CONTROLLED RELEASE FORMULATIONS COMPRISING DROTAVERINE OR SALT THEREOF

Abstract

The present invention provides controlled release formulations comprising Drotaverine or salt thereof or similar active agents which are prone to oxidative/hydrolytic degradation. The invention provides once or twice a day controlled release formulations of Drotaverine or salt thereof which avoids fluctuations of plasma levels, reduces pill burden and side effects owing to simplified dosage schedule, thereby improving patient compliance. The invention also provides methods of preparation of controlled release formulations of Drotaverine or salt thereof. The invention further provides controlled-release formulations of Drotaverine or salt thereof for treating at least one symptom of gastrointestinal, biliary, urological and gynecological disorders characterized by spastic conditions of smooth muscles in a subject.

Claims

1. A controlled-release formulation comprising Drotaverine or a salt thereof, a polymer or mixture of polymers, and at least one pharmaceutically acceptable excipient, wherein said formulation comprises at least one acidifying agent and from 0 to 10% by weight of antioxidants.

2. The formulation of claim 1, wherein the formulation comprises about 10 to about 300 mg of Drotaverine or salt thereof.

3. The formulation of claim 1 or 2, wherein the formulation comprises Drotaverine or salt thereof in the range of 15% to 60% (w/w) of the formulation.

4. The formulation of any of the preceding claims, wherein the Drotaverine salt is Drotaverine hydrochloride.

5. The formulation of claim 1, wherein said at least one acidifying agent is selected from the group consisting of Citric acid, Fumaric acid, Lactic acid, Maleic acid, Malic acid, Tartaric acid, and a combination thereof.

6. The formulation of claim 1, wherein the polymer or mixture of polymers is selected from the group consisting of Hypromellose, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose or salts thereof, Ethyl Cellulose, Carbomers, Methacrylic acids, Polyethylene Oxides (PEO), and a combination thereof.

7. The formulation of claim 6, wherein the polymer is Polyethylene oxide (PEO).

8. The formulation of claim 6, wherein the polymer or mixture of polymers is hydroxypropyl methylcellulose having an apparent viscosity ranging from about 100-150,000 cP, wherein, optionally, the polymer or mixture of polymers is K100, K4M, K15M, K100M, E4M, E10M, Methocel K100M CR, or a combination thereof.

9. The formulation of any one of the preceding claims, wherein the formulation comprises controlled-release polymer in the range of 05% to 30% (w/w) of the formulation.

10. The formulation of claim 1, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of gums, fillers, flow aids, lubricants, disintegrants, diluents, binders, lubricants, glidants, and a combination thereof.

11. The formulation of claim 10, wherein: the gums are selected from the group consisting of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate, acrylic polymers, and a combination thereof; the diluents are selected from the group consisting of microcrystalline cellulose, lactose, dicalcium phosphate, starch, and a combination thereof; the binders are selected from the group consisting of starch, polyvinylpyrrolidone, natural or synthetic gum, cellulosic polymers, and a combination thereof; the lubricants and glidants are selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and a combination thereof; and the disintegrants are selected from the group consisting of Sodium Starch Glycollate, Croscarmellose Sodium, Crospovidone, and a combination thereof.

12. The formulation of any one of the preceding claims, wherein the formulation is for oral delivery.

13. The formulation of claim 12, wherein the formulation is a tablet, mini-tablet, MUPS (Mul-tiple-Unit Pellet System) tablet or capsule.

14. The formulation of claim 13, wherein the formulation is in the form of single layered, bi-layered, multi-layered, coated, uncoated, or multi-coated pellets, granulates, or beads, which can be filled into capsules or compressed to tablets.

15. The formulation of any of the preceding claims, wherein the formulation comprises a controlled release portion and an immediate release portion.

16. The formulation of any of the preceding claims, wherein the formulation optionally comprises a functional or non-functional coating.

17. The formulation of any one of claims 13 to 16, wherein the tablet or capsule is prepared by a wet granulation, dry granulation/slugging or direct compression process.

18. The formulation of any one of claims 13 to 17, wherein the capsule comprises shells prepared by gelatin or non-gelatin based materials.

19. The formulation of any one of the preceding claims, wherein the formulation releases Drotaverine or salt thereof for at least 24 hours.

20. The formulation of any one of the preceding claims, wherein the formulation elicits a minimum effective concentration in plasma of a subject similar to immediate release dosage form within about 1 hour and the rest of the drug is gradually released over a period of about 12-24 hours to maintain the drug concentration within the therapeutic window of Drotaverine.

21. The formulation of any one of the preceding claims, wherein the formulation has a dissolution release profile in vitro of 25% to 40% after about 1 hour, 30% to 50% after about 2 hours, 40% to 65% after about 4 hours, 60% to 85% after about 8 hours and not less than about 85% after about 16 hours.

22. A controlled-release formulation comprising Drotaverine or a salt thereof, a polymer or mixture of polymers, and at least one pharmaceutically acceptable excipient.

23. A formulation of claim 22 wherein the formulation comprises about 10 to about 300 mg of Drotaverine or salt thereof.

24. The formulation of claim 23, wherein the formulation comprises Drotaverine or salt thereof in the range of 15% to 60% (w/w) of the formulation.

