WO1994025062A1

WO1994025062A1 - Oral pharmaceutical compositions containing renin inhibitors

Info

Publication number: WO1994025062A1
Application number: PCT/JP1994/000670
Authority: WO
Inventors: Hisami Yamaguchi; Masamichi Hattori; Rinta Ibuki; Hiromitsu Yoshida; Yasuo Shimazaki; Akio Kawamura; Toshiya Takahashi; Norio Ohnishi; Takehisa Hata
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1993-04-28
Filing date: 1994-04-22
Publication date: 1994-11-10
Also published as: AU6581194A

Abstract

This invention relates to an oral pharmaceutical composition characterized by comprising an amino acid derivative of general formula (I) wherein each symbol is as defined in the description, or a salt thereof and one or more ingredient(s) selected from the group consisting of tartaric acid, citric acid, higher alcohol, cyclodextrin, sucrose ester of fatty acid and polyglycerin ester of fatty acid.

Description

DESCRIPTION

ORALPHARMACEUTICALCOMPOSITIONSCONTAININGRENININHIBITORS

Technical Field

This invention relates to an oral pharmaceutical composition comprising a compound of general formula (I) given below or a salt thereof, which has renin- inhibitory activity, and more particularly to an oral pharmaceutical composition comprising said compound (I) or a salt thereof and one or more ingredient(s) selected from the group consisting of tartaric acid, citric acid, higher alcohol, cyclodextrin, sucrose ester of fatty acid and polyglycerin ester of fatty acid.

Accordingly, one object of this invention is to provide an oral pharmaceutical composition comprising said compound (I) or a salt thereof and one or more ingredient(s) selected from the group consisting of tartaric acid, citric acid, higher alcohol, cyclodextrin, sucrose ester of fatty acid and polyglycerin ester of fatty acid.

Further, another object of this invention is to provide a process for preparing an oral pharmaceutical composition comprising said compound (I) or a salt thereof and one or more ingredient(s) selected from the group consisting of tartaric acid, citric acid, higher alcohol, cyclodextrin, sucrose ester of fatty acid and polyglycerin ester of fatty acid.

Background Art

A compound of general formula (I) :

wherein R*-- is a lower alkyl group which may be substituted with a substituent selected from the group consisting of acyl, hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula :

in which R-> is hydrogen or an acyl group, and R^ is hydrogen or a lower alkyl group, R^ is hydrogen or a lower alkyl group, R^ is hydrogen or a lower alkyl group, R^ is a lower alkyl group, and

X is 0 or NH, or a salt thereof is known to be a substance having renin-inhibitory activity (cf. Japanese Patent Application Publication Nos. 19071/1988, 243674/1990, 279570/1992) and is expected to find application in the field of medicine as a therapeutic drug for hyper¬ tension, heart failure, etc..

For any renin inhibitors, the development of oral dosage forms is considered desirable in view of the above-mentioned indications but many of renin inhibitors reported so far are poorly absorbed from the gastrointestinal tract and this has been a major deterrent to the development of oral dosage forms. For the above compound (I) or salt thereof [hereinafter referred to collectively as compound (I)], too, attempts have been made to develop them as renin inhibitors for oral administration but a further improvement is needed in oral absorbability.

The inventors of this invention did much research for enhancing the oral absorption of compound (I) and found that tartaric acid, citric acid, higher alcohol, cyclodextrin, sucrose ester of fatty acid and/or polyglycerin ester of fatty acid contributes a great deal to improved absorbability of compound (I) after oral administration. They accordingly have completed this invention.

Disclosure of the Invention

The oral pharmaceutical composition of this inven¬ tion is characterized in that it comprises an active ingredient comprising compound (I) and one or more ingredient(ε ) selected from the group consisting of tartaric acid, citric acid, higher alcohol, cyclodextrin, sucrose ester of fatty acid and polyglycerin ester of fatty acid.

