der component render th~ uuitable a~ co~ponont~ o~ ~low-relea~e core~ ~or inge~tible substance~. Typically, the particulate ~ter~ al8 UBed herein will have particl~
~izes of abou~ 325 me~h or le8~, pr~fQrably about 400 ~e~h or le~ ba~ed on U.S~ tandard ~ieve.
The ionic particle~ u~ad are ge~erally eithsr i~organic, ~.g., minerals and clays, or organic, e.g., ion e~chan~e ~e~in~, ~odi~ied n~utral polymers. ~ix~ure~
of any o~ the~ type are operable. Two or ~ore o~ the 10 6ama 'cyp~ can be u~ed.
The par~icle~ are pref erably eithec silicious material~, e.g., kaolin, kaolin clay, ~ilica, mine~al ~ilicate~, etc., or ionic ocganic material~, ~uch a~
s~yrene copolymers bearing ~unctional isnic group6, and the lik~. Example~ of ~uch ionic copolymer~ are the styrenedivi~yl benzene copolymer~ bearing ~ulfonate, carboxylate, quaternary ammonium and/or ami~e sub6tituent~.
The ionic character of mineralfi and other u6eful ~ ciou6 particle~ i~ generally a6sociated with their p~a ~alue~ in aqueou~ ~edia. In gsneral, ~aolin and other clay~ o~ clay~ e matsrials having a ~ignificant ~urface ~harge den~i~y ~ill be operable.
~hile ~ot desi~i~g to be bound by a~y pa~ ular theory, Applicants believe tha~ an ele~tro-chemical bonding akin to, and po~&ibly involvi~g, ad~orptio~
oc~ur~ ~etween the active ingredient6 and the ionic particulate6.
In general, the quantities of io~i~ par~iculate ~aterial~ ~o be employed will be such ~ha~ th~ final do~age for~ will co~tain from about 20 to about 90 wt and pre~erably about 30 to about 30 wt % of thi i~redie~t.
Othe~ ~xcipients and ingredient~ conventio~ally e~ployed iQ th~ o~al 0rmulation6 for the admini ~ratio~
of biologi~ally bene~i~ial a~tive ~ubstance~ ca~ al~o be employed in th~ in6ta~t formulation~.
,., ~.
- ~ ~
~g~
Th~ method d~cribed herein is suitable ~or producin~ a variety of ~olid do~age/adminl~tratio~
~orms. Powders, pelle~s, granul~, and tablets ~hich co~taln one or ~o~e activ~ ingredients and the r~qui~it~
coating or me~bla~e of pa~ticulate a~d polymar can be produced.
~ hile ~olid products are preferred, semisolid~ and liquid~ ca~ also be trea~ed i~ acordan~e herewi~h.
10 ~
In gene ~1, any apparatus rea~onably suited ~or handling materials and ~ub~tance6 of the type~ de6cribad above can be u~ed i~ carrying out the inven~ion.
One pre~errQd production ~cheme, ~rom which a ~kllled artisan can e~trapolate, would involve the ~ollowing ~eeps:
(~) AdsQrbing active ingredien~ onto ionic pa~ticulate sub~ra~a or ~ilicious material;
~b) Mixing ehe produc of ~tep (a) with polymeric bi~der;
(~ layeri~q th~ ~u~pen~ion on solid inert ~ate~ial and (d) ~ncap8ulaei~g with neueral polymeri~ re~
A typical p~OCQ~ ~or the ~uspen~ion layering o~
sugar ~*eds i5 demon~tra~ed by ~he following:
No~ parail sugar ~e~d~ he range of 14-16~ were coa~ed with a ~u~pen~io~ of drug, kaolin and bi~der ~o produ~e es~remely ~ooth ~pherical drug pelle~. The~e p~lle~ were ~ub~eque~tly coated with a polymer d~per~ion .
~he procedure employed ~a6:
Kaolin wa~ ~uspended in water. Diphenhydrami~e HCl was ad¢o~bed on~o th~ kaolin of ~ixing with the kaolin ~u~pe~ion. To the drug/kaolin ~ixture, a~ a~u~ou~
bi~d2r ~oluti.on of hydroYyp~opyl ~ellulo~e in water was added. The c~6ultant su~pe~ion waB 6psayed at a ra~e of ~L~29b7~
o~to a ~luidizing bed o~ nonpareil ~ugar s~ed6 ~o yield pel let~ .
