FIELD OF INVENTION

The invention relates to oral pharmaceutical compositions comprising amorphous perindopril or its pharmaceutically acceptable salts, and mixtures thereof.

More particularly, the invention is related to oral pharmaceutical compositions comprising perindopril arginine, wherein said composition comprises stable amorphous solid dispersion of perindopril arginine in combination with pharmaceutically acceptable carriers and optionally other pharmaceutical excipients.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Perindopril is an antihypertensive compound which especially has an inhibitory action on certain enzymes such as carboxypolypeptidases, enkephalinases or kininase II. It inhibits especially the conversion of decapeptide angiotensin I to octapeptide angiotensin II (which is in certain cases responsible for arterial hypertension) by acting on the converting enzyme.

Chemically it is (2S)-2-[(1S)-1-carbethoxybutylamino]-l-oxopropyl- (2S,3aS,7aS)-perhydroindole-2-carboxylic acid of formula (I), known generically as perindopril and its pharmaceutically acceptable salts, specially salt of perindopril with tertiary butyl amine i.e., perindopril erbumine and perindopril with L-arginine i.e., perindopril arginine are commercially available versions of perindopril which are useful for the treatment of hypertension.

WO 03/087050 discloses the arginine salt of perindopril and its hydrates and compositions comprising it.

Perindopril arginine is known to exist in different polymorphic forms, for e.g., WO 2007/099216 discloses the P-crystalline form of perindopril arginine; its preparation and compositions comprising it.

Similarly, WO 2007/099217 discloses the a-crystalline form of perindopril arginine; its preparation and compositions comprising it.

New forms of pharmaceutical compounds provide an opportunity to improve the physicochemical and performance characteristics of such compounds. Further the discovery of new polymorphic forms may also help in identification of the potential advantages of a particular morph over the existing ones.

However, different polymorphs of a pharmaceutical compound generally suffer from the drawbacks of conversion to other crystalline forms on storage resulting in a concomitant change in not only the physical form and shape of their individual crystals, but also the associated physicochemical and biological characteristics. Ideally, molecules will revert back to the most thermodynamically stable form, this being the form with the least solubility and greater stability. Such thermodynamically stable forms generally possess suboptimal solubility and bioavailability.

To overcome this drawback, pharmaceutical scientists endeavor to provide amorphous forms of crystalline pharmaceutical compounds, which would have the strengths of the crystalline forms, viz. thermodynamically stability, and those of the amorphous form, viz. enhanced solubility, rapid onset of action and an enhanced bioavailability.

However, amorphous forms do have their own drawbacks, such as those of high hygroscopicity and physical instability. In case of perindopril arginine, the amorphous form is highly hygroscopic and tends to convert to crystalline form once it is exposed to atmosphere at normal conditions, thus suggesting the need for improvement in the present state of the art.

Thus there is a widely recognized need for, and it would be highly advantageous to have stable amorphous form of perindopril arginine and process for preparation thereof, to avoid limitations of the above problems.

It has been unexpectly found that the above problem can be addressed by incorporating amorphous perindopril arginine in a suitable polymeric carrier in the form of solid dispersion.

This and other such needs are addressed by the invention.

SUMMARY AND OBJECTIVE OF THE INVENTION

The invention relates to oral pharmaceutical compositions comprising amorphous perindopril or its pharmaceutically acceptable salts, and mixtures thereof.

More particularly, the invention is related to oral pharmaceutical compositions comprising perindopril arginine, wherein said composition comprises stable amorphous solid dispersion of perindopril arginine in combination with pharmaceutical acceptable carriers and optionally other pharmaceutical excipients.

In an embodiment, the invention provides stable amorphous perindopril arginine in combination with one or more pharmaceutically acceptable carrier.

In one embodiment, the invention provides stable amorphous solid dispersion of perindopril arginine in combination with one or more pharmaceutically acceptable carrier.

In an another embodiment, the invention provides a process for preparing stable amorphous solid dispersion of perindopril arginine, which comprises lyophilizing a solution of perindopril arginine alone or in combination with one or more pharmaceutically acceptable carrier.
In another embodiment, the invention provides oral pharmaceutical compositions comprising stable amorphous perindopril arginine solid dispersion and one or more pharmaceutically acceptable excipient.

In yet another embodiment, the invention provides a process for preparing oral pharmaceutical composition comprising stable amorphous perindopril solid dispersion and one or more pharmaceutically acceptable excipient.

Further embodiment of the invention provides for oral pharmaceutical compositions of perindopril arginine wherein the in-vitro dissolution release profile matches with the commercially available formulations of perindopril arginine.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1: X-ray powder diffraction of amorphous perindopril arginine active pharmaceutical ingredient (Initial).