The definitions used in general formula (I) and relevant specific examples as well as preferred working modes are explained in detail below. The term "lower" means a group having 1 - 7 carbon atoms unless otherwise indicated.

Suitable "lower alkyl" includes straight-chain or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, ethylbutyl, pentyl, isopentyl, hexyl, methylhexyl, heptyl or the like.

Suitable "aryl" includes phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl or the like, and the more preferred one is phenyl. Suitable "lower alkoxy" includes a straight-chain or branched alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, and the more preferred ones are C1-C4 alkoxy groups. Suitable "acyl" includes lower alkanoyl groups such as for yl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 4-methylvaleryl, etc., mono- or di(lower)alkylamino(lower)alkanoyl groups such as methylaminoacetyl, ethylaminopropionyl, dimethylaminobutyryl, etc., lower alkox (lower)alkanoyl groups such as methoxyacetyl, methoxypropionyl, ethoxypropionyl, etc . , aroyl groups such as benzoyl, toluoyl, etc., cyclo(lower)alkylcarbonyl groups such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentyl- carbonyl, cyclohexylcarbonyl, etc., amino acid residues whose amino groups may be protected, such as glycyl, benzoylglycyl, tert-butoxycarbonylglycyl, tert- butoxycarbonylleucyl, acetylleucyl, tert-butoxy- carbonylhistidyl, etc., carbamoyl, mono- or di(lower)- alkylcarbamoyl groups such as methylcarbamoyl, ethyl- carbamoyl, propylcarbamoyl, isopropylcarbamoyl, butyl- carbamoyl, pentylcarbamoyl, isobutylcarbamoyl, tert- butylcarbamoyl, dimeth lcarbamoyl, diethylcarbamoyl, methylethylcarbamoyl, methylisopropylcarbamoyl, methyl- isobutylcarbamoyl, etc_^, heterocyclic(lower)alkyl¬ carbamoyl groups such as picolylcarbamoyl, pyridyl- ethy1carbamoyl, thiazolylmethylcarbamoyl, morpholino- methylcarbamoyl, morpholinoethylcarbamoyl, etc., N- heterocyclic(lower)alkyl-N-lower alkylcarbamoyl groups such as N-picolyl-N-methylcarbamoyl, N-pyridylethyl-N- methy1carbamoyl, N-morpholinomethyl-N-ethylcarbamoyl, N-morpholinoethyl-N-methyl-carbamoyl, etc. , ar(lower)alkylcarbamoyl groups such as benzylcarbamoyl, phenethylcarbamoyl, benzhydrylcarbamoyl, etc., N- ar(lower)alkyl-N-lower alkylcarbamoyl groups such as N- benzyl-N-methylcarbamoyl, N-phenethyl-N-methyl- carbamoyl, N-phenethyl-N-ethylcarbamoyl, etc., N-aryl- N-lower alkylcarbamoyl groups such as N-phenyl-N- meth 1carbamoyl etc., lower alkoxycarbonyl(lower)alkyl- carbamoyl groups such as methoxycarbonylmethylcarba- moyl, ethoxycarbonylmethylcarbamoyl, ethoxycarbonyl- eth 1carbamoyl, etc., lower alkox (lower)alkylcarbamoyl groups such as methoxymethylcarbamoyl, methoxyethyl- carbamoyl, ethoxypropylcarbamoyl, etc., aroylcarbamoyl groups such as benzoylcarbamoyl, toluoylcarbamoyl, etc., heterocycliccarbamoyl groups such as pyridyl- carbamoyl, morpholinocarbamoyl, thiazolylcarbamoyl, etc., N-heterocyclic-N-lower alkylcarbamoyl groups such as N-pyridyl-N-methylcarbamoyl, N-thiazolyl-N-methyl- carbamoyl, etc., heterocycliccarbonyl groups and more preferably N-containing heterocyclic-N-ylcarbonyl groups which may be substituted with lower alkyl, such as morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl, 4-methyl-l-piperazinylcarbonyl, 1,2,3,6-tetrahydro-l-pyridylcarbonyl, etc., lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxy- carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy- carbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc., mono-(or di- or tri-)halo(lower)alkoxycarbonyl groups such as iodo- ethoxycarbonyl, dichloroethoxycarbonyl, trichloro- ethoxycarbonyl, trifluoromethoxycarbonyl, etc., hydroxy(lower)alkoxycarbonyl groups such as hydroxy- methoxycarbonyl, hydroxyethoxycarbonyl, hydroxypropoxy- carbonyl, hydroxybutoxycarbonyl, etc., ar(lower) alkoxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, 4-nitrobenzyloxycarbonyl, trityl- oxycarbonyl, benzhydryloxycarbonyl, etc. , lower alkenyloxycarbonyl groups such as vinyloxycarbonyl, allyloxycarbonyl, etc., lower alkanoyl(lower)alkoxy- carbonyl groups such as acetylmethoxycarbonyl, pro- pionylmethoxycarbonyl, acetylethoxycarbonyl, etc. , lower alkylsulfonyl groups such as mesyl, ethylsulfon- yl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc., arylsulfonyl groups such as phenylsulfonyl, tosyl, etc. or the like.

