The present invention relates to stabilized pharmaceutical compositions of Angiotensin Converting Enzyme (ACE) inhibitors using low amount of magnesium carbonate as the stabilizing agent; and process for preparation thereof.
Certain class of ACE inhibitors are unstable, in that they are highly susceptible to decomposition by cyclization, hydrolysis and oxidation. It is believed that one or more of these types of decomposition results when these compounds are formulated into pharmaceutical dosage forms.
Anti-hypertensive compounds such as quinapril, moexipril, enalapril, ramipril, indolapril and other structurally related ACE inhibitors undergo cyclization via internal nucleophilic attack to form substituted diketopiperazines. In addition they may form diacids via hydrolysis or may undergo oxidation. It is their conversion to these unwanted substances, which can result in lessened drug effectiveness in compositions containing these types of compounds.
Various approaches have been proposed and used to stabilize pharmaceutical compositions comprising ACE inhibitors of the class as mentioned herein. For example US patent 4743450 discloses the use of effective amount of alkali or alkaline earth metal salts and saccharides as stabilizers. The effective amount of alkali or alkaline earth metal salts is disclosed to vary from as low as 1 % w/w to as high as 90% w/w. However, all the examples cited herein use substantially higher amounts (> 45%) of magnesium carbonate in combination with hydrolysis minimizing agent as the stabilizer. Hence it appears that pharmaceutical compositions comprising ACE inhibitors of the class mentioned herein can be stabilized only with higher amount of alkali carbonate.
While magnesium carbonate acts as an effective stabilizer of ACE inhibitors, its use in pharmaceutical formulations in substantially higher quantities represent certain disadvantages in that magnesium carbonate, being a bulky powder, is difficult to formulate into dosage form because of its poor compressibility, moldability and flowability.
Hence, there exists a need of stabilizing ACE inhibitors in pharmaceutical compositions, using a comparatively low amount of alkali carbonates, which would not affect processing of dosage forms.
We have now developed a stabilized pharmaceutical composition of an ACE inhibitor that is susceptible to cyclization, hydrolysis and discoloration, using low amount of magnesium carbonate as stabilizing agent.
Hence in one aspect there is provided a stabilized pharmaceutical composition of ACE inhibitor comprising an effective amount of ACE inhibitor and 15 to 40% w/w of magnesium carbonate as stabilizing agent.
In another aspect there is provided a stabilized pharmaceutical composition of quinapril comprising an effective amount of quinapril and 15 to 40% w/w of magnesium carbonate as the stabilizing agent.
In another aspect there is provided a stabilized pharmaceutical composition of moexipril comprising an effective amount of moexipril and 15 to 40% w/w of magnesium carbonate as the stabilizing agent.
In another aspect there is provided a stabilized pharmaceutical composition of enalapril comprising an effective amount of enalapril and 15 to 40% w/w of magnesium carbonate as the stabilizing agent.
In another aspect there is provided a process for the preparation of stabilized pharmaceutical composition of ACE inhibitor, which process comprises the steps of (a) blending together an effective amount of an ACE inhibitor and 15 to 40% w/w of magnesium carbonate, (b) optionally granulating the blend, (c) blending with pharmaceutically inert excipients and (d) processing into a suitable solid dosage form.
In another aspect there is provided a process for the preparation of stabilized pharmaceutical composition of quinapril, which process comprises the steps of (a) blending together an effective amount of quinapril and 15 to 40% w/w of magnesium carbonate, (b) optionally granulating the blend (c) blending with pharmaceutically inert excipients and (d) processing into a suitable solid dosage form.
In another aspect there is provided a process for the preparation of stabilized pharmaceutical composition of moexipril, which process comprises the steps of (a) blending together an effective amount of moexipril and 15 to 40% w/w of magnesium carbonate, (b) optionally granulating the blend (c) blending with pharmaceutically inert excipients and (d) processing into a suitable dosage form.