Fig. 2: X-ray powder diffraction of amorphous perindopril arginine kept open at room temperature after 48 hrs.

Fig. 3: X-ray powder diffraction of solid dispersion of perindopril arginine with PVP (Initial).

Fig. 4: X-ray powder diffraction of solid dispersion of perindopril arginine with PVP after exposure to 40°C/ 75%RH for 48hrs.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to oral pharmaceutical compositions comprising amorphous perindopril or its pharmaceutically acceptable salts, and mixtures thereof.

More particularly, the invention is related to oral pharmaceutical compositions comprising perindopril arginine, wherein said composition comprises stable amorphous solid dispersion of perindopril arginine in combination with pharmaceutical acceptable carriers and optionally other pharmaceutical excipients.

An embodiment of the invention provides for solid dispersion of amorphous perindopril arginine in combination with one or more pharmaceutically acceptable carriers.

In another embodiment, the invention provides for oral pharmaceutical compositions comprising stable amorphous perindopril arginine solid dispersion and one or more pharmaceutically acceptable excipient.

In another embodiment, the invention provides for the process of preparation of stable amorphous perindopril arginine solid dispersion in combination with one or more pharmaceutically acceptable carriers.

Further embodiment of the invention also provide for the process of preparation of solid oral compositions comprising stable amorphous perindopril arginine solid dispersions in combination with pharmaceutically acceptable excipients.

In context of the invention, terms "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for perinodpril arginine.

The term "solid dispersion" as used herein refers to a solid system of amorphous perindopril arginine with one or more pharmaceutically acceptable carrier, wherein each particle of amorphous perindopril arginine is molecularly dispersed and intimately mixed with one or more carrier and thus forms a continuous matrix wherein the drug is homogeneously distributed in solution or in particulate form.

The term "amorphous" as used herein refers to a non-crystalline, porous particulate form exhibiting advantageous properties, over the crystalline perindopril arginine. Amorphous materials do not exhibit the three-dimensional long-range order found in crystalline materials but are structurally more similar to liquids where the arrangement of molecules is random.

The term "stable" as used herein refers to the ability or tendency to remain substantially in the same physical form for at least a certain period of time. The time period may be at least a month, preferably at least 6 months, more preferably at least a year, still more preferably at least 3 years, even still more preferably at least 5 years, when stored under ambient conditions.

Substantially the same physical form in this context means that at least 80%, preferably at least 90% and more preferably at least 99% of the amorphous form remains.

Amorphous solids are not crystalline and therefore do not give a definitive x-ray diffraction pattern. The preferred method of differentiating amorphous solid dispersion of perindopril arginine from other crystalline and non-crystalline forms of perindopril arginine is X-ray powder diffraction (XRPD). The XRPD pattern of amorphous perindopril arginine active ingredient and amorphous solid dispersion of perindopril arginine, as illustrated in Fig. 1, Fig. 3 and Fig. 4 respectively can be seen to lack discernible acute peaks. Thus, amorphous perindopril arginine, according to the present invention, is characterized in providing an X-ray powder diffraction pattern containing one or more broad diffuse halos having very low counts (i.e. see Fig. 1) in contrast to the sharp diffraction peaks characteristic of crystalline materials (i.e. see Fig. 2).

Thus, according to a further embodiment of the invention there is provided amorphous solid dispersion of perindopril arginine characterized in providing an X-ray powder diffraction pattern containing one or more broad diffuse halos, and preferably having very low counts (lacking any discernible peaks).

The term "broad diffuse halo" in the art, is a recognized term for the 'humps' observed in XRPD.

Other methods to distinguish amorphous form of perindopril arginine solid dispersion from crystalline form include Raman spectroscopy, solution calorimetry, differential scarming calorimetry, solid state nuclear magnetic resonance spectra (ssNMR) or infra-red spectroscopy. Each of these techniques is well established in the art.

The preferred method of differentiating amorphous perindopril arginine from other crystalline and non-crystalline forms is X-ray powder diffraction (XRPD).

An embodiment of the invention provides a stable solid amorphous dispersion of perindopril arginine in combination with one or more pharmaceutically acceptable inert carriers.
An embodiment of the invention provides a stable solid amorphous dispersion of perindopril arginine, wherein said perindopril arginine can be in crystalline form, a mixture of crystalline and amorphous form or purely amorphous form.

