Dose-dumping resistant tablets of acamprosate calcium

Abstract

The present invention provides pharmaceutical composition in the form of tablets of Acamprosate calcium resistant to dose-dumping in the stomach. The delayed release dose- dumping resistant tablets comprising Acamprosate calcium being coated with a seal coat in addition to an enteric polymer coat around the seal coat. The delayed release tablets are formulated to resist release of Acamprosate Calcium in the presence of alcohol for at least two hours. The delayed release tablets are suitable to incorporate 600 - 700 mg of Acamprosate Calcium.

Description

[0001] DOSE-DUMPING RESISTANT TABLETS OF ACAMPROSATE CALCIUM

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to dose-dumping resistant tablets of Acamprosate calcium.

[0004] BACKGROUND OF THE INVENTION

[0005] Acamprosate calcium is indicated for maintenance of abstinence from alcohol in patients with alcohol dependence. The delayed release tablets of 333 mg Acamprosate calcium are sold under the brand name Campral®. It is also authorized in the European Union as Campral EC to Merck Sante. The recommended dose of Campral® is two 333 mg tablets (i.e., each dose should total 666 mg) taken three times daily. Although, Lipha pharmaceuticals initially started marketing Acamprosate calcium delayed release tablets 333 mg in 1989; neither Lipha nor subsequently any other company, has introduced a higher strength of Acamprosate calcium in the market. It is known that Acamprosate calcium delayed release tablets 500 mg were used in clinical trials conducted by Lipha pharmaceuticals; and administered in a 2x500 mg twice daily regimen. It was found in subsequent clinical studies that the extent of absorption of Acamprosate was same with 2x333 mg thrice daily and 2x500 mg twice daily dosages. These regimens were found to be interchangeable by Lipha Pharmaceuticals. However, the rate of absorption of Acamprosate was not similar, when the dosages of tablets of 500 mg vs 333 mg were compared. Eurther, although the 2x500 mg twice daily dosage has the same extent of absorption as the 2x333 mg thrice daily dosage; 500 mg is not the currently approved strength for Campral®.

[0006] Acamprosate absorption mainly occurs in the lower digestive tract. Dose-dumping is a problem which needs to be averted in the case of Acamprosate Calcium. Acamprosate calcium has a good solubility in water. In the case of an enteric-coated tablets, there is always a chance that any disruption of the coating would lead to immediate dissolution of the tablet before moving into the lower digestive tract (through the stomach) for absorption. Besides, adverse reactions are more likely, and they lead to gastro-intestinal distress.

[0007] Upon administration, the intestinal absorption of Acamprosate occurs, mainly by passive diffusion. Acamprosate has poor physicochemical characteristics, which leads to poor intestinal permeation. Therefore, the time of the drug residence in the gastrointestinal tract has to be enough to achieve complete absorption. According to CNS Drug Reviews, Vol. 9, No. 4, 2003 page 365; a practical solution to improve the Acamprosate absorption would be to change the dosage form to individually coated granules that would release Acamprosate gradually and continuously, in the duodenum.

[0008] However, for a patient with shaky hands suffering from alcohol withdrawal symptoms, it is cumbersome to self-administer granules from a sachet. Patient compliance and adherence to dosage regimen of a patient struggling with abstinence from alcohol is questionable, in view of the complex dosage regimen of Campral®. There are challenges involved in providing a delayed release tablet that has bioavailability comparable to Campral® due to the chemical nature of Acamprosate, its high water-solubility and high variability in absorption. Besides, Campral® tablets are delayed release tablets and not immediate release tablets which is another challenge to be addressed for demonstrating comparable bioavailability.

[0009] Each Campral® tablet contains Acamprosate calcium 333 mg, equivalent to 300 mg of Acamprosate. To address these challenges, the present invention provides Acamprosate calcium delayed release tablets. The Acamprosate calcium delayed release tablets are dose-dumping resistant tablets. Tablets of higher strength (666 mg) are provided such that each tablet of 666 mg Acamprosate calcium has bioavailability comparable to 2 tablets of Campral®.

[0010] Further, Acamprosate calcium is known to exhibit polymorphism. Acamprosate Calcium was initially disclosed in DE 3019350 Al. Campral® tablets contain crystalline Form I of Acamprosate Calcium. A thermodynamically more stable Crystalline Form II of Acamprosate Calcium is disclosed in U.S. Patent no. 8,383,679. The U.S. patent discloses that there is tendency of Form I of Acamprosate Calcium to convert to more stable Form II in presence of water / moisture. Such conversion from one crystal form into another affects the dissolution rate of Acamprosate and therefore, affects reproducibility of release pattern of Acamprosate from the tablets.

[0011] The present invention provides enteric coated tablets of Acamprosate calcium Form I, wherein there is no conversion of the Acamprosate calcium Form I to Acamprosate calcium Form II.

[0012] OBJECT OF THE INVENTION

[0013] An object of the present invention is to provide dose-dumping resistant tablets of Acamprosate calcium.

[0014] It is another object of the invention to provide tablets of Acamprosate calcium of higher strength viz., 666 mg capable of resisting dose-dumping in the stomach upon oral administration.

[0015] SUMMARY OF THE INVENTION

[0016] The present invention relates to enteric coated tablets of Acamprosate calcium suitable for oral administration. The tablets of Acamprosate calcium are resistant to dose-dumping.

[0017] In an embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat.

[0018] In an aspect, of the embodiment, the present invention also relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat; and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least 2 hours in 0.1 N HC1; and wherein the tablet releases at least 80% of the Acamprosate after 2 hours in citrate-sodium hydroxide buffer of pH 6.8. In another embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least 2 hours in a medium containing 40% alcohol in 0.1 N HC1.

[0019] In an embodiment, the present invention relates to a tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the Acamprosate calcium is present in an amount of 600 mg to 700 mg.

[0020] In an embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising an uncoated tablet of Acamprosate calcium with one or more pharmaceutically acceptable excipients; a seal coat around the uncoated tablet in an amount of about 1.5 to 2% by weight of the uncoated tablet; and an enteric polymer coat around the seal coat in an amount of about 8 to 15% by weight of the tablet with the seal coat; wherein the delayed release tablet does not release Acamprosate calcium, for at least for 2 hours in 0.1 N HC1; or wherein the delayed release tablet does not release Acamprosate calcium for 2 hours in a medium containing 40% alcohol in 0.1 N HC1.

[0021] In an aspect, of the preceding embodiment the Acamprosate calcium is present in an amount above 60% by weight of the delayed release tablet.

