A gastroretentive composition comprising apixaban

Abstract

The present invention relates to a gastroretentive composition of Apixaban, 5 wherein said composition comprises Apixaban or pharmaceutically acceptable salts or prodrugs thereof, one or more gas generating agent, and one or more pH independent controlled release excipient. In one or more embodiments, composition is multiparticulate and / or controlled release.

Description

[0001] A GASTRORETENTIVE COMPOSITION COMPRISING APIXABAN

[0002] The present invention relates to a gastroretentive composition of Apixaban, wherein said composition comprises Apixaban or pharmaceutically acceptable salts or prodrugs thereof, one or more gas generating agent, and one or more pH independent controlled release excipient. In one or more embodiments, composition is multiparticulate and / or controlled release.

[0003] BACKGROUND OF INVENTION

[0004] Apixaban is a direct oral anticoagulant that prevents coagulation by inhibiting factor Xa. It has a large therapeutic index and can be given in fixed doses. However, some side effects reported includes bleeding and risk of thrombotic events upon premature discontinuation. There is an absence of or a limited choice of antidotes, some of which are also expensive. Additionally, currently marketed formulation is only immediate release dosage forms with dosage regimen of twice daily for adult and geriatric population.

[0005] Therefore, there is an urgent need to develop a composition with enhanced bioavailability that can deliver apixaban for extended period of time. Based on dissolution results, it is surprisingly found that the composition as per invention is capable to control the maximum apixaban concentration yet having desired bioavailability and also can deliver apixaban to facilitate once a daily administration.

[0006] The gastro retentive composition of the present invention provide gastro retentive release of apixaban with enhanced good bioavailability. Controlled release gastro retentive release composition of apixaban as per present invention provides extended release of apixaban thereby requiring only once a daily administration. DESCRIPTION OF DRAWINGS

[0007] Figure 1 : Percentage (%) drug release vs time profile curve for Immediate release and Controlled release composition of Ex 1, 2, 3, 4, 5 in 900 ml Dissolution media (0.1N HCl+0.05%SLS) in Apparatus - USP 1 Basket at 100 rpm.

[0008] DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention relates to a gastroretentive composition of Apixaban, wherein said composition comprises Apixaban or pharmaceutically acceptable salts or prodrugs thereof, one or more gas generating agent, and one or more pH independent controlled release excipient. In one or more embodiments, composition is multiparticulate and / or controlled release.

[0010] The words “controlled release”, “modified release” and “extended release” are used synonymously to mean non-immediate release dosage form of any size and shape, whether coated or uncoated.

[0011] The advantages a gastroretentive composition of present invention includes

[0012] • Optimum therapeutic drug concentration,

[0013] • Reduction of incidences and unwanted side effects,

[0014] • Predictable and reproducible release rates,

[0015] • Gastro-retentive delivery to ensure drug release in upper GIT,

[0016] • Reduced frequent dosing,

[0017] • Improve safety and efficacy ratio.

[0018] In an embodiment, the present invention relates a gastroretentive composition of Apixaban, wherein said composition comprises Apixaban or pharmaceutically acceptable salts or prodrugs thereof. In an embodiment, the present invention relates a gastroretentive controlled release composition of Apixaban, wherein said composition comprises Apixaban or pharmaceutically acceptable salts or prodrugs thereof.

[0019] In an embodiment, the present invention relates a gastroretentive composition of Apixaban, wherein said composition comprises a. Apixaban or pharmaceutically acceptable salts or prodrugs thereof, and b. one or more gas generating agent.

[0020] In an embodiment, the present invention relates a gastroretentive composition of Apixaban, wherein said composition comprises a. Apixaban or pharmaceutically acceptable salts or prodrugs thereof, and b. sodium bicarbonate.

[0021] In an embodiment, the present invention relates a gastroretentive composition of Apixaban, wherein said composition comprises a. Apixaban or pharmaceutically acceptable salts or prodrugs thereof, and b. one or more pH independent controlled release excipient.

[0022] In an embodiment, the present invention relates a gastroretentive composition of Apixaban, wherein said composition comprises a. Apixaban or pharmaceutically acceptable salts or prodrugs thereof, b. one or more gas generating agent, and c. one or more pH independent controlled release excipient.