Ths pellet~ were then coated with an aqueous polymeric di~peLsio~ o~ ethylcellulo~e (Aquacoatql~) a~d dried overniqht at 40"C.
The rel~a~e of drugs ~com the ~oated p211ets was ~tudied and found to follow 2~ro order up to 90% drug deplst ion .
_r aw~
The ~igur~ ~how~ the release prof ile o~ th~ pellet~
discussed in the Example. The upper cur~e show6 the prof ile for pallets without kaolin. The lowec 6how~ the profile for pellat~ with kaolin.
ExamQe 100 q of kaolin was mixed thoroughly with 500 g o~
deionized water. SOg of diphenhydramine HCl was di6-solved in the ~uspension and sti~red. 35 g of KlucellD
(hydroxy propyl cellulose~ was di~olYed in 165 g of deionized wate~ and mixed with ~he ~u6pen~ion.
The ~ixture wa& sprayed onto 150 g 14-16 me~h llanpareil ~eds. Ths drug layer~ pellet~ were coated wi~h Aquacoatt3 to a coati~g l~vel oP abou~ 7%. The d~ug relea~ from the water-layQred pellet6 was co~pared with that îro~ ilarly coated diphenhydra~ s Hf'l p~llet6.
Time Pe~cent Drug P~eleas~d ~R h'~l~ ~I:L~
0-5 -- 28.8 4.2 45.
oftan the ~low and su~ai~ed rel~ase o~ the ac~.ive i~-gredi~nt ov~r a relati~ely long p~eriod of ti~e, e.g., several hours. Such ~u~tain~d relea~e profila~ genecally a~20rd ~uch bene~it6 a~ maxlmum aosagQ delivery wit~
minimal compliance problem~ ~ince!, in the ca6e of drug~, the patie~ need not ta~e repeated do~age6 in orde~ to en~ure long-term drug relea~e.
The Inyention It ha~ been di~co~ered that solid preparatio~ ~or tha ad~ini6tration of pharmaceuticals and otAer active ~ub6ta~ce~ can be pro~uced having 6ustained release properties when the drug or other active ingredien~ i~
treated in accordance with a proce~ which comprises:
(1~ co~tacting at l~ast one active ~ubstance wit~
at least one ionically neutral poly~er and at lea~t one ionic par~iculate ~aterial or ad~rbe~t~
(2~ producing a co~posite o~ particulate ~aterial and active sub~ance in which ion pair~ bond the activ~
substance to the ~articulate ~aterial, or the active i8 ad30rbsd on th~ parti~ulate material and neu~ral polymer~
form binder ;
~3) coati~g the co~po~it~ produc~d witb a ~eu~ral polym~r; a~d S4~ recovering the produc~ of ~tep t3)-The composite produc~ made in ac~ordance with the process of the in~ention i~ believed ~o be ~he result of adsorptio~ a~d~o~ ionic bonding betwee~ the ~urfaces of the acti~e substance, e.g., drug, and the particulate ionic ~aterialO The bonding i~ balie~ad to be ~ore electroseatic than ~hemical i~ nature ~i~ce the ch~mical natur~ o~ ~one of the compone~ts ha6 been ~hown to be altered.
Advanta~es The proc~s of the inveneion has ~everal advantages S over prior ar2 me~hods of treating ac~ive 6ubs~ances.
Pirst, the product~ hava ben~icial release pro~ile6.
That i~, drug~ or other ac~iYe ingredient~ are ~eleaæed into the ~ystem o~ the patient/consumer gradu~lly oYer a period of up to several hour~ at a con~tant rate.
In addition, the permeability CharactQri6tic~ of the poly~er~containing me~br~nes can be modified by 6uitable adjustment of the ratio o the coating level~ o~ the neutral polymer.
Oth~r advantage~ and aspects o~ the invention will b~ made appar~ne by the following description.