In another aspect there is provided a process for the preparation of stabilized pharmaceutical composition of enalapril, which process comprises the steps of (a) blending together an effective amount of enalapril and 15 to 40% w/w of magnesium carbonate, (b) optionally granulating the blend (c) blending with pharmaceutically inert excipients and (d) processing into a suitable dosage form.
In another aspect, there is provided a method of treating hypertension by administering an ACE inhibitor to a subject in need thereof from a stabilized pharmaceutical composition of ACE inhibitor comprising an effective amount of ACE inhibitor and 15 to 40% w/w of magnesium carbonate as stabilizing agent.
In another aspect, there is provided a method of treating hypertension by administering quinapril to a subject in need thereof from a stabilized pharmaceutical composition of quinapril comprising an effective amount of quinapril and 15 to 40% w/w of magnesium carbonate as stabilizing agent.
In another aspect, there is provided a method of treating hypertension by administering moexipril to a subject in need thereof from a stabilized pharmaceutical composition of
moexipril comprising an effective amount of moexipril and 15 to 40% w/w of magnesium carbonate as stabilizing agent.
In another aspect, there is provided a method of treating hypertension by administering enalapril to a subject in need thereof from a stabilized pharmaceutical composition of enalapril comprising an effective amount of enalapril and 15 to 40% w/w of magnesium carbonate as stabilizing agent.
Pharmaceutical compositions of the present invention involve the use of low amount of magnesium carbonate as stabilizer, yet provides acceptable stabilization of ACE inhibitors, particularly quinapril, moexipril and enalapril against degradation. This is evident from the stability data for quinapril generated at controlled and accelerated conditions, listed herein for reference in Table 1 and Table 2. Use of low amount of magnesium carbonate, which is a bulky powder, permits for the easy processing of pharmaceutical compositions. Stability of ACE inhibitors may further be synergistically enhanced with the incorporation of hydrolysis minimizing agents in combination with magnesium carbonate.
The term "stabilized pharmaceutical composition" as used herein refers to chemical stability of ACE inhibitor against degradation due to cyclization, hydrolysis and oxidation wherein not more than 6% w/w, in particular not more than 4% w/w of related substances are formed on storage at 40 ± 2°C and 75±5% relative humidity for a period of 6 months.
The term "ACE inhibitor" as used herein includes ACE inhibitors having antihypertensive properties. Particularly quinapril, moexipril, enalapril, ramipril or indolapril; or pharmaceutically acceptable acid addition salts such as hydrochloride, hydrobromide, orthophosphate, benzoate, maleate, tartrate, succinate, citrate, salicylate, acetate and the like and combinations thereof may be used. Among these hydrochloride salts may be particularly used. Besides ACE inhibitors, various other drugs useful as combination therapy may be used in pharmaceutical compositions. Suitable categories of drugs that
may be employed in addition to ACE inhibitors may vary widely and generally represent any stable drug combination. Illustrative categories and specific examples include:Diuretics, such as hydrochlorothiazide; Antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate and chlophedianol hydrochloride; Antihistamines such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate and phenyltoloxamine citrate; Decongestants such as phenylephedrine hydrochloride, phenyl proponalamine hydrochloride, pseudoephedrine hydrochloride and ephedrine; various alkaloids, such as codeine phosphate, codeine sulfate and morphine and mineral supplements such as potassium chloride and the like.
The term "low amount of magnesium carbonate" as used herein refers to the use of magnesium carbonate in an amount less than about 45% w/w of the total pharmaceutical composition. In particular, the amount of magnesium carbonate to be used may vary from about 15% to about 40% w/w of the total pharmaceutical composition. Magnesium carbonate is a basic hydrated magnesium carbonate or a normal hydrated magnesium carbonate or a mixture of the two. It occurs as odourless, light, white, friable masses or as a bulky white powder and is widely accepted as an inert excipient in pharmaceutical and cosmetic compositions.
