JP2009508948A - Stable combination of amlodipine besylate and benazepril hydrochloride - Google Patents

Abstract

  The present invention provides a pharmaceutical composition comprising benazepril and amlodipine (wherein benazepril and amlodipine are in physical contact with each other) and a method for producing the same.

Description

Field of Invention :
The present invention relates to the field of combination therapy of amlodipine and benazepril.

Background of the invention :
In the fight against cardiovascular disease, our current weapons include angiotensin converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB). Combination therapy with ACEI and CCB includes hypertension, congestive heart failure, angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, surrounding vascular disease, left ventricle Effective synergistic results can be achieved in the treatment of various medical conditions, including hypertrophy, cognitive impairment, stroke, and headache. The combination of ACEI benazepril and CCB amlodipine is described by US Pat. No. 6,162,802 (the '802 patent).

Benazepril is 3-[[1- (ethoxycarbonyl) -3-phenyl- (1S) -propyl] amino] -2,3,4,5-tetrahydro-2-oxo-1H-1- (3S) -benzazepine It can be administered as benazepril hydrochloride, which is chemically identified as -1-acetic acid monohydrochloride (C ₂₄ H ₂₈ N ₂ O ₅ .HCl). Amlodipine is (RS) 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate _{(C 20 H 25 ClN 2 O} 5 .AC 6 H 6 O 3 S) as may be administered as chemically identified as amlodipine besylate.

  The combination of benazepril hydrochloride and amlodipine besylate is marketed in the United States by Novartis under the trade name LOTREL ™ as a capsule for oral administration. Capsules are formulated in 4 different strengths using 2.5 mg, 5 mg or 10 mg amlodipine besylate in an amount equal to amlodipine free base and 10 mg or 20 mg benazepril hydrochloride in the following available combinations: Provide: 2.5 / 10 mg, 5/10 mg, 5/20 mg and 10/20 mg. LOTREL ™ is indicated for the treatment of hypertension.

The '802 patent teaches that benazepril and amlodipine are physically incompatible materials; therefore, when incorporated into a single dosage form, they should be kept physically separate (Page 3, lines 48-50).
The inventor has surprisingly discovered a method for producing a pharmaceutical composition comprising both amlodipine and benazepril (which does not require physical separation of the two drug components). Such pharmaceutical compositions and methods for their production are provided herein.

Summary of invention :
In one aspect, the invention provides a stable pharmaceutical composition comprising benazepril, a solvate, ester or pharmaceutically acceptable salt thereof, and amlodipine, a solvate, ester or pharmaceutically acceptable salt thereof. provide. The pharmaceutical composition is stable, ie after about 3 months storage at about 40 ° C. at a relative temperature of about 75%, it is less than 2.5% by weight (s, s) -diacid, and / or with respect to benazepril. For amlodipine, it contains 0.3% by weight or less of impurity D. Preferably, benazepril is benazepril hydrochloride and amlodipine is amlodipine besylate.

In a preferred embodiment, benazepril and amlodipine are in physical contact with each other.
In another embodiment, the benazepril hydrochloride is prepared by wet granulation and the amlodipine besylate is prepared by dry processing.
In another embodiment, the present invention prepares a benazepril composition by wet granulation; prepares an amlodipine composition by dry processing; and contacts said benazepril composition and amlodipine composition to form a combined pharmaceutical composition Providing a method comprising: obtaining.

  The wet granulation is preferably one or more pharmaceutical excipients selected from the group consisting of benazepril hydrochloride and pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose. A granulating solution is added to obtain a wet granulate, wherein the granulating solution comprises water, and optionally polysorbate 80, povidone or both; a dry granulate Drying the wet granulate to obtain a powder; and pulverizing the dry granulate.

  The dry processing preferably screens a mixture of amlodipine besylate and one or more pharmaceutical excipients selected from the group consisting of dicalcium phosphate, sodium glycolate starch, microcrystalline cellulose, colloidal silicon dioxide. And blending the mixture.

In one embodiment, the dry processing further sifts one or more additional pharmaceutical excipients, preferably crospovidone and / or magnesium stearate; and the additional pharmaceutical excipient together with the mixture Includes blending.
In another embodiment, the method includes encapsulating a combined pharmaceutical composition.

  In one embodiment, the present invention provides about 5 to about 20% by weight of benazepril hydrochloride; about 15 to about 20% by weight of pregelatinized starch; about 25 to about 35, based on the total benazepril composition. Weight percent lactose monohydrate; about 10 to about 15 weight percent starch; about 5 weight percent crospovidone; about 15 to about 25 weight percent microcrystalline cellulose; about 0.1 to about 2 weight percent polysorbate 80 And a benazepril composition comprising about 5% by weight povidone.