25. The formulation of any one of claims 22 to 24, wherein the Drotaverine salt is Drotaverine hydrochloride.

26. The formulation of claim 22, wherein the polymer or mixture of polymers is selected from the group consisting of Hypromellose, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose or salts thereof, Ethyl Cellulose, Carbomers, Methacrylic acids, Polyethylene Oxides (PEO), and a combination thereof.

27. The formulation of claim 26, wherein the polymer or mixture of polymers is hydroxypropyl methylcellulose having an apparent viscosity ranging from about 100-150,000 cP, wherein, optionally, the polymer or mixture of polymers is K100, K4M, K15M, K100M, E4M, E10M, Methocel K100M CR, or a combination thereof.

28. The formulation of any one of claims 22 to 27, wherein the formulation comprises con-trolled-release polymer in the range of 05% to 30% (w/w) of the formulation.

29. The formulation of claim 22, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of gums, fillers, flow aids, lubricants, disintegrants, diluents, binders, lubricants, glidants, and a combination thereof.

30. The formulation of claim 29, wherein: the gums are selected from the group consisting of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate, acrylic polymers, and a combination thereof; the diluents are selected from the group consisting of microcrystalline cellulose, lactose, dicalcium phosphate, starch, and a combination thereof; the binders are selected from the group consisting of starch, polyvinylpyrrolidone, natural or synthetic gum, cellulosic polymers, and a combination thereof; the lubricants and glidants are selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and a combination thereof; and the disintegrants are selected from the group consisting of Sodium Starch Glycollate, Croscarmellose Sodium, Crospovidone, and a combination thereof.

31. The formulation of any one of claims 22 to 30, wherein the formulation is for oral delivery.

32. The formulation of claim 31, wherein the formulation is a tablet, mini-tablet, MUPS (Mul-tiple-Unit Pellet System) tablet or capsule.

33. The formulation of claim 32, wherein the formulation is in the form of single layered, bi-layered, multi-layered, coated, uncoated, or multi-coated pellets, granulates, or beads, which can be filled into capsules or compressed to tablets.

34. The formulation of any of one of claims 22 to 33, wherein the formulation comprises a con-trolled release portion and an immediate release portion.

35. The formulation of any of claims 22 to 34, wherein the formulation optionally comprises a functional or non-functional coating.

36. The formulation of any one of claims 22 to 35, wherein the formulation elicits a minimum effective concentration in plasma of a subject similar to immediate release dosage form within about 1 hour and the rest of the drug is gradually released over a period of about 12-24 hours to maintain the drug concentration within the therapeutic window of Drotaverine.

37. The formulation of any one of claims 22 to 36, wherein the formulation has a dissolution release profile in vitro of 25% to 40% after about 1 hour, 30% to 50% after about 2 hours, 40% to 65% after about 4 hours, 60% to 85% after about 8 hours and not less than about 85% after about 16 hours.

38. A method of preparing a single-layer controlled release tablet comprising Drotaverine or a salt thereof, the method comprising: (a) sieving and dry mixing Drotaverine or salt thereof with an acidifying agent, polymer and excipient to obtain a drug-excipient blend; (b) sieving and mixing extra-granular ingredients with the drug-excipient blend to obtain a formulation; (c) compressing the formulation to form the tablet.

39. A method of preparing a single or multi-layer tablet comprising Drotaverine or a salt thereof, the method comprising: (a) sieving and dry mixing Drotaverine or salt thereof with an acidifying agent, polymer and excipient to obtain a dry mix; (b) granulating the dry mix with a binder solution comprising at least polyvinylpyrrolidone and isopropyl alcohol to obtain granules; (c) drying the granules to obtain a desired Loss-on Drying of the dried granules; (d) milling the dried granules followed by sieving to obtain granules of specific size; (e) sieving extra-granular ingredients followed by mixing with the granules of specific size to obtain a formulation; and (f) compressing the formulation to form the tablet.

40. The method of claim 38 or 39, further comprising coating the tablet with one or more functional or non-functional coatings.

41. A method of treating at least one symptom of gastrointestinal, biliary, urological and gynecological disorders characterized by spastic conditions of smooth muscles, for instance, irritable bowel syndrome, biliary colics, cholecystolithiasis, cholecystitis, cholangitis, renal colics, nephrolithiasis, ureterolithiasis, pyelitis, cystitis, dysmenorrhoea, imminent abortion, or uterine tetanus in a subject in need thereof, comprising administering to the subject the formulation as claimed in any one of the claims 1 to 21 or 22 to 37.

42. The method of claim 41, wherein the formulation is administered as single layer, bi-layered, multi-layered, uncoated, coated or multicoated pellets, beads, or granules in tablet or capsule form.

43. Use of a formulation of any of claims 1 to 21, or 22 to 37 for treating at least one symptom of a gastrointestinal, biliary, urological or gynecological disorder characterized by spastic conditions of smooth muscles in a subject, comprising administering the formulation to the subject.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0103] FIG. 1: The FIGURE shows a representative release rate profile of a CR formulation of Drotaverine hydrochloride prepared in accordance with the present invention. The dissolution profile is shown as % drug release of Drotaverine hydrochloride against time (in hours).

