CA1332152C - Pharmaceutical composition of dihydropyridine compound - Google Patents
Pharmaceutical composition of dihydropyridine compoundInfo
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- CA1332152C CA1332152C CA000600631A CA600631A CA1332152C CA 1332152 C CA1332152 C CA 1332152C CA 000600631 A CA000600631 A CA 000600631A CA 600631 A CA600631 A CA 600631A CA 1332152 C CA1332152 C CA 1332152C
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- ethanol
- dimethyl
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- 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
- A61K9/146—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 organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- 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
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- 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
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Cardiology (AREA)
- Diabetes (AREA)
- Inorganic Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A parmaceutical composition comprising: a 1:1 solvate of 5-(5,5-dimethyl-1,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridine carboxylic acid 2-(phenyl(phenylmethyl)amino) ethyl ester P-oxide hydrochloride-ethanol (NZ-105) and hydroxypropyl-methylcellulose acetate succinate is disclosed. The composition can easily be prepared into tablets, capsules, granules, and powders, which exhibit an enhanced bioavailability, e.g. provides a high blood concentration of the active component NZ-105 and ensures a high total drug absorption.
A parmaceutical composition comprising: a 1:1 solvate of 5-(5,5-dimethyl-1,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridine carboxylic acid 2-(phenyl(phenylmethyl)amino) ethyl ester P-oxide hydrochloride-ethanol (NZ-105) and hydroxypropyl-methylcellulose acetate succinate is disclosed. The composition can easily be prepared into tablets, capsules, granules, and powders, which exhibit an enhanced bioavailability, e.g. provides a high blood concentration of the active component NZ-105 and ensures a high total drug absorption.
Description
1332152 :~ ~
~Il'LE OF ~HE INVENTION
PHARMACEUTICAL COMPOSITION OF DIHYDROPYRIDINE ::
COMPOUND
BACKGROUND OF THE INVENTION -~
Field_of the Invention~
Thi~ invention relates to a pharmaceutical composition comprising a lsl solvate of 5-(5,5-dimethyl- ~ :
1,3,2-dioxaphosphorin3ne-2-yl)-1,4-dihydro-2,6-dimethyl~
4-(3-nitrophenyl)-3-pyridine cnrboxylic acid 2-(phenyl~
(phenylmethyl)amino) ethyl ester P-ox~de hydrochloride~
ethanol (~uch a solvate ls herein abbreviated as ~NZ-105") possessing hypotensive activity. ~ `
Description of the Background: ~-The effective pharmaceutical component, NZ-105, of ~:
the composition of this $nvention $s a derivative of 1,4-dihydropyrid~ne-5-phosphonic acid and has the followlng chemical formulas C}~ ~11 ~ ~P11 ~
CH~Co~ ~C O2 CH2 C~Iz N ~ HC ~ C 2 H5 OH
C~J3 ~i CH3 CH2Ph wherein Ph represents a phenyl group. This is a novel .. .
compound possessing vasodilative and hypotensive activity :on account of lt~ calcium antagonistic act$vity and is useful .
as a cardiovascular drug. .~
~ A' 1 ~ ~
~ ~ .
~,,... ~
13321~2 Nicardipine and nifedipine are well known as 1,4-dihydropyridine-type compounds. Because of very poor solubility in water, these compounds can not be absorbed through gastrointestinal tracts in a sufficient amount.
Improvement in the solubility of these compounds has thus been desired in view of the promotion of their bioavailability. Various methods have been proposed to improve solubility of these compounds, including dissolving these compounds lnto an organic solvent, ~
pulverizing the compounds, utilizing multi-crystal forms, ~ -formulating a 8urface active agent or a polymeric compound, etc. Japanese Patent Publication No.
48810/1984, for example, proposes converting nicardipine hydrochloride into an amorphous type. ~apanese Patent Laid-open No. 123117/1987 discloses formulating an organic acid and a water soluble polymer to nicardipine hydrochloride to promote its solubility. Methylcellulose, ~;
hydroxypropylcellulose, hydroxypropylmethylcellulose, or a mixture of these compounds are used as water soluble polymerio~oompounds. Other polymeric compounds are polyvLnylpyrrolldone, methacrylic acid-methylacrylate ~ `
copolymer, carboxymethylethylcellulose, `~
hydroxypropylmethylcellulose phthalate, cellulose phthalate acetate, and the like.
Based on thi6 technological background, the present ~-inventors have studied the possibility of promoting the bioavailability of NZ-105 by pulverizing its crystals.
~; ' .' ~ 2 This method, however, did not result in an improvement in -~
the solubility of NZ-105 of a degree to promote its bioavailability.
Formulating a polymeric compound to NZ-105 was also studied. None of the above-mentioned polymers which have been proposed for use in conjunction with 1,4-dihydropyridine-type compounds gave a satisfactory improvement in the promotion of the solubility of NZ-105.
Besides, the formulation of such a polymer as -~
polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose into a preparation of NZ-105 required the use of a larger amount of a disintegrator in the tablet to ensure disintegration of the tablet in digestive organs resisting the binding force of these polymeric compounds. This entailed larger size tablets.
Other polymeric compounds, such as hydroxypropylmethyl~
cellulose phthalate, cellulose acetate phthalate, methac~rylic acid-methylmethacrylate copolymer, polyvinyl- ' acetaldiethylaminoacetate, and the like, required the use ;
of a relatively large amount of these compounds to be ,:~-formu}ated in order to improve the solubility of NZ-105 ~and to promote its bioavailability. This also entailed ~`
~ i ~ ! ': ., .
larger size tablets. ~ ;~
A need has there~ore existed ~or a stable composition .. ~ ~ . , of an NZ-lQ5 preparation possessing a sufficient bioavailability and easily prepared into tablets, capsules, granules, powders, etc. ~;
~ 3 ~ ~
: . ' .
The present inventors have conducted further studies in order to resolve the above-mentioned problems and found that by formulating hydroxypropylmethylcellulose acetate succinate (hereinafter abbreviated a~ ~HPMCAS") into NZ-105 a composition having a remarkably enhanced bioavailability and easily prepared into tablets, capsules, granules, powders, and the like could be obtained. Such a finding has led to the completion of the present invention.
,~
SUMMARY OF THE INVENTION
Accordingly, an ob~ect of the present invention is to provide a composition comprising NZ-105 and HPMCAS.
Another ob~ect of the present invention is to provide ~; a proces~ for preparing said composition which comprises disso1ving NZ-105 and HP~CAS into an organic solvent and removing the solvent by evaporation.
Other ob~ects, ~-atures and advantages of the ` invention will hereinafter become more readily apparent from~the followLng de-cription.
; DETAILED_Ey~çRIPTION OF THE INVENTION
ND PREFERRED EMBODIMEN~S
NZ-10l5 which is-the active pharmaceutical component of the composition of this invention can be prepared, for ~i.r example, according to the following process: ~
~' .' :;
-` 1332152 CH ~ 0~
COCH3 ~;
.
CH2Ph CH3- C= CHC02CH2CH2N (m) NH2 Ph ~. .
CH3 ~ N02 Ph CH3 ~ ~ ~ C02CH2CH2N () i` `~
(rJ) in ~hlch Ph have the meaning as previously defined.
6peclflcal1y,~th- process for producing NZ-105 (I) comprises the~reaction of a-(3-nitrobenzy1idene)-ace~tonylpho6phonic~acid 2,2-dimethylpropyl-ne ester (II) and~3-~a~minocrotonlc~a~cid 2-(N-benzyl-N-phenyl)aminoethyl ;~
ester~ ) in an~lnert solyent to~produoe -5~(5,~5-dlmethyl-l,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3~
pyridinecarboxylic acid 2-(phenyl-(phenylmethyl)amino) et ~ ester~P-oxlde ~IV)~or its solvate, followed by treatment~of ehe compound~(IV) or its sol~ate with ;;hydroehlic acld and ethanol.
Inert solvents which~can be used in tho abo~e ., -~ ' .
1332~52 reaction may be an alcohol, e.g. methanol, ethanol, propanol, isopropanol, etc., an ether, e.g.