Suitable "lower alkylthio" includes straight-chain or branched alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio or the like. The more preferred ones are i-C ^ alkylthio groups .

Suitable salts of compound (I) include conventional non-toxic salts, for example, organic acid addition salts such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc., inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc., salts with amino acids, such as aspartate, glutamate, etc. or the like.

Compound (I) may occur as stereoisomers, such as optical isomers and geometrical isomers, due to the asymmetric carbon and .double bond and these isomers are also included within the scope of this invention.

Higher alcohol used in this invention includes Cg- C20 straight-chain or branched, saturated or unsaturated alcohol such as cetyl alcohol, stearyl alcohol, oleyl alcohol or the like, in which more preferred ones are C14-C20 alcohol and the most preferred one is cetyl alcohol.

Cyclodextrin used in this invention includes - cyclodextrin, β-cyclodextrin, hydroxypropyl-β- cyclodextrin, γ-cyclodextrin, dimethyl-β-cyclodextrin or the like, in which the most preferred one is β- cyclodextrin.

Sucrose ester of fatty acid used in this invention includes sucrose ester of mono-, di-, tri- or poly-, saturated or unsaturated fatty acid such as sucrose ester of lauric acid, sucrose ester of myristic acid, sucrose ester of palmitic acid, sucrose ester of stearic acid, sucrose ester of oleic acid, etc., and mixture thereof, sucrose ester of hardening beef tallow fatty acid [e.g. DK ester F-160, D ester SS

(manufactured by Dai-ichi ogyo-Seiyaku Co., Ltd.)] or the like.

Polyglycerin ester of fatty acid used in this invention includes decaglycerin ester of fatty acid such as decaglycerin ester of monolauric acid [e.g. Decaglyn 1-L (trademark, manufactured by Nikko Chemicals Co., Ltd.)], decaglycerin ester of monostearic acid, etc. or the like.

The amount of tartaric acid or citric acid in the oral pharmaceutical composition of this invention is not so critical but is preferably 0.01 - 20 times and, for still better results 0.1 - 2 times, most preferably 0.5-1 times the amount of compound (I) contained in the composition. The amount of higher alcohol in the oral pharmaceutical composition of this invention is not so critical but is preferably 0.05 - 20 times and, for still better results 0.1 - 10 times, most preferably 0.2-4 times the amount of compound (I) contained in the composition.

The amount of cyclodextrin, sucrose ester of fatty acid and polyglycerin ester of fatty acid in the oral pharmaceutical composition of this invention is not so critical but is preferably 0.5 - 20 times and, for still better results, 0.5 - 3 times the amount of compound (I) contained in the composition.