DETAILED DESCRIPTION OF THE INVENTION

[0104] A large portfolio of polymers is available for CR drug delivery formulations/systems along with application expertise to meet specific formulation drug delivery which help development of new products. The controlled release polymer may be one or more Hypromellose, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, Carboxymethyl Cellulose or salts thereof, Ethyl Cellulose, Carbomers, Methacrylic acids and Polyethylene Oxides (nonionic polymers) are available in different pharmaceutical grades and offer a range of CR properties for a variety of dosage forms and processing methods. Variations in molecular weights and chemical substitutions provide innumerable ways to optimize formulation performance. Each range has fundamentally different hydrophilicity, hydrophobicity, wettability, pH dependent solubility, swelling and erosion characteristics to provide flexibility in control of the main mechanisms of release.

[0105] In some embodiments, the CR formulations of the present invention contain acidifying agents. The acidifying agent can be selected from, for example, Citric acid, Fumaric acid, Lactic acid, Maleic acid, Malic acid and Tartaric acid, or combinations thereof.

[0106] In some embodiments, the CR formulations of the present invention include Drotaverine or salts thereof, one or more hydrophilic polymers and one or more pharmaceutically acceptable excipients such that when administered orally the formulations release Drotaverine in a CR manner over a prolonged period of time.

[0107] In some embodiments, the formulations disclosed herein show an in vitro dissolution profile of Drotaverine or salts thereof, when measured using USP II Method, at about 75 rpm, in about 1000 ml, 0.1 N HCl (pH 1.2), at about 37±0.5° C., to be between about 25% and about 40% released after about 1 hour, between about 30% and about 50% released after about 2 hours, between about 40% and about 65% released after about 4 hours, and between about 60% and about 85% released after about 8 hours and NLT (not less than) about 85% after about 16 hours. In some embodiments, the formulation releases a sufficient amount of Drotaverine drug which allows for sufficient concentration of the drug in the blood stream to produce a quick therapeutic effect and thereafter provides uniform and slow drug release for about 16 hours which then maintains that effect for about 24 hours duration. Hence, in some embodiments, the present invention provides a modified release dosage form which would release about 20% of the drug within about 1 hour and the balance of about 80% would be released thereafter to ensure therapeutic action for about 24 hours as a once or twice a day drug delivery dosage form.

[0108] In some embodiments, the oral controlled release dosage formulations include polymers of low molecular weight polyethylene oxide (PEO) alone or in combination with hydroxypropylmethylcellulose (HPMC) with a non-ionic polymer and other tableting excipients and optionally one or more enteric polymers.

[0109] Thus, in some embodiments, the CR formulations of the present invention comprise the following: [0110] Drotaverine or its salts thereof, in the range of between about 10 to about 300 mg, e.g., about 40 to about 240 mg. Drotaverine is preferably present in an amount suitable for single or twice a day dosing. [0111] One or more active ingredients which are similar types of drug molecules in that they are sensitive to oxidative degradation. Non-limiting examples of drugs that are prone to oxidative degradation include Drotaverine, Mebeverine, Alevarine, Papaverine and pharmaceutically acceptable salts thereof. [0112] Disintegrants/Superdisintegrants viz. Sodium Starch Glycollate, Croscarmellose Sodium, and Crospovidone, may be selected alone or in combination to improve the IR-layer drug release. [0113] Polyethylene oxide (PEO) as a non-ionic homopolymer of ethylene oxide (CAS Registry Number 25322-68-3). PEO is chemically similar to polyethylene glycol, but has a high molecular weight in the range of 100,000 to 7 million g/mol. Pharmaceutical grades of PEO may have unique properties such as non-ionic, highly swelling, hydrophilic and thermo-plastic behaviour. PEOs are safe, non-toxic polymers that are not absorbed through the gas-tro-intestinal tract. PEO has an IID (Inactive Ingredient Database) limit of about 543.9 mg per tablet for oral applications. [0114] The “hydrophilic controlled-release polymer” may be selected, for instance, from one or more of cellulose derivatives selected from hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose; and gums selected from xanthan gum, karaya gum, locust bean gum, alginic acid and sodium alginate and acrylic polymers. The hydroxypropyl methylcellulose may be, for example, the commercially available products such as Methocel® premium product grades having specific apparent viscosities, e.g., viscosities ranging from about 100-150,000 cP (2% in water at 200° C.) such as K100, K4M, K15M, K100M, E4M, E10M; viscosities ranging from 80000-120,000 cP (2% in water at 200° C.) such as Methocel® K100M CR. It was observed that the amount of the hydrophilic polymer per unit dose of Drotaverine or salt thereof plays a major role in the release characteristic of the formulation. The amount of hydrophilic controlled-release polymer may range from about 05-30% w/w per unit weight of dosage form. [0115] The formulations may contain other release-retarding agents including hydrophobic polymers along with the combination of one or more hydrophilic polymers. However, hydrophilic polymers alone also can be used to obtain the controlled-release formulations with desirable characteristics achieved by the formulations disclosed herein. [0116] The controlled release formulation may also contain “pharmaceutically acceptable excipients” selected from, for example, one or more of diluents, binders, lubricants and glidants. [0117] The diluent may, for example, be selected from, for example, one or more of microcrystalline cellulose, lactose, dicalcium phosphate and starch. [0118] The binder may be selected from, for example, one or more of starch, polyvinylpyrrolidone, natural or synthetic gum and cellulosic polymers. [0119] The lubricants and glidants may be selected from, for example, one or more of talc, colloidal silicon dioxide and magnesium stearate. [0120] To protect Drotaverine hydrochloride from oxidative degradation, the developed formulations contain acidifying agents. [0121] The acidifying agent can be selected from, for example, alone or combination of Citric acid, Fumaric acid, Lactic acid, Maleic acid, Malic acid and Tartaric acid. [0122] The antioxidant can be selected from, for example, alone or combination of butylated hy-droxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thio-sulfate, propyl gallate, ascorbic acid and cysteine.