1,2-dimethoxyethane, THF, etc., an aromatic hydrocarbon, e.g. benzene, toluene, xylene, etc., a nitrile, e.g.
acetonitrile, benzonitrile, etc., an amide, e.g. DAM, DMF, N-methylpyrrolidone, etc., a sulfoxide, e.g. DMSO, sulfolane, etc., an ester, e.g. ethyl acetate, butyrolactone, etc., pyridine, or the like.
The reaction can be carried out at room temperature to 200C, preferably at 60-140C, for 1-100 hours, preferably for 5-20 hours. ;~
After the completion of the reaction, NZ-105 (I) can be obtained by treating the compound (IV) or its solvate with ethanol and hydrochloric acid.
HPMCAS used in thi~ invention is an acetic acid and succinic acid ester mixture of hydroxypropylmethyl-cellulose. An example of this mixture which can be gi~en is~"~Shinetsu AQOAT"~(Trade name, manufactured by Shinetsu Chemica}~Industries Co., Ltd.). A preferable range for the residual:group~composition in HPMCAS used in this invèntion,~ in terms of;an average value (succinoyl DS
value) Qf hydroxy group number substituted by succinoyl ;~
group per glucose residue in cellulose, is 0.1-0.4.
Further,~ it is des~irable that a ratio of succinoyl DS
value~and acetyl Dg value (succinoyl DS value/acetyl DS
value) be in a range of~0.1-0.8, e~pecially of 0.5-0.8.
An NZ-105 composition of this invention can be 13321~2 :`
......
prepared by dissolving NZ-lOS and HPMCAS in an organic solvent, removing the solvent by means of vacuum-drying, spray-drying, freeze-drying, or the like to produce powder or particles of NZ-105 and HPMCAS. Alternatively, with -the use of a filler par~icle as a core, NZ-105 and HPMCAS -can be spray coated by means of a fluidized bed granulation method, a centrifugal coating method, or pan ;
coating method to produce granules. The granules can also ;;
be prepared by adding a solvent to a filler and kneading ~, ~
the mixture, followed by drying.
An alcohol, e.g. methanol, ethanol, isopropanol, etc., acetone, methylene chloride, or the like can be used as a solvent for dissolving NZ-105 and HPMCAS. An example of a preferable solvent is a mixture of an alcohol such as ~`
ethanol or isopropanol and methylene chloride, with an alcohol/methylene chloride ratio of 1/0.4 to 1/5, - -~
especially of 1/0.7 to 1/1.5 by volume.
A desirable result can be obtained by formulating an amount of 1-7 parts by weight, especially ~-5 parts by weight of HPMCAS per unit wei~ht of NZ-105.
When the preparation of this invention is spray ~`
coated, either water soluble or insoluble filler, ~::
including crystalline lactose, granulous sugar, crystalline cellulose, calcium hydrogen phosphate anhydride, and the like, can be used as 8 core. Such a core material has a particle size normally of 100-400 mesh, and preferably of 150-300 mesh.
i :
~ 7 13321~2 .
The composition of this invention thus prepared can be used in a form of powder or granule, as they are or mixed with fillers. It ~an also be made into tablets, capsules, or pills together with disintegrants, binders, lubricants, or other ~dditives commonly used in the prepsration of drugs.
Examples of fillerQ which can be used include ~ugars, -~
e.g. lactose, sucrose, etc., glycitols, e.g. mannitol, sorbitol, xylitol, etc., starches, e.g. corn ~tarch, potato starch, wheat starch, rice starch, etc., crystalline cellulose, inorganic salts, e.g. calcium ~-hydrogen phosphate anhydride, synthetic aluminum silicate, `
-.
etc., ~nd the like.
Given as examples of disintegrators which can be used re starche~, e.g. corn ~tarch, potato starch, wheat starch, rice starch, etc., hydroxypropyl starch, calcium lt of carboxymethylcellulose, cross-linked sodium salt of~carboxymethylcellulose, croæs-linked polyvinylpyrrolidone, low-~ubstituted hydroxypropyl-oellulose, and~tho like. ~he use of 2-15% by weight, e~pecially 3-10% by weight, of disintegrants for the total -weight o~the composition is preferable, when the ! '.,; n"
c~omposltion 1g formed into tablets or capsules.
Binderæ which can be used include, for example, starches, e.g. corn ~tarch, potato ~tarch, wheat starch, rice~8tarch, etc., qelatinized starches, partially ~;
pregelatlnized starcho~, dextrin, sugars such as purified --13321~2 :: .
sugar, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, polyvinyl- :
pyrrolidone, and the like.
Examples of lubricant which can be used are talc, waxes, stearic acid, magnesium stearate, light anhydrous silicic acid, and the like.
In addition to the above-mentioned components, ~:
formulating such compounds as urea, surface active agents, -and the like is desirable when the composition is prepared ~: into a pharmaceutical preparation.
Other features of the invention will become apparent in the course of the following description of the exemplary embodiments which are given for illustration of the invention and are not ~ntended to be limiting thereof. ;~
~; EXAMPLES ~:
Reference Example 1 :~
13 g Qf ~-(3~-nitrobenzylidene)-acetnilphosphonic acid 2l2-dimethylpropylene ester (II) and 11.9 g of 3-aminocrotonic acid 2-(N-benzyl-N-phenyl)aminoethyl ester wer- mixed with 100 g of toluene and the mixture was refluxed for 2 hours while removing water produced in the .~:
reaction by azeotropic dehydration. 23.6 g of yellow crystals of one-mole toluene solvate of 5-(5,5-dimethyl- ~ .
1,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid 2-(phenyl-i :~ (phenylmethyl)amino) ethyl ester P-oxide (IV) was obtained i,, ~ : . .
:~; 9 ~:
: ::
"
1332~2 by cooling the reaction mixture to room temperature (yield: 85%).
The crystals were recrystallized in ethyl acetate to produce a compound without a solvent incorporated therein.
This last produced compound had a melting point and an NMR
spectrum described below.
m.p. 156-158C
NMR (CDC13) 0-66 (3H~ s)~ 0.99 (3H, 8)~ 2.25 (3H, s), 2.3 (3H, d, J=2.5Hz), 3.5-3.7 (4H, m), 4.1-4.4 (4H, m), 4.51 (2H, s), 4.9 (lH, d, J=10.9Hz), 6.47 ~lH, d, J=4.2Hz), 6.67 l3H, m), 7.1-7.35 (8H, m), 7.58 (lH, d, J=6.6Hz), 7.96 (lH, m), 8.07 (lH, t, J=1.9Hz) ; (2~ 193.1 g~of the toluene solvate (IV) prepared in ~ ;
(l) above was dissolved into 996 g of ethanol under ;heating.~51~g of~21% hydrochloric acid-ethanol was added to~the~solution and~the mixture was cooled to room ~`~
tomperature~to;~produce 185.2 g of hydrochloride of 1 mol nol~solvabe~of~compound ~IV~) which is the target c ~ ~und~N~-105~,~as yellow~cry tals (yield: 97.2%).
p ~l49-}ssoc~d~ompo~ed) - 60 g of NZ-105, 180 g of HPMCAS, and 30 g of urea `;~
w~é~ro disso ~èd into~`3~1iter of an~ethanol-methyléno;
ch ~ r`ido~(l/1 by Yolumet~ mixed solvent. The solution was sprayed onto;~120~g~of calcium hydrogen phosphate anhydride using~a~fluidized bod granulation appàratus and dried to obtain granules. 130 g of the granules were mixed and thoroughly blended with 23.6 g of crystalline cellulose, 12 g of crosæ-linked polyvinylpyrrolidone, 0.4 g of light ~nhydrous 8ilicic acid, and 1 g of magnesium gtesrste.
The mixture was press molded to produce tablets each containing 20 mg of NZ-105 nnd having a 7.5 mm diameter and weighing 167 mg.
Example 2 40 g of NZ-105, 120 g of HPNCAS (Shinetsu AQOAT, LG-type; manufactured by Shinetsu Chemical Industries Co., Ltd.), and 20 g of urea were dissolved into 2 liter of an ethanol-methylene chloride (1/1 by volume) mixed solvant.
The solution was sprayed onto 200 g of calcium hydrogen phosphate anhydride using a fluidized bed granulation , apparatus and dried to obtain granules. 95 g of the granules thus prepared were mixed and thoroughly blended with 19 g of crystalline cellulose, 10 g of carboxymethylcellulose calcium, and 1 g of magnesium stearate. The mixture wa~ press molded to produce tablets each containing 20 mq of NZ-lOS and having a 9 mm diameter and weighing 2S0 mg.
