WO2008068577A2

WO2008068577A2 - Pharmaceutical compositions

Info

Publication number: WO2008068577A2
Application number: PCT/IB2007/003705
Authority: WO
Inventors: Nilendu Sen; Sunil Mirajkar
Original assignee: Glenmark Pharmaceuticals Ltd
Current assignee: Glenmark Pharmaceuticals Ltd
Priority date: 2006-12-01
Filing date: 2007-11-30
Publication date: 2008-06-12
Anticipated expiration: 2009-06-01
Also published as: WO2008068577A3

Abstract

A solid pharmaceutical composition comprising (a) a diuretic; and (b) an angiotensin-converting enzyme (ACE) inhibitor, wherein about 100% of the particle size of the diuretic pass through a standard 60# mesh screen is disclosed.

Description

PHARMACEUTICAL COMPOSITIONS

PRIORITY

[0001] This application claims the benefit under 35 U.S.C. §119 to U.S.

Provisional Application No. 60/873,875, filed on December 8, 2006, and entitled "PHARMACEUTICAL COMPOSITIONS" and to Indian Provisional Application No. 1987/MUM/2006, filed on December 1, 2006, and entitled "PHARMACEUTICAL COMPOSITION COMPRISING PERINDOPRIL AND INDAPAMIDE AND PROCESS FOR MANUFACTURING THE SAME", the contents of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Technical Field

[0002] The present invention relates generally to a pharmaceutical composition containing a diuretic; and an angiotensin-converting enzyme (ACE) inhibitor, a process for its preparation and a method for the treatment of arteriolo-capillary microcirculatory disorders.

2. Description of the Related Art

[0003] ACE inhibitors are known. One example of an Ace inhibitor is perindopril erbumine, also known as (2S,3aS,7aS)-l-[(S)-N-[(S)-l-Carboxy-butyl]alanyl]hexahydro- 2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1), can be represented by the structure of Formula I:

I

The tert-butylamine salt of perindopril, also known as perindopril erbumine, is the form commercially sold under the trade name Aceon^®. Perindopril is the free acid form of perindopril erbumine and is an ethyl ester of a non-sulfhydryl ACE inhibitor. Perindopril is a pro-drug and is metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite. Perindopril is ordinarily used to treat hypertension.

[0004] The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium.

[0005] Indapamide, also known as 4-chloro-N-(2-methyl-l-indolinyl)-3- sulfamoylbenzamide, has a molecular weight of 365.84. Indapamide can be represented by the structure of Formula II:

Ct₆H₁₆CfN₃O₅S _(π)_

[0006] Indapamide is an oral antihypertensive/diuretic. Its molecule contains both a polar sulfamoyl chlorobenzamide moiety and a lipid- soluble methylindoline moiety. It differs chemically from the thiazides in that it does not possess the thiazide ring system and contains only one sulfonamide group. The compound is a weak acid, pK_a= 8.8, and is soluble in aqueous solutions of strong bases. It is a white to yellow- white crystalline (tetragonal) powder.

[0007] Indapamide contains both a polar sulfamoyl chlorobenzamide moiety and a lipid- soluble methylindoline moiety. Indapamide bears a structural similarity to the triazide diuretics which are known to decrease vascular smooth muscle reactivity. However, it differs chemically from the thiazides in that it does not possess the thiazide ring system and contains only one sulfonamide group. Indapamide appears to cause vasodilation, probably by inhibiting the passage of calcium and other ions (sodium, potassium) across membranes. This same effect may cause hypokalemia in susceptible individuals. Indapamide has also been shown to cause uterine myometrial relaxation in experimental animals. Overall, indapamide has an extra-renal antihypertensive action resulting in a decrease in vascular hyper reactivity and a reduction in total peripheral and arteriolar resistance.