[0123] In some embodiments, the CR formulations of Drotaverine or salt thereof may be obtained in form of tablet, bead, pellet or capsule. The tablet may be an uncoated tablet, coated tablet, or mini-tablets. For instance, the CR formulations may be a single layer matrix tablet or bi-layer, tri-layer or multi-layered tablets with or without a functional or non-functional coating. A functional film coating is a coating that has a direct influence on the drug release of API (active pharmaceutical ingredient) of the solid oral dosage form (e.g. tablet, capsule, granule or pellet) examples include Ethyl cellulose dispersion with soluble polymer or enteric polymer based dispersion with water soluble ingredients. While a non-functional film coating is not directly influence the drug release of the API. The examples include HPMC based film costing dispersion with or without flavour to enhance the product acceptability of bitter tasting drugs like Drotaverine. The tablet may be prepared by wet granulation, dry granulation/slugging, or direct compression processes.

[0124] The input raw materials are selected to ensure there is minimal level of free water, which can be detrimental in causing degradation of Drotaverine hydrochloride. The manufacturing process, especially wet granulation process, required studies may be performed to adjust the levels of residual moisture content in the final drug product.

[0125] In some embodiments, the compressed tablets may be coated with suitable film forming compositions.

[0126] Based on the properties of Drotaverine IR tablets known in the field of art, the theoretical but hitherto unmet drug release pattern depicting bioavailability and pharmacokinetic properties for a ‘once-a-day dosage form’ of Drotaverine would be as follows:

TABLE-US-00001 Time (hours) % Release (Range)  1 25-40  2 30-50  4 40-65  8 60-85 16 NLT 85

[0127] The inventors of the present invention undertook several formulation trials comprising of one or combination of CR polymer, filler and other pharmaceutical auxiliary components and tried dry and wet granulation manufacturing process to arrive at the CR release formulations of Drotaverine or salt thereof described above. Initial experiments were undertaken as a monolayer and bi-layered tablet formulations. However, despite executing several trials, it was really difficult to control release profile as per theoretical release pattern which is evident in the following Tables 1 and 2 for monolayer tablets and Tables 3 and 4 for bi-layer tablets.

TABLE-US-00002 TABLE 1 Mono-layer tablet formulations prepared by different manufacturing processes Batch No. DTV-01 DTV-02 DTV-03 DTV-04 DTV-05 DTV-09 Mfg. Process Slugging Slugging Slugging Wet gran. Wet gran. Wet gran. (DG) (DG) (DG) (IPA) (IPA) (IPA) Percent Material (%) Drotaverine 26.7 26.7 26.7 26.7 26.7 53.3 Hydrochloride Polyox WSR 303 50 45 15 Methocel — — — 15 10 HPMC K 15 M Polyox WSR 301 20 14.9 MCC 45 — 10 23.3 18.3 11.1 Methocel 27.3 22.3 17.3 20 15 HPMC K 100 M PVP K-30 4 4 6 IPA MCC 5 5 3.3 Colloidal 0.5 0.5 0.5 0.5 0.5 0.7 Silicon dioxide Lubrication Magnesium 0.5 0.5 0.5 0.5 0.5 0.7 Stearate

TABLE-US-00003 TABLE 2 Dissolution Release profile of mono-layer tablet formulations of Table 1 Dissolution Release profile % % % % % % Time Batch No. (Target Release) DTV-01 DTV-02 DTV-03 DTV-04 DTV-05 DTV-09 1 hour (25-40%).sup.  7 5 6 6 6 10 2 hours (30-50%) 12 8 9 11 10 18 4 hours (40-65%) 26 18 16 23 19 38 8 hours (60-85%) 61 40 40 54 37 73 .sup. 16 hours (NLT 85%) 100 100 100 100 100 100

TABLE-US-00004 TABLE 3 Bi-layer tablets formulations Batch No. (% w/w) Component DTV-15 DTV-42 DTV-45 DTV-56 DTV-57 Drug 36 40 40 40 40 CR Polymer 45 36 22.5 13 29 Filler 14 15 26 37 21 Binder 4.7 5 6 5 4 Flow aid 0.5 1 1 1 1 Disintegrant — 1 1.5 3 3 Stabilizer — 2 3 1 2 Colorant 0.02 0.02 0.02 0.02 0.02