Example 3 50 g of NZ-105, 150 g of HPMCAS (Shinetsu AQOAT, LF~
type; manufactured by Shinetsu Chemical Industries Co., Ltd.) and 25 g of urea w~re dissolved into 3 liters of an ethanol-methylene chloride (1/1 by volume) mixed solvent.
The Qolution was sprayed onto 800 g of crystalline lactose using a fluidized bed granulation apparatus and dried to ~-obtain granules. The granules thus prepared were screened through a #12 sieve (openings: 1,400 ~m) and a #42 sieve (openings: 355 ~m) to obtain granules having particle size of 1,400-355 ~m. The granules contained 20 mg of NZ-105 per 410 mg.
Example 4 50 g of NZ-105, 150 g of HPMCAS (Shinetsu AQOAT, LF~
type; manufactured by Shinetsu Chemical Industries Co., Ltd.) and 25 g of urea were dissolved into 3 liter of an ~. -~
ethanol-methylene chloride (1/1 by volume) mixed ~olvent. -;- -The solution was sprayed onto 200 g of calcium hydrogen ~`
phosphate anhydride using a fluidized bed granulation apparatus and dried to obtain granules. 85 g of the granules thus prepared were mixed and thoroughly blended ;~-~
with 40 g of crystalline cellulose and 10 g of càrboxymethylcellulose calcium, and the mixture waæ filled l`
into No. l capsules,~270 mg per capsule, to produce c~p uIeE c~ch contaInlng 20 g of NZ-105. ~ ~
50~g oS NZ-~1;05, 250 g of HPMCAS (Shinetsu AQOAT, LF- ~ :
t~ e; manufactured by Shinetsu Chemical Industries Co., Ltd.) and 25 g of urea were dissolved into 3 liter of an ethanol-methyl`ene chloride (l/l by volume) mixed solvent.
Thè ~olutlon was~sprayed~onto 250 g of oalcium hydrogen pho~phate~anhydride usLng a fluidizod~bed granulation apparatu8~ and dried to obtain granules. 105 g of the ; 12 granules thus prepared were mixed and thoroughly blended,, with 35 g of crystalline cellulose and 15 g of , carboxymethylcellulose calcium, and the mixture was filled into No. 1 capsules, 310 mg per capsule, to produce capsules each containing 20 mg of NZ-105.
Example 6 4 g of NZ-105 and 12 g of HPMCAS (Shinetsu AQOAT, LF-type; manufactured by Shinetsu Chemical Industries Co., Ltd.) were dissolved into 100 ml of an ethanol-methylene . ~ ;, ~ .
chloride (1/4 by volume) mixed solvent. 30 g of lactose was added to and thoroughly dispersed into the solution..
The liquid thus prepared was dried in vacuo. The dried - ' materlal was pulverized to produce a powdery material. '~
10.7 g of corn starch and 0.3 g of talc were added to 23 g of the powdery materlal. The mixture was well blended and filled~into No. l capsules, 340 mg per capsule, to produce ,cap&ules each :containing 20 mg of NZ-105.
Comparativ~e ~xample 1 4~ g;of~NZ-105 and 12 g of ';;~
oxypropylmethylaellulose 2910 (TC-5 B type;
manùfa~tured,~by Shinetsu Chemical Industries Co., Ltd.)~ ;
were~dissolved lnto lOO~ml of an ethanol-methylene chloride ~ 4 by volume~;;mlxed solvent. 30 g of lactose'~
was~àdded~to and thoroughly diSpersed into the solution.
The~liquid thus prepared was dried in vacuo. The dried ma~terial was~pulv~eri~z-d into powder. 10.7 g of corn';'~
8tarch and 0.3 g of talo were added to 23 g of the powder.
13 -~
::
The mixture wa~ well blended and filled into No. 0 cap~ules, 340 mg per cap~ule, to produce cspsules each ~ont~ining 20 mg of NZ-105.
Comparative Example 2 4 g of NZ-105 and 12 ~ of hydroxypropylmethyl-cellulose phthalate (HPMCP, HP-55 type; manufactured by Shinet~u Chemical Industries Co., Ltd.) were dissolved into 100 ml of an ethanol-methylene chloride (1/4 by volume) mixed solvent. 30 g of lactose was added to and thoroughly dispersed into the ~olution. The liquid thus prepared was dried in vacuo. The dried material was -pulverized into powder. Capsules each containing 20 mg of ;~-NZ-105 were prepared in the same manner as Comparative Example 1 using this powdery material.
Comparative Example 3 4 g of NZ-105 and 12 g of methacrylic acid-methyl methacrylate copolymer ~Euydragit L-type, manufactured by Rohm and Haas Co.) were dissolved into 100 ml of an ;
ethanol-mothylene chloride (1~4 by volume) mixed solvent.
30 9 of lactose was added to and thoroughly dispersed into the solution. The liquid thus prepared was dried in f, ~ ', 1 f vacuo. The dried material was pulverized to produce powder. Capaules each containlng 20 mg of NZ-105 were prepar~d in the same manner as Comparative Exa~ple 1 using ;~;
~he powder. ;--- ~
Comparative Example 4 - ;
4 ~ of NZ-105 and 12 g of polyvinylacetaldiethylamino * Trademark- 14 ~
. '.:.~ ~,', 13321~2 acetate (AEA, manufactured by Sankyo Co., Ltd.) were dissolved into 100 ml of an ethanol-methylene chloride (1/4 by volume) mixed solvent. 30 g of lactose was added to and thoroughly dispersed into the solution. The liquid thus prepared was dried in vacuo. The dried material was pulverized to produce a powdery material. Capsules each -containing 20 mg of NZ-105 were prepared in the same ~ ;
manner as Comparative Example 1 using this powdery material.
Comparative Example 5 50 g of NZ-105, 150 g of polyvinylacetaldiethylamino acetate (AEA, manufactured by Sankyo Co., Ltd.), and 25 g of urea were dissolved into 3 liter of an ethanol-methylene chloride (1/4 by volume) mixed solvent. The solution was sprayed onto 300 g of calcium hydrogen ;~
phosphate anhydride using a fluidized bed granulation appa~ratus and dried to obtain granules. 105 g of the granules~were mlxed and blended thoroughly with 75 g of crystalline cellulose~calsium, 20 g of carboxymethyl-cèllulose. The mixture was filled into No. 0 capsules, 400 mg~per~capsule, to~produce capsules each containing 20 t~
mg of NZ-105.
Comparative Example 6 20 9~of NZ-105~pulverized to an average size of 6 ~m, 210 g of lactose, 100 g of corn starch, and lO g of ca~rboxymethylcellulose calcium were mixed and thoroughly ;;
blended. The blend was filled into No. 0 capsules, 340 mg ~; 15 . , . .:
: : .
per capsule, to produce capsules each containing 20 mg of NZ-105.
Test Example 1 Dissolution Test~
A dissolution test wa~ conducted on the preparations prepared ~n Example 6 and Comparative Examples 1-4 (esch containing 20 ~g of NZ-105) according to the following conditionss Test Method: Diæsolution test of Japanese ...
Pharmacopeia, ~-.
11th Revis~on (Paddle Method) ~`~
Test Fluids Japanese`Pharmacopeia first fluid (Comparative Example 4) and Japanese ; Pharmacopeia second fluid (Example 6, .`;~.
<~
Comparative Example 1-3), 500 ml.