Description o~ ~he Invention The invention comprises the proce6s as sum~arized above. In general, it can be sai~ to re6ide in a method which call~ for:
~O (1) cont~cting one or more drugs or othsr active sub~tances with a particulate ~aterial ~hich ha~ ionic and/o~ adsorbent character, (2~ ~roduciQg a co~po~its of t~ese three i~gre-ient~, which composite comprise~:
a) the product of the interaction, presum-ably the elecero-chemical bonding, between the ~ur~a~es sf the particulat2 material a~d the active compone~t;
b~ a neu~ral polymer that acts as a binder, and .. 30 c) a neutral polymer which form~ the membrane that partially con~rol~ ~he eate of relea~e of the actiYe component afger inge~tio~; and (3~ recov~ring t~e product o~ ~Sep t2~.
Drug relea~e i~ believed to be eontrolled by desorption fron the ad~orbent or di6as~0ciation of the ion pair and the enca~ing me~brane (i.e. th~
coati~g).
~25~
Ac~ive SubstancQs The activ0 co~ponent or lngredient to be treated in accorda~ce with ~he invention is a biologically active sub~tance. A wide variety of active ~aterials ar~ conte~-5 pl~ed. Chi~f among them are drugs Of pharmaceuticals,vi~amins, ~ineral~ and other ~sycholo.gical sub~tances which have beneficial biologieal ef~cts a~ter in~e~tion.
The ~ollowins i~ ~82~1y a sampling of the type~ o~
acti~e ~ub0tance~ whi~h can be employed. Su~h ub~ta~c~s include ac~tylcholine, noradr~nalin, ~ero~onin, calli~
cretin, gastri~, secretin, adren.alin, i~ulin. glucagon, ACTH, growth hormone, genadotropi~ hor~one, oxytocin, vasopre~sin, thyroxinf tQsticular hor~on~ (te6to~erone), ovarian hormone (es~radiol~ corpus luteum ~or~one, luteal hormo~e (progesterone), adrenocor~ical hormone, pro6ta-gladin, various antihi~aminic agen~s, antihyp~rten~ive~, va~odilators, va~oprotector6, ~tomachics and digestive6, anti-diarrheals and inte~tinal ab~orbers, con~acepti~e~, ant~phlogi6tic, acetysalicylic acid, ibuprof~n, phenacetin, mefenamic acid, maproxen, tiaramide, indo-~athaci~, vita~ins, variou6 enzyme~, a~titu~or agents (bleomyci~, sarco~y~in, actinomycin D, cyclophosphamide, nit~ogen ~u~ta~d. tr~ethylene thiophos~horamid2, mercap~o-- purine, metho- treYale, thorou-acil, mitomyci~ C, car~ino-philin, chromomyci~ 2(2-t~cahydro-~uryl)-5 fluorouracil et~), radio~ha~maceuticals, antibiotic~
(~trepto~ycins, chloramphenicols, te~racycline~, erythLo-mycins, trichomycin~, bacitracin6, coli~tins, polymixins, gra~icidin~, penicillin6, g~i6eofulvin~, etc.), 6ul-- 30 fanilamide and it~ derivatives, anti~uberculosi6 drug~
(TB prepara~ions), anti~yphili~ic , antilep, various biological preparatio~ (vaccines, anti6erum~ toxin~ and a~titoxin~, etc.~ a~bicides, a~thelmintics, ata~axocs, (anti~ataract agents, a~tiglaucoma agent.s, etc.), variou~
fi~h drugs, agricultural drug~, interfe-onO auxin, gibberelline, cytoki~in, ab~inthic acid, o~her phy~o-hormone~, ~ex pheromone, aggrega~ien pheromone, alarm _ .
~h~ro~one, trall pheromone. ca~t pharo~on~, other ~hero~ones, and the like. l~ixtures can be used.
The active ingredie~ will generally comprise about 0.001 to about 50 ~c %, preferably about 0.001 ~o abou~
5 40 wt t, of ~ch* final dc~age for~, based on total weight.
N~y~
The bindec Of matrl:~ portio~l of the co~posite ~ade in accorda~ce wit:h 'ctle instant pS'OC~l~B ia a polymeric material having no ionizable group~ i~ it~ backbone or 10 elsewhers in it~ structure. By "ionizable gro~ps" i~
rleane group~ which, when pr3~ent in appropr iate vehicle~3, dis~ociate to ~ufnish positively and negative cha~ged specie~. One typical ionically..neutral polymer is hydr~propyl cellulo~e.
.. _ . _ _ _ ... . ..