TABLE-US-00005 TABLE 4 Dissolution Release profile of bi-layer tablet formulations of Table 2 (%) (%) (%) (%) (%) Time Target release Batch No. (hours) Range (%) DTV-15 DTV-42 DTV-45 DTV-56 DTV-57 1 25-40 36 24 25 20 20 2 30-50 45 40 39 33 32 4 40-65 59 41 47 45 41 8 60-85 93 51 53 63 59 16 NLT 85% 100 66 70 86 84

[0128] Subsequently, few of these trial batch tablets were exposed to accelerated stability conditions and evaluated for impurity profiling. For understanding chemical degradation characteristics of the CR formulations, a prototype formulation was exposed to ‘forced degradation studies’ and results are presented in below Table 5. It was observed that there were unknown impurities at levels of nearly 2-3% w/w for accelerated condition exposed samples. Therefore, in order to develop stable CR formulations with desired profile, pre-formulation studies of Drotaverine drug characteristics were undertaken to determine some of key physicochemical properties such as solubility, dissolution, assay and related substances parameters and drug stability characteristics etc.

TABLE-US-00006 TABLE 5 Chemical degradation characteristics of proposed CR formulation exposed to ‘Forced/accelerated degradation studies’ Batch No. DTV-042 DTV-042 DTV-042 DTV-042 Condition ACID BASE PEROXIDE CONTROL Degradation Degradation Degradation Name of % % % % Impurity RRT w/w RRT w/w RRT w/w RRT w/w Drotaverine No impurities observed Amine Drotaverine Acid Drotaverine Amide Drotaverladine 1.67 0.02 1.67 0.03 1.67 1.08 1.66 0.91 Highest 0.20 0.20 0.20 3.15 individual unknown impurity Total Impurities 0.51 0.76 1.89 24.58

[0129] The results of the study were most surprising. In view of the fact that Drotaverine is susceptible to oxidative and hydrolytic degradation, it was assumed that adding an antioxidant would increase the stability thereof. However, addition of an antioxidant improved the stability only marginally. On the contrary, and to the utmost surprise of the inventors, addition of an acidifying agent resulted in remarkable improvement in stability resulting in a controlled release formulation of Drotaverine. The study demonstrates that incorporation of small amount of antioxidant to obtain stable CR release formulations is advantageous in order to avoid oxidative degradation of Drotaverine or salt thereof or active agents which are prone to oxidative/hydrolytic degradation. Additionally, the results indicate that addition of an acidifier alone or in combination with minor amounts of antioxidant also helps in developing stable CR formulation of Drotaverine and salt thereof.

[0130] The inventors of present invention surprisingly found that stable CR dosage formulations of Drotaverine or salt thereof with reduced degradation (and having 12-24 hours duration of release profile) can be achieved only with addition of acidifying agent and without or with minor amounts of antioxidant. The inventors further developed different CR formulations as monolayer or multilayer; MUPS tablets, coated, uncoated, tablets, as pellets or mini-tablets filled in capsules. These developed tablets may be coated with non-functional or functional coating. The capsule shells are based on gelatin or non-gelatin polymer. The formulations of the present invention can be tablets or capsules containing immediate and prolonged release portions demonstrating biphasic drug release profile. This ensures instant bioavailability similar to IR tablets, which is particularly desirable in the case of patients suffering from pain conditions. The IR portion comprises a mixture of excipients and stabilizers and suitable quantity of active substance allowing immediate release action similar to IR tablets along with CR drug portion comprising appropriate quantities of polymers, excipients and stabilizers interspersed with suitable portion of active drug ensuring medicament release in a controlled manner over 12-24 hours duration.

[0131] The present invention provides a controlled-release formulation comprising Drotaverine or salt thereof, at least one acidifying agent and a polymer or mixture of polymers along with at pharmaceutically acceptable excipients wherein said formulation is substantially free of anti-oxidants. The anti-oxidant may be present from 0 to 10% (w/w) of the formulation.

[0132] Exemplary CR formulations of the present invention are provided in Table 6 with % range of respective ingredients as per developed formulations.

TABLE-US-00007 TABLE 6 Exemplary CR formulations of the present invention Component % w/w range Active Drug 15-60 Filler 13-55 Colorant 0.1-0.6 Stabilizer 0.5-10  Binder 3-9 Disintegrant 0.5-8   Flow aid 0.2-1.5 Lubricant 0.2-2   CR Polymer  5-30

[0133] The developed CR formulations were prepared in different dosage forms viz. tablets or capsules prepared by direct blending, direct compression, dry granulation or wet granulation-based technology. For wet granulation manufacturing process, the granulating fluid may be hydro-alcoholic or non-aqueous granulating fluid viz. alcoholic solvents.

[0134] The method of preparing a single-layer controlled release tablet comprising formulation of Drotaverine or salt thereof comprises (a) sieving and dry mixing active ingredients with acidifying agent, polymer and excipient to obtain drug-excipient blend; (b) sieving and mixing extra-granular ingredients with the drug-excipient blend obtained in step (a); (c) compressing the formulation of step (b) to form the tablet.

[0135] The method of preparing single or multi-layered tablet comprising Drotaverine or salt thereof, the method comprising: (a) sieving and dry mixing active ingredients with acidifying agent, polymer and excipient to obtain dry mix; (b) granulating dry mix by binder solution comprising at least polyvinylpyrrolidone and isopropyl alcohol to obtain granules; (c) drying granules to obtain desired Loss-on Drying of dried granules; (d) milling dried granules followed by sieving to obtain granules of specific size; (e) sieving extra-granular ingredients followed by mixing with granules obtained in step ‘d’; (f) compressing the formulation of step (e) to form the tablet.