Temperatures 37 ~ 0.5C
Stirr1ngs 100 rpm Quantitative Analysiæs Test solutions were filtered : :through a ~Millipore" filter (0.2 ~m). The . ~
: filtrate was diluted with methanol to a ; ~`
~Il'LE OF ~HE INVENTION
PHARMACEUTICAL COMPOSITION OF DIHYDROPYRIDINE ::
COMPOUND
BACKGROUND OF THE INVENTION -~
Field_of the Invention~
Thi~ invention relates to a pharmaceutical composition comprising a lsl solvate of 5-(5,5-dimethyl- ~ :
1,3,2-dioxaphosphorin3ne-2-yl)-1,4-dihydro-2,6-dimethyl~
4-(3-nitrophenyl)-3-pyridine cnrboxylic acid 2-(phenyl~
(phenylmethyl)amino) ethyl ester P-ox~de hydrochloride~
ethanol (~uch a solvate ls herein abbreviated as ~NZ-105") possessing hypotensive activity. ~ `
Description of the Background: ~-The effective pharmaceutical component, NZ-105, of ~:
the composition of this $nvention $s a derivative of 1,4-dihydropyrid~ne-5-phosphonic acid and has the followlng chemical formulas C}~ ~11 ~ ~P11 ~
CH~Co~ ~C O2 CH2 C~Iz N ~ HC ~ C 2 H5 OH
C~J3 ~i CH3 CH2Ph wherein Ph represents a phenyl group. This is a novel .. .
compound possessing vasodilative and hypotensive activity :on account of lt~ calcium antagonistic act$vity and is useful .
as a cardiovascular drug. .~
~ A' 1 ~ ~
~ ~ .
~,,... ~
13321~2 Nicardipine and nifedipine are well known as 1,4-dihydropyridine-type compounds. Because of very poor solubility in water, these compounds can not be absorbed through gastrointestinal tracts in a sufficient amount.
Improvement in the solubility of these compounds has thus been desired in view of the promotion of their bioavailability. Various methods have been proposed to improve solubility of these compounds, including dissolving these compounds lnto an organic solvent, ~
pulverizing the compounds, utilizing multi-crystal forms, ~ -formulating a 8urface active agent or a polymeric compound, etc. Japanese Patent Publication No.
48810/1984, for example, proposes converting nicardipine hydrochloride into an amorphous type. ~apanese Patent Laid-open No. 123117/1987 discloses formulating an organic acid and a water soluble polymer to nicardipine hydrochloride to promote its solubility. Methylcellulose, ~;
hydroxypropylcellulose, hydroxypropylmethylcellulose, or a mixture of these compounds are used as water soluble polymerio~oompounds. Other polymeric compounds are polyvLnylpyrrolldone, methacrylic acid-methylacrylate ~ `
copolymer, carboxymethylethylcellulose, `~
hydroxypropylmethylcellulose phthalate, cellulose phthalate acetate, and the like.
Based on thi6 technological background, the present ~-inventors have studied the possibility of promoting the bioavailability of NZ-105 by pulverizing its crystals.
~; ' .' ~ 2 This method, however, did not result in an improvement in -~
the solubility of NZ-105 of a degree to promote its bioavailability.
Formulating a polymeric compound to NZ-105 was also studied. None of the above-mentioned polymers which have been proposed for use in conjunction with 1,4-dihydropyridine-type compounds gave a satisfactory improvement in the promotion of the solubility of NZ-105.
Besides, the formulation of such a polymer as -~
polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose into a preparation of NZ-105 required the use of a larger amount of a disintegrator in the tablet to ensure disintegration of the tablet in digestive organs resisting the binding force of these polymeric compounds. This entailed larger size tablets.
Other polymeric compounds, such as hydroxypropylmethyl~
cellulose phthalate, cellulose acetate phthalate, methac~rylic acid-methylmethacrylate copolymer, polyvinyl- ' acetaldiethylaminoacetate, and the like, required the use ;
of a relatively large amount of these compounds to be ,:~-formu}ated in order to improve the solubility of NZ-105 ~and to promote its bioavailability. This also entailed ~`
~ i ~ ! ': ., .
larger size tablets. ~ ;~
A need has there~ore existed ~or a stable composition .. ~ ~ . , of an NZ-lQ5 preparation possessing a sufficient bioavailability and easily prepared into tablets, capsules, granules, powders, etc. ~;
~ 3 ~ ~
: . ' .
The present inventors have conducted further studies in order to resolve the above-mentioned problems and found that by formulating hydroxypropylmethylcellulose acetate succinate (hereinafter abbreviated a~ ~HPMCAS") into NZ-105 a composition having a remarkably enhanced bioavailability and easily prepared into tablets, capsules, granules, powders, and the like could be obtained. Such a finding has led to the completion of the present invention.
,~
SUMMARY OF THE INVENTION
Accordingly, an ob~ect of the present invention is to provide a composition comprising NZ-105 and HPMCAS.
Another ob~ect of the present invention is to provide ~; a proces~ for preparing said composition which comprises disso1ving NZ-105 and HP~CAS into an organic solvent and removing the solvent by evaporation.
Other ob~ects, ~-atures and advantages of the ` invention will hereinafter become more readily apparent from~the followLng de-cription.
; DETAILED_Ey~çRIPTION OF THE INVENTION
ND PREFERRED EMBODIMEN~S
NZ-10l5 which is-the active pharmaceutical component of the composition of this invention can be prepared, for ~i.r example, according to the following process: ~
~' .' :;
-` 1332152 CH ~ 0~
COCH3 ~;
.
CH2Ph CH3- C= CHC02CH2CH2N (m) NH2 Ph ~. .
CH3 ~ N02 Ph CH3 ~ ~ ~ C02CH2CH2N () i` `~
(rJ) in ~hlch Ph have the meaning as previously defined.
6peclflcal1y,~th- process for producing NZ-105 (I) comprises the~reaction of a-(3-nitrobenzy1idene)-ace~tonylpho6phonic~acid 2,2-dimethylpropyl-ne ester (II) and~3-~a~minocrotonlc~a~cid 2-(N-benzyl-N-phenyl)aminoethyl ;~
ester~ ) in an~lnert solyent to~produoe -5~(5,~5-dlmethyl-l,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3~
pyridinecarboxylic acid 2-(phenyl-(phenylmethyl)amino) et ~ ester~P-oxlde ~IV)~or its solvate, followed by treatment~of ehe compound~(IV) or its sol~ate with ;;hydroehlic acld and ethanol.
Inert solvents which~can be used in tho abo~e ., -~ ' .
1332~52 reaction may be an alcohol, e.g. methanol, ethanol, propanol, isopropanol, etc., an ether, e.g.
1,2-dimethoxyethane, THF, etc., an aromatic hydrocarbon, e.g. benzene, toluene, xylene, etc., a nitrile, e.g.
acetonitrile, benzonitrile, etc., an amide, e.g. DAM, DMF, N-methylpyrrolidone, etc., a sulfoxide, e.g. DMSO, sulfolane, etc., an ester, e.g. ethyl acetate, butyrolactone, etc., pyridine, or the like.
The reaction can be carried out at room temperature to 200C, preferably at 60-140C, for 1-100 hours, preferably for 5-20 hours. ;~
After the completion of the reaction, NZ-105 (I) can be obtained by treating the compound (IV) or its solvate with ethanol and hydrochloric acid.
HPMCAS used in thi~ invention is an acetic acid and succinic acid ester mixture of hydroxypropylmethyl-cellulose. An example of this mixture which can be gi~en is~"~Shinetsu AQOAT"~(Trade name, manufactured by Shinetsu Chemica}~Industries Co., Ltd.). A preferable range for the residual:group~composition in HPMCAS used in this invèntion,~ in terms of;an average value (succinoyl DS
value) Qf hydroxy group number substituted by succinoyl ;~
group per glucose residue in cellulose, is 0.1-0.4.
Further,~ it is des~irable that a ratio of succinoyl DS
value~and acetyl Dg value (succinoyl DS value/acetyl DS
value) be in a range of~0.1-0.8, e~pecially of 0.5-0.8.
An NZ-105 composition of this invention can be 13321~2 :`
......
prepared by dissolving NZ-lOS and HPMCAS in an organic solvent, removing the solvent by means of vacuum-drying, spray-drying, freeze-drying, or the like to produce powder or particles of NZ-105 and HPMCAS. Alternatively, with -the use of a filler par~icle as a core, NZ-105 and HPMCAS -can be spray coated by means of a fluidized bed granulation method, a centrifugal coating method, or pan ;
coating method to produce granules. The granules can also ;;
be prepared by adding a solvent to a filler and kneading ~, ~
the mixture, followed by drying.
An alcohol, e.g. methanol, ethanol, isopropanol, etc., acetone, methylene chloride, or the like can be used as a solvent for dissolving NZ-105 and HPMCAS. An example of a preferable solvent is a mixture of an alcohol such as ~`
ethanol or isopropanol and methylene chloride, with an alcohol/methylene chloride ratio of 1/0.4 to 1/5, - -~
especially of 1/0.7 to 1/1.5 by volume.