[0008] Low-dose drug combinations have been proposed in International

Guidelines for use in patients with hypertension. The fixed low-dose combination of perindopril 2 mg with indapamide 0.625 mg combines an angiotensin converting enzyme (ACE) inhibitor with a non-thiazide diuretic. Co-administration of perindopril and indapamide did not have any clinically significant effects on the pharmacokinetic profile of either agent in healthy volunteers. In experimental models of hypertension, perindopril/indapamide restored endothelial function, improved microvascular density, reduced left ventricular and aortic hypertrophy, and reversed renal end-organ damage. Once daily oral perindopril 2mg/indapamide 0.625 mg normalised blood pressure (BP) in 83.6% of elderly patients with essential hypertension (diastolic BP was reduced to < or =90mm Hg) and 81.7% of those with isolated systolic hypertension (systolic BP was reduced to less than 160mm Hg) after approximately 1 year of treatment. BP normalization was sustained in 79.8% of patients throughout the study. Fixed low-dose perindopril/indapamide had a tolerability profile similar to that of placebo in clinical trials; most adverse events were of mild to moderate severity. Co-administration of the two agents reduced the incidence of hypokalemia compared with indapamide alone. Diuretics, commonly known as "water pills", help your body get rid of unneeded water and salt through the urine thereby making it easier for your heart to pump. (Drugs. 1999 Aug;58(2):297-302; pp. 303-4.)

[0009] U.S. Patent No. 6,653,336 discloses the use of a combination of an angiotensin converting enzyme inhibitor (CEI) and of a diuretic for producing pharmaceutical compositions intended for the treatment of arteriolo-capillary microcirculatory disorders. It would be desirable to provide improved to provide improved solid pharmaceutical composition is provided comprising (a)a diuretic; and (b) an angiotensin-converting enzyme (ACE) inhibitor.

U.S. Patent No. 6653336 ('336 Patent), herein incorporated by reference, invention relates to the use of a combination of an angiotensin converting enzyme inhibitor (CEI) and of a diuretic for producing pharmaceutical compositions intended for the treatment of arteriolo- capillary microcirculatory disorders. This patent in example 1 and 2 discloses the innovator's composition. While the inventors of the present invention tried reproducing example 1 and example 2 of '336 patent' using conventional technique, product was not found to bioequivalent to the marketed tablets formulation (Coversyl Plus), Indapamide fasting study data shows after reproducing the '336 disclosed formulation by conventional method , the ratio of means for the Indapamide Ln-transformed parameters Cmax, AUC (0-t), AUC --(O-oo) and tl/2 of means are 111.91 %, 110.76 %, 110.75 % and 104.75 % respectively. The 90 % Confidence Intervals for Cmax, AUC (0-t) and AUC -<0-∞) are (95.38 - 131.31) %, (100.45 - 122.12) % and (100.63 - 121.88) % respectively, Perindopril fasting study data under fasting conditions of the study, the ratio of means for the Perindopril Ln-transformed parameters Cmax, AUC (0-t), AUC ^(O-∞) and tl/2 of means are 80.43 %, 83.51 %, 83.76 % and 100.58 % respectively. The 90 % Confidence Intervals for Cmax, AUC (0-t) and AUC -(0-∞) are (69.42 - 93.18) %, (73.42 - 94.99) % and (73.64 - 95.27) % respectively .And Perindoprilate fasting study data under fasting conditions of the study, the ratio of means for the Perindoprilate Ln-transformed parameters Cmax, AUC (0-t), AUC -(0-∞) and tl/2 of means are 91.98 %, 92.86 %, 96.18 % and 106.75 % respectively. The 90 % Confidence Intervals for Cmax, AUC (0-t) and AUC - (O-∞) are (81.75 - 103.49) %, (87.85 - 98.16) % and (85.69 - 107.94) % respectively. As per the bioequivalence guidelines, test product is not bioequivalent to the Innovator's marketed product with respect to both Perindopril and Indapamide at the same time surprisingly the inventors of this application found that when the particle size of Indapamide is increased by roll compaction technique, the resultant product is expected to be bioequivalent to the 'Coversyl Plus'. SUMMARY OF THE INVENTION

[0010] In accordance with one embodiment of the present invention, a solid pharmaceutical composition is provided comprising (a) a diuretic; and (b) an angiotensin- converting enzyme (ACE) inhibitor; wherein about 100% of the particle size of the diuretic pass through a standard 60# mesh screen.