[0022] In another embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat that is devoid of an enteric polymer; and an enteric polymer coat around the seal coat.

[0023] In an embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat that is devoid of an enteric polymer; and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least 2 hours in 0.1 N HC1.

[0024] In an aspect, of the embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat that is devoid of an enteric polymer; and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least 2 hours in 0.1 N HC1; and wherein the tablet releases at least 80% of the Acamprosate after 2 hours in citrate-sodium hydroxide buffer of pH 6.8.

[0025] In a specific embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising either 333 mg or 666 mg of Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat; and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least 2 hours in 0.1 N HC1.

[0026] In a specific embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising either 333 mg or 666 mg of Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat; and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least 2 hours in 0.1 N HC1; and wherein the tablet releases at least 80% of the Acamprosate after 2 hours in citrate-sodium hydroxide buffer of pH 6.8.

[0027] In another embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the composition is devoid of a swellable hydrophilic polymer.

[0028] In another specific embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the composition is devoid of a carbomer.

[0029] In another specific embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the tablet maintains its integrity in 75% relative humidity for 6 months; and wherein the thickness of the enteric coat is from 200 p to 450 p and that of the seal coat is from 50 p to 150 p.

[0030] In an alternative specific aspect, of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of the delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; wherein the composition is devoid of a swellable hydrophilic polymer.

[0031] In an alternative further specific aspect, of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of the delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; wherein the composition is devoid of a carbomer.

[0032] In an alternative specific embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising 666 mg of Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat devoid of an enteric polymer and an enteric polymer coat around the seal coat; wherein the tablet maintains its integrity in 75% relative humidity for 6 months; and wherein the thickness of the enteric coat is from 200 p to 450 p and that of the seal coat is from 50 p to 150 p.

[0033] In an alternative specific aspect, of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of the delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; wherein the composition is devoid of a swellable hydrophilic polymer.

[0034] In an alternative further specific aspect, of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of the delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; wherein the composition is devoid of a carbomer.

[0035] In an alternative specific embodiment, the present invention provides a tablet comprising 666 mg of Acamprosate Calcium Form I and one or more pharmaceutically acceptable excipients; the tablet being coated with an enteric polymer and having a seal coat below the coat of the enteric polymer; wherein the tablet is substantially free of Acamprosate Calcium Form II.

[0036] In an alternative specific aspect, of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of the delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; wherein the composition is devoid of a swellable hydrophilic polymer.

[0037] In an alternative further specific aspect, of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of the delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; wherein the composition is devoid of a carbomer.

[0038] BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Fig. 1 illustrates the X-ray Powder Diffraction (XRPD) spectrum of a sample of Acamprosate Calcium tablets as per Example 1.

[0040] Fig. 2 illustrates the effect of disintegration test on Acamprosate tablets without seal coat.

[0041] Fig. 3 illustrates no effect on tablet shape, appearance and integrity after storage for 6 months at 40°C and 75 % relative humidity

[0042] DESCRIPTION OF THE INVENTION

[0043] The present invention provides tablets of Acamprosate calcium suitable for oral administration. The tablets of Acamprosate calcium of the present invention are resistant to dosedumping. More particularly, the tablets of Acamprosate calcium of the present invention are resistant to dose dumping in the stomach after oral administration.

[0044] Alcohol consumption disorders occur in humans as a result of frequent and long-term alcohol usage. Alcohol withdrawal syndrome is the result of long-term alcohol abuse. Alcohol withdrawal syndrome raises the possibility of relapse and shortens the length of abstinence. Individuals with alcohol consumption disorder may only abstain from alcohol for a short period of few hours. It is specifically undesirable if dose dumping of Acamprosate occurs in the stomach due to presence of acid and / or alcohol.

[0045] Dose-dumping is the sudden unintended release of a drug from a dosage form. This is an undesired event, if it occurs at an undesired location in the gastro-intestinal tract. In the case of Acamprosate, its release in stomach is of no significance for the intended use as it is mainly absorbed by intestinal absorption. The term dose-dumping is generally used, in context of sudden release of entire drug content from its modified release dosage form. Dose-dumping is prevented by the tablets of the present invention. The tablets of the present invention comprise of Acamprosate Calcium compressed together with one or more pharmaceutically acceptable excipients and have a seal coat in addition to an enteric coat. An in vitro dissolution test for the tablets included two stages: an acid stage of pH 1, to demonstrate the integrity of the enteric coat, and a drug release phase at a higher pH. The tablets of the present invention are characteristically resistant to dissolution during the acid stage and release their Acamprosate content during the drug release phase at a higher pH. It has been demonstrated that the tablets of the present invention are resistant to drug release even in highly acidic medium for two hours despite having a greater percentage by weight, of the hydrophilic drug, i.e., Acamprosate calcium. Therefore, it can be deduced that the tablets are resistant to dose-dumping in the contents of the stomach for at least two hours. This observation is significant for the higher strength of Acamprosate tablets.

[0046] Due to the formula and process provided in the present invention, it has been possible to prepare stable 666 mg strength of Acamprosate Calcium tablets in a single unit dosage form. It is exactly double the strength of marketed Campral® tablets. There was no necessity of preparing two separate blends for compression of two different strengths viz., 333 mg and 666 mg of Acamprosate Calcium tablets. The present invention improved the manufacturing process efficiency. The same blend for compression is used to prepare both the strengths of Acamprosate Calcium tablets. 666 mg tablets enhance patient compliance by helping a patient (suffering from alcohol withdrawal symptoms) to adhere to the simplified dosage regimen of 1 tablet thrice a day, i.e., 3 x 666 mg daily dosing. One tablet of 666 mg enteric coated Acamprosate Calcium, for oral administration has bioavailability comparable to two 333 mg Campral® delayed release tablets, at the same daily dosage.

[0047] In an embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising an Acamprosate calcium in an amount of about 666 mg with one or more pharmaceutically acceptable excipients; wherein the delayed release tablet has bioavailability comparable to that of a reference product, in terms of AUC parameter; wherein the reference product is two delayed release tablets of Acamprosate calcium having 333 mg of Acamprosate calcium each.

[0048] Pharmacokinetic assessment was based on the plasma levels of Acamprosate measured by blood sampling at regular intervals of time after administration to a subject of one delayed tablet of 666 mg Acamprosate calcium of the present invention.

[0049] The AUC parameter is a plot of plasma concentration vs time (of taking the blood sample).