The coating poly~er6 are derived from acrylic ester~, cellulosics and polyvinyl e~ter~ and ether~ and/or other functionally equivalent monom~r~ . While Che f inal polyiners are es~entially neu~-ral, the pre~ence of acid, salt or other moieties which do no~c ~ignif ican~ly e~ect 20 'che ionic r~eu~rali'cy of tlle polymers is p@rmis~ible.
U~eful coating polymer~ are u6ually 6upplied as aqueou~ ti~per6ions. ~hey can also be solvent-based coat-ing system~. The presenc~ o~ one or Dlore co-diluents i~
contemplated. E~os~ver, disper6ions con~aining water as 25 the only ~ilue~t are pr~ferred ~or ~afe~y rea~on~.
I~ th~ ~inal do~age îorm, the poly~eric material will co~prise about 10 to about 50 wt ~, preferably about 10 to about 40 wt ~6, based o~l to~al weight.
The Par~ ulate Ionic ~qaterial U6eful particulate material~ are tho6e who~e ionic character make ths~ candidate6 for participation i~l ~he ion pai~ bondZ; or ad60rption to be ~ormed between the surf2ee of the acti~e ~ubstance and the ~ur~ace of the ionic particulate.
~ahile particle ~ize ig ~lOt criti~alt it i~ generally advisable to employ particle6 who~e rheological proper-ties isl combinatioll with 'che aqueous polymeric bi~der component render th~ uuitable a~ co~ponont~ o~ ~low-relea~e core~ ~or inge~tible substance~. Typically, the particulate ~ter~ al8 UBed herein will have particl~
~izes of abou~ 325 me~h or le8~, pr~fQrably about 400 ~e~h or le~ ba~ed on U.S~ tandard ~ieve.
The ionic particle~ u~ad are ge~erally eithsr i~organic, ~.g., minerals and clays, or organic, e.g., ion e~chan~e ~e~in~, ~odi~ied n~utral polymers. ~ix~ure~
of any o~ the~ type are operable. Two or ~ore o~ the 10 6ama 'cyp~ can be u~ed.
The par~icle~ are pref erably eithec silicious material~, e.g., kaolin, kaolin clay, ~ilica, mine~al ~ilicate~, etc., or ionic ocganic material~, ~uch a~
s~yrene copolymers bearing ~unctional isnic group6, and the lik~. Example~ of ~uch ionic copolymer~ are the styrenedivi~yl benzene copolymer~ bearing ~ulfonate, carboxylate, quaternary ammonium and/or ami~e sub6tituent~.
The ionic character of mineralfi and other u6eful ~ ciou6 particle~ i~ generally a6sociated with their p~a ~alue~ in aqueou~ ~edia. In gsneral, ~aolin and other clay~ o~ clay~ e matsrials having a ~ignificant ~urface ~harge den~i~y ~ill be operable.
~hile ~ot desi~i~g to be bound by a~y pa~ ular theory, Applicants believe tha~ an ele~tro-chemical bonding akin to, and po~&ibly involvi~g, ad~orptio~
oc~ur~ ~etween the active ingredient6 and the ionic particulate6.
In general, the quantities of io~i~ par~iculate ~aterial~ ~o be employed will be such ~ha~ th~ final do~age for~ will co~tain from about 20 to about 90 wt and pre~erably about 30 to about 30 wt % of thi i~redie~t.
Othe~ ~xcipients and ingredient~ conventio~ally e~ployed iQ th~ o~al 0rmulation6 for the admini ~ratio~
of biologi~ally bene~i~ial a~tive ~ubstance~ ca~ al~o be employed in th~ in6ta~t formulation~.
,., ~.
- ~ ~
~g~
Th~ method d~cribed herein is suitable ~or producin~ a variety of ~olid do~age/adminl~tratio~
~orms. Powders, pelle~s, granul~, and tablets ~hich co~taln one or ~o~e activ~ ingredients and the r~qui~it~
coating or me~bla~e of pa~ticulate a~d polymar can be produced.
~ hile ~olid products are preferred, semisolid~ and liquid~ ca~ also be trea~ed i~ acordan~e herewi~h.
10 ~
In gene ~1, any apparatus rea~onably suited ~or handling materials and ~ub~tance6 of the type~ de6cribad above can be u~ed i~ carrying out the inven~ion.
