WO2014009817A1

WO2014009817A1 - Pharmaceutical composition of febuxostat

Info

Publication number: WO2014009817A1
Application number: PCT/IB2013/052164
Authority: WO
Inventors: Veerababu TADURI; Chidhambaram MUTHULINGAM; Minal Patel; Viswaprasad Varanasi
Original assignee: Alembic Pharmaceuticals Limited
Priority date: 2012-07-12
Filing date: 2013-03-19
Publication date: 2014-01-16
Also published as: EP2925306A1

Abstract

The present invention relates to a solid oral preparation of febuxostat and to a process for preparation thereof. More particularly, it relates to a solid oral preparation of febuxostat which is stable and has desired pharmacokinetic properties.

Description

PHARMACEUTICAL COMPOSITION OF FEBUXOSTAT

TECHNICAL FIELD:

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.

BACKGROUND ART:

Febuxostat, 2-[3-cyano-4- (2-methylpropoxy)phenyl)-4-methylthiazole-5-carboxylic acid is a non-purine, XO inhibitor and has structure as represented by formula I.

FORMULA I

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.

The international application WO92/09279 & U.S. Patent No. 5,614,520 generically discloses febuxostat and its pharmaceutically acceptable salts.

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. Generally, 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.

Thus, depending upon the physiological properties of a drug molecule, proper choice of polymorph or its particle size in developing a formulation may sometime be essential or non-essential.

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.

Further as said in this patent, US 6,225,474 and WO 99/65885 were silent about what the industrial superiority means as it did not provide evidence (data) supporting the fact that the crystal A is preferred in view of industrial superiority.

The drawbacks of febuxostat forms other than crystal form-A are explained in U.S. 7,361,676.

US Pat. No. 7,361,676 suggests that; there is a crystal form that is suitable for preparing preparations, independently from the characteristics of the crystals (including amorphous) of drug substances. From which, it is now to be understood that; polymorphic form which is suitable in view of industrial superiority not necessarily means superior in formulation too to give desired pharmacokinetic properties; rather it is the design of formulation itself which may be more important.

Prior art discloses various crystal forms of febuxostat, but, only crystal A has been used in tablet formulation.

Tablet formulation disclosed in U.S. 7,361,676 uses crystal-A, however, the use of crystal A also does not come without limitations.

The 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 μηι, 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.

Hence, the advantages of crystal-A in formulation were limited to use of a particular particle size range.

Moreover, the 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.

Thus, manufacturing of crystal-A is a cumbersome, lengthier and non-economic process as well.

For at least these reason there exist a need to explore the possibility for use of other crystal forms which can be used in formulation to give desired pharmacokinetic properties, has simpler and economic process of manufacturing, and, thus enables over all cost effective production of febuxostat product. 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.

Hence in particular a need exist to develop a stable solid preparation of febuxostat with crystal-G, which is stable and has desired pharmacokinetic properties.

Therefore, 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.

SUMMARY OF THE INVENTION:

In one aspect, the present invention provides a stable solid oral preparation comprising; micronized febuxostat Form-G along with one or more pharmaceutically acceptable excipients.

In another aspect; there is provided a process for preparation of stable solid oral preparation; which process 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.

BRIEF DESCRIPTION OF THE DRAWING:

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

DETAILED DESCRIPTION OF THE INVENTION:

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. For said purpose, 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.

The desired crystal forms of febuxostat were also obtainable by following the process disclosed in article; M. Hasegawa et. al, "Heterocycles (1998), 47(2), 857-864, JP Patent 06,345,724 and US Patent 5,614,520.

Thus, in one of the preferred embodiment, present invention provides a stable solid oral preparation comprising; micronized febuxostat form-G along with one or more pharmaceutically acceptable excipients.

The "micronized" as used herein refers to febuxostat form-G having preferably particle size distribution of; D₉₀ less than 30μιη, D₅₀ less than 1-5μηι and D₁₀ less than 1 μιη.

However, there is no particular restriction to the average particle size of the crystal of the drug substance in the solid preparation and therefore, the average particle diamter can be 3 μπι or greater and 30 μιη 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. For example, 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.

Examples of the 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.

Examples of the disintegrating agent for the solid preparation of the invention 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.