[0023] In an embodiment, the present invention relates a gastroretentive controlled release composition of Apixaban, wherein said composition comprises a. Apixaban or pharmaceutically acceptable salts or prodrugs thereof, b. one or more gas generating agent, and c. one or more pH independent controlled release excipient. In an embodiment, the present invention relates a gastroretentive composition of Apixaban, wherein said composition comprises a. Apixaban or pharmaceutically acceptable salts or prodrugs thereof, b. sodium bicarbonate, and c. one or more pH independent controlled release excipient.

[0024] In an embodiment, the present invention relates a gastroretentive controlled release composition of Apixaban, wherein said composition comprises a. Apixaban or pharmaceutically acceptable salts or prodrugs thereof, b. sodium bicarbonate, and c. one or more pH independent controlled release excipient.

[0025] In one or more preferred embodiments, pH independent controlled release excipient is pH independent controlled release polymer. In one or more preferred embodiment, composition of present invention comprises apixaban base.

[0026] In one or more preferred embodiments, gastroretentive composition of Apixaban as per present invention is multiparticulate dosage form selected from pellets, pellets in capsule, pellets in tablets, minitablets, minitablets in capsules etc. In a preferred embodiment, gastroretentive controlled release composition as present invention is coated reservoir type and optionally contains one or more pore forming agents. A gastroretentive composition of Apixaban as per present invention is administered orally.

[0027] In one or more embodiments, the present invention also relates to a process for preparation of gastroretentive composition of Apixaban, wherein said process comprises a. preparing core pellets comprising i. Apixaban or pharmaceutically acceptable salts or prodrugs thereof, and ii. one or more gas generating agent, b. coating core pellets of step (a) with one or more pH independent controlled release excipient, c. Optionally, filing pellets of step (b) in a capsule or compressing pellets of step (b) into tablet.

[0028] In one or more preferred embodiments, gas generating agent is sodium bicarbonate. In one or more preferred embodiments, pH independent controlled release excipient is pH independent controlled release polymer.

[0029] APIXABAN

[0030] Apixaban is a Factor Xa inhibitor. Apixaban is approved for medical use in the European Union, and in the United States. It is also on the World Health Organization's List of Essential Medicines. Apixaban is currently marketed under brand name Eliquis as immediate release oral dosage form.

[0031] Apixaban is an anticoagulant used to treat and prevent blood clots in patients with non-valvular atrial fibrillation and to prevent stroke by directly blocking factor Xa. It is also used to prevent blood clots after hip or knee replacement surgery and in people with a history of blood clots. It is used as an alternative to warfarin and does not require blood tests or dietary examination.

[0032] The gastroretentive composition of Apixaban comprises Apixaban in an amount of 2.5mg to 50 mg. In one or more preferred embodiments, Apixaban in an amount of 5mg, lOmg, 15mg or 20mg.

[0033] The gastroretentive composition of Apixaban preferably comprises Apixaban base. Alternatively, gastroretentive composition of present invention may comprises pharmaceutically acceptable salt or prodrug of apixaban. GAS GENERATING AGENTS

[0034] Gas generating agents works by generating gas like carbon dioxide when dosage form comes in contact with acidic gastric fluids. Further, it reduces the bulk density and thus keeps dosage form floating in the gastric fluid. Non limiting examples of gas generating agents include sodium bicarbonate and calcium carbonate. pH INDEPENDENT CONTROLLED RELEASE EXCIPIENTS pH independent controlled release excipient are excipient which dissolves independent of the pH of the fluid. pH independent controlled release excipient may be polymeric or non-polymeric. Non limiting examples of polymeric pH independent controlled release excipients includes certain grades of Eudragits grade polymers like RLPO, RSPO; ethyl cellulose, extended release grades of hyproxypropylmethylcellulose. Non limiting examples of non-polymeric pH independent controlled release excipients includes naturally occurring controlled release excipients like chitosan, guar gum and waxes.

[0035] GASTRORETENTIVE COMPOSITION

[0036] Gastroretentive composition is the site-specific drug delivery at the stomach. Gastroretentive compositions are designed to retain dosage form into stomach and drug being released majorly in stomach in immediate release or extended release form.

[0037] Gastroretentive composition may be prepared as monolithic or multiparticulate dosage form. In a preferred embodiment, the composition of present invention is multiparticulate including pellets, pellets in capsule, pellets in tablet, minitablets, minitablets in capsules etc. Gastroretentive controlled release composition may be matrix or reservoir type. Multi-particulate Gastroretentive composition can be prepared by fluid bed processor or extrusion spheronization process and can be formulated in unit dose capsules or compressed into tablets.