A desirable result can be obtained by formulating an amount of 1-7 parts by weight, especially ~-5 parts by weight of HPMCAS per unit wei~ht of NZ-105.
When the preparation of this invention is spray ~`
coated, either water soluble or insoluble filler, ~::
including crystalline lactose, granulous sugar, crystalline cellulose, calcium hydrogen phosphate anhydride, and the like, can be used as 8 core. Such a core material has a particle size normally of 100-400 mesh, and preferably of 150-300 mesh.
i :
~ 7 13321~2 .
The composition of this invention thus prepared can be used in a form of powder or granule, as they are or mixed with fillers. It ~an also be made into tablets, capsules, or pills together with disintegrants, binders, lubricants, or other ~dditives commonly used in the prepsration of drugs.
Examples of fillerQ which can be used include ~ugars, -~
e.g. lactose, sucrose, etc., glycitols, e.g. mannitol, sorbitol, xylitol, etc., starches, e.g. corn ~tarch, potato starch, wheat starch, rice starch, etc., crystalline cellulose, inorganic salts, e.g. calcium ~-hydrogen phosphate anhydride, synthetic aluminum silicate, `
-.
etc., ~nd the like.
Given as examples of disintegrators which can be used re starche~, e.g. corn ~tarch, potato starch, wheat starch, rice starch, etc., hydroxypropyl starch, calcium lt of carboxymethylcellulose, cross-linked sodium salt of~carboxymethylcellulose, croæs-linked polyvinylpyrrolidone, low-~ubstituted hydroxypropyl-oellulose, and~tho like. ~he use of 2-15% by weight, e~pecially 3-10% by weight, of disintegrants for the total -weight o~the composition is preferable, when the ! '.,; n"
c~omposltion 1g formed into tablets or capsules.
Binderæ which can be used include, for example, starches, e.g. corn ~tarch, potato ~tarch, wheat starch, rice~8tarch, etc., qelatinized starches, partially ~;
pregelatlnized starcho~, dextrin, sugars such as purified --13321~2 :: .
sugar, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, polyvinyl- :
pyrrolidone, and the like.
Examples of lubricant which can be used are talc, waxes, stearic acid, magnesium stearate, light anhydrous silicic acid, and the like.
In addition to the above-mentioned components, ~:
formulating such compounds as urea, surface active agents, -and the like is desirable when the composition is prepared ~: into a pharmaceutical preparation.
Other features of the invention will become apparent in the course of the following description of the exemplary embodiments which are given for illustration of the invention and are not ~ntended to be limiting thereof. ;~
~; EXAMPLES ~:
Reference Example 1 :~
13 g Qf ~-(3~-nitrobenzylidene)-acetnilphosphonic acid 2l2-dimethylpropylene ester (II) and 11.9 g of 3-aminocrotonic acid 2-(N-benzyl-N-phenyl)aminoethyl ester wer- mixed with 100 g of toluene and the mixture was refluxed for 2 hours while removing water produced in the .~:
reaction by azeotropic dehydration. 23.6 g of yellow crystals of one-mole toluene solvate of 5-(5,5-dimethyl- ~ .
1,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid 2-(phenyl-i :~ (phenylmethyl)amino) ethyl ester P-oxide (IV) was obtained i,, ~ : . .
:~; 9 ~:
: ::
"
1332~2 by cooling the reaction mixture to room temperature (yield: 85%).
The crystals were recrystallized in ethyl acetate to produce a compound without a solvent incorporated therein.
This last produced compound had a melting point and an NMR
spectrum described below.
m.p. 156-158C
NMR (CDC13) 0-66 (3H~ s)~ 0.99 (3H, 8)~ 2.25 (3H, s), 2.3 (3H, d, J=2.5Hz), 3.5-3.7 (4H, m), 4.1-4.4 (4H, m), 4.51 (2H, s), 4.9 (lH, d, J=10.9Hz), 6.47 ~lH, d, J=4.2Hz), 6.67 l3H, m), 7.1-7.35 (8H, m), 7.58 (lH, d, J=6.6Hz), 7.96 (lH, m), 8.07 (lH, t, J=1.9Hz) ; (2~ 193.1 g~of the toluene solvate (IV) prepared in ~ ;
(l) above was dissolved into 996 g of ethanol under ;heating.~51~g of~21% hydrochloric acid-ethanol was added to~the~solution and~the mixture was cooled to room ~`~
tomperature~to;~produce 185.2 g of hydrochloride of 1 mol nol~solvabe~of~compound ~IV~) which is the target c ~ ~und~N~-105~,~as yellow~cry tals (yield: 97.2%).
p ~l49-}ssoc~d~ompo~ed) - 60 g of NZ-105, 180 g of HPMCAS, and 30 g of urea `;~
w~é~ro disso ~èd into~`3~1iter of an~ethanol-methyléno;
ch ~ r`ido~(l/1 by Yolumet~ mixed solvent. The solution was sprayed onto;~120~g~of calcium hydrogen phosphate anhydride using~a~fluidized bod granulation appàratus and dried to obtain granules. 130 g of the granules were mixed and thoroughly blended with 23.6 g of crystalline cellulose, 12 g of crosæ-linked polyvinylpyrrolidone, 0.4 g of light ~nhydrous 8ilicic acid, and 1 g of magnesium gtesrste.
The mixture was press molded to produce tablets each containing 20 mg of NZ-105 nnd having a 7.5 mm diameter and weighing 167 mg.
Example 2 40 g of NZ-105, 120 g of HPNCAS (Shinetsu AQOAT, LG-type; manufactured by Shinetsu Chemical Industries Co., Ltd.), and 20 g of urea were dissolved into 2 liter of an ethanol-methylene chloride (1/1 by volume) mixed solvant.
The solution was sprayed onto 200 g of calcium hydrogen phosphate anhydride using a fluidized bed granulation , apparatus and dried to obtain granules. 95 g of the granules thus prepared were mixed and thoroughly blended with 19 g of crystalline cellulose, 10 g of carboxymethylcellulose calcium, and 1 g of magnesium stearate. The mixture wa~ press molded to produce tablets each containing 20 mq of NZ-lOS and having a 9 mm diameter and weighing 2S0 mg.
Example 3 50 g of NZ-105, 150 g of HPMCAS (Shinetsu AQOAT, LF~
type; manufactured by Shinetsu Chemical Industries Co., Ltd.) and 25 g of urea w~re dissolved into 3 liters of an ethanol-methylene chloride (1/1 by volume) mixed solvent.
The Qolution was sprayed onto 800 g of crystalline lactose using a fluidized bed granulation apparatus and dried to ~-obtain granules. The granules thus prepared were screened through a #12 sieve (openings: 1,400 ~m) and a #42 sieve (openings: 355 ~m) to obtain granules having particle size of 1,400-355 ~m. The granules contained 20 mg of NZ-105 per 410 mg.
Example 4 50 g of NZ-105, 150 g of HPMCAS (Shinetsu AQOAT, LF~
type; manufactured by Shinetsu Chemical Industries Co., Ltd.) and 25 g of urea were dissolved into 3 liter of an ~. -~
ethanol-methylene chloride (1/1 by volume) mixed ~olvent. -;- -The solution was sprayed onto 200 g of calcium hydrogen ~`
phosphate anhydride using a fluidized bed granulation apparatus and dried to obtain granules. 85 g of the granules thus prepared were mixed and thoroughly blended ;~-~
with 40 g of crystalline cellulose and 10 g of càrboxymethylcellulose calcium, and the mixture waæ filled l`
into No. l capsules,~270 mg per capsule, to produce c~p uIeE c~ch contaInlng 20 g of NZ-105. ~ ~
50~g oS NZ-~1;05, 250 g of HPMCAS (Shinetsu AQOAT, LF- ~ :
t~ e; manufactured by Shinetsu Chemical Industries Co., Ltd.) and 25 g of urea were dissolved into 3 liter of an ethanol-methyl`ene chloride (l/l by volume) mixed solvent.
Thè ~olutlon was~sprayed~onto 250 g of oalcium hydrogen pho~phate~anhydride usLng a fluidizod~bed granulation apparatu8~ and dried to obtain granules. 105 g of the ; 12 granules thus prepared were mixed and thoroughly blended,, with 35 g of crystalline cellulose and 15 g of , carboxymethylcellulose calcium, and the mixture was filled into No. 1 capsules, 310 mg per capsule, to produce capsules each containing 20 mg of NZ-105.