  In another embodiment, the present invention provides about 2 to about 10% by weight amlodipine besylate; about 25 to about 30% by weight dicalcium phosphate; about 1 to about 2% by weight, based on the total amlodipine composition. About 50% to about 60% by weight microcrystalline cellulose; about 1% by weight colloidal silicon dioxide; about 5% by weight crospovidone; and about 0.2 to about 2% by weight magnesium stearate. An amlodipine composition comprising is provided.

Specific description of the invention :
In one aspect, the invention provides a stable pharmaceutical composition comprising benazepril, a solvate, ester or pharmaceutically acceptable salt thereof, and amlodipine, a solvate, ester or pharmaceutically acceptable salt thereof. provide. The general term amlodipine as used herein refers to the free base form. In the stable pharmaceutical composition of the present invention, benazepril is preferably benazepril hydrochloride and amlodipine is preferably amlodipine besylate.

  The pharmaceutical composition is stable, i.e. the pharmaceutical composition contains low levels of degradation products. In part, the composition delays and / or avoids degradation of the active ingredient, thereby reducing the amount of impurities present in the active ingredient after storage. The main degradation product of benazepril is (s, s) -diacid (benazepri rat), which is an active metabolite of benazepril. The main degradation product of amlodipine is impurity D (-ethyl 5-methyl 2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -6-methylpyridine-3,5-dicarboxylate) is there. The specifications for the degradation products of benazepril and amlodipine are summarized in Table 1.

  In one embodiment, after about 3 months at about 40 ° C. and a relative temperature of about 75%, the pharmaceutical composition is 2.5 wt% or less (s, s) -diacid with respect to benazepril; and / or with respect to amlodipine And 0.3% by weight or less of impurity D.

  In a preferred embodiment, benazepril and amlodipine are in physical contact with each other. Examples of physical contact are physical contact at an uncoated interface between tablet layers, physical catalyst in a liquid oral or injectable fluid medium, and a blended mixture of two active ingredients. Includes physical contact. In a preferred embodiment, a blended mixture comprising two active ingredients is also used as a capsule filler.

  The pharmaceutical composition preferably comprises about 10 to about 20 mg, more preferably about 10 to about 20 mg of benazepril hydrochloride. Preferably, the amount of amlodipine besylate corresponds to about 2.5 to about 10 mg of amlodipine free base. More preferably, the amount of amlodipine besylate corresponds to about 2.5 mg, about 5 mg or about 10 mg of amlodipine free base. Preferably, the benazepril: amlodipine ratio corresponds to a weight ratio of about 2: 1 to about 4: 1, more preferably about 2: 1 or about 4: 1.

  In one embodiment, benazepril hydrochloride is prepared by wet granulation and amlodipine besylate is prepared by dry processing. Wet granulation and dry processing are further described in detail below.

  In one aspect, the present invention provides a method for producing a pharmaceutical composition comprising both benazepril and amlodipine. A pharmaceutical composition comprising both benazepril and amlodipine is referred to as a combined pharmaceutical composition. The method includes the steps of preparing a benazepril composition by wet granulation; preparing an amlodipine composition by dry processing; and contacting the benazepril composition and the amlodipine composition to obtain a combined pharmaceutical composition. FIG. 1 shows a preferred embodiment of this method.

  Wet granulation is preferably a combination of benazepril hydrochloride and one or more pharmaceutical excipients; a granulation solution is added to obtain a wet granulation, wherein the granulation solution is water And optionally comprising one or more pharmaceutical excipients; drying the wet granulate to obtain a dry granulate; and comminuting the dry granulate. Pharmaceutical excipients are further described in detail below. For benazepril compositions, preferred pharmaceutical excipients include pregelled starch, lactose monohydrate, starch, crospovidone, microcrystalline cellulose, polysorbate 80 and povidone.

  Dry processing preferably includes sieving a mixture of amlodipine besylate and one or more pharmaceutical excipients; and blending the mixture. If necessary, a sieving step is performed to avoid inclusion of aggregates and foreign material. For amlodipine compositions, preferred pharmaceutical excipients include dicalcium phosphate, sodium glycolate starch, microcrystalline cellulose, and colloidal silicon dioxide. Preferably, the mixture is sieved through 30 mesh.