[0011] In accordance a second embodiment of the present invention, a process for preparing a pharmaceutical composition is provided comprising combining a diuretic and a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor in solid form.

[0012] In accordance a third embodiment of the present invention, a solid pharmaceutical composition is provided comprising (a) indapamide and (b) perindopril, wherein about 100% indapamide particle passing through 60# mesh or at least about 75% indapamide particles are retained on 100# or at most about 25% indapamide particles are retained on 80#.

[0013] In accordance with another embodiment of the present invention, a tablet composition is provided comprising perindopril as one active ingredient and indapamide as another active ingredient, wherein the composition is a physicochemically stable composition.

DEFINITIONS

[0014] The term "treating" or "treatment" of a state, disorder or condition as used herein means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0015] The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated. [0016] The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.

[0017] The term "pharmaceutically acceptable salts and esters" as used herein means those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulphate salts and the like. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts, and the like. [0018] The term "subject" or "a patient" or "a host" as used herein refers to mammalian animals, preferably human

[0019] The combination of (a) and (b) of the pharmaceutical composition of the present invention is believed to be clinically more effective due to the synergistic effects than the existing products alone or in combinations in the market. The pharmaceutical composition of the present invention is believed to be a bioequivalent product to Coversyl Plus. For example, the pharmaceutical composition of the present invention is believed to be a bioequivalent product to Coversyl Plus when the 100% of the particle size of the diuretic indapamide pass through a 60# mesh screen or at least about 75% of the particle size of the diuretic are retained on a 100# mesh screen or at most about 25% of the particle size of the diuretic are retained on s 80# mesh screen wherein the present particle size is achieved by using roll compaction technique (Mini Roll compactor machine of Make: Chamunda Pharma machinery pvt.ltd. (Clit) and Model: CPMMRC- 100/25 is used for roll compaction.).

DETAILED DESCRIPTION QF THE PREFERRED EMBODIMENTS [0020] The present invention is directed to a solid pharmaceutical composition is provided comprising (a) a diuretic; and (b) an angiotensin-converting enzyme (ACE) inhibitor; wherein 100% of the particle size of the diuretic pass through a standard 60# mesh screen. In one embodiment at least about 75% of the particle size of the diuretic are retained on 100# mesh screen. In another embodiment, at most about 25% of the particle size of the diuretic are retained on a 80# mesh screen. The particle size can be achieved using a roll compaction technique (e.g., Mini Roll compactor machine (Chamunda Pharma machinery pvt.ltd. (Clit) and Model CPMMRC-100/25)).

[0021] Suitable diuretics for use herein include indapamide and the like. Suitable

ACE inhibitors for use herein include perindopril, captopril, enalapril, lisinopril, delapril, fosinopril, quinapril, ramipril, spirapril, imidapril, trandolapril, benazepril, cilazapril, temocapril, pharmaceutically acceptable salts thereof and their addition salts with a pharmaceutically acceptable acid or base and the like and mixtures thereof. A preferred ACE inhibitor is perindopril or perindopril erbumine.

[0022] The pharmaceutical composition of the present invention can contain one or more pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include diluents, glidants, lubricants and the like and mixtures thereof.