[0136] The following non-limiting examples further illustrate the CR formulations of Drotaverine or salt thereof, and process of making such formulations.

Example 1

[0137] Drotaverine CR formulations prepared as ‘Single Layer’ tablets by Direct Compression method in following manner:

TABLE-US-00008 Ingredient % w/w Dry mixing Drotavarine HCl 26.7 Non-ionic poly (ethylene oxide) polymer (Polyox 10 WSR 301) Water-solublehighmolecularweight 45 poly(ethylene oxide) polymer (Polyox WSR 303) MCC 17.3 Extra-granular Colloidal silicon dioxide 0.5 Magnesium stearate 0.5

Example 2

[0138] Drotaverine CR formulation prepared as ‘Single Layer’ tablets by Wet Granulation method in the following manner:

TABLE-US-00009 Ingredient % w/w Dry mixing Drotavarine HCl 26.67 HPMC K 15 15 HPMC K 100 10 Polyox WSR 303 20 MCC 18.3 Binder Preparation IPA q.s. PVP K 30 4 Extra-granular MCC 5 Colloidal silicon dioxide 0.5 Magnesium stearate 0.5

Example 3

[0139] Drotaverine CR formulation prepared as ‘Bi-Layer’ tablets by Wet Granulation method:

TABLE-US-00010 Bi-layered IR portion CR portion Ingredient % w/w % w/w Dry mixing Drotavarine HCl 54.55 52.94 HPMC K 100 — 17.65 Polyox WSR 301 — 17.65 Sodium starch glycolate 3.64 — MCC 31.8 5.88 Brilliant Blue 0.2 — Binder Preparation IPA q.s. q.s. PVP K 30 4.5 3.53 Extra granular MCC 4.5 1.47 Colloidal silicon dioxide 0.5 0.44 Magnesium stearate 0.5 0.44

Example 4

[0140] Drotaverine CR formulation prepared as ‘Bi-Layer’ tablets by Wet Granulation method:

TABLE-US-00011 Bi-layered IR portion CR portion Ingredient % w/w % w/w Dry mixing Drotavarine HCl 40 40 HPMC K 100 — 22.44 Polyox WSR 303 — 22.44 Sodium starch glycolate 4.8 — MCC 42 7.56 Brilliant Blue 0.2 Binder Preparation IPA q.s. q.s. PVP K 30 6 4.67 Extra-granular MCC 6 2 Colloidal silicon dioxide 0.6 0.44 Magnesium stearate 0.6 0.44

Example 5

[0141] Drotaverine CR formulation prepared as ‘Bi-Layer’ tablets by Wet Granulation method:

TABLE-US-00012 Bi-layered IR portion CR portion Ingredient % w/w % w/w Dry mixing Drotavarine HCl 46.67 37.78 HPMC K 100 — 22.44 Polyox WSR 303 — 22.44 Sodium starch glycolate 4.8 — MCC 35.3 9.78 Brilliant Blue 0.2 — Binder Preparation IPA q.s. q.s. PVP K 30 6 4.67 Extra-granular MCC 6 2 Colloidal silicon dioxide 0.6 0.44 Magnesium stearate 0.6 0.44

[0142] Optionally the compressed tablet can be coated with functional and non-functional coating agents.

Example 6

[0143] Drotaverine CR formulation prepared as ‘Bi-Layer’ tablets by Wet Granulation method (60 mg strength)

TABLE-US-00013 Bi-layered IR portion CR portion Ingredient mg mg Dry mixing Drotavarine HCl 15 45 HPMC K 100 — 25 Polyox WSR 303 — 25 Sodium starch glycolate 2 — MCC 16 9 Brilliant Blue 0 Binder Preparation IPA q.s. q.s. PVP K 30 2 5 Extra-granular MCC 2 2 Colloidal silicon dioxide 0.2 0.5 Magnesium stearate 0.2 0.5

Example 7

[0144] Drotaverine CR formulation prepared as ‘Bi-Layer’ tablets by Wet Granulation method (120 mg strength)

TABLE-US-00014 Bi-layered IR portion CR portion Ingredient mg mg Dry mixing Drotavarine HCl 30 90 HPMC K 100 — 50 Polyox WSR 303 — 50 Sodium starch glycolate 4 — MCC 32 17 Brilliant Blue 0.2 Binder Preparation IPA q.s. q.s. PVP K 30 5 11 Extra-granular MCC 5 5 Colloidal silicon dioxide 0.4 1 Magnesium stearate 0.4 1

Example 8

[0145] Drotaverine CR formulation prepared as ‘Bi-Layer’ tablets by Wet Granulation method (180 mg strength)

TABLE-US-00015 Bi-layered IR portion CR portion Ingredient mg mg Dry mixing Drotavarine HCl 45 135 HPMC K 100 — 76 Polyox WSR 303 — 76 Sodium starch glycolate 5 — MCC 47 26 Brilliant Blue 0 Binder Preparation IPA q.s. q.s. PVP K 30 7 16 Extra-granular MCC 7 7 Colloidal silicon dioxide 1 2 Magnesium stearate 1 2

Example 9

[0146] Drotaverine CR formulation prepared as ‘Bi-Layer’ tablets by Wet Granulation method (240 mg strength).