[0050] AUC refers to the area under the time / plasma concentration curve which denotes the extent of drug (Acamprosate) that reaches the systemic circulation after administration, measured by estimating the concentration of Acamprosate in each of the plasma samples from blood withdrawn from the subject, as mentioned above.

[0051] In an embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising an Acamprosate calcium in an amount of about 666 mg with one or more pharmaceutically acceptable excipients; wherein the delayed release tablet has bioavailability such that the AUC is about 2866 ng hr.mL

[0052] In an embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium in an amount of about 666 mg with one or more pharmaceutically acceptable excipients; wherein the composition when administered to a subject at least 3 times a day, provides an AUC such that the T / R ratio is about 0.99 to 1.10 under fasted and fed conditions.

[0053] The T / R ratio is the ratio of the test formulation (T) to the reference formulation (R) denoting the difference between two drug formulations.

[0054] Here T refers to the AUC value after administering Acamprosate calcium 666 mg tablets of present invention and R refers to the reference product AUC value after administering reference product Campral® EC Gastro-resistant tablets 333 mg (2 x 333 mg) of Merck Serono Ltd.

[0055] In an embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat.

[0056] In an embodiment, the tablet is loaded with more than 60% by weight of Acamprosate Calcium which is hydrophilic in nature. The enteric coat comprises of polymers which are resistant to acid and do not allow for release of Acamprosate into the acid for at least 2 hours. Upon administration, the tablets would not release Acamprosate in the stomach. The dumping of the dose does not occur, as the integrity of the enteric-coat is maintained. A seal coat applied around the tablet before the enteric coat ensures that the coating of enteric polymer is applied efficiently around the tablet. The seal coat ensures the integrity of the enteric coat, as it provides a smooth surface on the uncoated tablet for uniform application of the enteric polymer coating. It was observed that without the seal coat, the integrity of enteric coat is disturbed, and the tablets appear to have a blistered appearance due to ingress of moisture. During disintegration test performed to check integrity of the enteric coat by immersing the tablets for two hours in 0.1N HC1; it was observed that the coating film had swelled on surface and from edges of tablets. Acamprosate Calcium forms more than 60% of the tablet weight, and itself is a highly hydrophilic drug freely soluble in water. Thus, it can enhance the ingress of moisture. This further emphasizes the importance of having a seal coat below the enteric coat. The normal gastric emptying time is 90 minutes to 120 minutes. It is therefore significant that the tablets serve the objective of preventing the release of Acamprosate in acidic medium for at least two hours. In another embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least two hours in 0.1 N HC1.

[0057] In an aspect of the preceding embodiments, the present invention also relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least two hours in 0.1 N HC1; and wherein the tablet releases at least 80% of the Acamprosate after two hours in citrate-sodium hydroxide buffer of pH 6.8.

[0058] In another embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: an uncoated tablet of Acamprosate calcium with one or more pharmaceutically acceptable excipients; a seal coat around the uncoated tablet in an amount of about 1.5 to 2% by weight of the uncoated tablet; and an enteric polymer coat around the seal coat in an amount of about 8 to 15% by weight of the tablet with the seal coat; wherein the delayed release tablet does not release Acamprosate calcium, for at least for two hours in 0.1 N HC1.

[0059] In another embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: an uncoated tablet of Acamprosate calcium with one or more pharmaceutically acceptable excipients; a seal coat around the uncoated tablet in an amount of about 1.5 to 2% by weight of the uncoated tablet; and an enteric polymer coat around the seal coat in an amount of about 8 to 15% by weight of the tablet with the seal coat; wherein the delayed release tablet does not release Acamprosate calcium for 2 hours in a medium containing 40% alcohol in 0.1 N HC1.

[0060] The term “Citrate-sodium hydroxide buffer of pH 6.8” unless stated otherwise, means 150 ml of 2N NaOH, 21.014 gm of citric acid and ultra-pure water added to prepare 1000 ml of buffer.

[0061] The term “0.1 N HC1” unless stated otherwise, means 900 ml of 0.1 M HC1 as a dissolution medium.

[0062] The term “40% alcohol in 0.1 N HC1” unless stated otherwise, means 900 ml of 40% Alcohol in 0.1N Hydrochloric acid as a dissolution medium.

[0063] The term “Delayed-release tablet” or “Gastro-resistant Tablets” unless stated otherwise, means enteric-coated tablet to prevent an appreciable release of the Acamprosate calcium until the tablet has passed through the stomach to prevent the Acamprosate calcium from being destroyed or inactivated by gastric juices.

[0064] In a further aspect of the preceding embodiments, the Acamprosate Calcium is present in the compositions in an amount from 600 mg to 700 mg. In a specific aspect, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: either 333 mg or 666 mg of Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; and wherein the tablet does not release the Acamprosate, for at least two hours in 0.1 N HC1.

[0065] In another specific aspect, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: either 333 mg or 666 mg of Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least two hours in 0.1 N HC1; and wherein the tablet releases at least 80% of the Acamprosate after two hours in citrate-sodium hydroxide buffer of pH 6.8.

[0066] The thickness of the seal coating and enteric coating was derived from experimentation to optimize the release of Acamprosate from the delayed release tablets. The thickness of seal coat and enteric coat as provided was found to be sufficient to withstand the humidity conditions of 75% for a long period of at least 6 months, without losing integrity of the tablets.

[0067] In another specific embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the tablet maintains its integrity in 75% relative humidity for 6 months; and wherein the thickness of the enteric coat is from 200 p to 450 p and that of the seal coat is from 50 p to 150 p.

[0068] In an aspect of the above embodiment, the seal coat around the uncoated tablet is in an amount of about 1.5 to 2% by weight of the uncoated tablet. In a further aspect, the seal coat contains methacrylic acid-methyl methacrylate copolymer (EUDRAGIT® L100).

[0069] In an aspect of the above embodiment, the enteric polymer coat around the seal coat is in an amount of about 8 to 15% by weight of the tablet with the seal coat.

[0070] Seal coating is provided in the tablet compositions of the present invention, to help in maintaining the integrity of the enteric coat and to provide a barrier to the ingress of moisture. However, presence of an enteric polymer in the seal coating, though useful, can affect the release of Acamprosate from the tablets. More than 80% release from Acamprosate at a higher pH of about 6.8 is also a factor of importance for facilitating maximum absorption of Acamprosate. In one of the methods to achieve this objective, it would be preferable to avoid an enteric polymer in the seal coat.

[0071] In another embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat that is devoid of an enteric polymer and an enteric polymer coat around the seal coat.

[0072] In an embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat that is devoid of an enteric polymer and an enteric polymer coat around the seal coat; and wherein the tablet does not release the Acamprosate, for at least two hours in 0.1 N HC1.

