Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles

Definitions

• the present invention relates to a solid oral preparation of febuxostat and process for preparation thereof. More particularly, it relates to a solid oral preparation of febuxostat which is stable and has desired pharmacokinetic properties.
• Febuxostat is administrated in the form of tablets that are marketed in the USA and the EU under the name ULORIC® for the chronic management of hyperuricemia patients with gout.
• U.S. Patent No. 6225474 and International publication WO 99/65885 discloses six crystalline forms of febuxostat viz. crystal A, crystal B, crystal C, crystal D, crystal G and amorphous form of Febuxostat. It is described that crystals A, C and G are useful in view of retention of a crystal form in long term storage. Among them, crystal A is preferred in view of industrial superiority.
• the selection of polymorph or its particle size for its use in preparing any pharmaceutical composition is critical as that decides the processing properties, such as in case of handling, processing, storage stability, purification etc of the material in any formulation.
• a right choice of polymorph of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It may increase the choices in hand for a scientist working on formulation optimization, for example, by providing a product with different properties e.g. better processing or handing characteristics, improved dissolution profile, or improved shelf life etc.
• U.S. Pat. No. 7361676 discloses a tablet formulation comprising crystal-A which is stated as stable and having little variation in the dissolution profiles.
• Patent stated that it is not always possible to obtain preparations having no-variation in the dissolution profiles of drugs, even if such a crystal form is used as is thought to be most stable in a physical stability test.
• Prior art discloses various crystal forms of febuxostat, but, only crystal A has been used in tablet formulation.
• solubility of form A is limited, as it has a value of 0.22 mg/ml. Therefore, to get the desired pharmacokinetic profile; drug crystals were required to be present in diameter range of 12.9 to 26.2 ⁇ , as only this particular particle size range would give the desired results of consistency in disintegration time, uniformity of content, CV values and friability of the tablet, against a tablet with particle size outside this range.
• form-A is difficult to make as form A is said to be obtainable in pure form only in a quite narrow window of temperature and methanol / water ratio in the region I as shown in Fig 1 of EP 1020454.
• the process to obtain pure form A is especially critical, as different polymorphic forms of Febuxostat are obtainable from the same solvent system.
• Form-G of Febuxostat is such a crystal that has simpler and economic process of manufacturing and can be used in the formulation to give desired pharmacokinetic properties.
• the principal object of the present invention is to provide a solid preparation of the febuxostat which is stable and has desired pharmacokinetic properties.
• Another object of the present invention is to provide a solid preparation of the febuxostat, which uses crystal form-G, and still is stable and has desired pharmacokinetic properties.
• the present invention provides a stable solid oral preparation comprising; micronized febuxostat Form-G along with one or more pharmaceutically acceptable excipients.
• a process for preparation of stable solid oral preparation comprises the steps of; i) mixing micronized febuxostat form-G with one or more of pharmaceutically acceptable excipients; and ii) formulating the mixture of step (i) into suitable dosage form.
• FIG 1 is a graph showing dissolution profile comparison of Innovator product 'Reference' (Uloric ® 80mg) and Alembic product 'test' (Febuxostat Tablets 80mg) in media; 0.05 M (pH 6.8) Potassium Phosphate Buffer/ Paddle/ 75 rpm/ 900 ml
• the present invention relates to a solid oral preparation of febuxostat and to a process for preparation thereof. More specifically, the present invention relates to a solid oral preparation which comprises febuxostat form-G, which may further be micronized.
• Micronization is the process of reducing the average diameter of a solid material's particles.
• any of conventional methods including but not limited to, such as milling, grinding, crushing, cutting or modern techniques such as RESS process (Rapid Expansion of Supercritical Solutions), the SAS method (Supercritical Anti- Solvent) and the PGSS method (Particles from Gas Saturated Solutions) can be used.
• the crystals of the febuxostat can be produced by the method described in, for example, international publications viz. WO 92/09279 and WO 99/065885.
• present invention provides a stable solid oral preparation comprising; micronized febuxostat form-G along with one or more pharmaceutically acceptable excipients.
• micronized refers to febuxostat form-G having preferably particle size distribution of; D 90 less than 30 ⁇ , D 50 less than 1-5 ⁇ and D 10 less than 1 ⁇ .
• the average particle diamter can be 3 ⁇ or greater and 30 ⁇ or less (as determined by an image analysis)
• the solid preparation of the present invention may comprises one or more of tablet, capsule, tablet in tablet, tablet in capsule, pellet, granules, powder, pellets in capsule, granules in capsule, spheroids, beads, pill and like other dosage forms suitable for administration.
• a tablet may contain, in addition to micronized febuxostat form-G, one or more other suitable excipients selected from the group comprising of diluents/fillers, lubricants, binders, disintegrants, glidants, surfactants and like.
• the crystal of the drug substance of the invention is contained in the solid preparation of the invention; preferably in an amount of 1 to 60 parts by weight based on 100 parts by weight of the solid preparation.
• excipients for the solid preparation of the invention include corn starch, pregelatinized starch, partly pregelatinized starch, lactose, lactose anhydride, crystalline cellulose, D-mannitol and dibasic calcium phosphate. Particularly the lactose, crystalline cellulose, starches or their combination are preferable.