  In one embodiment, the dry processing further comprises sieving one or more additional pharmaceutical excipients; and blending the additional pharmaceutical excipient with the mixture, ie, the amlodipine composition. To do. In a preferred embodiment, the additional pharmaceutical excipient is blended with the amlodipine composition after it is combined with the benazepril composition. Preferred additional pharmaceutical excipients include crospovidone and magnesium stearate. Preferably, crospovidone is screened through 30 mesh. Preferred magnesium stearate is sieved through 50 mesh.

  In one embodiment, the method includes encapsulating a combined pharmaceutical composition. In a preferred embodiment, the method comprises benazepril hydrochloride and one or more pharmaceutical additives selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose. In combination with the form; add granulation solution to obtain wet granulate, wherein said granulation solution comprises water, polysorbate 80 and povidone; said wet to obtain dry granulation One or more medicaments selected from the group consisting of amlodipine besylate and dicalcium phosphate, sodium glycolate starch, microcrystalline cellulose, colloidal silicon dioxide; The mixture of excipients is screened through a 30 mesh screen; the mixture and the dry granulate are blended to form a combined pharmaceutical composition; Sieving crospovidone through a sieving sieve; blending the crospovidone with the combined pharmaceutical composition; sieving magnesium stearate through a 50 mesh sieve; and combining with the magnesium stearate Blending with the pharmaceutical composition; and encapsulating the combined pharmaceutical composition.

  In one embodiment, the present invention provides about 5 to about 20% by weight of benazepril hydrochloride; about 15 to about 20% by weight of pregelatinized starch; about 25 to about 35, based on the total benazepril composition. Weight percent lactose monohydrate; about 10 to about 15 weight percent starch; about 5 weight percent crospovidone; about 15 to about 25 weight percent microcrystalline cellulose; about 0.1 to about 2 weight percent polysorbate 80 And a benazepril composition comprising about 5% by weight povidone.

  In another embodiment, the present invention provides about 2 to about 10% by weight amlodipine besylate; about 25 to about 30% by weight dicalcium phosphate; about 1 to about 2% by weight, based on the total amlodipine composition. About 50% to about 60% by weight microcrystalline cellulose; about 1% by weight colloidal silicon dioxide; about 5% by weight crospovidone; and about 0.2 to about 2% by weight magnesium stearate. An amlodipine composition comprising is provided.

The composition of the present invention can be prepared as a medicament to be administered orally. Suitable forms for oral administration include solid forms such as tablets, powders, granules, capsules.
In addition to the active ingredient, the compositions of the present invention can include one or more excipients or adjuvants. An excipient is an inert ingredient added to a pharmaceutical composition to dilute it or to form it or impart consistency. Adjuvants aid the action of the active ingredient. The choice of excipients and adjuvants, and the amount used, can be readily determined by the formulation scientist based on experience in the field and consideration of standard methods and reference studies.

  Diluents can increase the bulk of a solid pharmaceutical composition and make it easier for patients and care providers to handle pharmaceutical dosage forms containing the composition. Diluents for solid compositions include, for example, microcrystalline cellulose (eg, AVICEL ™), microcellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dicalcium phosphate Includes dihydrate, calcium triphosphate, mannitol, powdered cellulose, and sorbitol.

  Solid pharmaceutical compositions that are compressed into dosage forms, such as tablets, can contain excipients that have the effect of helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include sodium carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropylcellulose (eg, KLUCEL ™), hydroxypropylmethylcellulose (eg, METHOCEL ™), methylcellulose, povidone ( For example, KOLLIDON ™, PLASDONE ™), pregelatinized starch, and starch.

  The dissolution rate of a compressed solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include carboxymethylcellulose calcium, croscarmellose sodium (eg Ac-Di-Sol ™), crospovidone (eg KOLLIDON ™, POLYPLASDONE ™), microcrystalline cellulose, polacrilin potassium , Pregelatinized starch, sodium starch glycolate (eg, EXPLOTAB ™) and starch.

  Lubricants can be added to improve the flowability of the uncompressed solid composition and to improve dosage accuracy. Excipients that can function as lubricants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, and talc.

  Where a dosage form, such as a tablet, is made by compression of a powdered composition, the composition is subjected to compression from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surface of the punches and dyes that can cause acquisition by products of pits and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid , Talc and zinc stearate.

  The dose of the present invention may be a composition, preferably a capsule (either hard or soft shell) containing the powdered or granulated solid composition of the present invention. The shell is made from gelatin and optionally includes plasticizers such as glycerin and sorbitol, and opacifiers or colorants.