Where necessary, the composition of this invention^' may further contain those additives which are conven¬ tionally used in pharmaceutical formulation, such as a disintegrator, lubricant, excipient, coloring agent, effervescent agent or the like. There is no limitation on dosage form. Thus, for oral administration, the composition can be used in such forms as powders, fine granules, granules, capsules, tablets, pills, liquid preparations, or the like.

Suitable disintegrator includes starches (e.g. potato starch, corn starch, hydroxypropylstarch, carboxymethylstarch sodium, etc.), cellulose deriva¬ tives (e.g. carboxymethylcellulose calcium, carboxy- ethylcellulose sodium, carboxymethylcellulose, low- substitution hydroxypropylcellulose, crystalline cellulose, etc.), polyvinylpyrrolidone, croscarmellose sodium or the like. Suitable lubricant includes talc, waxes (e.g. bleached beeswax, hydrogenated oil, etc.), stearic acid compounds (e.g. stearic acid, magnesium stearate, calcium stearate, etc.) or the like. Suitable excipient includes sugars (e.g. lactose, sucrose, D- mannitol, etc.), starches (e.g. corn starch etc.), inorganic salts of calcium (e.g. calcium hydrogen phosphate, calcium sulfate, etc.) or the like. Suitable coloring agent includes yellow oxide of ion, tar dyes or the like. Suitable effervescent agent includes a tartaric acid-sodium hydrogen carbonate system or the like. These are not exclusive choices, however, and any materials that are commonly used in the art can be utilized.

Where desired, the composition can be processed into a dosage form such as one coated with an enteric coating agent such as hydroxypropylmethylcellulose phthalate. Furthermore, the tartaric acid or citric acid in this invention can be expected to double as a release enhancing agent.

The composition of this invention can be produced by blending compound (I) with one or more ingredient(s) selected from the group consisting of tartaric acid, citric acid, higher alcohol, cyclodextrin, sucrose ester of fatty acid and polyglycerin ester of fatty acid, and, optionally, further with conventional additives.

The method of production includes the conventional procedures. Moreover, such compositions as mentioned above can be comminuted for reducing the particle size. Such comminution can be made by the conventional procedures .

The powdery mixture so produced can be further processed, if desired, into various dosage forms by the processes well established in the art, such as pulve¬ rization, sieving, kneading, granulation, compression, coating or the like. These processes can each be carried out in the conventional manner.

In case that cyclodextrin is contained in the composition of this invention, an inclusion compound of compound (I) and cyclodextrin may be formed, and said inclusion compound is .also included within the scope of this invention.

Some representative test data are given below for showing the effect of the invention.

Test compounds

(2S,3S)-2-[N°--[ (S)-2-[N-Methyl-N-[2-{N-(morpholino- carbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3- phenylpropionyl]-N^-methyl-L-histidyl]amino-1- cyclohexyl-3-hydroxy-6-methylheptane hydrochloride (hereinafter referred to Compound A)

(2S,3S)-2-[N⁰⁶-[ (S)-2-{N-(2-Morpholinocarbonylethyl)-N- methylaminocarbonyloxy}-3-phenylpropionyl]-N^α-methyl-L- histidyl]amino-l-cyclohexyl-3-hydroxy-6-methylheptane hydrochloride

(hereinafter referred to Compound B)

Test 1 Solubility test

Method

An aqueous solution of the test compound (2 ml, concentration: 20 mg/ml, about pH 4) was prepared and maintained at 37°C. A solution of β-cyclodextrin, DK ester SS or Decaglyn 1-L in two-fold salt concentration of Second Fluid of The Pharmacopoeia of Japan (2 ml, concentration: 10 mg/ml, pH 6.8) was added thereto. The solubility of the test compound was determined by high performance liquid chromatography. Results

* a solution of two-fold concentration of Second Fluid of The Pharmacopoeia of Japan concentration: 20 mg/ml - l i ¬

lt is apparent from the above test results that the solubility of the compound (I) is greatly improved by cyclodextrin, sucrose ester of fatty acid or polyglycerin ester of fatty acid.