• the excipients are contained in an amount of 30 to 90 parts by weight, and more preferably 40 to 80 parts by weight, based on 100 parts by weight of the solid preparation.
• disintegrating agent for the solid preparation of the invention examples include carmellose sodium, carmellose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium and crospovidone. Particularly the croscarmellose sodium and partly pregelatinized starch are preferable.
• the disintegrating agent is contained in an amount of 1 to 30 parts by weight, preferably 1.5 to 20 parts by weight, based on 100 parts by weight of the solid preparation.
• the binders for the solid preparation of the invention may be those known to the persons in the art. Particularly preferable binders are hydroxypropyl cellulose, hydroxy propylmethyl cellulose, and polyvinyl pyrrolidone.
• the binder is contained in an amount of 0.5 to 25 parts by weight, and preferably 1 to 20 parts by weight, based on 100 parts by weight of the solid preparation of the invention.
• the lubricants for the solid preparation of the invention may be those known to the persons in the art. Particularly preferable lubricants are magnesium stearate, calcium stearate, stearic acid, talc, glyceryl behenate, hydrogenated vegetable oil and sodium stearyl fumarate.
• the lubricant is contained in an amount of 0.1 to 2 parts by weight, and preferably 0.5 to 1 parts by weight, based on 100 parts by weight of the solid preparation of the invention.
• the surfactants for the solid preparation of the invention may be those known to the persons in the art. Particularly preferable surfactants are sodium lauryl sulfate, polysorbates, poloxamers, cremophors and polyethylene glycol.
• the surfactant is contained in an amount of 0.5 to 20 parts by weight, and preferably 2 to 10 parts by weight, based on 100 parts by weight of the solid preparation of the invention.
• binders There may be added known binders, lubricants, coating agents, diluents, colorants, agents to the solid preparation of the invention to improve the physical properties, appearance, etc. of the preparation.
• the preparation of present invention may be prepared by conventional techniques well known to those skilled in the art such as wet granulation, direct compression, dry compaction (slugging) and like other as is suitable.
• the solid preparations of the invention can be produced by compressing a mixture of the crystals of the drug substance of the invention with excipients.
• one method for the production includes mixing the crystals of the drug substance of the invention with the materials for the preparation by a suitable mixer, and directly compressing the mixture to tablets.
• Other methods include a dry granulating step to produce granules for tablets using dry granulating machines or roller compacters, and a wet granulating step to produce granules for tablets using water, ethanol and solutions containing binders when necessary.
• the micronized febuxostat form-G can be mixed with pharmaceutically acceptable excipients and can be granulated with aqueous/binder solution.
• Granules can be dried. Dried granules can be further mixed with other pharmaceutically acceptable excipients and formulated into suitable dosage forms.
• the tablet can be produced, for example, through granulating, sieving, mixing and tableting steps. Further, it is possible to coat the surface of the tablet by adding a coating step-to the production steps mentioned above.
• the tablet of present invention has acceptable content uniformity and less variation in the dissolution profile.
• the invention may be further illustrated by the following non-limiting example of febuxostat tablet.
• Febuxostat form-G Lactose monohydrate (Granulac 200), Microcrystalline cellulose (Avicel PH 101), Hydroxypropyl cellulose (HPC LF) (only 40 % part add in Drymix) and Croscarmellose sodium (Ac-di-sol) weigh and pass through 25 # (ASTM) by using mechanical sifter.
• HPC LF hydroxy propyl cellulose
• binder solution into dry mixed blend of step 1 within 2-4 minutes at slow impeller speed and fast chopper speed. Add additional quantity of purified (approx. 25 % of binder solution) water within 4-5 minutes at slow impeller speed and fast chopper speed. Kneading to be done for 1-2 minute at slow impeller speed and fast chopper speed (If required)]
• the tablets so obtained are coated in a suitable coater using Opadry II pink (10% w/w in water) by controlling the in-process parameters to obtain 3.0 % weight gain.
• the characteristic properties of the present formulation can be demonstrated by showing the dissolution profile of the product.
• the dissolution of the active ingredient may be determined using standard procedures well known to those skilled in the art (e.g. the dissolution test procedures, such as the Rotating Basket Method (Apparatus I) or Paddle Method (Apparatus II), disclosed in the U.S. Pharmacopeia (USP).
• the dissolution test procedures such as the Rotating Basket Method (Apparatus I) or Paddle Method (Apparatus II), disclosed in the U.S. Pharmacopeia (USP).
• Such procedures include those in which the formulation product is immersed in an aqueous medium such as water or hydrochloric acid and aliquots of the medium are withdrawn at various time points over a period of 24 hours. The aliquots are analyzed using high pressure liquid chromatography (HPLC) with UV detection to determine the concentration of dissolved active ingredient using standard methodology.
• HPLC high pressure liquid chromatography
• the dissolution profile is determined by using Apparatus II method in media of 0.05 M (pH 6.8) Potassium Phosphate Buffer/ Paddle/ 75 rpm/ 900 ml.
• the febuxostat product was orally administered to patients, the pharmacokinetic blood samples were collected, drug was measured from the collected plasma samples.
• the pharmacokinetics values of Cmax, Tmax, AUC(O-t), AUC(O-oo) and Cmax/AUC (0- ⁇ ) were calculated.
• test product shows the bioequivalence to the reference product.
• Example 2 Formulation of Example 2 is prepared by following the process of Example 1.

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• 2013
  • 2013-03-19 EP EP13716064.4A patent/EP2925306A1/de not_active Ceased
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