FIELD OF INVENTION
The present invention relates to oral pharmaceutical compositions comprising ACE inhibitor and a polymer. More particularly, the present invention is directed to pharmaceutical compositions comprising ramipril and a water-soluble polymer that stabilizes ramipril against decomposition into degradation products, during formulation and subsequent storage. The invention further relates to process of manufacturing such ramipril compositions.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ART
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.
Ramipril, chemically is (2S, 3aS, 6aS) - 1 [(S)-N-[(S)-l-carboxy-3-phenylpropylalanyl] octahydrocyclopenta [b] pyrroIe-2-carboxylic acid, I-ethyl ester (CAS No. 087333-19-5) is an angiotensin converting enzyme (ACE) inhibitor. It is an important ACE inhibitor used in the treatment of cardiovascular disease, especially hypertension, and it is one of the most frequently prescribed drugs for congestive heart failure. In hypertensive patients (hereinafter patient and subject can be used interchangeably), ramipril is known to reduce peripheral arterial resistance causing a reduction in blood pressure without a compensatory rise in heart rate.
ACE inhibitors work by blocking the action of ACE in human subjects and animals by binding to the zinc component of the ACE. Various ACE inhibitors are known, for example, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril and pharmaceutically acceptable forms. These drugs are highly susceptible to degradation during its manufacturing, and storage.

In general, drug stability is an important consideration during the design, manufacture and storage of pharmaceutical compositions. Drugs that lack stability can degrade into degradant products which can cause side effects or in some cases, can cause a decrease in the efficacy and bioavailability of the drug itself
U.S. 4,587,258 and EP 115,345 Bl disclose ramipril and its homologues along with their pharmaceutically acceptable salts. Ramipril is commercially sold as ALTACE® and is available in 1.25 mg, 2.5 mg, 5 mg and 10 mg strengths.
Even though ramipril is. without question, one of the most important ACE inhibitors available today, current ramipril formulations show a considerable degree of instability depending on the auxiliaries used, the manufacturing process and the storage.
In a recent communication from the British Pharmacopoeia, it was noted that the considered acceptable potency range of ramipril in a formulated product over its shelf life, was set between 90-105%. Standard potency limits have not, therefore, been applied, with the implication that ramipril is less stable in tablet or capsule formulations than the majority of products. It would, therefore, be desirable to develop a stable formulation that can comply with the 90-105% potency range over the expected shelf life of the product.
The degradation of ramipril is believed to occur mainly via two pathways: (a) hydrolysis to ramipril-diacid; and (b) cyclization or condensation to ramipril-diketopiperazine, also referred herein as ramipril-DKP. These ramipril-diacid and ramipril-DKP compounds are result of cyclization, condensation and or breakdown arising from exposure to heat, air, moisture, mechanical stress, compaction or other interactions or events. It is also known that the stability can be influenced by the choice of suitable auxiliaries, and that a significant cause of decomposition is the mechanical stress associated with the manufacturing process, especially when the active substance ramipril, is present in a mixture with auxiliaries and compressed to form tablets.