Test 2 Oral absorption test-1

Method

Male S.D. rats (body weights 200 - 270 g), fasted overnight, were used in groups of 3. The dosing samples shown below were respectively administered orally to the rats in the dose of 10 mg/kg. After the administration, the blood was serially withdrawn from the femoral artery and the concentration of the test compound was determined by high performance liquid chromatography.

Dosing sample

Formulation Formulation 1 Control

Compound A 20 mg 20 mg

β-cyclodextrin 46 mg -

Purified water 10. ml 10 ml

Results

The test results are shown below in the table. The maximum plasma concentration (Cmax, μg/ml) and the area under the plasma concentration-time curve (AUCo_6 h_r, μg<>hr/ml) are shown together as oral absorption parameters. Each value is the mean ± standard error. Formulation n Cmax ^AUC0-6 hr (μg/ml) (μg«hr/ml)

1 3 1.02+0.15 0.95 + 0.17

Control 3 0.80+0.10 0.56 ± 0.07

Test 3 Oral absorption test-2 Method

Male S.D. rats (body weights 200 - 270 g), fasted overnight, were used in groups of 3. The dosing samples shown below were respectively administered orally to the rats in the dose of 32 mg/kg. After the administration, the blood was serially withdrawn from the femoral artery and the concentration of the test compound was determined by high performance liquid chromatography.

Dosing sample

Formulation Formulation 2 Control

Compound A 64 mg 64 mg

Tartaric acid 32 mg -

Purified water 10 ml 10 ml Results

Formulation n Cmax ^AUC0-6 hr (μg/ml) (μg«hr/ml)

2 3 0.4010.08 1.38 + 0.30

Control 3 0.21+0.64 0.64 ± 0.13

Test 4 Oral absorption test-3 Method

The test was carried out according to a similar manner to that of Test 3.

Dosing sample

Formulation Formulation 3 Control

Compound A 64 mg 64 mg

Cetyl alcohol 128 mg -

Sorbitan sesqui- oleate 12.-3 mg 12.8 mg

(surfactant)

Purified water 10 ml 10 ml Results

Formulation n Cmax ^AUC0-6 hr (μg/ml) (μg«hr/ml)

3 3 0.70+0.15 1.45 ± 0.41

Control 3 0.24x0.05 0.88 ± 0.12

It is apparent from the above test results that the oral pharmaceutical composition of this invention is superior to the cyclodextrin-free control composition, the tartaric acid-free control composition or the higher alcohol-free control composition in the oral absorbability of compound (I).

Examples

The following examples are intended to describe this invention in further detail. Example 1

Compound A 200 parts β-Cyclodextrin 465 parts Crystalline cellulose 20 parts

Tartaric acid 185 parts

Sodium hydrogen carbonate 210 parts Crosslinked polyvinylpyrrolidone 10 parts Magnesium stearate 25 parts Hydroxypropylmethyicellulose

2910 30 parts

Hydroxypropylmethyicellulose phthalate 220824 50 parts

Effervescent enteric tablets according to the above formula were manufactured by the conventional method.

Example 2

Compound B 200 parts DK ester SS 400 parts

Crystalline cellulose 20 parts

Tartaric acid 185 parts

Sodium hydrogen carbonate 210 parts Crosslinked polyvinylpyrrolidone 10 parts Magnesium stearate 25 parts

Hydroxypropylmethyicellulose 2910 30 parts

Hydroxypropylmethyicellulose phthalate 220824 50 parts Effervescent enteric tablets according to the above formulation were manufactured by the conventional method.

Example 3 Compound A 200 parts

Decaglyn 1-L 400 parts Crystalline cellulose 20 parts

Tartaric acid 185 parts

Sodium hydrogen carbonate 210 parts Crosslinked polyvinylpyrrolidone 10 parts _/ Magnesium stearate 25 parts

Effervescent tablets according to the above formulation were manufactured by the conventional method.