  In any given case, the most appropriate administration will depend on the nature and severity of the condition being treated, but the most preferred route of the present invention is oral. Dosages are conveniently provided in unit dosage form and can be prepared by any method well known in the pharmaceutical industry.

  A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then in the presence of a liquid, typically water that causes agglomeration of the powder into granules, Further mixed. The granules are screened and / or pulverized, dried and then screened to the desired particle size and / or pulverized. The granulate can then be filled into capsules, optionally with other ingredients. This step is a preferred step for the benazepril component of the present invention.

  Granule compositions can be conveniently prepared by dry granulation. For example, a blended composition of active agent and excipient is compressed into a sludge or sheet and then comminuted into a compressed granulate. Subsequently, the compressed granulate is compressed into tablets or filled into capsules. This technique is more appropriate for the amlodipine component of the present invention, and the use of a blended powder composition of amlodipine and excipients is more preferred.

The capsule filling of the present invention can comprise any of the foregoing blends and granulates described above, however, mixed with a dry blended powder composition of amlodipine and excipients. Most preferred are capsules containing benazepril granulate prepared by wet granulation.
Although the present invention has been described with respect to certain preferred embodiments, the present invention will now be further illustrated by the following non-limiting examples.

Example 1: Amlodipine besylate / benazepril hydrochloride capsule :
Capsules containing both benazepril hydrochloride and amlodipine besylate were produced by the following method.

Preparation of Benazepril Hydrochloride Granules-Part I :
The following materials were mixed in a granulator mixer: pregelatinized starch (starch STA-RX-1500), lactose monohydrate NF (100 mesh), benazepril hydrochloride, starch NF, crospovidone NF and fine Crystalline cellulose NF (Avicel PH 101). A granulation solution was prepared by adding purified water USP to a mixture of polysorbate 80NF and PVP K-30 (Povidone USP) with mixing and continuing mixing until dissolution. The granulation solution was then added to the granulator mixer and mixed until a granulate was obtained. The granulate was then dried in a fluid bed dryer. The dried granulate was then pulverized in a shaking granulator and placed in a container.

Dry Blend (Amlodipine)-Part II :
The following materials were screened: amlodipine besylate, dicalcium phosphate USP anhydrous (powder) and sodium glycolate starch NF. The screened material was then transferred to a blender and blended. Microcrystalline cellulose and colloidal silicon dioxide were screened, added to the blend in the blender and mixed. The mixture was then transferred to a container.

Amlodipine and Benazepril Hydrochloride Combination-Part III :
The granulate from Part I and the dry mixture from Part II were placed in a blender and blended. Crospovidone was sieved and added to the blender and the mixture was blended. Next, the magnesium stearate was screened and added to the blender and the mixture was blended.

Encapsulation-Part IV :
The final blend of Part III was filled into capsules. Specific compositions are listed in Table 2.

Example 2: Stability study :
The degradation products of amlodipine besylate / benazepril hydrochloride capsules were measured by HPLC over 3 months at 40 ° C. and 75% relative humidity. The results are summarized in Table 3 below.

2 shows a flow chart for a method of manufacturing a capsule comprising a mixture of benazepril and amlodipine.

Claims (22)