[0038] The multiparticulate composition of present invention has following advantages:

[0039] • Easy of manufacturing,

[0040] • Scalable with large quantities,

[0041] • High content uniformity,

[0042] • Inpatients administration via nasogastric feeding tube,

[0043] • Pediatric administration with vehicle like water, apple juice and apple sauce without crushing,

[0044] • Protection of apixaban from moisture and hydrolysis. Reduced degradation leads to reduced likelihood of adverse effects.

[0045] The pharmaceutical composition of the present invention may additionally contain one or more pharmaceutically acceptable excipients that may include a glidant, a binder, a diluent, a lubricant, a surfactant, a coating agent, a colourant and a combination thereof.

[0046] Glidant is used to improve powder flow properties. Non limiting examples of glidants includes magnesium stearate, colloidal silicon dioxide, corn starch talc and a combination thereof.

[0047] Binder is used to make the powder more cohesive. Non limiting examples of binders includes methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethylcellulose, pregelatinized starch, polyvinylpyrrolidone (PVP) and a combination thereof. Diluents is used as fillers and improving content uniformity. Non limiting examples of diluents can includes lactose, dibasic calcium phosphate, starch, pregelatinized starch, calcium carbonate, microcrystalline cellulose, mannitol, and a combination thereof.

[0048] Lubricants is used to reduce friction. Non limiting examples of lubricant includes magnesium stearate, calcium stearate, sodium stearyl fumarate, glyceryl monostearate, and a combination thereof. Having described the invention with reference to the different embodiments of the invention, other embodiments will become apparent to one skilled in the art from consideration of the specifications.

[0049] The innovation is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications to the composition may be practiced without departing from the scope of this invention.

[0050] EXAMPLES

[0051] Example- 1 Procedure

[0052] 1. Apixaban, Microcrystalline cellulose and sodium bicarbonate were mixed and then granulated with hypromellose solution.

[0053] 2. The wet mass is then extruded through Dom extruder.

[0054] 3. Extrudates were spheronised in spheroniser. 4. Wet spheres were dried in tray dryer.

[0055] 5. Dried pellets were coated in fluidized bed with solution consist of Eudragit RSPO / RLPO, Triethyl citrate and talc.

[0056] Obtained extended release (ER) coated pellets were evaluated for floating lag time and buoyancy. Floating lag time in 0.1 N HC1 observed less than 30 min and found buoyant for at least 12 hour. Example-2 Procedure:

[0057] 1. Apixaban, Microcrystalline cellulose and sodium bicarbonate were mixed and then granulated with hypromellose solution.

[0058] 2. The wet mass is then extruded through Dom extruder.

[0059] 3. Extrudates were spheronised in spheroniser. 4. Wet spheres were dried in tray dryer.

[0060] 5. Dried pellets were coated in fluidized bed with solution consist of Eudragit RSPO / RLPO, Triethyl citrate and talc.

[0061] Obtained ER coated pellets were evaluated for floating lag time and buoyancy. Floating lag time in 0.1 N HC1 observed less than 15 min and found buoyant for at least 12 hour.

[0062] Dissolution Results: Dissolution for the above example 1 and example 2 was performed in 900 ml Dissolution media (0. IN HCl+0.05%SLS) in Apparatus - USP 1 Basket at 100 rpm. Results obtained are as below:

[0063] Example-3

[0064] *Not present in final formulation except traces.

[0065] Procedure:

[0066] 1. Dissolve Hypromellose and sodium bicarbonate in purified water. Add apixaban in resulting solution under stirring and homogenize for few minutes. Filter the resulting dispersion through suitable sieve.

[0067] 2. Load sugar sphere in to fluid bed processor equipped with bottom spray assembly. Set desired parameters for drug layering and spray drug suspension onto sugar sphere. After completion of suspension spray, dry the drug layered pellets for few minutes at desired temperature.

[0068] 3. Polymeric coating dispersion was prepared by dissolving Eudragit RLPO and RSPO in to solvent mixture of Isopropyl alcohol, acetone and purified water followed by addition of TEC and talc under continuous stirring.