[0073] In an aspect of the preceding embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat that is devoid of an enteric polymer; and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least two hours in 0.1 N HC1; and wherein the tablet releases at least 80% of the Acamprosate after two hours in citrate-sodium hydroxide buffer of pH 6.8.

[0074] In a specific aspect, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising either 333 mg or 666 mg of Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat that is devoid of an enteric polymer; and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least two hours in 0.1 N HC1.

[0075] In another specific aspect, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: either 333 mg or 666 mg of Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat that is devoid of an enteric polymer; and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least 2 hours in 0.1 N HC1; and wherein the tablet releases at least 80% of the Acamprosate after 2 hours in citrate-sodium hydroxide buffer of pH 6.8.

[0076] One of the excipients known to be fast hydrating are carbomers. Depending on their proportion, inclusion of carbomers in the delayed release tablets may be detrimental due to inherent mucoadhesive properties of the of carbomers, such as for example Carbopol® polymers. One of the methods to achieve this objective is to preferably avoid the inclusion of carbomers in the delayed release tablet compositions of Acamprosate calcium.

[0077] In another specific embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the composition is devoid of a carbomer.

[0078] In another embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising: Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the thickness of the enteric coat is from 200 p to 450 p and that of the seal coat is from 50 p to 150 p; and wherein the composition is devoid of an enteric polymer in the seal coat; and optionally wherein the composition is devoid of a carbomer.

[0079] In an aspect of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of a delayed release tablet; wherein the amount of Acamprosate calcium in the composition is 333 mg or 666 mg. In an aspect of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of a delayed release tablet; wherein the tablet maintains its integrity in 75% relative humidity for 6 months.

[0080] In another embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet, comprising: Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat and an enteric polymer coat around the seal coat; wherein the thickness of the enteric coat is from 200 p to 450 p and that of the seal coat is from 50 p to 150 p; and wherein the composition is devoid of a carbomer; and optionally, wherein the composition is devoid of an enteric polymer in the seal coat.

[0081] In an aspect of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of a delayed release tablet; wherein the amount of Acamprosate calcium in the composition is 333 mg or 666 mg.

[0082] In an aspect of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of a delayed release tablet; wherein the tablet maintains its integrity in 75% relative humidity for 6 months.

[0083] Form I of Acamprosate calcium is preferably used to provide the delayed release tablets. However, it is known that the Form I is susceptible to conversion into a thermodynamically more stable Form II of Acamprosate calcium. Due to the synergy between the seal coat and the enteric polymer coatings that are applied on the tablets; the ingress of moisture into the tablets is prevented. The seal coat acts as a barrier between the hydrophilic Acamprosate calcium and moisture from the surroundings. The enteric coat around the seal coat provides an additional barrier between the seal coat and the moisture from surroundings. The combined effect of the seal coat and enteric coat enables to maintain the integrity of the tablets. Therefore, since the ingress of moisture is prevented, the conversion of Form I Acamprosate calcium to Form II of Acamprosate calcium is avoided. As a result, it can be deduced that the rate of release of Acamprosate calcium from the tablets would be reproducible.

[0084] In an embodiment, the present invention provides pharmaceutical composition in the form of the delayed release tablet, comprising: Acamprosate calcium Form I and one or more pharmaceutically acceptable excipients; the tablet being coated with an enteric polymer and having a seal coat below the coat of the enteric polymer; wherein the tablet is substantially free of Acamprosate Calcium Form II.

[0085] In an aspect of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of the delayed release tablet, comprising: Acamprosate calcium and one or more pharmaceutically acceptable excipients; wherein the composition is devoid of a carbomer.

[0086] In an alternative aspect of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of the delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; wherein the composition is devoid of an enteric polymer in the seal coat. In an alternative aspect, of the preceding embodiment, the present invention relates to the pharmaceutical composition in the form of the delayed release tablet comprising Acamprosate calcium and one or more pharmaceutically acceptable excipients; wherein the thickness of the enteric coat is from 200 p to 450 p and that of the seal coat is from 50 p to 150 p; and optionally, wherein the composition is devoid of a carbomer; and optionally, wherein the composition is devoid of an enteric polymer in the seal coat.

[0087] Examples of ingredients for the seal coating of tablets of the present invention are shellac, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose and zein. Commercially available Opadry® Clear 03K19229 (containing triacetin, hydroxypropylmethyl cellulose and talc) is the most preferred for the seal coating of the tablets.

[0088] The minimum coating thickness of the seal coating layer is from 50 p to 150 p, most preferably about 100 p.

[0089] The coating thickness can be determined by in-line approaches like optical coherence tomography and near-infrared spectroscopy; and off-line methods like height, weight and diameter-gain.

[0090] In an optional embodiment, the seal coating layer comprises poly(methacrylic acid, methyl methacrylate) 1: 2 or other enteric polymer material.

[0091] The enteric coating of the tablets is such that it gradually dissolves or gets eroded, upon exposure to a higher pH environment of about pH 6.8 and constantly releases Acamprosate at a rate, such that at least 80% of the Acamprosate, is released from the tablet within 2 hours.

[0092] In an embodiment, the present invention relates to a pharmaceutical composition in the form of a delayed release tablet comprising 666 mg of Acamprosate calcium and one or more pharmaceutically acceptable excipients; the tablet being coated with a seal coat that is devoid of an enteric polymer; and an enteric polymer coat around the seal coat; wherein the tablet does not release the Acamprosate, for at least 2 hours in 0.1 N HC1; and wherein the tablet releases at least 80% of the Acamprosate after 2 hours in citrate-sodium hydroxide buffer of pH 6.8.

[0093] Examples of the polymers for enteric coating are cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polymethacrylic acid-ethyl acrylates, methacrylic acid-ethyl acrylate copolymer (Eudragit® L 30D 55), methacrylic acid-methyl methacrylate copolymer (Eudragit® L100), polymethacrylic acid- methyl methacrylates and compatible mixtures thereof. Examples of commercially available enteric coating systems are: Eudragit® L100, Eudragit® L30D, Eudragit® L100-55, Sureteric®, Acryl-Eze®, Aquarius® Control ENA and Aquacoat® ECD. Eudragit® L 30D 55 is the most preferred for the enteric coating of the tablets.

[0094] Eudragit® L 30 D-55 is an aqueous dispersion of an anionic copolymer, based on methacrylic acid and ethyl acrylate.