[0023] The term "diluent" as used herein is intended to mean a substance that acts as filler in the formulation. Suitable diluents include, by way of example, microcrystalline cellulose, starch, lactose monohydrate, dicalcium phosphate, starch and the like and combinations thereof and other material known to those of ordinary skill in the art. [0024] The term "glidant" as used herein can be any glidant typically used in the pharmaceutical art for oral solid dosage forms. Examples include colloidal silicon dioxide, talc alone and magnesium stearate and the like and combinations thereof. The amount of glidants varies widely and will ordinarily ranges from about 0.1 % to about 5.0 % by weight, based on the total weight of the composition. [0025] The term "lubricant" as used herein can be any lubricant typically used in the pharmaceutical art for oral solid dosage forms. Example include stearate salts such as calcium stearate, magnesium stearate, zinc stearate and the like, stearic acid, talc, hydrogenated vegetable oil, vegetable oil derivatives, silica, silicones, high molecular weight polyalkyllene glycol and saturated fatty acids and the like and mixtures thereof. The amount of lubricant varies widely and will ordinarily ranges from about 0.1 % to about 5.0 % by weight, based on the total weight of the composition. [0026] The pharmaceutical compositions of the present invention may also contain other optional ingredients that are also typically used in pharmaceutical compositions such as, for example, coloring agents, preservatives, flavorings, and the like. [0027] In one embodiment, a pharmaceutical composition is a combination product of perindopril or a salt thereof and indapamide or a salt thereof in the form a stable pharmaceutical tablet formulation wherein about 100% indapamide particle passes through 60# or at least about 75% indapamide particles are retained on 100# or at most about 25% indapamide particles are retained on 80#.

[0028] The pharmaceutical compositions of the present invention in solid form are preferably tablets. Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.

[0029] The pharmaceutical compositions can be prepared using dry/wet granulation technique or any other suitable technique that is known to the person skilled in the art to obtain a tablet. [0030] The process can involve Roll Compaction of indapamide API compacted through a Roll- Compactor. The compacted mass of indapamide API is passed through a #80 mesh followed by dry mixing of pharmaceutically acceptable excipients with the drugs followed by lubrication and compression.

[0031] The following example is provided to enable one skilled in the art to practice the invention and is merely illustrative of the invention. The examples should not be read as limiting the scope of this invention.

EXAMPLE 1

[0032] Preparation of Perindopril-Indapamide Tablets (4/1.25 mg) [0033] The ingredients and amounts for this example are set forth below in Table

1.

TABLE l

[0034] Manufacturing Process

[0035] Roll Compaction: indapamide API Compacted through Roll - Compactor

Mini (Roll compactor machine of Make: Chamunda Pharma machinery pvt.ltd. (Clit) and Model: CPMMRC- 100/25). The compacted mass was passed through a #80 mesh screen. [0036] Dry Mixing: (a) perindopril, hydrophobic colloidal silicon dioxide and lactose monohydrate were mixed together and sifted through a #40 mesh screen. The sifted mass was then mixed for 3 minutes at 12 rpm. (b) indapamide, hydrophobic colloidal silicon dioxide and lactose monohydrate were mixed together and sifted through

#40 mesh screen. The sifted mass was then mixed for 3 minutes at 12 rpm. (c) microcrystalline cellulose followed by the mixtures of (a) and (b) were loaded in a blender and mixed for 3 minutes, (d) the blend of step (c) was sifted through a #40 mesh screen, again reloaded into the blender and mixed for 10 minutes.

[0037] Lubrication: Magnesium stearate (Previously sifted through a # 60 mesh screen) was added to the blend of step (d) and mixed for 5 minutes.

[0038] Compression: The lubricated blend was compressed into tablets using suitable punch and die set.

EXAMPLE 2

[0039] Preparation of Perindopril-Indapamide Tablets (2/0.625 mg) [0040] The ingredients and amounts for this example are set forth below in Table

2.

TABLE 2

[0041] Manufacturing Process

[0042] Roll Compaction: indapamide API Compacted through Roll - Compactor

Mini (Roll compactor machine of Make: Chamunda Pharma machinery pvt.ltd. (Clit) and Model: CPMMRC-100/25). The compacted mass was passed through a #80 mesh screen. [0043] Dry Mixing: (a) perindopril, hydrophobic colloidal silicon dioxide and lactose monohydrate were mixed together and sifted through a #40 mesh screen. The sifted mass was then mixed for 3 minutes at 12 rpm. (b) indapamide, hydrophobic colloidal silicon dioxide and lactose monohydrate were mixed together and sifted through #40 mesh screen. The sifted mass was then mixed for 3 minutes at 12 rpm. (c) microcrystalline cellulose followed by the mixtures of (a) and (b) were loaded in a blender and mixed for 3 minutes, (d) the blend of step (c) was sifted through a #40 mesh screen, again reloaded into the blender and mixed for 10 minutes.