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. For example, 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.

When followed the wet granulation method, 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.

When the solid preparation is made in a form of a tablet, 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.

Example 1

Febuxostat Tablets 40, 80 & 120 mg

Procedure:

Sifting:

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.

Binder Solution Preparation:

Remaining quantity of hydroxy propyl cellulose (HPC LF) (60% part) add slowly in to the required quantity of purified water under stirring until to get clear solution.

Granulation:

Sifted material load into rapid mixer granulator and dry-mix for 10 minutes at slow impeller speed and chopper at off position.

Add 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)]

Drying:

Carry out the drying in rapid dryer at 60°C medium air flow till the LOD is NMT 2.50 % w/w (at 105°C by halogen moisture analyzer). Record LOD after specified time interval.

Sizing:

Sift the dried granules through vibratory sifter equipped with 30 # (ASTM). Mill the retained granules in multimill equipped with 1.0 mm Screen at medium speed with knives forward.

Record the yield and Assay of sized & milled Granules. Calculate the Quantity of Extra granular materials based on the yield.

Sifting of extra-granular Material:

Sift Microcrystalline cellulose (Avicel PH 102), Cross carmellose sodium (Ac-di-sol) and Colloidal silicon dioxide (Aerosil) through 40# (ASTM) and collect in polyethylene bag. Sift Magnesium Stearate through 40 # S.S. sieve and collect in separate polyethylene bag.

Blending and Lubrication:

Load the sifted and milled granules into Conta Blender and add sifted extra-granular material into Conta blender and mix for 10 minutes at 12 rpm.

Add Sifted Magnesium Stearate to the blender containing blend of Step.1 and carry out mixing for 5 minutes at 12 rpm.

Compression:

The blend is compressed in a suitable compression machine using Capsule shaped Coating:

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). 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.

For present formulation, 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.

Following is the dissolution data obtained for example 1 in pH 6.8 Acetate Buffer. Table 1

From the above table, it is apparent that solid preparation with form-G (Test) gives the dissolution profile comparative to Innovator product (reference). Thus, as is seen, formulation of the present invention provides consistently acceptable dissolution profile.

Further a bioequivalence study for test product under fasting and fed conditions was also performed, results of which are given below in tablet 2.

Table 2

In process of bio-study, 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.

From the results of above table 2; it appears that pharmacokinetic values of test product were in line with that of reference product, i.e. in the acceptance limit of 80-125% of reference; hence the test product shows the bioequivalence to the reference product. Example 2

Febuxostat Tablets 40. 80 & 120 mg

Procedure:

Formulation of Example 2 is prepared by following the process of Example 1.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We claim:

1. A solid oral composition comprising micronized febuxostat form-G and one or more pharmaceutically acceptable excipients.

2. The composition of claim 1, wherein said micronized febuxostat form-G has particle size distribution of; D90 less than 30μιη, D₅o less than 1-5μηι and D1₀ less than 1 μιη.

3. The composition of claim 2, wherein average particle diameter of said form-G is from 3 μιη to 30 μιη.

4. The composition of claim 1, wherein said excipients are one or more selected from diluents/fillers, lubricants, binders, disintegrants, glidants, surfactants and like.

5. The composition of claim 4, wherein said excipients comprises one or more of corn starch, pregelatinized starch, partly pregelatinized starch, lactose, lactose monohydrate, lactose anhydride, crystalline cellulose, microcrystalline cellulose, D-mannitol, dibasic calcium phosphate, hydroxypropyl cellulose, croscarmellose sodium, poloxamer, Colloidal silicon dioxide, magnesium stearate, any pre-mix or mixture thereof.

6. A solid oral composition prepared by a process comprising the steps of:

i) mixing micronized febuxostat form-G particles with one or more of pharmaceutically acceptable excipients; and

ii) formulating the mixture of step (i) into suitable dosage form.

7. A process for preparation of a solid oral composition comprising the steps of:

ii) formulating the mixture of step (i) into suitable dosage form.

8. The process of claim 7, optionally include the step of coating the dosage form.

9. The composition of claim 1, in the form of a tablet, capsule, pellet, granule, powder, pellets in capsule, granules or spheroids.

10. A solid oral composition of febuxostat substantially as herein described and illustrated.