A pharmaceutical composition comprising a) Benazepril or a solvate thereof, or a pharmaceutically acceptable salt thereof, and b) Amlodipine or a solvate thereof, or a pharmaceutically acceptable salt thereof. The benazepril and amlodipine are not physically separated from each other and after about 3 months at about 40 ° C. and about 75% relative temperature,
i) with respect to benazepril, up to 2.5% by weight of (s, s) -diacid; and / or
ii) A pharmaceutical composition comprising not more than 0.3% by weight of impurity D with respect to amlodipine.   The pharmaceutical composition according to claim 1, wherein the benazepril and amlodipine are in physical contact with each other.   The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is encapsulated.   The pharmaceutical composition according to claim 1, wherein the benazepril is benazepril hydrochloride.   The pharmaceutical composition according to claim 1, wherein the amlodipine is amlodipine besylate.   The pharmaceutical composition according to claim 1, wherein the benazepril is prepared by wet granulation and the amlodipine is prepared by dry processing. a) preparing a benazepril composition by wet granulation;
b) preparing an amlodipine composition by dry processing; and c) contacting the benazepril composition and the amlodipine composition, and optionally adding excipients to obtain a combined pharmaceutical composition Method.   8. The method of claim 7, wherein the benazepril composition comprises benazepril hydrochloride and one or more pharmaceutical excipients.   The benazepril composition comprises one or more pharmaceutical excipients selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, microcrystalline cellulose, polysorbate 80 and povidone. The method of claim 8 comprising: The benazepril composition is based on the total benazepril composition,
a) about 5 to about 20% by weight of benazepril hydrochloride;
b) about 15 to about 20% by weight of pregelatinized starch;
c) about 25 to about 35% by weight lactose monohydrate;
d) about 10 to about 15 weight percent starch;
e) about 5% by weight of crospovidone;
f) about 15 to about 25% by weight of microcrystalline cellulose;
10. The method of claim 9, comprising g) about 0.1 to about 2% by weight polysorbate 80; and h) about 5% by weight povidone. Preparation of benazepril composition by wet granulation,
a) combining benazepril hydrochloride with one or more pharmaceutical excipients selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose;
b) adding a granulation solution to obtain a wet granulation, wherein said granulation solution comprises water and optionally polysorbate 80, povidone or both;
8. The method of claim 7, comprising: c) drying the wet granulate to obtain a dry granulate; and d) pulverizing the dry granule.   8. The method of claim 7, wherein the amlodipine composition comprises amlodipine besylate and one or more pharmaceutical excipients.   8. The method of claim 7, wherein the amlodipine composition comprises one or more pharmaceutical excipients selected from the group consisting of dicalcium phosphate, sodium glycolate starch, microcrystalline cellulose, colloidal silicon dioxide. The amlodipine composition is based on the total amlodipine composition,
a) about 2 to about 10% by weight of amlodipine besylate;
b) about 25 to about 30% by weight of dicalcium phosphate;
c) about 1 to about 2 weight percent sodium glycolate starch;
14. The method of claim 13, comprising d) about 50 to about 60% by weight of microcrystalline cellulose; and e) about 1% by weight of colloidal silicon dioxide.   The method of claim 7, wherein the optionally added excipient comprises crospovidone and magnesium stearate.   8. The optionally added excipient comprises from about 1 to about 5% by weight crospovidone and from about 0.2 to about 2% by weight magnesium stearate, based on the total amlodipine composition. the method of. Preparation of amlodipine composition by dry processing,
a) screening a mixture of amlodipine besylate and one or more pharmaceutical excipients selected from the group consisting of dicalcium phosphate, sodium glycolate starch, microcrystalline cellulose, colloidal silicon dioxide; and b) 8. The method of claim 7, comprising blending the mixture. a) screening one or more additional pharmaceutical excipients selected from the group consisting of crospovidone and magnesium stearate; and b) blending the additional pharmaceutical excipients with the mixture The method of claim 7 comprising.   8. The method of claim 7, further comprising encapsulating the combined pharmaceutical composition. a) combining benazepril hydrochloride with one or more pharmaceutical excipients selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose;
b) adding a granulation solution to obtain a wet granulation, wherein said granulation solution comprises water, polysorbate 80 and povidone;
c) drying the wet granulate to obtain a dry granulate;
d) pulverizing the dried granulate;
e) A mixture of amlodipine besylate and one or more pharmaceutical excipients selected from the group consisting of dicalcium phosphate, sodium glycolate starch, microcrystalline cellulose, colloidal silicon dioxide through a 30 mesh sieve. Divided;
f) blending the mixture and the dry granulate to form a combined pharmaceutical composition;
g) sifting crospovidone through a 30 mesh sieve;
h) blending the crospovidone and the combined pharmaceutical composition;
i) sifting magnesium stearate through a 50 mesh screen;
8. The method of claim 7, comprising j) blending the magnesium stearate and the combined pharmaceutical composition; and k) encapsulating the combined pharmaceutical composition. For the total benazepril composition,
a) about 5 to about 20% by weight of benazepril hydrochloride;
b) about 15 to about 20% by weight of pregelatinized starch;
c) about 25 to about 35% by weight lactose monohydrate;
d) about 10 to about 15 weight percent starch;
e) about 5% by weight of crospovidone;
f) about 15 to about 25% by weight of microcrystalline cellulose;
g) a benazepril composition comprising about 0.1 to about 2% by weight of polysorbate 80; and h) about 5% by weight of povidone. For the total amlodipine composition,
a) about 2 to about 10% by weight of amlodipine besylate;
b) about 25 to about 30% by weight of dicalcium phosphate;
c) about 1 to about 2 weight percent sodium glycolate starch;
d) about 50 to about 60% by weight of microcrystalline cellulose;
e) about 1% by weight of colloidal silicon dioxide;
f) an amlodipine composition comprising about 5 wt% crospovidone; and g) about 0.2 to about 2 wt% magnesium stearate.

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