Suitable pharmaceutically acceptable inert carriers which can be used in combination with amorphous perindopril arginine to form the solid dispersion include but are not limited to hydrophilic carriers like polymers of N-vinyl pyrrolidone commonly known as polyvinylpyrrolidone (PVP), gums, cellulose derivatives, cyclodextrins, gelatins, hypromellose, hypromellose phthalate, sugars, polyhydric alcohols, polyethylene glycol, polyethylene oxides, polyoxyalkylene derivatives, methacrylic acid copolymers, polyvinyl alcohol, propylene glycol derivatives and the like.

Useful pyrrolidones include, but are not limited to homopolymers or copolymers of N-vinyl pyrrolidone. Such polymers are known to form complexes with a variety of compounds. The water-soluble forms of N-vinyl pyrrolidone are available in a variety of viscosity and molecular grades and may be chosen from and but not limited, to PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-90, PVP K-120, cros-povidone and the like; cellulose derivatives such as ethyl cellulose, hypromellose, hydroxypropyl cellulose, microcrystalline cellulose and the like. Any of the above mentioned pharmaceutically acceptable carriers could be chosen, including their mixtures.

Any pharmaceutical carrier is acceptable as long as it allows the formation of stable amorphous solid dispersion of perindopril arginine as described herein, is compatible with perindopril arginine and is acceptable for pharmaceutical use. The choice of such a carrier is within the scope of imderstanding of a person skilled in the art and is not limited by the above listed examples.

The weight ratio between of amorphous perindopril arginine and pharmaceutical carrier ranges between about 1:0.01 to about 1: 100.

In an another embodiment, the invention provides a process for preparing stable amorphous solid dispersion of perindopril arginine, which comprises lyophilizing a solution of perindopril arginine alone or in combination with one or more pharmaceutically acceptable carrier. The process may include optionally further drying of the perindopril arginine solution.

The solution of perindopril arginine can be obtained by dissolving the drug in a suitable solvent. The solvent which can be used, can be any solvent from the various classes of solvents such as for example alcohols, glycols, acids, water, aprotic polar solvents or mixtures thereof Preferably water or a hydro-alcoholic solvent or their aqueous combinations in various ratios without any limitations are included within the scope of the invention.

In order to get the amorphous solid dispersion of perindopril arginine, the solvent have to be dried or removed from perindopril arginine solution. The solvent(s) can be removed from the solution by techniques known in the art which includes but are not limited to distillation, evaporation, oven drying, tray drying, rotational drying, spray drying, freeze-drying, fluid bed drying, flash drying, spin flash drying and the like. Preferably, the process of lyophilization is employed to get the amorphous solid dispersion of perindopril arginine.

The process may optionally include further drying of the product in the presence or absence of inert atmosphere. Other conventional drying methods known in the art can also be used.

In another embodiment, the invention provides oral pharmaceutical compositions comprising stable amorphous perindopril arginine solid dispersion and one or more pharmaceutically acceptable excipient.

In yet another embodiment, the invention provides a process for preparing oral pharmaceutical composition comprising stable amorphous perindopril solid dispersion and one or more pharmaceutically acceptable excipient.

The amorphous solid dispersion of perindopril arginine of the invention can be formulated as solid compositions for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferably the composition in the form of tablets, mini-tablets, capsules or granules are preferred. In these compositions, the active substance in the form of amorphous solid dispersion is mixed with one or more pharmaceutically acceptable excipients.

According to the invention, weight of the orally administrable composition comprising from about Img to about 25mg of perindopril arginine in the form of amorphous solid dispersion ranges between about 25mg to about 450mg; or more preferably between about 75 mg to about 250mg.

Pharmaceutically acceptable excipients which can be used in preparation of the composition according to the invention may include, but are not limited to diluents such as microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, calciirai carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcivmi phosphate, magnesium carbonate, magnesium oxide and the like; binders such as PVP, cellulose derivatives such as hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, carboxy methyl cellulose sodium, starch and the likes; disintegrants such as cros-povidone, sodium starch glycolate, starch and its derivatives, low- substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose and the like; glidant and lubricants such as colloidal silicon dioxide, talc, stearic acid and its salts and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to fihn former, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Compositions according to the invention are prepared by forming a homogenous matrix in which the active ingredient in the form of amorphous solid dispersion is combined with other pharmaceutically acceptable excipients and are granulated suitably, compressing granulates and other optional excipients into tablets and then optionally coating this matrix tablet with an outer film coat.

To form the tablet matrix or core, granulation techniques such as dry granulation or wet granulation is employed. In dry granulation, the ingredients are blended in dry form, made denser by slugging or compaction and reduced to granules by grinding or milling, using suitable equipments. The ground particles or granules are then compressed into tablet form in conventional maimer using lubricants, glidants, etc., which can take any of the conventional shapes, e.g..

round, elongated, oval, etc. A tablet press fitted with suitably sized punches and dies is used to form the tablet core.