TABLE-US-00016 Bi-layered IR portion CR portion Ingredient mg mg Dry mixing Drotavarine HCl 60 180 HPMC K 100 — 100.96 Polyox WSR 303 — 100.96 Sodium starch glycolate 7.2 — MCC 63.2 34 Brilliant Blue 0.32 Binder Preparation IPA q.s. q.s. PVP K 30 9 21 Extra-granular MCC 9 9 Colloidal silicon dioxide 0.8 2 Magnesium stearate 0.8 2

Example 10

[0147] Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg strength)

TABLE-US-00017 IR Portion CR Portion Ingredients (in mg) (in mg) Intra-granular Material Drotaverine HCl 75.00 165.00 Sodium Starch Glycollate 7.00 MCC 35.70 133.60 HPMC K 100M — 54.00 HPMC K 4M — 54.00 Colloidal Silicon Dioxide — 2.00 Colouring agent 0.20 — Binder Solution Citric Acid 3.60 8.40 IPA q.s. q.s. PVP K 30 9.00 25.00 Extra-granular Material MCC 18.00 5.00 Colloidal Silicon Dioxide 0.45 1.00 Colouring agent 0.15 Magnesium Stearate 0.90 2.00

Example 11

[0148] Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg strength)

TABLE-US-00018 IR Portion ER Portion Ingredients (in mg) (in mg) Intra-granular Material Drotaverine HCl 60.00 180.00 Sodium Starch Glycollate 7.00 — MCC 23.40 186.10 HPMC K 100M — 38.40 HPMC K 4M — 38.40 Colloidal Silicon Dioxide — 2.00 Colouring agent 0.20 — Sodium Metabisulfite 0.90 2.1 Binder Solution IPA q.s. q.s. PVP K 30 9.00 25.00 Extra-granular Material MCC 18.00 5.00 Colloidal Silicon Dioxide 0.45 1.00 Colouring agent 0.15 — Magnesium Stearate 0.90 2.00

Example 12

[0149] Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg strength)

TABLE-US-00019 IR Portion ER Portion Ingredients (in mg) (in mg) Intra granular Material Drotaverine HCl 60.00 180.00 Sodium Starch Glycollate 7.20 — MCC 60.80 29.50 HPMC K 100M — 100.96 Polox WSR 303 — 100.96 Colloidal Silicon Dioxide — 2.00 Colouring agent 0.20 — Sodium Metabisulfite 1.50 4.5 Binder Solution IPA q.s. q.s. PVP K 30 9.00 21.00 Extra granular Material MCC 9.45 7.08 Colloidal Silicon Dioxide 0.80 2.00 Colouring agent 0.15 — Magnesium Stearate 0.90 2.00

Example 13

[0150] Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg strength)

TABLE-US-00020 IR Portion CR Portion Ingredients (in mg) (in mg) Intra-granular Material Drotaverine HCl 60.00 180.00 Sodium Starch Glycollate 7.00 MCC 24.30 188.20 HPMC K 100M — 38.40 HPMC K 4M — 38.40 Colloidal Silicon Dioxide — 2.00 Colouring agent 0.20 — Binder Solution IPA q.s. q.s. PVP K 30 9.00 25.00 Extra-granular Material MCC 18.00 5.00 Colloidal Silicon Dioxide 0.45 1.00 Colouring agent 0.15 Magnesium Stearate 0.90 2.00

Example 14

[0151] Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg strength)

TABLE-US-00021 IR Portion CR Portion Ingredients (in mg) (in mg) Intra-granular Material Drotaverine HCl 75.00 165.00 Sodium Starch Glycollate 7.00 MCC 34.80 131.50 HPMC K 100M — 54.00 HPMC K 4M — 54.00 Colloidal Silicon Dioxide — 2.00 Colouring agent 0.20 — Sodium Metabisulfite 0.9 2.1 Binder Solution Citric Acid 3.6 8.4 IPA q.s. q.s. PVP K 30 9.00 25.00 Extra-granular Material MCC PH 18.00 5.00 Colloidal Silicon Dioxide 0.45 1.00 Colouring agent 0.15 Magnesium Stearate 0.90 2.00

Example 15

[0152] Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg strength)

TABLE-US-00022 IR Portion CR Portion Ingredients (in mg) (in mg) Intra granular Material Drotaverine HCl 75.00 165.00 Crospovidone 10.00 MCC 31.80 131.50 HPMC K 100M — 80.00 HPMC K 4M — 28.00 Colloidal Silicon Dioxide — 2.00 Colouring agent 0.20 — Sodium Metabisulfite 2.0 2.1 Binder Solution Maleic Acid 2.5 8.4 IPA q.s. q.s. PVP K 30 15.00 25.00 Extra-granular Material MCC 12.00 5.00 Colloidal Silicon Dioxide 0.45 1.00 Colouring agent 0.15 Magnesium Stearate 0.90 2.00

Example 16

[0153] Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg strength)