Hydrolysis minimizing agents may be particularly used in those compositions, wherein the hydrolysis impurities produced are present in substantially higher amounts. Hydrolysis minimizing agent includes any agent that protects the ACE inhibitor from hydrolytic degradation and compatible with magnesium carbonate; and does not interfere with magnesium carbonate's function in the composition.
Examples include saccharides such as mannitol, lactose, dicalcium phosphate, and the like. The concentration of hydrolysis minimizing agent may range from about 5% w/w to about 90% w/w. In particular hydrolysis minimizing agent at a concentration of from about 10% w/w to about 80% w/w may be used.
The term "pharmaceutical composition" as used herein includes solid dosage forms like tablet, capsule, caplet, pill, powder, spheroid and granule, and the like.
In one of the embodiments there is provided a stabilized pharmaceutical composition of ACE inhibitor, comprising an effective amount of ACE inhibitor, 15 to 40% w/w of magnesium carbonate, optionally a hydrolysis-minimizing agent and other pharmaceutically acceptable inert excipients.
The term "pharmaceutically acceptable inert excipients" as used herein includes all physiologically inert excipients used in the pharmaceutical art of dispensing. Examples include diluents, binders, disintegrants, coloring agents, flavoring agents and lubricants / glidants.
Specific examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and the like and combinations thereof.
Specific examples of binders include polyvinyl pyrrolidone, methylcellulose, hydroxypropyl cellulose, HPMC, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol and the like and combinations thereof.
Specific examples of disintegrants include microcrystalline cellulose, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, sodium starch glycollate and the like and combinations thereof.
Specific examples of lubricants and glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose
esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax and the like and combinations thereof.
Specific examples of coloring agents include any FDA approved colors for oral use.
Stable pharmaceutical compositions of ACE inhibitors, particularly quinapril, moexipril and enalapril may be prepared by processes known in the prior art for example, by comminuting, mixing, granulation, melting, sizing, filling, drying, molding, immersing, coating, compressing, extrusion-spheronization etc.
In one of the embodiments stabilized pharmaceutical composition of ACE inhibitor may be prepared by (a) blending together an effective amount of an ACE inhibitor, 15 to 40% w/w of magnesium carbonate and other pharmaceutically acceptable inert excipients (b) adding a granulating fluid to the blend to form a moist mass; (c) drying and sizing the granules; (d) blending the granules with pharmaceutically inert excipients and; (e) processing into a suitable dosage form.
In another embodiment, stabilized pharmaceutical composition of ACE inhibitor may be prepared by (a) blending together an effective amount of ACE inhibitor, 15 to 40% w/w of magnesium carbonate and other pharmaceutically acceptable inert excipients (b) dry granulating the blend by roller compactor or slugging; (c) sizing the granules and (d) blending the granules with pharmaceutically inert excipients and (e) processing into a suitable dosage form.
In another embodiment, stabilized pharmaceutical composition of ACE inhibitor may be prepared by (a) blending together an effective amount of ACE inhibitor, 15 to 40% w/w of magnesium carbonate and other pharmaceutically acceptable inert excipients and (b) processing into a suitable dosage form.
In yet another embodiment, stabilized pharmaceutical composition of ACE inhibitor may be prepared by (a) blending together an effective amount of ACE inhibitor, 15 to 40%
w/w of magnesium carbonate and other pharmaceutically acceptable inert excipients (b) adding a granulating fluid or solution or dispersion of pharmaceutically acceptable inert excipient in the granulating fluid to the blend to form a moist mass; (c) passing the wet mass through an extruder equipped with a screen; (d) spheronizing the extrudate in a spheronizer; (e) drying and sizing the spheroids and (f) processing into a suitable dosage form.
Processing into suitable dosage form can be done by filling the granules or powder obtained from the above processes in to capsules or compressing to form the tablet.