The major degradation product Identified in the British Pharmacopoeia is the diketopiperazine derivative (impurity D). The limits imposed by the British Pharmacopoeia on the diketopiperazine derivative infer that the loss in potency over the shelf life of the product would be expected to be due to the conversion of ramipril to the diketopiperazine degradation product. A limit of 8% and 6% for this degradant is applied to the capsule and tablet formulation respectively, and therefore by simple mass balance, the potency could fall below the standard lower limit of 90%. The limit imposed on other impurities including ramiprilat (impurity E) is set at levels below 0,5% and, therefore, such impurities as degradation products are considered to be undesirable.
There are many prior-arts which disclose ACE inhibitors compositions, such as that of ramipril and tried to overcome the formulation instability.
WO 03/059330 suggested that mechanical stress-induced degradation of ACE inhibitors such as ramipril, spirapril, lisinopril, enalapril, quinapril, benazepril or structurally-related ACE inhibitors can be avoided by coating a core of diluents and other formulating agents with a layer the ACE inhibitor. The core is compressed prior to coating with the ACE inhibitor, thereby avoiding the need to compress the ACE inhibitor and thus avoiding mechanical stress-induced degradation.
U.S. 4,743,450, U.S. 6,869,963, U.S. 2005/0142196 & U.S. 2003/0215526 describes compositions comprising ACE inhibitor (i.e. ramipril), and alkali or alkaline earth metal carbonate wherein the ACE inhibitor is stabilized against degradation.
U.S. 4,743,450 discloses that stable compositions containing ACE inhibitors can be produced using certain additives as stabilizers. Specifically, this patent discloses that the inorganic salts of metals of Group I and II of the Periodic Table act as stabilizers of ACE inhibitor containing formulations susceptible to certain types of degradation.

U.S. 2005/0202081 discloses use of inert cores which are coated with a seal coat polymer layer. Ramipril is layered upon this coated core and a final film coat is put above the drug layer, thereby preventing direct contact of ramipril with the excipients in the compressed tablet. Interestingly, this application states that the core should be inert or contain a drug other than ramipril. Purportedly, this is to prevent ramipril from degradation due to mechanical stress.
U.S. 2005/0069586, U.S. 2007/0212409, U.S.2008/0058404 discloses method of preparing a stable composition by forming an intimate admixture of the drug/ derivative and a lubricant and then blending the intimate admixture with at least one excipient. Preferably the final blend is transformed into solid unit dosage form.
U.S. 2006/0045911 discloses composition comprising ramipril or its pharmaceutically acceptable salt and an ammonio-methacrylate copolymer in a pharmaceutically acceptable carrier medium.
U.S. 5,442,008 and U.S. 5,151,433 from Hoechst, both discloses a method of making ramipril formulation by coating the drug with a polymeric coat [3 to 25% w/w of polymer w.r.t. the drug] to form cushioned agglomerates and then compressing the cushioned agglomerates so formed.
In view of the prior art, there lies a need to provide a stable and cost effective oral pharmaceutical formulations comprising ramipril or its pharmaceutically acceptable sah without utilizing expensive and or complicated technology. The present invention addresses the above drawbacks and relates to a stable, cost effective solid oral dosage form of ramipril where ramipril is granulated with a water soluble polymer and at least a pharmaceutically acceptable diluent, and wherein a buffering agent may not be required for imparting stability to the formulation.

SUMMARY AND OBJECTIVES OF THE INVENTION
Hoechst overcame the stability issues of ramipril by applying a commercially expensive and technically complicated technology (coating ramipril with a polymer) prior to compression where the coating composition contains polymer from about 3 to 25% relative to the weight of ramipril as well as the coated ramipril agglomerates were again mixed with a buffer to produce as stable formulation.
Surprisingly we have now discovered that the prior coating of ACE inhibitor utilizing expensive and complicated technology can be avoided by intimately mixing and granulating ACE inhibitor with a polymer in a very small amount i.e. below 3 % to produce a stable ramipril formulation, and a need of stabilizer/ buffering agent is avoided.
The present invention is based in part, that stable oral dosage forms comprising ACE inhibitor can be achieved by first intimately mixing a polymer and a pharmaceutically acceptable excipients with ACE inhibitor during manufacturing process. Without being limited to one particular theory, the inventors of the present invention believe that the intimate mixing and granulation of polymer and pharmaceutically acceptable excipients produces a ramipril granule in a conventional manner and that is able to protect the ramipril from physical and environmental stress that, under normal conditions, would cause the ramipril to degrade into degradant products such as ramipril-DKP and ramipril-diacid.
According to the present invention, there is provided a stable, cost effective solid oral dosage form comprising a) an active agent comprising an effective amount of an ACE inhibitor and its pharmaceutically acceptable salt thereof; b) a water-soluble polymer and c) pharmaceutically acceptable diluents, wherein the ACE inhibitor is intimately mixed and granulated with the water-soluble polymer and a diluent, prior to compression and where a buffering agent may not be required to impart stability to the final composition.