TABLE-US-00023 IR Portion CR portion Ingredients (in mg) (in mg) Intra granular Material Drotaverine HCl 75.00 165.00 Crospovidone 10.00 MCC 31.80 131.50 HPMC K 100M — 50.00 HPMC K 4M — 58.00 Colloidal Silicon Dioxide — 2.00 Colouring agent 0.20 — Butyl hydroxy Toluene 1.0 2.1 Binder Solution Tartaric acid 3.5 8.4 IPA q.s. q.s. PVP K 30 15.00 25.00 Extra granular Material MCC 12.00 5.00 Colloidal Silicon Dioxide 0.45 1.00 Colouring agent 0.15 Magnesium Stearate 0.90 2.00

Example 17

[0154] Drotaverine CR formulation granules prepared by Wet Granulation method (240 mg strength)

TABLE-US-00024 IR Portion CR portion Ingredients (in mg) (in mg) Intra granular Material Drotaverine HCl 75.00 165.00 Crospovidone 10.00 MCC 31.80 131.50 HPMC K 100M — 50.00 HPMC K 4M — 58.00 Colloidal Silicon Dioxide — 2.00 Colouring agent 0.20 — Butyl hydroxy Toluene 1.0 2.1 Binder Solution Tartaric acid 3.5 8.4 IPA q.s. q.s. PVP K 30 15.00 25.00 Extra granular Material MCC 12.00 5.00 Colloidal Silicon Dioxide 0.45 1.00 Colouring agent 0.15 Magnesium Stearate 0.90 2.00

Example 18

[0155] Drotaverine CR formulation MUPS (Multiple-Unit Pellet System) tablets (240 mg strength)

TABLE-US-00025 MUPS Tablets Qty. Per unit Ingredients (in mg) Drotaverine HCl 240.00 HPMC 12.00 Polysorbate-80 12.00 Citric Acid 6.00 Talc 5.00 Sugar Spheres 355-425 μm 80.00 Ethyl Cellulose Coating dispersion 20.00 Microcrystalline Cellulose (MCC) 173.00 Magnesium Stearate 4.00 Colloidal Silicon Dioxide 4.00

Example 19

[0156] Drotaverine CR formulation capsules with CR pellets (240 mg strength)

TABLE-US-00026 Capsule with CR Pellets Qty. Per capsule Ingredients (in mg) Drotaverine HCl 240.00 HPMC 12.00 Polysorbate-80 12.00 Fumaric Acid 5.00 Butyl Hydroxy Anisole 3.00 Talc 5.00 Sugar Spheres 355-425 μm 80.00 Ethyl Cellulose Coating dispersion 20.00 Starch 15.00 Stearic Acid 4.00 Colloidal Silicon Dioxide 4.00

In-Vitro Dissolution Profile

[0157] The formulations of the present invention are illustrated in but not limited to the examples given hereinabove. A representative drug dissolution release rate profile for an exemplary formulation of the present invention is depicted in FIG. 1. The developed formulation is evaluated for ‘In-vitro dissolution profile’ using USP II Method, at 75 rpm, in 1000 ml, 0.1 N HCl (pH 1.2), at 37±0.5° C. The dissolution release profile of CR formulations of the present invention in-vitro is found to be between about 25% and about 40% released after about 1 hour, between about 30% and about 50% released after about 2 hours, between about 40% and about 65% released after about 4 hours, and between about 60% and about 85% released after about 8 hours and NLT about 85% after about 16 hours.

Chemical Stability:

[0158] Impurities in new drug products such as degradation products of the drug substance or reaction products of the drug substance with an excipient and/or immediate container closure system are collectively referred to as “degradation products”. Generally, impurities present in the new drug substance need not be monitored or specified in the new drug product unless they are also degradation products.

[0159] The present invention provides stable CR formulations of Drotaverine or salt thereof or similar active agents which are prone to oxidative/hydrolytic degradation. The developed formulations have improved chemical stability wherein individual unknown impurity levels are less than 0.2% w/w (as per currently available globally acceptable standards for drug products).

Non-Limiting Advantages of the CR Formulations of the Present Invention:

[0160] 1. The CR formulations of Drotaverine, developed by extensive trials and developing effective ratios of polymers, binders, excipients vis-à-vis active drug, achieve a target drug release rate from a single ingestible dosage form and achieves maintenance of a target MEC for about 24 hours. [0161] 2. The CR formulations disclosed herein are designed to achieve an immediate onset of action and sustained release profile. For instance, a sufficient (therapeutic) amount of the Drotaverine drug is released within about 1 hour after administration to achieve plasma levels similar to an immediate release dosage form and the rest of the drug is gradually released over a period of about 12-24 hours to maintain the drug concentration within the therapeutic window. [0162] 3. The CR formulations of Drotaverine are capable of being formulated as single or multi-layered tablets or multicoated mini-tablets, pellets or beads filled in capsules. [0163] 4. The formulations of Drotaverine are capable of being manufactured by direct compression, dry granulation, wet granulation or fluidized bed processing methods.

[0164] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the embodiments disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. In addition, where this application has listed the steps of a method or procedure in a specific order, it may be possible, or even expedient in certain circumstances, to change the order in which some steps are performed, and it is intended that the particular steps of the method or procedure claims set forth herein below not be construed as being order-specific unless such order specificity is expressly stated in the claim.