[0095] Enteric polymers are applied as solutions in organic or aqueous solvents. The solvents commonly employed are water, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, methylene chloride and combinations thereof. The coating thickness of the enteric coating layer is from 200 p to 450 p, preferably from 200 p to 300 p. The enteric polymer is present in an amount of 25 mg to 70 mg. The weight of the tablet without the enteric coat is in a range from 900 mg to 1100 mg; or in a range from 400 mg to 600 mg.

[0096] Preferably, the coating material of the present invention also comprises a plasticizer. Appropriate plasticizers include polyethylene glycol, propylene glycol, dibutyl phthalate, diethyl phthalate, tributyl citrate, triacetin, and triethyl citrate. Generally, the coating material comprises the plasticizer in an amount from 0% to 50% by weight of the enteric polymer, preferably from 2% to 25% by weight of the enteric polymer, more preferably from 5% to 20% by weight of the enteric polymer.

[0097] Coating can be achieved by methods such as, by using fluidized bed equipment, perforated pans, pan coating, compression coating, spray methods, or by drenching.

[0098] In an embodiment, the present invention provides the tablet as per any one of the above embodiments and aspects, wherein the enteric polymer is present in the composition in an amount from 25 mg to 70 mg.

[0099] In an embodiment, the present invention provides the tablet as per any one of the above embodiments and aspects, wherein the weight of the tablet without the enteric coat is not less than 900 mg and not more than 1100 mg.

[0100] In an embodiment, the present invention provides the tablet as per any one of the above embodiments and aspects, wherein the seal coat is present in the composition in an amount from 8 mg to 25 mg.

[0101] In another embodiment, the present invention provides the tablet as per any one of the above embodiments and aspects, wherein the seal coat is present in the composition in an amount from 15 mg to 25 mg.

[0102] Tablets provided as per the present invention are for oral administration and they include pharmaceutically acceptable excipients. Examples of suitable excipients include microcrystalline cellulose, magnesium silicate, crospovidone, sodium starch glycolate, polyvinyl pyrrolidone, colloidal anhydrous silica, talc and magnesium stearate.

[0103] The granules comprising Acamprosate calcium are prepared by granulating one or more pharmaceutically acceptable excipients together with Acamprosate Calcium. A rapid mixer granulator is suitable for the granulation process. Suitable pharmaceutically acceptable excipients like one or more binders, disintegrants and diluents are used to prepare the granules. Examples of binders are starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, methylcellulose, hypromellose, sodium carboxymethylcellulose, polyethylene glycol and methylcellulose. Some of the preferred binders are polyvinylpyrrolidone and hypromellose.

[0104] Examples of diluents are lactose, sucrose, mannitol, sorbitol, xylitol, calcium phosphate, calcium carbonate, calcium sulfate, microcrystalline cellulose and silicified microcrystalline cellulose. Examples of disintegrants are starch, cellulosic derivatives like methyl cellulose, hydroxypropyl cellulose, croscarmellose, cross-linked polyvinylpyrrolidone and sodium starch glycolate. Some of the preferred disintegrants are croscarmellose and sodium starch glycolate.

[0105] Suitable lubricants and glidants are blended with the granules to aid the lubrication of granules and assist the flow through the hopper of the tableting machine, while punching into tablets. For example, a suitable glidant is colloidal silicon dioxide or talc; and suitable lubricants include talc, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate and polyethylene glycol, and magnesium stearate.

[0106] In another alternative aspect, the present invention provides a tablet according to any one of the above embodiments; wherein the dosage form comprises of Acamprosate calcium in an amount of about 55% w / w to 75% w / w; a diluent in an amount of about 8% w / w to 15 % w / w; a disintegrant in an amount of about 0.25% w / w to 8 % w / w; a binder in an amount of about 5 % w / w to 15% w / w; a glidant in an amount of about 0.05 % w / w to 2 % w / w; a lubricant in an amount of about 0.5 % w / w to 3 % w / w of the tablet; a seal coating in an amount of about 1% w / w to 2.5% w / w of the tablet and a coating of enteric polymer in an amount of 5% w / w to about 15% w / w of the tablet.

[0107] In another alternative aspect, the present invention provides a tablet according to any one of the above embodiments; wherein the dosage form comprises of Acamprosate Calcium in an amount of about 55 %w / w to 65 %w / w; a diluent in an amount of about 9 %w / w to 13 %w / w; a disintegrant in an amount of about 0.25 %w / w to 1.5 %w / w; a binder in an amount of about 5 %w / w to 12 %w / w; a glidant in an amount of about 0.05 %w / w to 1.5 %w / w; a lubricant in an amount of about 0.5 %w / w to 2.5 %w / w of the tablet; a seal coating in an amount of about 1 %w / w to 2.5 %w / w of the tablet and a coating of enteric polymer in an amount of 5 %w / w to about 15 %w / w of the tablet.

[0108] The tablets coated with enteric polymer are further optionally, lubricated with a lubricant like talc.

[0109] Wet granulation is one of the methods to prepare compositions of the present invention. The method involves mixing together of ingredients and Acamprosate calcium in a suitable equipment like a rapid mixer granulator. The mixture is wetted with binder solution, preferably in purified water; and granulated in the granulator. The wet granules are dried in a fluid bed dryer or a fluid bed processor with loss on drying as an indicator for desired dryness of the granules. The dried granules are lubricated with glidant and / or lubricant and compressed into tablets. The compressed tablets are coated with seal coating and dried. The seal coated tablets are coated with coating of enteric polymer and dried.

[0110] Particle size distribution of Acamprosate Calcium was used to prepare the granules; such that 90% of Acamprosate Calcium particles had a particle size less than 150 microns and 50% of Acamprosate Calcium particles had a particle size less than 50 microns.

[0111] Acamprosate Calcium is known to exist in two polymorphic forms I and II. Conversion from one crystal form into another results in a change in the dissolution rate of the active compound, which means that the original release of the active compound from the medicament is no longer reproducible. Therefore, it is desirable to avoid a change in polymorphic form of Acamprosate Calcium while making tablets thereof, and also throughout the shelf life of the tablets. Surprisingly, the present invention provides 666 mg enteric coated tablets of Acamprosate Calcium Form I, wherein there is no conversion of the Acamprosate Calcium Form I to Acamprosate Calcium Form II. The present invention provides 666 mg enteric coated tablets of Acamprosate Calcium Form I, devoid of Acamprosate Calcium Form II. The present invention provides a tablet comprising 666 mg of Acamprosate Calcium Form I and one or more pharmaceutically acceptable excipients; the tablet being coated with an enteric polymer and having a seal coat below the coat of the enteric polymer; wherein the tablet is substantially free of Acamprosate Calcium Form II.