The wet granulation technique can also be used. According to this procedure, the dry active ingredient, other diluents are blended, for example, in a planetary mixer or a rapid mixer granulator. The powders are wetted with a granulating liquid like water, isopropyl alcohol or acetone or dichloromethane and other hydro-alcoholic solvents such as isopropyl alcohol-water mixture. Binders may be included in the granulating liquid. The moist mass is granulated, e.g., by forcing through a screen of suitable mesh size, dried, and, if desired, the particles further reduced in size. Granulates are then compressed in conventional manner, using lubricants, glidants, etc., as required.

The core can optionally be coated with a film coat, which provides an aesthetic appeal or can also provide some functional role such as moisture protection, taste masking etc. The film coat may comprise polymers such as cellulose derivatives such as one which is commercially available as Opadry®.

Conventional coating machines, for example, pan coaters, rotary drum- type coaters, Wurster-type fluidizing coaters and fluidizing coaters may be employed in the method of the invention.
Further embodiment of the invention provides for pharmaceutical compositions of perindopril arginine wherein the in-vitro dissolution release profile matches with the commercially available compositions of perindopril arginine.

The compositions according to the invention can be used for treatment of hypertension, symptomatic heart failure, coronary artery disease, congestive heart disease and any other such disease conditions.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any maimer.

A. Amorphous solid dispersion of perindopril arginine
Example: 1

Ingredients mg

Perindopril arginine (amorphous) 2.5

PVP K-30 25

Purified water q.s.

Brief manufacturing procedure:

1. Perindopril arginine and PVP K-30 are dissolved in purified water.

2. Above solution is defreezed at -20°C for 2-3 hours.

3. Previously chilled round bottom flask is attached to the lyophilizer at room temperature.

4. Vacuum is applied and pressure is reduced to a range of 70-130 mTorr.

5. Solution of step 2 is lyophilized in above conditions for 48 hrs to get the dry powder.

The amorphous solid dispersion prepared according to Example 1 was subjected to stress conditions at 40°C/ 75%RH for 48 hours, and the X-ray diffraction pattern obtained (Fig. 3 and Fig. 4) demonstrate the amorphous nature of the solid dispersion of perindopril arginine both initially (Fig. 3) as well as after being subjected to stress conditions (Fig. 4) vis-a-vis amorphous perindopril arginine being kept at room temperature in the open for 48 hrs (Fig. 2), which converts to various crystalline forms.
These X-ray diffraction patterns of the solid dispersion of amorphous perindopril arginine demonstrate that perindopril arginine is in the form of molecular dispersion both in initial samples as well as in the stressed samples.

Preliminary impurity profile generated for the solid amorphous dispersion of perindopril arginine also demonstrates its stability under the stressed conditions. The data for the same is given below:

Impurity Initial 40°C/ 75%RH

(48 Hrs)

Imp B Not Detected Not Detected Imp F 0.34 0.26
B. Compositions comprising amorphous perindopril arginine

Example 2:
Ingredients mg/tab
Perindopril arginine (Amorphous) 2.50
PVP K-30 25.00
Methanol q.s.
Mannitol 75.30
Sodium starch glycolate 5.00
Hydrophobic silica 1.10
Magnesium stearate 1.10
Core weight 110.00
Opadry AMB 2.75
Coated Tablet weight 112.75

Brief Manufacturing Procedure:

1. Perindopril arginine and PVP K-30 is dissolved in methanol and sprayed on maimitol in fluid bed processor.

2. Granules of step 1 are mixed with sodixmi starch glycolate.

3. Hydrophobic siUca and magnesinm stearate is mixed with the blend of step 2.

4. Blend of step 3 compressed in to tablets.

5. Tablets of step 4 coated in perforated coating pan with Opadry AMB keeping product bed temperature about 30°C.

Example 3:

Ingredients mg/tab

Perindopril arginine (Amorphous) 2.50
PVP K-30 25.00
Methanol q.s.
Magnesium oxide 0.55
Maimitol 74.75
Sodium starch glycolate 5.00
Hydrophobic silica 1.10
Magnesivim stearate 1.10
Core weight 110.00
Opadry AMB 2.75
Coated Tablet weight 112.75

Brief Manufacturing Procedure:

1. Perindopril arginine, PVP K-30 and magnesium oxide are dispersed in methanol and sprayed on mannitol in fluid bed processor.