Another aspect of the invention is to provide a stable oral solid dosage form of an ACE inhibitor having a very small amount of polymer, preferably below 3% by weight to the total weight of composition.
Another aspect of the invention is to provide a process of manufacturing a pharmaceutical composition comprising ramipril and a water-soluble polymer.
Further object of the invention is to provide a comparable dissolution profile matching with the compositions of the present invention and the commercially available immediate release tablets of ramipril being marketed under the brand name of ALTACE®.
As presently contemplated, in one broad form, the invention also provides a process to make pharmaceutical compositions comprising the following steps:
(a) Intimate admixture comprising dissolving the ACE inhibitor or a
pharmaceutical acceptable salt thereof in a polymer solution;
(b) Granulate this solution with a pharmaceutically acceptable excipients to form a granulate;
(c) Blending the dry granulate with pharmaceutically acceptable excipients; and
(d) Compressing the blend to form tablets.
DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF THE INVENTION:
The present invention is related to a solid oral dosage form comprising a) an active agent comprising an effective amount of an ACE inhibitor and its pharmaceutically acceptable salt thereof; b) a water-soluble polymer and c) optionally pharmaceutically acceptable excipients, wherein the ACE inhibitor is intimately mixed and granulated with a polymer and other pharmaceutically acceptable excipients prior to compression.

The solid oral dosage form according to the invention wherein, the active agent ramipril or a pharmaceutically acceptable salt thereof, is preferably present in the amount from about 1.25 -20 mg, For e.g. in the dose of 1.25, 2.5, 5.0 & 10 mg per unit dosage form.
The solid oral dosage form may further comprise pharmaceutically acceptable additives known in the art. The term 'pharmaceutically acceptable additive' includes 'pharmaceutically acceptable excipients' within its ambit and the singular term includes plural as well. Pharmaceutically acceptable additives include disintegrants, binders, lubricants, glidants, fillers or diluents and the like.
The water-soluble polymers according to the invention are the one selected from among hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), methyl cellulose, carboxymethyl cellulose sodium (NaCMC), sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum, and the like
In the pharmaceutical composition, the pharmaceutically acceptable fillers or diluents, which include, but are not limited to mannitol, confectioner's sugar, compressible sugar, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dextrin, dextrose, lactose, magnesium oxide, maltodextrin, maltose, polydextrose, starch, pre-gelatinized starch and the like can be used.
Examples of suitable disintegrants according to the invention include but are not limited to starch, pre-gelatinized starch, sodium starch glycolate, cross-linked sodium carboxymethylcellulose, clays (e.g., magnesium aluminum silicate), microcrystalline cellulose, and others as known in the art.
Examples of suitable binders according to the invention include but are not limited to acacia, cellulose derivatives (such as methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose.

hydroxyethylcellulose), gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, starch paste, sucrose, sorbitol, pregelatinized starch, gum tragacanth, alginic acids and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites, and the like.
Examples of suitable glidants according to the invention include but are not limited to silicon dioxide, colloidal silicon dioxide, fumed silicon dioxide, sodium aluminosilicate, calcium silicate, asbestos free talc, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, stear-o-wet C and the like wherein colloidal silicon dioxide is the preferred glidant.
Examples of suitable lubricants according to the invention include but are not limited to magnesium stearate, talc, stearic acid, glyceryl behenate, sodium oleate, sodium stearyl fumarate, and others known in the art. Preferably, the lubricant is sodium stearyl fumarate.
Solvents that can be used to make polymer solution include aqueous and non-aqueous solvents, in a particularly preferred embodiment, the aqueous solvent consists essentially of water. Alternatively, the solvent comprises a mixture of water and alcohol.
The amount of each type of additive employed, e.g. glidant, binder, disintegrant, filler or diluent and lubricant may vary, within ranges conventional to the art. Thus for example, the amount of glidant may vary within a range of from 0.1 to 10% by weight, in particular 0.1 to 5% by weight, e.g. 0.1 to 0.5% by weight; the amount of disintegrant may vary within a range of from 2 to 20% by weight, e.g. \5% by weight; the amount of filler or diluent may vary within a range of from 5-60% by weight; whereas the amount of lubricant may vary within a range of from 0.1 to 5% by weight.
The solid oral dosage forms according to the invention can be prepared by intimate admixture comprising dissolving the active ingredient in a solution/dispersion of pharmaceutically acceptable polymer, ii) granulating