[0112] The present invention and its embodiments and aspects will be further explained in detail by the following non-limiting examples.

[0113] EXAMPLES:

[0114] EXAMPLE 1:

[0115] Quantitative Composition for 666 mg tablets of Acamprosate Calcium

[0116] $ Opadry® Clear 03K19229 contains triacetin, hydroxypropylmethyl cellulose and talc

[0117] * Eudragit® L 30 D-55 is an aqueous dispersion of an anionic copolymer, based on methacrylic acid and ethyl acrylate

[0118] € not present in the final product

[0119] Table 1: Quantitative Composition of Delayed Release Tablets of Acamprosate Calcium 666 mg

[0120] Procedure:

[0121] 1. Acamprosate Calcium, microcrystalline cellulose, magnesium silicate, crospovidone, Sodium starch glycolate & polyvinyl pyrrolidone were sifted through 20# mesh sieve and mixed in a rapid mixer granulator.

[0122] 2. The mixture of step 1 , was granulated using purified water in the rapid mixer granulator.

[0123] 3. The wet granules of step 2, were dried in fluid bed processor / dryer

[0124] 4. The dried granules were sized by passing through a mill and sifting through 40# mesh sieve.

[0125] 5. The sized granules were pre-lubricated by mixing with crospovidone, colloidal anhydrous silica and talc in a blender to prepare a lubricated blend.

[0126] 6. Magnesium Stearate passed through #40 mesh was added to blend of step 5, and mixed.

[0127] 7. The blend of step 6, was compressed using suitable punch set to obtain uncoated tablets

[0128] 8. Purified water was added to Opadry clear under continuous stirring and after complete addition stirred for 45 minutes to prepare a seal coating solution.

[0129] 9. The uncoated tablets were coated uniformly with the seal coating solution of step 8, till weight gain of 2 %w / w.

[0130] 10. Purified water was added to propylene glycol & talc under continuous stirring.

[0131] 11. Material of step 10, was added to Eudragit® L30D 55 in a beaker under stirring, and further stirred for 45 minutes after addition.

[0132] 12. The tablets of step 9, were coated uniformly, till weight gain of 10%w / w was achieved.

[0133] 13. The tablets were allowed to dry.

[0134] 14. Talc was sprinkled evenly, over the tablets of step 13.

[0135] Dissolution Studies of tablets prepared in Example 1

[0136] Dissolution parameters:

[0137] Table 2: Dissolution parameters

[0138] Preparation of Dissolution medium:

[0139] Acid stage (0.1M Hydrochloric acid):

[0140] 85 ml of concentrated hydrochloric acid was transferred to a vessel containing 1000 ml water and mixed well and diluted to 10,000 ml with water, and pH of solution was noted.

[0141] Buffer stage (pH 6.8 Buffer):

[0142] 150 ml of 2 M sodium hydroxide was diluted to 1000 ml with 0.1 M citric acid monohydrate, mixed well and pH was adjusted to 6.8 ± 0.05 with 0.5 M citric acid if necessary.

[0143] Preparation of diluent: Water and Methanol were mixed in the ratio of 900: 100 v / v, and sonicated to degas.

[0144] Standard stock solution: Standard solution containing 0.46 mg / ml of Acamprosate calcium was prepared in the diluent. a) Acid stage:

[0145] 4 ml of standard stock solution diluted to 25 ml with 0.1N Hydrochloric acid. The solution contains about 0.07 mg / ml of Acamprosate calcium. b) Buffer stage:

[0146] 4 ml of standard stock solution diluted to 25 ml with diluent. The solution contains about 0.07 mg / ml of Acamprosate calcium.

[0147] Dissolution was carried out separately for Acid stage & Buffer stage as follows:

[0148] Dissolution method and sample: (For Acid stage)

[0149] One tablet was placed in each of the 6 dissolution vessels of the apparatus containing 900 ml of 0.1 M HC1. The dissolution apparatus was run as per the dissolution parameters for 2 hours. At specified time interval, 10 ml sample aliquot from each dissolution vessel was withdrawn and filtered through 0.45 pm nylon syringe filter. Dissolution method and sample: (For Buffer stage)

[0150] Immediately after completion of acid stage, the basket arm was brought upward and acid stage medium decanted completely from the vessel carefully; and replaced with 900 ml of pH 6.8 buffer of temperature of 37°C ± 0.5 °C. The dissolution apparatus was run as per dissolution parameters. At specified time interval, 10 ml sample aliquot from each dissolution vessel was withdrawn and filtered through 0.45 pm nylon syringe filter. Upon withdrawal of each sample aliquot, an equal amount of dissolution medium was added to each dissolution vessel.

[0151] 2 ml of the filtered solution was diluted to 20 ml by the diluent.

[0152] The content of Acamprosate released was measured in the samples by High Performance Liquid Chromatography (HPLC). HPLC operation is well known to a person skilled in the art.

[0153] Chromatography conditions: triethylamine buffer^ Buffer prepared by adding and mixing 5.0 ml of triethylamine with 1000 ml of water and adjusting the pH to 4.00 ± 0.05 with Ortho-phosphoric acid; and filtering the solution through 0.45 pm Nylon membrane filter.

[0154] Table 3: Chromatography conditions

[0155] Calculation:

[0156] The % Release of Acamprosate calcium per tablet calculated with respect to label claim using following expression.

[0157] For acid stage:

[0158] AT WS 4 900 P 100

[0159] For buffer stage: AT WS 4 900 20 P 100

[0160] — x — — x — x - x — x - x - F CF

[0161] AS 50 25 1 2 100 LC wherein,

[0162] AT : Area of Acamprosate calcium peak in sample preparation chromatogram,

[0163] AS : Average area of Acamprosate calcium peak in standard preparation chromatogram,

[0164] WS : Weight of Acamprosate calcium reference / working standard in mg,

[0165] P : % Purity of Acamprosate calcium reference / working standard on as is basis,

[0166] LC : Label claim in mg i.e., strength of the tablet in mg

[0167] CF : Correction factor

[0168] Note: Determine amount of drug dissolved at various time intervals making necessary correction for amount of dissolution medium withdrawn and replaced.

[0169] CF (in wherein, X = % release calculated at each interval before applying CF.