[0069] 4. Resulting polymeric dispersion was sprayed onto drug layered pellets at desired parameters. After completion of polymeric coating, dry the polymer coated pellets for few minutes at desired temperature.

[0070] 5. Polymer coated pellets were lubricated with talc and filled in capsules.

[0071] Obtained extended release (ER) coated pellets were evaluated for floating lag time and buoyancy. Floating lag time in 0.1 N HC1 observed less than 10 min and found buoyant for at least 18 hours.

[0072] Example-4

[0073] *Not present in final formulation except traces.

[0074] Procedure:

[0075] 1. Dissolve Hypromellose and sodium bicarbonate in purified water. Add apixaban in resulting solution under stirring and homogenize for few minutes. Filter the resulting dispersion through suitable sieve.

[0076] 2. Load sugar sphere in to fluid bed processor equipped with bottom spray assembly. Set desired parameters for drug layering and spray drug suspension onto sugar sphere. After completion of suspension spray, dry the drug layered pellets for few minutes at desired temperature. 3. Polymeric coating dispersion was prepared by dissolving Eudragit RLPO and RSPO in to solvent mixture of Isopropyl alcohol, acetone and purified water followed by addition of TEC and talc under continuous stirring.

[0077] 4. Resulting polymeric dispersion was sprayed onto drug layered pellets at desired parameters. After completion of polymeric coating, dry the polymer coated pellets for few minutes at desired temperature.

[0078] 5. Polymer coated pellets were lubricated with talc and filled in capsules.

[0079] Obtained extended release (ER) coated pellets were evaluated for floating lag time and buoyancy. Floating lag time in 0.1 N HC1 observed more than 30 min.

[0080] Example-5

[0081] *Not present in final formulation except traces. Procedure:

[0082] 1. Dissolve Hypromellose and sodium bicarbonate in purified water. Add apixaban in resulting solution under stirring and homogenize for few minutes. Filter the resulting dispersion through suitable sieve.

[0083] 2. Load sugar sphere in to fluid bed processor equipped with bottom spray assembly. Set desired parameters for drug layering and spray drug suspension onto sugar sphere. After completion of suspension spray, dry the drug layered pellets for few minutes at desired temperature.

[0084] 3. Polymeric coating dispersion was prepared by dissolving Ethyl cellulose and Hypromellose in to solvent mixture of Isopropyl alcohol and Dichloromethane followed by addition of TEC and talc under continuous stirring.

[0085] 4. Resulting polymeric dispersion was sprayed onto drug layered pellets at desired parameters. After completion of polymeric coating, dry the polymer coated pellets for few minutes at desired temperature.

[0086] 5. Polymer coated pellets were lubricated with talc and filled in capsules.

[0087] Obtained extended release (ER) coated pellets were evaluated for floating lag time and buoyancy. Floating lag time in 0.1 N HC1 observed less than 10 min and found buoyant for at least 18 hours.

Claims

CLAIMS AIM1. A gastroretentive composition of Apixaban, wherein said composition comprises a. Apixaban or pharmaceutically acceptable salts or prodrugs thereof, and b. one or more gas generating agent.

2. A gastroretentive composition of Apixaban according to claim 1, wherein said gas generating agent is sodium bicarbonate.

3. A gastroretentive composition of Apixaban according to claim 1, wherein said composition is modified release composition.

4. A gastroretentive composition of Apixaban according to claim 3, wherein said composition further comprises one or more pH independent controlled release excipient.

5. A gastroretentive composition of Apixaban according to claim 4, wherein said pH independent controlled release excipient is pH independent controlled release polymer.

6. A gastroretentive composition of Apixaban according to claim 5, wherein said pH independent controlled release polymer is polymethacrylate copolymer.

7. A gastroretentive composition of Apixaban according to claim 2, wherein said composition is multiparticulate.

8. A process for preparation of gastroretentive composition of Apixaban, wherein said process comprises a. preparing core pellets comprising i. Apixaban or pharmaceutically acceptable salts or prodrugs thereof, and ii. one or more gas generating agent,b. coating core pellets of step (a) with one or more pH independent controlled release excipient.

9. A process for preparation of gastroretentive composition of Apixaban according to claim 8, wherein said gas generating agent is sodium bicarbonate.

10. A process for preparation of gastroretentive composition of Apixaban according to claim 8, wherein said pH independent controlled release excipient is pH independent controlled release polymer.

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