Example 6 4 g of NZ-105 and 12 g of HPMCAS (Shinetsu AQOAT, LF-type; manufactured by Shinetsu Chemical Industries Co., Ltd.) were dissolved into 100 ml of an ethanol-methylene . ~ ;, ~ .
chloride (1/4 by volume) mixed solvent. 30 g of lactose was added to and thoroughly dispersed into the solution..
The liquid thus prepared was dried in vacuo. The dried - ' materlal was pulverized to produce a powdery material. '~
10.7 g of corn starch and 0.3 g of talc were added to 23 g of the powdery materlal. The mixture was well blended and filled~into No. l capsules, 340 mg per capsule, to produce ,cap&ules each :containing 20 mg of NZ-105.
Comparativ~e ~xample 1 4~ g;of~NZ-105 and 12 g of ';;~
oxypropylmethylaellulose 2910 (TC-5 B type;
manùfa~tured,~by Shinetsu Chemical Industries Co., Ltd.)~ ;
were~dissolved lnto lOO~ml of an ethanol-methylene chloride ~ 4 by volume~;;mlxed solvent. 30 g of lactose'~
was~àdded~to and thoroughly diSpersed into the solution.
The~liquid thus prepared was dried in vacuo. The dried ma~terial was~pulv~eri~z-d into powder. 10.7 g of corn';'~
8tarch and 0.3 g of talo were added to 23 g of the powder.
13 -~
::
The mixture wa~ well blended and filled into No. 0 cap~ules, 340 mg per cap~ule, to produce cspsules each ~ont~ining 20 mg of NZ-105.
Comparative Example 2 4 g of NZ-105 and 12 ~ of hydroxypropylmethyl-cellulose phthalate (HPMCP, HP-55 type; manufactured by Shinet~u Chemical Industries Co., Ltd.) were dissolved into 100 ml of an ethanol-methylene chloride (1/4 by volume) mixed solvent. 30 g of lactose was added to and thoroughly dispersed into the ~olution. The liquid thus prepared was dried in vacuo. The dried material was -pulverized into powder. Capsules each containing 20 mg of ;~-NZ-105 were prepared in the same manner as Comparative Example 1 using this powdery material.
Comparative Example 3 4 g of NZ-105 and 12 g of methacrylic acid-methyl methacrylate copolymer ~Euydragit L-type, manufactured by Rohm and Haas Co.) were dissolved into 100 ml of an ;
ethanol-mothylene chloride (1~4 by volume) mixed solvent.
30 9 of lactose was added to and thoroughly dispersed into the solution. The liquid thus prepared was dried in f, ~ ', 1 f vacuo. The dried material was pulverized to produce powder. Capaules each containlng 20 mg of NZ-105 were prepar~d in the same manner as Comparative Exa~ple 1 using ;~;
~he powder. ;--- ~
Comparative Example 4 - ;
4 ~ of NZ-105 and 12 g of polyvinylacetaldiethylamino * Trademark- 14 ~
. '.:.~ ~,', 13321~2 acetate (AEA, manufactured by Sankyo Co., Ltd.) were dissolved into 100 ml of an ethanol-methylene chloride (1/4 by volume) mixed solvent. 30 g of lactose was added to and thoroughly dispersed into the solution. The liquid thus prepared was dried in vacuo. The dried material was pulverized to produce a powdery material. Capsules each -containing 20 mg of NZ-105 were prepared in the same ~ ;
manner as Comparative Example 1 using this powdery material.
Comparative Example 5 50 g of NZ-105, 150 g of polyvinylacetaldiethylamino acetate (AEA, manufactured by Sankyo Co., Ltd.), and 25 g of urea were dissolved into 3 liter of an ethanol-methylene chloride (1/4 by volume) mixed solvent. The solution was sprayed onto 300 g of calcium hydrogen ;~
phosphate anhydride using a fluidized bed granulation appa~ratus and dried to obtain granules. 105 g of the granules~were mlxed and blended thoroughly with 75 g of crystalline cellulose~calsium, 20 g of carboxymethyl-cèllulose. The mixture was filled into No. 0 capsules, 400 mg~per~capsule, to~produce capsules each containing 20 t~
mg of NZ-105.
Comparative Example 6 20 9~of NZ-105~pulverized to an average size of 6 ~m, 210 g of lactose, 100 g of corn starch, and lO g of ca~rboxymethylcellulose calcium were mixed and thoroughly ;;
blended. The blend was filled into No. 0 capsules, 340 mg ~; 15 . , . .:
: : .
per capsule, to produce capsules each containing 20 mg of NZ-105.
Test Example 1 Dissolution Test~
A dissolution test wa~ conducted on the preparations prepared ~n Example 6 and Comparative Examples 1-4 (esch containing 20 ~g of NZ-105) according to the following conditionss Test Method: Diæsolution test of Japanese ...
Pharmacopeia, ~-.
11th Revis~on (Paddle Method) ~`~
Test Fluids Japanese`Pharmacopeia first fluid (Comparative Example 4) and Japanese ; Pharmacopeia second fluid (Example 6, .`;~.
<~
Comparative Example 1-3), 500 ml.
Temperatures 37 ~ 0.5C
Stirr1ngs 100 rpm Quantitative Analysiæs Test solutions were filtered : :through a ~Millipore" filter (0.2 ~m). The . ~
: filtrate was diluted with methanol to a ; ~`
2-fold volume, followed by mea~urement of the absorbance at 330 n~.
The results are shown in Table 1.
Tri~d-~-rk `~
16 `i~
, ,. ~
13321~2 . ~
Tested Dissolution (~g/ml) Preparations 5 min 10 min 15 min 20 min 25 min 30 min Example 6 22.2 32.5 32.2 30.3 29.8 30.0 _ _ _ . _ Comparative2.1 2.1 1.8 1.9 1.2 1.5 Example 1 .
Comparative12.6 13.0 10.7 9.8 7.0 4.2 Example 2 Comparative9.7 15.1 13.9 15.0 15.4 16.2 Example 3 Comparative2.2 11.3 15.7 17.0 17.8 17.8 -.
Example 4 ;----- -The capsule of Comparative Example 4 was tested using Japanese Pharmacopeia first fluid (pH 1.2), since this cap~ule contained polyvinylacetaldiethylamino acetate -., which is a polymeric compound dissolvable at an acidic pH :
~ value.
''h'~ able 1 demonstrates that the capsule of Example 6 exhlbits higher dissolution than the capsules of Comparative Examples 1-4 using polymeric compounds other than HPMCAS. The capsule of Comparative Example 1 using hydroxypropylmethylcellulose 2910 which is a water soluble polymer dissolved very little throughout the test period.
In the test using the capsule of Comparative Example 2 containing hydroxypropylmethylcellulose phthalate which is ~ ~`
the pH~dependent, alXali soluble-type polymeric compound ~ .
."; . ~ ~
as HPMCAS, recrystallization of NZ-105 took place 10 ~i~; minute9 after 8tart of the test and the dissolution began ~r .
: 17 ~:
" 1332152 to decline. The capsule of Comparative Example 3 ~
containing methacrylic acid-methyl methacrylate copolymer, ;
which is pH dependent, alkali soluble-type polymer, and the capsule of Comparative Example 4 containing polyvinylacetaldiethylamino acetate, which is also pH
dependentl acidic soluble-type polymers, although did not recrystallize NZ-105, exhibited dissolutions a~out 1/2 of that of the capsule using HPMCAS, evidencing that they are undesirable in view of practical bioavailability. ~;
Test Example 2 Blood Concentration~
The preparations prepared in Examples 1-5 and Comparative Examples~5 nnd 6, each containlng 20 mg of NZ-105, were orally admlnistered to Beagle dogs ~weight: - ;;
about l0 kg) which were fasted overnight. Blood was ~;~
collected from ench dog 0.5, 1, 2, 3, 4, and 6 hours after -t~he~ administrntion. ~The measurement of the blood concentration~of~NZ~-105~was carried out by means of HPLC -- -on NZ-lO5~extraat snmples from~plnsma. The blood concentrations and thelr pnr _e~er~ nre shown l~ Tnble 2.