[0170] The results are mentioned below:

[0171] RSD = Relative Standard Deviation

[0172] Table 4: Dissolution study results for 666 mg Acamprosate Delayed Release tablets of Example 1 and (2 tablets in 1 jar) of 333 mg Campral® Gastro-resistant tablets

[0173] Observations: It can be clearly observed that the tablet of Example 1 has exhibited a similar dissolution behavior at all the time points mentioned in Table 4, as compared to 2 tablets of 333 mg each of Campral® Gastro-resistant tablets. From the dissolution study it can also be deduced that 1 tablet of 666 mg of Example 1 can have bioavailability comparable to 2 tablets of 333 mg Campral® Gastro-resistant tablets.

[0174] Dissolution parameters

[0175] Preparation of Dissolution medium:

[0176] Acid stage (0.1M Hydrochloric acid):

[0177] 85 ml of concentrated hydrochloric acid was transferred to a vessel containing 1000 ml water and mixed well and diluted to 10,000 ml with water.

[0178] 40% Alcohol in 0.1N Hydrochloric acid:

[0179] Mixed 6000 ml of 0.1 N HC1 with 4000 ml of alcohol, mixed well and sonicated to degas.

[0180] Note: - During degassing / sonication covered the media suitable lead or aluminium foil to avoid evaporation of alcohol (approx. 5 minutes).

[0181] Preparation of diluent: Mixed Water and Methanol in the ratio of 900: 100 v / v. mixed well and sonicated to degas. Standard stock solution: Weighed and transferred 23 mg of Acamprosate calcium Working Standard in 50 ml of volumetric flask add 30 ml of diluent and sonicate to dissolve. Made up the volume with diluent.

[0182] Standard solution:

[0183] Diluted 4 ml of standard stock solution to 25 ml with diluent.

[0184] Procedure:

[0185] One tablet was placed in each of the 6 dissolution vessels of the apparatus containing 900 ml of 40% Alcohol in 0.1 N Hydrochloric acid. The dissolution apparatus was run as per the dissolution parameters for 2 hours. At specified time interval, 10 ml sample aliquot from each dissolution vessel was withdrawn and filtered through 0.45 pm nylon syringe filter.

[0186] 2 ml of the filtered solution was diluted to 20 ml by the diluent.

[0187] Note: Test batch - one tablet in one jar and Campral® Gastro-resistant tablets - 2 tablets in one jar

[0188] The content of Acamprosate calcium released was measured in the samples by High Performance Liquid Chromatography (HPLC). HPLC operation is well known to a person skilled in the art.

[0189] Table 3: Chromatography conditions

[0190] Tri-ethylamine Buffer: - Buffer prepared by adding and mixing 5.0 ml of triethylamine with 1000 ml of water and adjusting the pH to 4.00 ± 0.05 with Ortho-phosphoric acid; and filtering the solution through 0.45 pm Nylon membrane filter.

[0191] Calculation:

[0192] The % Release of Acamprosate calcium per tablet calculated with respect to label claim using following expression. AT WS 4 900 20 P 100

[0193] — x — — x — x - x — x - x - F CF

[0194] AS 50 25 1 2 100 LC wherein,

[0195] AT : Area of Acamprosate calcium peak in sample preparation chromatogram,

[0196] AS : Average area of Acamprosate calcium peak in standard preparation chromatogram,

[0197] WS : Weight of Acamprosate calcium reference / working standard in mg,

[0198] P : % Purity of Acamprosate calcium reference / working standard on as is basis,

[0199] LC : Label claim in mg i.e., strength of the tablet in mg

[0200] CF : Correction factor

[0201] Note: Determined amount of drug dissolved at various time intervals making necessary correction for amount of dissolution medium withdrawn and replaced.

[0202] CF (in wherein, X = % release calculated at each interval before applying CF.

[0203] The results are mentioned below:

[0204] RSD = Relative Standard Deviation

[0205] Table 5: Alcohol-Induced Dose Dumping study results for 666 mg Acamprosate Delayed Release tablets of Example 1 and of 333 mg Campral® Gastro-resistant tablets Observation:

[0206] 1. It can be clearly observed that Acamprosate Calcium delayed release tablets 666 mg Example

[0207] 1 shows no release at all the time points mentioned in Table 5

[0208] 2. Drug release for tablets of Campral® shows approximately 80 % release at 120 minutes Example 2

[0209] Quantitative Composition for tablets of Acamprosate Calcium

[0210] $ Opadry® Clear 03K19229 contains triacetin, hydroxypropylmethyl cellulose and talc

[0211] * Eudragit® L 30 D-55 is an aqueous dispersion of an anionic copolymer, based on methacrylic acid and ethyl acrylate

[0212] € not present in the final product

[0213] Table 6: Quantitative Composition of Delayed Release Tablets of Acamprosate Calcium 666 mg and 333 mg

[0214] Procedure:

[0215] 1. Acamprosate Calcium, microcrystalline cellulose, magnesium silicate and Crospovidone XL were sifted through 20# mesh sieve and mixed in a rapid mixer granulator.

[0216] 2. The mixture of step 1, was granulated using Eudragit L30-D55 followed by purified water in the rapid mixer granulator.

[0217] 3. The wet granules of step 2, were partial dried and wet milled using co mill, and dried in fluid bed dryer

[0218] 4. The dried granules were sized by passing through a mill and sifting through 40# mesh sieve.

[0219] 5. The sized granules were pre-lubricated by mixing with colloidal anhydrous silica and sodium starch glycolate in a blender to prepare a lubricated blend.

[0220] 6. Magnesium Stearate passed through #60 mesh was added to blend of step 5, and mixed.

[0221] 7. The blend of step 6, was compressed using suitable punch set to obtain uncoated tablets

[0222] 8. Purified water was added to Opadry clear under continuous stirring and after complete addition stirred for 45 minutes to prepare a seal coating solution.

[0223] 9. The uncoated tablets were coated uniformly with the seal coating solution of step 8, till weight gain of 0.5 %w / w.

[0224] 10. Purified water was added to propylene glycol & talc under continuous homogenization.

[0225] 11. Material of step 10, was added to Eudragit® L30D 55 in a beaker under stirring, and further stirred for 45 minutes after addition.

[0226] 12. The tablets of step 9, were coated uniformly, till weight gain of approx. 9 %w / w was achieved.

[0227] 13. The tablets were allowed to dry.

[0228] 14. Talc was sprinkled evenly, over the tablets of step 13.

[0229] Table 7: Dissolution study results for 666 mg Acamprosate Delayed Release tablets of Example 2 and (2 tablets in 1 jar) of 333 mg Campral® Gastro-resistant tablets

[0230] Observation: 1. From the respective data it is observed that the drug release for tablets of Example 2 is 95.3 % at Q point, i.e., 120 minutes which is matching with reference product Campral® 333mg Gastro- resistant tablets i.e. two tablets in one jar.