One pre~errQd production ~cheme, ~rom which a ~kllled artisan can e~trapolate, would involve the ~ollowing ~eeps:
(~) AdsQrbing active ingredien~ onto ionic pa~ticulate sub~ra~a or ~ilicious material;
~b) Mixing ehe produc of ~tep (a) with polymeric bi~der;
(~ layeri~q th~ ~u~pen~ion on solid inert ~ate~ial and (d) ~ncap8ulaei~g with neueral polymeri~ re~
A typical p~OCQ~ ~or the ~uspen~ion layering o~
sugar ~*eds i5 demon~tra~ed by ~he following:
No~ parail sugar ~e~d~ he range of 14-16~ were coa~ed with a ~u~pen~io~ of drug, kaolin and bi~der ~o produ~e es~remely ~ooth ~pherical drug pelle~. The~e p~lle~ were ~ub~eque~tly coated with a polymer d~per~ion .
~he procedure employed ~a6:
Kaolin wa~ ~uspended in water. Diphenhydrami~e HCl was ad¢o~bed on~o th~ kaolin of ~ixing with the kaolin ~u~pe~ion. To the drug/kaolin ~ixture, a~ a~u~ou~
bi~d2r ~oluti.on of hydroYyp~opyl ~ellulo~e in water was added. The c~6ultant su~pe~ion waB 6psayed at a ra~e of ~L~29b7~
o~to a ~luidizing bed o~ nonpareil ~ugar s~ed6 ~o yield pel let~ .
Ths pellet~ were then coated with an aqueous polymeric di~peLsio~ o~ ethylcellulo~e (Aquacoatql~) a~d dried overniqht at 40"C.
The rel~a~e of drugs ~com the ~oated p211ets was ~tudied and found to follow 2~ro order up to 90% drug deplst ion .
_r aw~
The ~igur~ ~how~ the release prof ile o~ th~ pellet~
discussed in the Example. The upper cur~e show6 the prof ile for pallets without kaolin. The lowec 6how~ the profile for pellat~ with kaolin.
ExamQe 100 q of kaolin was mixed thoroughly with 500 g o~
deionized water. SOg of diphenhydramine HCl was di6-solved in the ~uspension and sti~red. 35 g of KlucellD
(hydroxy propyl cellulose~ was di~olYed in 165 g of deionized wate~ and mixed with ~he ~u6pen~ion.
The ~ixture wa& sprayed onto 150 g 14-16 me~h llanpareil ~eds. Ths drug layer~ pellet~ were coated wi~h Aquacoatt3 to a coati~g l~vel oP abou~ 7%. The d~ug relea~ from the water-layQred pellet6 was co~pared with that îro~ ilarly coated diphenhydra~ s Hf'l p~llet6.
Time Pe~cent Drug P~eleas~d ~R h'~l~ ~I:L~
0-5 -- 28.8 4.2 45.
2 17.B 61.7 ~ 4~ g 77 . 4 . 6 67.~ P~6.4 84.8 ~2.~
95.9 97.1 lZ 100 . 1:) 100 . O
Reasonable ~rariation~, ~uch a6 tho~e which would 35 oc~ur to a skilled arti~an, can be made h~reila without departi~g fro~ the ficope o~ the il~vention~
. ~
.
.~, .
95.9 97.1 lZ 100 . 1:) 100 . O
Reasonable ~rariation~, ~uch a6 tho~e which would 35 oc~ur to a skilled arti~an, can be made h~reila without departi~g fro~ the ficope o~ the il~vention~
. ~
.
.~, .
Claims (10)
1. A process for treating a biologically active substance which comprises the steps of:
a) contacting at least one active substance substance with at least one ionically neutral polymer and at least one ionic particulate material;
b) producing a composite of neutral polymeric binder, particulate material and active substance in which ion pairs bond the active substance to the particulate material and the core is coated with a neutral coating of polymer to form a membrane; and c) recovering the product of step (2).
a) contacting at least one active substance substance with at least one ionically neutral polymer and at least one ionic particulate material;
b) producing a composite of neutral polymeric binder, particulate material and active substance in which ion pairs bond the active substance to the particulate material and the core is coated with a neutral coating of polymer to form a membrane; and c) recovering the product of step (2).