Example 4

Compound A 600 parts

Lactose 45 parts d-Tartaric acid 300 parts Hydrous silicon dioxide 80 parts Crosslinked polyvinylpyrrolidone 270 parts Magnesium stearate 54 parts

Tablets according to the above formula were manufactured by the conventional method.

Example 5

Compound A 600 parts

Lactose 195 parts

Citric acid 150 parts Hydrous silicon dioxide 80 parts

Crosslinked polyvinylpyrrolidone 270 parts Magnesium stearate 54 parts

Tablets according to the above formulation were manufactured by the conventional method.

Example 6

Compound A 400 parts

Cetyl alcohol 400 parts

Lactose 105 parts Crosslinked polyvinylpyrrolidone 80 parts

Magnesium stearate 15 parts

Example 7

(2S,3S)-2-[N -[N-[N-Methyl-N-{2-(N-morpholino- carbonyl-N-methylamino)ethyl}aminocarbonyl]-L- phenylalanyl]-N°--methyl-L-histidyl]amino-1- cyclohexyl-3-hydroxy-5-ethylheptane hydrochloride (hereinafter referred to Compound C)

200 parts β-Cyclodextrin 465 parts

Crystalline cellulose - 20 parts Tartaric acid 185 parts Sodium hydrogen carbonate 210 parts Crosslinked polyvinylpyrrolidone 10 parts

Magnesium stearate 25 parts

Hydroxypropylmethyicellulose

2910 30 parts

Hydroxypropylmethyicellulose phthalate 220824 50 parts

Example 8

Compound C 600 parts

Lactose 45 parts d-Tartaric acid 300 parts Hydrous silicon dioxide 80 parts

Crosslinked polyvinylpyrrolidone 270 parts

Magnesium stearate 54 parts

Example 9

Compound C 400 parts

Cetyl alcohol 400 parts

Lactose 105 parts Crosslinked polyvinylpyrrolidone 80 parts

Magnesium stearate 15 parts

Claims

1. An oral pharmaceutical composition, which comprises an amino acid derivative of the general formula :

wherein R¹ is a lower alkyl group which may be substituted with a substituent selected from the group consisting of acyl, hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula :

in which R~^> is hydrogen or an acyl group, and R6 is hydrogen or a lower alkyl group, R^ is hydrogen or a lower alkyl group, R3 is hydrogen, or a lower alkyl group,

R^ is a lower alkyl group, and X is 0 or NH, or a salt thereof and one or more ingredient(s) selected from the group consisting of tartaric acid, citric acid, higher alcohol, cyclodextrin, sucrose ester of fatty acid and polyglycerin ester of fatty acid.

2. An oral pharmaceutical composition according to claim 1, which comprises an amino acid derivative of claim 1 or a salt thereof and tartaric acid.

3. An oral pharmaceutical composition according to claim 1, which comprises an amino acid derivative of claim 1 or a salt thereof and cetyl alcohol.

4. An oral pharmaceutical composition according to claim 1, which comprises an amino acid derivative of claim 1 or a salt thereof and β-cyclodextrin.

5. An oral pharmaceutical composition according to claim 2, 3 or 4, in which an amino acid derivative is the one wherein R¹ is a lower alkyl group substituted with a group of the formula :

in which R^*^ is hydrogen or morpholinocarbonyl, and R^ is hydrogen or a lower alkyl group.

6. A process for preparing an oral pharmaceutical composition, which comprises blending an amino acid derivative of claim 1 or a salt thereof with one or more ingredient(s) selected from the group consisting of tartaric acid, citr c acid, higher alcohol, cyclodextrin, sucrose ester of fatty acid and polyglycerin ester of fatty acid.

7. Use of an amino acid derivative of claim 1 or a salt thereof in the preparation of an oral pharmaceutical composition, together with one or more ingredient(s) selected from the group consisting of tartaric acid, citric acid, higher alcohol, cyclodextrin, sucrose ester of fatty acid and polyglycerin ester of fatty acid.