The tablets may be further coated with one or more functional and/or non-functional layers comprising film-forming materials, using conventional coating techniques, if desired. Examples of film forming material include water soluble coating materials of celluloses such as hydroxy propyl cellulose, hydroxy propyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxy ethyl cellulose; enteric coating material of celluloses such as hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, carboxy methyl ethyl cellulose and cellulose acetate phthalate; and other enteric film coating materials such as methacrylic acid copolymer, shellac and the like. Alternatively, coating may be performed using commercially available ready to coat preparations such as various grades of Opadry®.
Specific examples of solvents used as granulating fluid and for preparing solution/dispersion of coating substances include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like.
The invention is further illustrated by the following examples, which is for illustrative purpose and should not be construed as limiting the scope of the invention in any way.
Examples 1-4
(Table Removed)
*Equivalent to quinapril 5, 10, 20 and 40 mg for Examples 1-4, respectively
Quinapril tablets as per Examples 1-4 were prepared by the following steps.
1. Quinapril hydrochloride was blended with magnesium carbonate.
2. Intragranular microcrystalline cellulose was blended with the blend of step 1.
3. Povidone was dissolved in purified water.
4. Blend of step 2 was granulated with solution of step 3.
5. The above granules were dried in fluidized bed dryer at 60-65°C, till LOD was
between 1.5-4% and suitably sieved.
6. Extragranular microcrystalline cellulose and crospovidone were blended with
granules of step 5.
7. The mixture of step 6 was blended with magnesium stearate and compressed into
tablets.
8. Finally the compressed tablets were coated with a solution of Opadry to a target
weight build up of about 3%.
Stability Studies
The tablets of example 4, as prepared above were subjected to stability studies both under controlled temperature conditions (25 ± 2°C / 60 ± 5% RH) and accelerated conditions (40 ± 2°C / 70 ± 5% RH). The tablets were analyzed periodically for related substances using HPLC technique over a period of 6 months. The results of the study thus obtained are listed below in Table 1 and 2.
Tablet: Controlled Room Temperature (25 ± 2°C / 60 ± 5% RH) Stability Data of
Quinapril Tablets of Ex-4

(Table Removed)
ND- Not detected
* - Compound A is Diketopiperazine derivative
** - Compound B is Quinaprilat
Table 2: Accelerated (40 ± 2°C / 70 ± 5% RH) Stability Data of Quinapril Tablets of
Ex-4
(Table Removed)
ND- Not detected
* - Compound A is Diketopiperazine derivative
** - Compound B is Quinaprilat
Results of the stability studies as listed above clearly indicate the importance of low amount of magnesium carbonate in stabilizing ACE inhibitors in pharmaceutical compositions, with the amount of impurities being within the acceptable USP limit of 3.6% w/w.

WE CLAIM:
1. A stable pharmaceutical composition comprising an effective amount of ACE
inhibitor and 15 to 40% w/w of magnesium carbonate as stabilizer.
2. The stable pharmaceutical composition according to claim 1 wherein ACE inhibitor
may be selected from the group consisting of quinapril, moexipril, enalapril, ramipril,
indolapril; and pharmaceutically acceptable acid addition salts thereof.
3. The stable pharmaceutical composition according to claim 2, wherein the acid
addition salt may be selected from the group consisting of hydrochloride,
hydrobromide, orthophosphate, benzoate, maleate, tartarate, succinate, citrate,
salicylate, acetate and combinations thereof.
4. The stable pharmaceutical composition according to claims 2 and 3, wherein the
ACE inhibitor is quinapril hydrochloride.
5. The stable pharmaceutical composition according to claims 2 and 3, wherein the
ACE inhibitor is moexipril hydrochloride.
6. The stable pharmaceutical composition according to claims 2 and 3, wherein the
ACE inhibitor is enalapril hydrochloride.
7. A stable pharmaceutical composition comprising an effective amount of quinapril
and 15 to 40% w/w of magnesium carbonate as stabilizer.