2. The process of claim 1 wherein the particulate material is of acidic or basic character prior to step (a).
3. The process of claim 2 wherein the particulate material is selected from the group consisting of:
kaolin, non-kaolin clay, ion exchange resins having acidic of basic character and mixtures thereof.
kaolin, non-kaolin clay, ion exchange resins having acidic of basic character and mixtures thereof.
4. The process of claim 1 wherein the particulate material is kaolin.
5. The process of Claim 1 wherein the neutral polymeric binder is selected from the group consisting of cellulosic ethers, acrylics, and polyvinyl esters.
6. The process of claim 4 wherein the neutral polymer is a water insoluble aqueous polymer selected from the group consisting of acrylic resins, cellulosics, and polyvinyl esters.
7. The process of claim 6 wherein the polymer is supplied as an aqueous dispersion containing a copolymer derived form monomers selected form acylic esters, methacrylic esters, and mixtures thereof.
8. The process of claim 1 wherein the particulate material is an ion-exchange resin having acidic or basic character.
9. The process of claim 8 wherein the ion exchange resin contains at least one ionic group selected from the group consisting of sulfonates, carboxylates, quaternary ammonium groups, amine groups, and mixtures thereof.
10. The process of claim 9 wherein the ion exchange resin is strongly acidic.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US875,146 | 1986-06-17 | ||
| US06/875,146 US4810501A (en) | 1986-06-17 | 1986-06-17 | Sustained release pharmaceutical preparations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1297016C true CA1297016C (en) | 1992-03-10 |
Family
ID=25365278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000539906A Expired - Fee Related CA1297016C (en) | 1986-06-17 | 1987-06-17 | Sustained release pharmaceutical preparations |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4810501A (en) |
| EP (1) | EP0249949B1 (en) |
| JP (1) | JPS63258406A (en) |
| KR (1) | KR950003609B1 (en) |
| AT (1) | ATE83649T1 (en) |
| AU (1) | AU611085B2 (en) |
| CA (1) | CA1297016C (en) |
| DE (1) | DE3783163T2 (en) |
| DK (1) | DK305287A (en) |
| ES (1) | ES2053470T3 (en) |
| FI (1) | FI872652A (en) |
| GR (1) | GR3006981T3 (en) |
| NO (1) | NO872499L (en) |
| NZ (1) | NZ220722A (en) |
| PH (1) | PH24152A (en) |
| PT (1) | PT85105B (en) |
| ZA (1) | ZA873851B (en) |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8707416D0 (en) * | 1987-03-27 | 1987-04-29 | Wellcome Found | Pharmaceutical formulations |
| US4996047A (en) * | 1988-11-02 | 1991-02-26 | Richardson-Vicks, Inc. | Sustained release drug-resin complexes |
| US4999189A (en) * | 1988-11-14 | 1991-03-12 | Schering Corporation | Sustained release oral suspensions |
| US5186930A (en) * | 1988-11-14 | 1993-02-16 | Schering Corporation | Sustained release oral suspensions |
| GB9025372D0 (en) * | 1990-11-22 | 1991-01-09 | Nat Res Dev | Pharmaceutical dosage forms |
| US5683719A (en) * | 1990-11-22 | 1997-11-04 | British Technology Group Limited | Controlled release compositions |
| US5358723A (en) * | 1991-11-26 | 1994-10-25 | Warner-Lambert Company | Process and composition for the development of controlled release gemfibrozil dosage form |
| US5472712A (en) * | 1991-12-24 | 1995-12-05 | Euroceltique, S.A. | Controlled-release formulations coated with aqueous dispersions of ethylcellulose |
| US5968551A (en) * | 1991-12-24 | 1999-10-19 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
| US5681585A (en) | 1991-12-24 | 1997-10-28 | Euro-Celtique, S.A. | Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer |
| US5348747A (en) * | 1992-03-05 | 1994-09-20 | American Home Products Corporation | Pharmaceutical coating sugars |
| US5429822A (en) * | 1992-03-13 | 1995-07-04 | Cambridge Scientific, Inc. | Biodegradable bursting release system |
| KR950703935A (en) * | 1992-11-30 | 1995-11-17 | 밋첼 아이, 커시너 | Pharmaceutical compositions that block taste |
| US5456917A (en) * | 1993-04-12 | 1995-10-10 | Cambridge Scientific, Inc. | Method for making a bioerodible material for the sustained release of a medicament and the material made from the method |
| FR2723846B1 (en) * | 1994-08-24 | 1997-06-13 | Hi Pharmtech | SOLID PHARMACEUTICAL FORM FOR THE ADMINISTRATION OF A LIPOSOLUBLE LIQUID ACTIVE SUBSTANCE |
| DK0824344T3 (en) * | 1995-05-09 | 2005-08-15 | Phoqus Pharmaceuticals Ltd | Powdered composition for electrostatic coating of pharmaceutical substrates |
| US7008668B2 (en) * | 1995-05-09 | 2006-03-07 | Phoqus Pharmaceuticals Limited | Powder coating composition for electrostatic coating of pharmaceutical substrates |
| GB9623634D0 (en) * | 1996-11-13 | 1997-01-08 | Bpsi Holdings Inc | Method and apparatus for the coating of substrates for pharmaceutical use |
| US6479082B1 (en) | 1996-12-23 | 2002-11-12 | Wm. Wrigley, Jr. Co. | Process of increasing flavor release from chewing gum using hydroxypropyl cellulose and product thereof |
| AU8293498A (en) | 1997-07-02 | 1999-01-25 | Euro-Celtique S.A. | Stabilized sustained release tramadol formulations |
| EP0943341A1 (en) * | 1998-02-18 | 1999-09-22 | Oscar Gold | Procedure to prepare granulated compositions that contain erythromycin macrolides and procedure to prepare pharmaceutical compositions that contain said macrolides |
| CN1348333A (en) | 1999-04-01 | 2002-05-08 | Wm.雷格利Jr.公司 | Long flavor duration releasing structures for chewing gum |
| GB0002305D0 (en) * | 2000-02-01 | 2000-03-22 | Phoqus Limited | Power material for electrostatic application |
| FR2807771A1 (en) * | 2000-04-12 | 2001-10-19 | Atofina | Hydrophilic modification of various substrates using treatment in aqueous medium containing water-soluble and heat-sensitive polymer, at temperature not lower than that of critical solubility temperature of polymer |
| WO2003020242A1 (en) * | 2001-08-29 | 2003-03-13 | Srl Technologies, Inc. | Sustained release preparations |
| GB2420298B (en) * | 2003-06-18 | 2006-08-23 | Phoqus Pharmaceuticals Ltd | Method and apparatus for the application of powder material to substrates |
| GB0330171D0 (en) * | 2003-12-30 | 2004-02-04 | Phoqus Pharmaceuticals Ltd | Method and apparatus for the application of powder material to substrates |
| GB0407312D0 (en) * | 2004-03-31 | 2004-05-05 | Phoqus Pharmaceuticals Ltd | Method and apparatus for the application of powder material to substrates |
| US20050265955A1 (en) * | 2004-05-28 | 2005-12-01 | Mallinckrodt Inc. | Sustained release preparations |
| EP2441460A1 (en) * | 2005-06-30 | 2012-04-18 | Ipsen Pharma | GLP-1 pharmaceutical compositions |
| DK1915137T3 (en) | 2005-08-10 | 2013-11-04 | Add Advanced Drug Delivery Technologies Ltd | Controlled-release oral preparation |
| KR101402592B1 (en) * | 2006-03-06 | 2014-06-17 | 에스케이바이오팜 주식회사 | Transdermal Composition Using Piroxicam-Inorganic Complex and Patch System Comprising the Same |
| US20080081067A1 (en) * | 2006-10-03 | 2008-04-03 | Gupta Manishkumar | Sustained release pharmaceutical compositions of venlafaxine and process for preparation thereof |