[0044] Lubrication: Magnesium stearate (Previously sifted through a # 60 mesh screen) was added to the blend of step (d) and mixed for 5 minutes. [0045] Compression: The lubricated blend was compressed into tablets using suitable punch and die set.

EXAMPLE 3

[0046] The in vitro dissolution profile achieved in pH 4.5 acetate buffer at 75 rpm, for the tablet of Example 1 was comparable with that of the innovators Coversyl Plus tablets as shown below in Table 3.

Table 3

[0047] It has been observed by the inventors of this application that indapamide particle size D₉o=48 microns results in a bioequivalent product as compared to Coversyl Plus (Indapamide) when formulated using conventional methods for the present combination. The inventors believe that by roll compaction of indapamide having particle size U₉o= 48 micron, one could achieve the product which is bioequivalent to innovator's Coversyl Plus.

[0048] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Claims

WHAT IS CLAIMED IS:

1. A solid pharmaceutical composition comprising (a) a diuretic; and (b) an angiotensin-converting enzyme (ACE) inhibitor; wherein about 100% of the particle size of the diuretic passes through a standard 60# mesh screen.

2. The pharmaceutical composition of claim 1, wherein the diuretic is indapamide.

3. The pharmaceutical composition of claims 1 and 2, wherein the ACE inhibitor is selected from the group consisting of perindopril, captopril, enalapril, lisinopril, delapril, fosinopril, quinapril, ramipril, spirapril, imidapril, trandolapril, benazepril, cilazapril temocapril, pharmaceutically acceptable salts thereof and combinations thereof.

4. The pharmaceutical composition of claim 1, wherein the (ACE) inhibitor is perindopril erbumine.

5. The pharmaceutical composition of claims 1-4, wherein about 100% of the diuretic particles pass through a 60# or at most about 25 % of the diuretic particles are retained on a 100# mesh screen.

6. The pharmaceutical composition of claims 1-5, further comprising one or more pharmaceutically acceptable excipients.

7. The pharmaceutical composition of claims 1-6, further comprising about 0.1 % to about 5.0 % by weight of a glidant, based on the total weight of the composition.

8. The pharmaceutical composition of claims 1-7, further comprising about 0.1 % to about 5.0 % by weight of a lubricant, based on the total weight of the composition.

9. The pharmaceutical composition of claims 1-8, in the form of a tablet.

10. A process for preparing a solid pharmaceutical composition comprising (a) roll compacting a diuretic; (b) passing the compacted mass through a 60-100 mesh screen; (c) dry mixing one or more pharmaceutically acceptable excipients and an ACE inhibitor; (d) lubricating the dry mix; and (e) compressing the lubricated dry mix.

11. The process of claim 10, wherein the diuretic is indapamide.

12. The process of claims 10 and 11, wherein the ACE inhibitor is selected from the group consisting of perindopril, captopril, enalapril, lisinopril, delapril, fosinopril, quinapril, ramipril, spirapril, imidapril, trandolapril, benazepril, cilazapril temocapril, pharmaceutically acceptable salts thereof and combinations thereof.

13. The process of claim 10, wherein the (ACE) inhibitor is perindopril erbumine.

14. The process of claims 10-13, wherein about 100% of the diuretic particles pass through a 60# or at most about 25 % of the diuretic particles are retained on a 100# mesh screen.

15. A solid pharmaceutical composition comprising (a) a diuretic; and (b) an angiotensin-converting enzyme (ACE) inhibitor; wherein about 75% of the particle size of the diuretic passes through a standard 80# mesh screen.

16. The use of a pharmaceutical composition according to claims 1-9 in the treatment of arteriolo-capillary microcirculatory disorders in a subject in need of treatment.