pharmaceutically acceptable excipients with this intimate admixture to form granulate Hi) granulate can optionally be blended with other excipients to form a final blend that is preferably transformed into solid unit dosage form, such as a tablets.
The term "intimate admixture" as used in the context of the present invention implies to a mixture of closely-packed components, such as those exemplified herein, for example granules, as opposed to a simple blend. An intimate admixture can be obtained, for example, by co-precipitation, co-milling, compression, granulation, or the like.
Preferably, the intimate admixture is in granular form. Granules can be formed, for example, by dry granulation or wet granulation. Wet granulation techniques are known in the art and involve mixing the ingredients with a solvent, such as ethanol or isopropyl alcohol, and drying the mixture to obtain granules. Dry granulation can be performed, for example, by compaction or slugging. Compaction techniques are well known in the art and typically include the use of a roller compactor. Slugging is a common technique in the field and involves the use of a roller machine to produce slugs and passing the slugs through a mill or an oscillating granulator to form granules.
The pharmaceutical composition of the present invention is preferably in solid unit dosage form, more preferably in tablet form. Conventional tableting processes can be employed, e.g., by forming a tablet from a desired mixture of ingredients into the appropriate shape using a conventional tablet press. Tablet formulation and processing techniques are generally known in the field.
According to the present invention, the use of hydroxypropylmethyl cellulose (HPMC) in sufficient amounts makes it possible to use pharmaceutical excipients conventionally used in the art to obtain oral stable pharmaceutical formulations comprising ramipril or its pharmaceutically acceptable salt with acceptable levels of impurity D. The preferred water soluble polymer i.e. HPMC may be used in amounts ranging from 0.5% to 2.5% by total weight of the tablet.

HPMC is used in an amount sufficient to provide a formulation that is stable, i.e. the impurity D during the shelf life of the formulation is less than 1%.
In one embodiment of the invention, the pharmaceutical composition is prepared by a process comprising:
(a) Intimate admixture comprising dissolving the ACE inhibitor or a
pharmaceutical acceptable salt thereof in a polymer solution;
(b) Granulating this solution with a pharmaceutically acceptable excipients to
form a granulate;
(c) Blending the dry granulate with pharmaceutically acceptable excipients; and
(d) Compressing the blend to form tablets.
One of the preferred embodiments of the invention involves a solid oral dosage form, which comprises as
a) the active agent in a unit dose of about 1.25 - 40% by weight to the total weight of formulation;
b) a water-soluble polymer [approx 0.5%-2.5% by weight to the total weight of composition];
c) pharmaceutical ly acceptable diluents in an amount about 5-60 % w/vv of the dosage form intimately mixed and granulated with ACE inhibitor.
The pharmaceutical compositions of the present invention have increased stability and shelf-life compared to current formulations. Additionally, the pharmaceutical compositions of the present invention allow ramipril to maintain potency, assuring health care providers and patients that they are giving and receiving consistent and exact treatment. The invention also contemplates reducing the rate of ramipril-DKP formation, especially under formulation and extended storage conditions. There is, therefore, a concomitant reduction in unit

cost for medicaments according to the invention over previously known formulations.
The functions and advantages of these and other embodiments of the present invention will be more fully understood from the examples below. The following examples are intended to illustrate the benefits of the present invention, but do not exemplify the full scope of the invention.
EXAMPLE 1:
Unit Composition