2. Granules of step 1 are mixed with sodium starch glycolate.

3. Hydrophobic silica and magnesium stearate are mixed with the blend of step 2.

4. Blend of step 3 compressed in to tablets.

5. Tablets of step 4 coated in perforated coating pan with Opadry AMB keeping product bed temperature about 30°C.

Example 4:

Ingredients mg/tab
Perindopril arginine (Amorphous) 2.50
PVP K-30 10.00 Methanol q.s.
Mannitol 28.00
Sodium starch glycolate 0.90
Crospovidone 2.25
Hydrophobic silica 0.45
Magnesium stearate 0.90
Core weight 45.00
Opadry AMB 1.00
Coated Tablet weight 46.00

Brief Manufacturing Process:

1. Perindopril arginine and PVP K-30 are dissolved in methanol and sprayed on mannitol and crospovidone blend in fluid bed processor to prepare granules.

2. Granules of step 1 are mixed with sodium starch glycolate.

3. Hydrophobic silica and magnesium stearate are mixed with the blend of step 2.

4. Blend of step 3 compressed in to tablets.

5. Tablets of step 4 coated in perforated coating pan with Opadry AMB keeping product bed temperature about 30°C.

Stability Studies

Compositions comprising amorphous perindopril arginine, disclosed above were subjected to stability studies and the tablets packed in HDPE bottle were stressed at 40°C and 75% relative humidity for 3 months, to record the degradation products and related substances formed. Impvirity profile generated for said tablets comprising amorphous dispersion of perindopril arginine is shown below in comparison with that of the commercially available Coversyl™ tablets.

Stability of the compositions according to the invention was comparable with commercially available Coversyl™ tablets.

Product Coversyl™ Example 4 Coversyl™ Example 4
Duration Initial Initial 3 months 3 months
[Condition] [40°C/75%RH] [40°C/75%RH]
Impurity % w/w % w/w % w/w % w/w
Impurity B 0.17 0.19 0.55 0.76
Impurity F 0.20 0.20 0.28 0.38
Highest unknown 0.08 0.06 0.15 0.17
Total Impurities 0.71 1.03 1.89 2.51

Dissolution Studies

Compositions comprising amorphous perindopril arginine, disclosed above were studied for drug release in the conditions enumerated below and compared with the commercially available Coversyl TM tablets. Drug release of said compositions according to the invention was comparable with commercially available Coversyl™ tablets.

Media: O.IN HCl Volume: 900mL Apparatus: USPII [Paddle] Rotational Speed: 50 rpm
% Drug Release Time(min) Coversyl™ Example 4

10 77 73
15 91 85
30 98 90
45 98 98

WE CLAIM

1. An amorphous solid dispersion comprising:

i. perindopril or a pharmaceutically acceptable salts thereof;

ii. a pharmaceutically acceptable carrier and optionally other excipients;

wherein said perindopril or a pharmaceutically acceptable salts thereof within the dispersion is in substantially amorphous form.

2. A pharmaceutical composition comprising an amorphous solid dispersion of perindopril or a pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, wherein said perindopril or its pharmaceutically acceptable salts thereof within the composition is in substantially amorphous form.

3. The amorphous solid dispersion according to claim 1, wherein said perindopril is present as perindopril arginine.

4. The amorphous solid dispersion according to claim 1, wherein said pharmaceutically acceptable carrier is selected from the group comprising hypromellose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, hyromellose phthalate, methacrylic acid copolymers, gelatin and gums.

5. The amorphous solid dispersion according to claim 4, wherein said pharmaceutically acceptable carrier is polyvinylpyrrolidone.

6. A process of preparing an amorphous solid dispersion, comprising:

i. forming a mixture comprising perindopril or a pharmaceutically acceptable salts thereof, a pharmaceutically acceptable carrier, optionally other excipient, and a solvent; and

ii. lyophilizing said mixture to result in an amorphous dispersion;
wherein said perindopril or a pharmaceutical acceptable salt thereof within the dispersion is in substantially amorphous form.

7. The process according to claim 6, wherein said solvent is water or a mixture of water and a water miscible organic solvent.

8. The pharmaceutical composition according to claim 2, wherein said pharmaceutically acceptable excipient is selected among diluents, fillers, binders, disintegrants, solubilizers, surfactants, glidants and lubricants.

9. The pharmaceutical composition according to claim 2, wherein said composition is in the form of tablets, capsules, pellets, granules, powders, dispersion or sachets.

10. The amorphous solid dispersion according to claim 1, wherein said dispersion is a lyophilized mixture of perindopril or a pharmaceutically acceptable salts thereof, a pharmaceutically acceptable carrier and optionally other excipient.