A
13321~2 Blood Concentrations (ng/ml) Parameters -Tested ----- .Preparations0.5 1 2 3 4 6 (hrs)Cmax Tmax AUC
Example 1 71.1 48.0 23.4 16.3 11.1 8.3 71.1 0.5 153.0 Example 2 22.6 30.7 17.9 10.2 5.3 0.0 30.7 1.0 78.1 Example 3 35.4 72.5 29.9 13.4 5.9 0.0 72.5 1.0 134.0 :
Example 4 8.4 54.5 52.1 19.9 7.4 0-.0 54.5 1.0 141.8 Example 5 0.0 41.4 87.2 43.5 21.5 8.7 87.2 2.0 211.5 Comparative 0.0 0.0 14.5 14.9 6.4 0.0 14.9 3.0 49.7 Example 5 :
Comparative 0.0 0.0 0.0 0.0 0.0 0,0 0.0 0.0 0.0 ~:
Example 6 ,,s~ ~
Cmax: Maximum blood concentration (ng/ml) max: Time required to arrive at the maximum blood concentration (hour) '~ ' AUC; The area under the blood concentration-time ~ ~' curvo (ng.hour/ml) The compos;itlon of the prosent invention can provide '~
a high blood concentration of tho pharmaceutical component NZ-105~and ensures the high total drug abisorption ~AUC), ?.~5~ and can easily be prepared into pharmaceutical reparations such as capsules, granules, powders, tablets, and thta like.
Obviously, numerous modifications and variations of the ; preo-nt invention are possLblo in light of the above teachings. It is therofore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
.. ~.
,~ . .
" ~
;. `` . 1 9 . ;~ . .
The results are shown in Table 1.
Tri~d-~-rk `~
16 `i~
, ,. ~
13321~2 . ~
Tested Dissolution (~g/ml) Preparations 5 min 10 min 15 min 20 min 25 min 30 min Example 6 22.2 32.5 32.2 30.3 29.8 30.0 _ _ _ . _ Comparative2.1 2.1 1.8 1.9 1.2 1.5 Example 1 .
Comparative12.6 13.0 10.7 9.8 7.0 4.2 Example 2 Comparative9.7 15.1 13.9 15.0 15.4 16.2 Example 3 Comparative2.2 11.3 15.7 17.0 17.8 17.8 -.
Example 4 ;----- -The capsule of Comparative Example 4 was tested using Japanese Pharmacopeia first fluid (pH 1.2), since this cap~ule contained polyvinylacetaldiethylamino acetate -., which is a polymeric compound dissolvable at an acidic pH :
~ value.
''h'~ able 1 demonstrates that the capsule of Example 6 exhlbits higher dissolution than the capsules of Comparative Examples 1-4 using polymeric compounds other than HPMCAS. The capsule of Comparative Example 1 using hydroxypropylmethylcellulose 2910 which is a water soluble polymer dissolved very little throughout the test period.
In the test using the capsule of Comparative Example 2 containing hydroxypropylmethylcellulose phthalate which is ~ ~`
the pH~dependent, alXali soluble-type polymeric compound ~ .
."; . ~ ~
as HPMCAS, recrystallization of NZ-105 took place 10 ~i~; minute9 after 8tart of the test and the dissolution began ~r .
: 17 ~:
" 1332152 to decline. The capsule of Comparative Example 3 ~
containing methacrylic acid-methyl methacrylate copolymer, ;
which is pH dependent, alkali soluble-type polymer, and the capsule of Comparative Example 4 containing polyvinylacetaldiethylamino acetate, which is also pH
dependentl acidic soluble-type polymers, although did not recrystallize NZ-105, exhibited dissolutions a~out 1/2 of that of the capsule using HPMCAS, evidencing that they are undesirable in view of practical bioavailability. ~;
Test Example 2 Blood Concentration~
The preparations prepared in Examples 1-5 and Comparative Examples~5 nnd 6, each containlng 20 mg of NZ-105, were orally admlnistered to Beagle dogs ~weight: - ;;
about l0 kg) which were fasted overnight. Blood was ~;~
collected from ench dog 0.5, 1, 2, 3, 4, and 6 hours after -t~he~ administrntion. ~The measurement of the blood concentration~of~NZ~-105~was carried out by means of HPLC -- -on NZ-lO5~extraat snmples from~plnsma. The blood concentrations and thelr pnr _e~er~ nre shown l~ Tnble 2.
A
13321~2 Blood Concentrations (ng/ml) Parameters -Tested ----- .Preparations0.5 1 2 3 4 6 (hrs)Cmax Tmax AUC
Example 1 71.1 48.0 23.4 16.3 11.1 8.3 71.1 0.5 153.0 Example 2 22.6 30.7 17.9 10.2 5.3 0.0 30.7 1.0 78.1 Example 3 35.4 72.5 29.9 13.4 5.9 0.0 72.5 1.0 134.0 :
Example 4 8.4 54.5 52.1 19.9 7.4 0-.0 54.5 1.0 141.8 Example 5 0.0 41.4 87.2 43.5 21.5 8.7 87.2 2.0 211.5 Comparative 0.0 0.0 14.5 14.9 6.4 0.0 14.9 3.0 49.7 Example 5 :
Comparative 0.0 0.0 0.0 0.0 0.0 0,0 0.0 0.0 0.0 ~:
Example 6 ,,s~ ~
Cmax: Maximum blood concentration (ng/ml) max: Time required to arrive at the maximum blood concentration (hour) '~ ' AUC; The area under the blood concentration-time ~ ~' curvo (ng.hour/ml) The compos;itlon of the prosent invention can provide '~
a high blood concentration of tho pharmaceutical component NZ-105~and ensures the high total drug abisorption ~AUC), ?.~5~ and can easily be prepared into pharmaceutical reparations such as capsules, granules, powders, tablets, and thta like.
Obviously, numerous modifications and variations of the ; preo-nt invention are possLblo in light of the above teachings. It is therofore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
.. ~.
,~ . .
" ~
;. `` . 1 9 . ;~ . .
Claims (2)
1. A pharmaceutical composition comprising: (i) a 1:1 solvate of 5-(5,5-dimethyl-1,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridine carboxylic acid 2-(phenyl(phenylmethyl)amino) ethyl ester P-oxide hydrochloride-ethanol and (ii) hydroxypropylmethyl-cellulose acetate succinate.