Brief manufacturing procedure:
1. Sift ingredient no. 1 & 2 through suitable screen.
2. Dissolve ingredient no. 2 in purified water.
3. Disperse ingredient no. I into the solution of step 2.
4. Load ingredient no. 3 in Rapid mixer granulator.
5. Add the dispersion of step 3 into step 4 in RMG and granulate.
6. Sift the wet mass of step 6 through suitable screen.
7. Dry the material of step 6 in Vacuum tray dryer.
S. Sift the dried granules of step 7 through suitable screen
9. Blend the granules of step 8 with the ingredient no. 4, 5 and 6.
10. Compress the core tablets of respective strengths, using rotary compression machine.

EXAMPLE 2:
Unit Composition

Brief manufacturing procedure:
1. Sift ingredient no. 1 & 2 through suitable screen.
2. Dissolve ingredient no. 2 in purified water.
3. Disperse ingredient no. 1 into the solution of step 2,
4. Load ingredient no. 3 in Rapid mixer granulator.
5. Add the dispersion of step 3 into step 4 in RMG and granulate.
6. Sift the wet mass of step 6 through suitable screen.
7. Dry the material of step 6 in Vacuum tray dryer.
8. Sift the dried granules of step 7 through suitable screen
9. Blend the granules of step 8 with the ingredient no.4, 5 and 6.
10. Compress the core tablets of respective strengths, using rotary compression machine.
Stability Studies:
The stability of the compositions disclosed in Examples 1 & 2 is carried out in HDPE bottles with screw on cap at 40°C / 75% RH for 3 months. The comparative results for Impurity D and Impurity E are given in Table 1 and Table 2 respectively.


The above stability data of the compositions prepared according to the present invention compiles with the current guidelines laid down by the British pharmacopeia, thus emphasizing the usefulness of the invention.
Dissolution Studies:
Comparative study of dissolution profile of ramipril l0mg tablets of present invention (examples 1& 2) with the commercially available ALTACE® l0 mg tablets are shown in Table 3.
Table 3:

WE CLAIM:
1. An oral pharmaceutical composition comprising an admixture of an effective amount of an ACE inhibitor or its pharmaceutically acceptable salt with a water-soluble polymer and optionally other pharmaceutically acceptable excipients.
2. The composition according to claim 1, wherein said admixture is in granular
form.
3. The composition according to claim 1, wherein said effective amount of the water-soluble polymer ranges from about 0.5% to about 2.5% by weight of total weight of the composition.
4. The composition according to claim 3, wherein said water-soluble polymer is selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, and guar gum.
5. The composition according to claim 4, wherein said water-soluble polymer is hydroxypropylmethylcellulose.
6. The composition according to claim 1, wherein said pharmaceutically
acceptable excipients include microcrystalline cellulose.
7. The composition according to claim 1, wherein said ACE inhibitor is selected from the group consisting of ramipril, quinapril, moexipril, fosinopril, enalapril, perindopril, and trandolapril.
8. The composition according to claim 7, wherein said ACE inhibitor is ramipril.
9. A process of preparing an oral pharmaceutical composition of ramipril
comprising:
i) preparing a solution of water-soluble polymer in a solvent, where in said water-

soluble polymer ranges from about 0.5% to about 2.5% by weight of total weight of the composition;
ii) mixing ramipril with above polymer solution, to form an admixture;
iii) granulating pharmaceutically acceptable excipients with said admixture to form granulate;
iv) optionally, blending said granulate with other pharmaceutically acceptable excipients and
v) transforming above blend into final composition.
10. The pharmaceutical composition of claim !, having a comparable dissolution profile to that of ALT ACE® 10 mg tablets.