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EP-4117638-B1 - CONTROLLED RELEASE FORMULATIONS COMPRISING DROTAVERINE OR SALT THEREOF

EP4117638B1EP 4117638 B1EP4117638 B1EP 4117638B1EP-4117638-B1

Inventors

  • BERLIA, Sushma Paul
  • BERLIA, Nishant
  • SINGH, GURVINDER
  • BHANDARI, Sunder Singh
  • Diwan, Anupama

Dates

Publication Date
20260506
Application Date
20210309

Claims (15)

  1. A formulation comprising a controlled release portion and an immediate release portion, wherein the formulation comprises 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 anti-oxidants.
  2. The formulation of claim 1, wherein the formulation comprises 10 to 300 mg of Drotaverine or salt thereof.
  3. The formulation of claim 1 or claim 2, wherein the Drotaverine salt is Drotaverine hydrochloride.
  4. 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.
  5. 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.
  6. The formulation of claim 5, wherein the polymer or mixture of polymers is hydroxypropyl methylcellulose having an apparent viscosity ranging from 0.1-150 Pa·s (100-150,000 cP) (2% in water at 20° C).
  7. The formulation of any one of the preceding claims, wherein the formulation comprises controlled-release polymer in the range of 5% to 30% (w/w) of the formulation.
  8. 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.
  9. The formulation of claim 1, comprising up to 10% by weight of anti-oxidant.
  10. The formulation of claim 9, wherein the antioxidant is chosen from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid and cysteine, or combinations thereof.
  11. The formulation of any of the preceding claims, wherein the formulation optionally comprises a functional or non-functional coating.
  12. The formulation of any one of the preceding claims, wherein the formulation has a dissolution release profile in vitro, when measured using USP II Method, at 75 rpm, in 1000 ml, 0.1 N HCl (pH 1.2), at 37±0.5° C, of 25% to 40% after 1 hour, 30% to 50% after 2 hours, 40% to 65% after 4 hours, 60% to 85% after 8 hours and not less than about 85% after 16 hours.
  13. 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.
  14. 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.
  15. A formulation of any of claims 1 to 12 for use in the treatment of 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

FIELD OF THE INVENTION In some aspects, the present invention relates to controlled release formulations comprising Drotaverine or salt thereof or similar active agents those are prone to oxidative and hydrolytic degradation and methods of preparation thereof. In some aspects, the invention relates to treatment of symptoms of gastrointestinal, biliary, urological and/or gynaecological disorders characterized by spastic conditions of smooth muscles by administering the controlled release formulations of the present invention. BACKGROUND OF THE INVENTION It is well known in the field of art to prepare formulations which provide controlled release of pharmacologically active substances on oral administration to humans and animals. Controlled release (CR) formulations decrease the frequency of administration required to maintain therapeutically effective plasma drug levels. In addition, by producing more constant blood levels, such formulations can reduce the large changes in plasma levels observed between doses. Controlled release formulations are intended to provide a longer period of pharmacological action after administration than is ordinarily achieved after administration of immediate-release (IR) dosage forms. Such longer periods of response provide therapeutic benefits that are not achieved by immediate release preparations. Furthermore, controlled release preparations result in better patient compliance. Drotaverine HCl [(Z)-1-(3,4-diethoxybenzylidene)-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline] is a benzylisoquinoline derivative, and is an analogue of papaverine. The molecular weight of Drotaverine is 397.50 g/mol and the Empirical Formula is C24H31NO4. Drotaverine is a potent spasmolytic which acts directly on the smooth muscles by inhibiting phosphodiesterase activity and is devoid of any anticholinergic side effects. Drotaverine is a selective inhibitor of phosphodiesterase isoenzyme IV and has been found useful in controlling spastic disorders of smooth muscle. Drotaverine has a dual mechanism of action. Firstly, it inhibits enzyme phosphodiesterase IV (PDE IV). This causes an increase in cyclic adenosine monophosphate level (cAMP) in smooth muscles, resulting in a decrease in concentration of free calcium ions (Ca2+). Secondly, it inhibits calmodulin (CM), which is a calcium binding protein. The decrease in Ca2+ ions along with the inhibition of calmodulin leads to inhibition of "Calmodulin-Calcium complex" (CM-Ca2+) formation. This process inhibits myosin light chain kinase enzyme (MLCK), leading to dephosphorylation of the actomyosin phosphate complex and thus causing normalization of smooth muscles. Drotaverine is a highly potent and safe antispasmodic (spasmolytic) agent, suitable for oral and parenteral administration. Drotaverine is currently marketed as a conventional IR product indicated in spasmodic pain of smooth muscles. It relieves and prevents smooth muscle spasm of various organs regardless of their function and innervation. Primarily, the drug alone and in combination is indicated in the treatment of various gastrointestinal, biliary, urological and/or gynecological disorders characterized by spastic conditions of smooth muscles. For example, Drotaverine is indicated in: i) spastic conditions of the gastrointestinal tract: irritable bowel syndrome, biliary colics and spastic conditions of the biliary tract such as cholecystolithiasis, cholecystitis, cholangitis.ii) renal colics and spastic conditions of the urogenital tract: nephrolithiasis, ureterolithiasis, pyelitis, cystitis.iii) spastic conditions of the uterus: dysmenorrhoea, imminent abortion, uterine tetanus. It is also widely used for augmentation of labor, in the therapy of spastic pain due to gastric and duodenal ulcer and prior to instrumental diagnostic procedures. The approved daily doses are 120-240 mg (in 2-3 divided doses) in adults, 40-120 mg (in 2-3 divided doses) in children between 1-6 years of age and 80-200 mg (in 2-5 divided doses) in children over 6 years. Due to its non-anticholinergic nature, Drotaverine can safely be prescribed for a long duration. Drotaverine has been registered in more than 50 countries, in Europe, Asia, Africa and Central America. In indications like irritable bowel syndrome (IBS), where pain is the predominant symptom, antispasmodics have been and remain the main agents for therapy. Drotaverine exhibits a normalizing effect on intestinal smooth muscle, which helps in alleviating pain and does not have side effects like anticholinergics. Anticholinergic antispasmodics are avoided in IBS where constipation is present (IBS-Constipation is a predominant symptom). Drotaverine brings relief of spasm in IBS by its unique site-specific action and causes normalization of smooth muscle contraction. Thus, it does not cause constipation, making it suitable for use in all types of IBS (Diarrhea predominant IBS, Constipation predominant IBS, and mixed IBS). The antispasmodic Drotaverine has long b