2. A process for preparing a pharmaceutical composition comprising: (i) a 1:1 solvate of 5-(5,5-dimethyl-1,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridine carboxylic acid 2-(phenyl-(phenylmethyl)amino) ethyl ester P-oxide hydrochloride-ethanol and (ii) hydroxypropylmethyl-cellulose acetate succinate, which comprises dissolving (i) a 1:1 solvate of 5-(5,5-dimethyl-1,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridine carboxylic acid 2-(phenyl(phenylmethyl)amino) ethyl ester P-oxide hydrochloride-ethanol and (ii) hydroxypropylmethylcellulose acetate succinate into an organic solvent,and removing said organic solvent by evaporation.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13226288 | 1988-05-30 | ||
| JP132262/188 | 1988-05-30 | ||
| JP1050471A JP2528706B2 (en) | 1988-05-30 | 1989-03-02 | Pharmaceutical composition of dihydropyridine compound |
| JP50471/1989 | 1989-03-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1332152C true CA1332152C (en) | 1994-09-27 |
Family
ID=26390939
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000600631A Expired - Lifetime CA1332152C (en) | 1988-05-30 | 1989-05-25 | Pharmaceutical composition of dihydropyridine compound |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4983593A (en) |
| EP (1) | EP0344603B1 (en) |
| JP (1) | JP2528706B2 (en) |
| CA (1) | CA1332152C (en) |
| DE (1) | DE68900356D1 (en) |
| ES (1) | ES2051920T3 (en) |
| GR (1) | GR3003615T3 (en) |
| NZ (1) | NZ229309A (en) |
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| WO1997034610A1 (en) * | 1996-03-18 | 1997-09-25 | Nissan Chemical Industries, Ltd. | Process for producing efonidipine hydrochloride preparations |
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| US6056977A (en) | 1997-10-15 | 2000-05-02 | Edward Mendell Co., Inc. | Once-a-day controlled release sulfonylurea formulation |
| US6350786B1 (en) † | 1998-09-22 | 2002-02-26 | Hoffmann-La Roche Inc. | Stable complexes of poorly soluble compounds in ionic polymers |
| ES2306646T3 (en) * | 1999-02-09 | 2008-11-16 | Pfizer Products Inc. | COMPOSITIONS OF BASIC PHARMACOS WITH INCREASED BIODISPONIBILITY. |
| ATE404178T1 (en) * | 1999-02-10 | 2008-08-15 | Pfizer Prod Inc | DEVICE WITH MATRIX-CONTROLLED ACTIVE RELEASE |
| DE60042352D1 (en) * | 1999-02-10 | 2009-07-23 | Pfizer Prod Inc | Osmotic system for administering active substances containing solid amorphous dispersions |
| US6706283B1 (en) | 1999-02-10 | 2004-03-16 | Pfizer Inc | Controlled release by extrusion of solid amorphous dispersions of drugs |
| ES2307482T3 (en) * | 1999-02-10 | 2008-12-01 | Pfizer Products Inc. | SOLID PHARMACEUTICAL DISPERSIONS. |
| DE60038536T2 (en) | 1999-09-30 | 2009-06-10 | Penwest Pharmaceuticals Co. | MATRIX SYSTEM WITH DELAYED RELEASE FOR HIGHLY SOLUBLE ACTIVE SUBSTANCES |
| WO2001045674A1 (en) * | 1999-12-20 | 2001-06-28 | Cocensys, Inc. | Process for producing nanometer particles by fluid bed spray-drying |
| JP2003518485A (en) * | 1999-12-23 | 2003-06-10 | ファイザー・プロダクツ・インク | Pharmaceutical composition giving improved drug concentration |
| US7115279B2 (en) | 2000-08-03 | 2006-10-03 | Curatolo William J | Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors |
| WO2002038126A2 (en) * | 2000-11-08 | 2002-05-16 | Aeromatic-Fielder Ag | A process for production of particles for pharmaceutical compositions having increased bioavailability |
| DE10058772A1 (en) * | 2000-11-27 | 2002-06-06 | Falk Pharma Gmbh | Process for the preparation of readily soluble pharmaceutical formulations and corresponding formulations |
| JP2004534812A (en) | 2001-06-22 | 2004-11-18 | ファイザー・プロダクツ・インク | Pharmaceutical composition of dispersion of drug and neutral polymer |
| EP1401399A2 (en) * | 2001-06-22 | 2004-03-31 | Pfizer Products Inc. | Pharmaceutical compositions containing polymer and drug assemblies |
| AR038375A1 (en) * | 2002-02-01 | 2005-01-12 | Pfizer Prod Inc | PHARMACEUTICAL COMPOSITIONS OF INHIBITORS OF THE PROTEIN OF TRANSFER OF ESTERES DE COLESTERILO |
| WO2005117834A1 (en) * | 2004-05-27 | 2005-12-15 | Janssen Pharmaceutica N.V. | Solid dispersions of a basic drug compound and a polymer containing acidic groups |
| MXPA06013891A (en) * | 2004-05-28 | 2007-01-26 | Pfizer Prod Inc | Pharmaceutical compositions with enhanced performance. |
| EP1829549A1 (en) * | 2004-12-17 | 2007-09-05 | Ono Pharmaceutical Co., Ltd. | Amorphous composition |
| US20080213383A1 (en) * | 2005-09-06 | 2008-09-04 | Astellas Pharma Inc. | Fine particles of poorly water-soluble drug having enteric material adsorbed on particle surface |
| WO2008063888A2 (en) | 2006-11-22 | 2008-05-29 | Plexxikon, Inc. | Compounds modulating c-fms and/or c-kit activity and uses therefor |
| US20100190777A1 (en) | 2007-07-17 | 2010-07-29 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
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| US9149434B2 (en) * | 2007-12-03 | 2015-10-06 | Tomita Pharmaceutical Co., Ltd. | Core particle for pharmaceutical preparation |
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| CR20170089A (en) | 2009-04-03 | 2017-07-17 | Plexxikon Inc | PROPANE-ACID COMPOSITIONS-1 - SULFONIC {3- [5- (4-CHLORINE-PHENYL) -1H-PIRROLO [2,3-B] PIRIDINA-3-CARBONIL] -2,4-DIFLUORO-PHENIL} -AMIDA AND THE USE OF THE SAME |
| US8329724B2 (en) | 2009-08-03 | 2012-12-11 | Hoffmann-La Roche Inc. | Process for the manufacture of pharmaceutically active compounds |
| WO2011031620A1 (en) * | 2009-09-11 | 2011-03-17 | Transtech Pharma, Inc. | Solid compositions comprising an oxadiazoanthracene compound and methods of making and using the same |
| NZ599866A (en) | 2009-11-06 | 2014-09-26 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor |
| JP5792807B2 (en) | 2010-06-14 | 2015-10-14 | ダウ グローバル テクノロジーズ エルエルシー | Hydroxypropyl methylcellulose acetate succinate with improved substitution of acetate and succinate |
| MA34948B1 (en) | 2011-02-07 | 2014-03-01 | Plexxikon Inc | COMPOUNDS AND METHODS FOR MODULATING KINASE, AND INDICATIONS THEREOF |
| TWI558702B (en) | 2011-02-21 | 2016-11-21 | 普雷辛肯公司 | Solid forms of a pharmaceutically active substance |
| US8591944B2 (en) | 2011-03-08 | 2013-11-26 | Zalicus Pharmaceuticals Ltd. | Solid dispersion formulations and methods of use thereof |
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| AR106018A1 (en) | 2015-08-26 | 2017-12-06 | Achillion Pharmaceuticals Inc | ARYL, HETEROARYL AND HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS |
| AU2017290593A1 (en) | 2016-06-27 | 2019-01-03 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
| US20190030003A1 (en) * | 2017-03-21 | 2019-01-31 | Bioduro, Llc | Gastrointestinal-protective formulations for oral delivery of proteins and peptides |
| JP2021535112A (en) | 2018-08-20 | 2021-12-16 | アキリオン ファーマシューティカルズ，インコーポレーテッド | Pharmaceutical compounds for the treatment of medical disorders of complement D factor |
| EP3866773A4 (en) | 2018-10-16 | 2022-10-26 | Georgia State University Research Foundation, Inc. | Carbon monoxide prodrugs for the treatment of medical disorders |
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|---|---|---|---|---|
| JPS5948810A (en) | 1982-09-10 | 1984-03-21 | Sony Corp | Mask of data for magnetic recording body and reproducing method therefor |
| JPS62123117A (en) | 1985-11-22 | 1987-06-04 | Nippon Chemiphar Co Ltd | Nicardipine hydrochloride composition for oral administration |
| CN1016063B (en) * | 1986-01-22 | 1992-04-01 | 日产化学工业株式会社 | Process for preparing dihydropyridine-5-phosphonic acid cyclic propylene ester |
| IL81419A0 (en) * | 1986-01-30 | 1987-08-31 | Syntex Inc | Long acting sustained release pharmaceutical compositions containing dihydropyridines and their preparation |
-
1989
- 1989-03-02 JP JP1050471A patent/JP2528706B2/en not_active Expired - Lifetime
- 1989-05-24 ES ES89109381T patent/ES2051920T3/en not_active Expired - Lifetime
- 1989-05-24 EP EP89109381A patent/EP0344603B1/en not_active Expired - Lifetime
- 1989-05-24 DE DE8989109381T patent/DE68900356D1/en not_active Expired - Fee Related
- 1989-05-25 CA CA000600631A patent/CA1332152C/en not_active Expired - Lifetime
- 1989-05-26 NZ NZ229309A patent/NZ229309A/en unknown
- 1989-05-30 US US07/358,144 patent/US4983593A/en not_active Expired - Lifetime
-
1992
- 1992-01-22 GR GR920400057T patent/GR3003615T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US4983593A (en) | 1991-01-08 |
| DE68900356D1 (en) | 1991-11-28 |
| ES2051920T3 (en) | 1994-07-01 |
| GR3003615T3 (en) | 1993-03-16 |
| JP2528706B2 (en) | 1996-08-28 |
| JPH0249728A (en) | 1990-02-20 |
| EP0344603B1 (en) | 1991-10-23 |
| NZ229309A (en) | 1991-06-25 |
| EP0344603A1 (en) | 1989-12-06 |
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