| CN106068222B (en) * | 2014-04-16 | 2018-04-17 | 株式会社小松制作所 | Idle pulley, crawler type running device and abrasion plate |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2897121A (en) * | 1957-06-04 | 1959-07-28 | Upjohn Co | Pharmaceutical composition |
| US3119738A (en) * | 1962-04-12 | 1964-01-28 | Wisconsin Alumni Res Found | Medication for ruminants |
| US3594470A (en) * | 1968-02-19 | 1971-07-20 | Abbott Lab | Chewable tablets including coated particles of pseudoephedrine-weak cation exchange resin |
| FR2183546B1 (en) * | 1972-05-10 | 1975-06-20 | Servier Lab | |
| US4011061A (en) * | 1975-03-20 | 1977-03-08 | Minnesota Mining And Manufacturing Company | Articles providing sustained release and method of making |
| US4284444A (en) * | 1977-08-01 | 1981-08-18 | Herculite Protective Fabrics Corporation | Activated polymer materials and process for making same |
| DE2908794C2 (en) * | 1978-03-09 | 1984-09-13 | Japan Atomic Energy Research Institute, Tokio/Tokyo | Process for the production of a polymer preparation containing a physiologically active substance |
| US4221778A (en) * | 1979-01-08 | 1980-09-09 | Pennwalt Corporation | Prolonged release pharmaceutical preparations |
| US4308251A (en) * | 1980-01-11 | 1981-12-29 | Boots Pharmaceuticals, Inc. | Controlled release formulations of orally-active medicaments |
| IT1176853B (en) * | 1984-10-02 | 1987-08-18 | Eurand Spa | PROCEDURE FOR OBTAINING A CONTROLLED RELEASE FORMULATION OF WATER SOLUBLE COMPONENTS |
| US4600645A (en) * | 1985-01-31 | 1986-07-15 | Warner-Lambert Company | Process for treating dosage forms |
-
1986
- 1986-06-17 US US06/875,146 patent/US4810501A/en not_active Expired - Fee Related
-
1987
- 1987-05-27 ZA ZA873851A patent/ZA873851B/en unknown
- 1987-06-12 AU AU74196/87A patent/AU611085B2/en not_active Ceased
- 1987-06-13 KR KR1019870005994A patent/KR950003609B1/en active IP Right Grant
- 1987-06-15 PH PH35410A patent/PH24152A/en unknown
- 1987-06-15 FI FI872652A patent/FI872652A/en not_active IP Right Cessation
- 1987-06-16 DK DK305287A patent/DK305287A/en not_active Application Discontinuation
- 1987-06-16 AT AT87108670T patent/ATE83649T1/en not_active IP Right Cessation
- 1987-06-16 ES ES87108670T patent/ES2053470T3/en not_active Expired - Lifetime
- 1987-06-16 JP JP62148160A patent/JPS63258406A/en active Pending
- 1987-06-16 NO NO872499A patent/NO872499L/en unknown
- 1987-06-16 DE DE8787108670T patent/DE3783163T2/en not_active Expired - Fee Related
- 1987-06-16 EP EP87108670A patent/EP0249949B1/en not_active Expired - Lifetime
- 1987-06-16 NZ NZ220722A patent/NZ220722A/en unknown
- 1987-06-17 PT PT85105A patent/PT85105B/en unknown
- 1987-06-17 CA CA000539906A patent/CA1297016C/en not_active Expired - Fee Related
-
1993
- 1993-02-04 GR GR930400231T patent/GR3006981T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO872499L (en) | 1987-12-18 |
| ZA873851B (en) | 1987-11-25 |
| PH24152A (en) | 1990-03-22 |
| EP0249949A2 (en) | 1987-12-23 |
| ATE83649T1 (en) | 1993-01-15 |
| GR3006981T3 (en) | 1993-06-30 |
| ES2053470T3 (en) | 1994-08-01 |
| EP0249949B1 (en) | 1992-12-23 |
| AU611085B2 (en) | 1991-06-06 |
| FI872652A0 (en) | 1987-06-15 |
| KR950003609B1 (en) | 1995-04-17 |
| PT85105B (en) | 1990-03-08 |
| FI872652A (en) | 1987-12-18 |
| PT85105A (en) | 1987-07-01 |
| US4810501A (en) | 1989-03-07 |
| AU7419687A (en) | 1987-12-24 |
| DE3783163T2 (en) | 1993-04-22 |
| KR880000106A (en) | 1988-03-23 |
| NZ220722A (en) | 1990-06-26 |
| NO872499D0 (en) | 1987-06-16 |
| DK305287D0 (en) | 1987-06-16 |
| DE3783163D1 (en) | 1993-02-04 |
| JPS63258406A (en) | 1988-10-25 |
| DK305287A (en) | 1987-12-18 |
| EP0249949A3 (en) | 1988-03-16 |
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