8. A stable pharmaceutical composition comprising an effective amount of moexipril
and 15 to 40% w/w of magnesium carbonate as stabilizer.
9. A stable pharmaceutical composition comprising an effective amount of enalapril
and 15 to 40% w/w of magnesium carbonate as stabilizer.
10.The stable pharmaceutical composition according to claims 1, 7, 8 or 9 wherein the
amount of magnesium carbonate may vary from about 25% w/w to about 35% w/w
of total composition. 11. The stable pharmaceutical composition according to claims 1, 7, 8 or 9 wherein the
composition further comprises hydrolysis minimizing agent. 12.The stable pharmaceutical composition according to claim 11 wherein the hydrolysis
minimizing agent is selected from the group consisting of saccharides such as
mannitol, lactose; dicalcium phosphate and mixtures thereof.
13. The stable pharmaceutical composition according to claims 1, 7, 8, 9 or 11, wherein
the composition further comprises one or more pharmaceutically acceptable inert
excipients.
14. The stable pharmaceutical composition according to claim 13 wherein
pharmaceutically acceptable inert excipients may be selected from the group
consisting of diluents, binders, disintegrants, coloring agents, flavoring agents and
lubricants / glidants.
15. The stable pharmaceutical composition according to claims 1, 7, 8, 9 or 11, wherein
the pharmaceutical composition is a solid dosage form selected from the group
consisting of powder, tablet, granule, pellet, spheroid, caplet and capsule.
16.The stable pharmaceutical composition according to claim 15 wherein the
pharmaceutical composition is a tablet. 17. The stable pharmaceutical composition according to claims 1, 7, 8, 9, 11 or 13,
wherein the pharmaceutical composition is coated with a functional or non-functional
film forming polymer.
18. A process for the preparation of stabilized pharmaceutical composition of ACE
inhibitor which process comprises the steps of (a) blending together an effective
amount of ACE inhibitor, 15 to 40% w/w of magnesium carbonate as stabilizer (b)
optionally granulating the blend (c) blending the granules with pharmaceutically inert
excipients and processing into a suitable dosage form.
19. The process according to claim 18, wherein the ACE inhibitor may be selected from
the group consisting of quinapril, moexipril, enalapril, ramipril, indolapril; and
pharmaceutically acceptable acid addition salts thereof.
20. The process according to claim 19, wherein the acid addition salt may be selected
from the group consisting of hydrochloride, hydrobromide, orthophosphate,
benzoate, maleate, tartarate, succinate, citrate, salicylate, acetate and combinations
thereof.
21.The process according to claims 19 and 20, wherein the ACE inhibitor is quinalapril
hydrochloride. 22.The process according to claims 19 and 20, wherein the ACE inhibitor is moexipril
hydrochloride.
23. The process according to claims 19 and 20, wherein the ACE inhibitor is enalapril
hydrochloride.
24. The process according to claim 18, wherein the blend of step (b) is granulated.
25. The process according to claim 24, wherein granulation is carried out by wet
granulation or dry granulation technique.
26.The process according to claim 25, wherein granulation is carried out by wet granulation technique.
27. The process according to claim 26, wherein wet granulation is carried out using a
granulating fluid selected from the group consisting of methylene chloride, isopropyl
alcohol, acetone, methanol, ethanol, water and combinations thereof.
28. The process according to claim 18 wherein the blend of step (a) is further processed
by extrusion-spheronization.
29. The process according to claim 18, wherein (a) further contains a hydrolysis
minimizing agent.
30.The process according to claim 26 wherein the hydrolysis minimizing agent is selected from the group comprising of saccharides such as mannitol, lactose; dicalcium phosphate and mixtures thereof.
31. A method of treating hypertension by administering an ACE inhibitor to a subject in need thereof from a stabilized pharmaceutical composition of ACE inhibitor comprising an effective amount of ACE inhibitor and 15 to 40% w/w of magnesium carbonate as stabilizing agent.