[0231] 2. Both Campral® and tablets of Example 2 show similar dissolution profile as F2 value is 71.66 for 2 tablets of Campral® i.e., 333mg Vs one tablet of test, i.e., 666mg.

[0232] From the dissolution study, it can also be deduced that 1 tablet of 666 mg of Example 2 would be having bioavailability comparable to 2 tablets of 333 mg Campral® Gastro-resistant tablets.

[0233] Example 3 Quantitative Composition for tablets of Acamprosate Calcium

[0234] Table 8: Quantitative Composition of Delayed Release Tablets of Acamprosate Calcium

[0235] Procedure:

[0236] 1. Acamprosate Calcium, microcrystalline cellulose, magnesium silicate and

[0237] Crospovidone XL- 10, Sodium starch Glycolate and Povidone K 30 were sifted through 20# mesh sieve and mixed in a rapid mixer granulator.

[0238] 2. The mixture of step 1 , was granulated using purified water in the rapid mixer granulator.

[0239] 3. The wet granules of step 2, were dried in fluid bed processor / dryer

[0240] 4. The dried granules were sized by passing through a mill and sifting through 40# mesh sieve.

[0241] 5. The sized granules were pre-lubricated by mixing with sodium starch glycolate colloidal silicon dioxide, in a blender to prepare a lubricated blend.

[0242] 6. Magnesium Stearate passed through #60 mesh was added to blend of step 5, and mixed.

[0243] 7. The blend of step 6, was compressed using suitable punch set to obtain uncoated tablets.

[0244] 8. Purified water was added to Eudragit L100 under continuous stirring and after complete addition stirred for 45 minutes to prepare a seal coating solution.

[0245] 9. The uncoated tablets were coated uniformly with the seal coating solution of step 8, till weight gain of 2 %w / w.

[0246] 10. Purified water was added to propylene glycol & talc under continuous stirring.

[0247] 11. Material of step 10, was added to Eudragit® L30D 55 in a beaker under stirring, and further stirred for 45 minutes after addition.

[0248] 12. The tablets of step 9, were coated uniformly, till weight gain of 10%w / w was achieved.

[0249] 13. The tablets were allowed to dry.

[0250] 14. Talc was sprinkled evenly, over the tablets of step 13.

[0251] Randomized, single-dose, cross-over study

[0252] In a randomized, single-dose, cross-over study, healthy volunteers were dosed with Acamprosate Calcium Gastro-resistant Tablets 666 mg compositions according to the Example 3 (Test) to compare the bioavailability of Acamprosate in these compositions relative to Campral® EC Gastro-resistant tablets 333 mg (2 x 333 mg) of Merck Serono Ltd (Reference) administered at equivalent dose. Pharmacokinetic assessment was based on the plasma levels of Acamprosate measured by blood sampling at regular intervals after administration. Table 9 shows the AUC details of present invention and marketed product available in the 333mg strength. The term “AUC” refers to the area under the time / plasma concentration curve which denotes the extent of drug reaches the systemic circulation after administration.

[0253] The T / R ratio is the ratio of the test formulation (T) to the reference formulation (R) denoting the difference between two drug formulations

[0254] Table 9: Results From the above table, it is evident that Acamprosate Calcium Gastro-resistant Tablets 666mg had a comparable bioavailability against the reference product administered at equivalent dose of 666mg (2 x 333 mg tablets) under both fasting and fed conditions.

Claims

We claim:

1. A pharmaceutical composition in the form of a delayed release tablet, comprising: an uncoated tablet of Acamprosate calcium; with one or more pharmaceutically acceptable excipients; a seal coat around the uncoated tablet in an amount of about 1.5 to 2% by weight of the uncoated tablet; and an enteric polymer coat around the seal coat in an amount of about 8 to 15% by weight of the tablet with the seal coat; wherein the delayed release tablet does not release Acamprosate calcium, for at least for two hours in 0.1 N HCl; or wherein the delayed release tablet does not release Acamprosate calcium for two hours in a medium containing 40% alcohol in 0.1 N HC1.

2. The pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from microcrystalline cellulose, magnesium silicate, crospovidone, sodium starch glycolate, polyvinyl pyrrolidone, colloidal anhydrous silica, talc and magnesium stearate.

3. The pharmaceutical composition as claimed in claim 1, wherein the enteric polymer in the enteric polymer coat is selected from cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polymethacrylic acid-ethyl acrylate, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer and polymethacrylic acid-methyl methacrylate.

4. The pharmaceutical composition as claimed in claim 1, wherein the enteric polymer is an aqueous dispersion of an anionic copolymer, based on methacrylic acid and ethyl acrylate.

5. The pharmaceutical composition as claimed in claim 1, wherein the seal coat contains methacrylic acid-methyl methacrylate copolymer.

6. The pharmaceutical composition as claimed in claim 1, wherein the Acamprosate calcium is present in an amount above 60% by weight of the delayed release tablet.

7. The pharmaceutical composition as claimed in claim 1, wherein the Acamprosate calcium is present in an amount of about 333 mg or 666 mg; wherein the seal coat comprises of methacrylic acid-methyl methacrylate copolymer; wherein the enteric polymer coat comprises of methacrylic acid-ethyl acrylate copolymer; and wherein the one or more pharmaceutically acceptable excipients are selected from a group comprising of microcrystalline cellulose, magnesium silicate, crospovidone, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and talc.

8. The pharmaceutical composition as claimed in claim 1, wherein the Acamprosate calcium is present in an amount of about 333 mg or 666 mg; wherein the seal coat comprises of triacetin, hydroxypropylmethyl cellulose and talc; wherein the enteric polymer coat comprises of methacrylic acid-ethyl acrylate copolymer; and wherein the one or more pharmaceutically acceptable excipients are selected from a group comprising of microcrystalline cellulose, magnesium silicate, crospovidone, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and talc.

9. A pharmaceutical composition in the form of a delayed release tablet comprising Acamprosate calcium in an amount of about 666 mg with one or more pharmaceutically acceptable excipients; wherein the composition when administered to a subject at least 3 times a day, provides an AUC such that the T / R ratio is about 0.99 to 1.10 under fasted and fed conditions.

10. A pharmaceutical composition in the form of a delayed release tablet comprising an Acamprosate calcium in an amount of about 666 mg with one or more pharmaceutically acceptable excipients; wherein the delayed release tablet has bioavailability such that the AUC is about 2866 ng hr.mL

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