PHARMACEUTICAL FORMULATIONS COMPRISING EXEMESTANE

INTRODUCTION

The present invention relates to pharmaceutical formulations comprising exemestane and antioxidants or chelating agents. More specifically, the invention includes pharmaceutical compositions comprising exemestane and antioxidants or chelating agents for oral administration. The invention also includes pharmaceutical compositions comprising exemestane which are film coated. Also included are processes for preparing such compositions and methods of using such compositions for treating hormone-dependent cancers in mammals.

Cancers, including estrogen dependent cancers, are generally thought to result from a multistep process, in which a series of somatic mutations, and/or chromosomal changes occur. Each step results in a greater deviation from normal cellular behavior, until cells lose the normal ability to regulate their own growth and therefore proliferate. The altered cells first proliferate into a precancerous neoplasm, which progresses in stages toward metastatic cancer. This process is known as tumor progression. On the other hand, for instance approximately 30% of breast cancers are hormone-sensitive and are treated with a variety of agents other than oophorectomy (surgical or radiological), including anti-estrogens, progestins and aromatase inhibitors.

The drug compound having an adopted name "exemestane" has a chemical name 6-methylenandrosta-1,4-diene-3,17-dione, is a white to slightly yellow crystalline powder, practically insoluble in water, and has structural Formula I.

Formula I

Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone.

Exemestane is absorbed well from the gastrointestinal tract. The evaluation of the absolute bioavailability in humans was not possible due to the absence of a suitable intravenous formulation. However, indirect evidence indicates that bioavailability is likely limited by its relatively high first-pass metabolism effect.

Commercially, exemestane is available in an immediate release (IR) tablet formulation sold as AROMASIN® by the Pharmacia & Upjohn Co. division of Pfizer Inc. and containing 25 mg of exemestane. AROMASIN tablets contain conventional excipients used in immediate release (IR) formulations and are sugar-coated.

The poor water solubility of drugs can affect their oral administration and absorption. When poor water solubility is associated with poor chemical stability properties due to oxidative reactions under stress conditions (for example heat, moisture and light) the bioavailability of oral formulations of the drug could further decrease.

Oxidative reactions occur in common oral dosage forms such as uncoated tablets, powders, fine granules, hard gelatin capsules, causing the drug content to decrease and visual alterations (for example color changes), that can occur either during the manufacturing process and storage, and can be overcome by coating the dosage form.
Non-conventional oral dosage forms can overcome and increase the low water solubility of compounds thus impacting not only the stability but also the dissolution properties, the oral absorption and bioavailability of the active ingredient.

Traditional formulation skills and knowledge may suggest selection of appropriate stabilizing agents for overcoming oxidation degradations and improving chemical stability.

Exemestane is oxidation-susceptible and a poorly water-soluble drug. This compound has low water solubility, about 80μ g/ml, that could affect the oral administration and absorption of this active drug. Besides exemestane exhibits poor chemical stability properties due to oxidative reaction under stressed conditions. In order to improvise the dissolution properties, exemestane can be used in the micronized form or can be formulated as solid dispersions. Conventional antioxidant agents such as ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG) and the like have been shown to be not compatible with solid dispersions formulated using conventional excipients either due to physical incompatibility and chemical degradations.

Antioxidant agents such as ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG) and chelators like ethylenediaminetetraaceticacid (EDTA) and the like are frequently used for the stabilization of conventional immediate release (IR) dosage forms of oxidation sensitive drugs. Improved stability effects can be obtained adding stabilizing agents that can at the same time adversely affect the dissolution properties of the dosage form. Compatibility is also an issue when formulating dosage forms containing oxidation prone active ingredients with appropriate stabilizing agents. The amount of antioxidants or chelators used for the stabilization of dosage forms also has to be taken into consideration while formulating these dosage forms. Using large amounts of these substances for stabilization may not be advisable, as they may prove to be toxic when used in such large amounts.

There remains a need for stable formulations of exemestane using conventional antioxidants and chelating agents which do not affect dissolution properties of the dosage form and does not pose any compatibility issues. International Application Publication No. WO 2005/074890 describes pharmaceutical formulations with improved stability comprising at least one oxidation-susceptible and poorly water-soluble drug, as an active ingredient, and a water soluble derivative of vitamin E as an antioxidant agent. Improvement in chemical stability of oxidation susceptible and poorly water-soluble drugs formulated in a hydrophilic carrier based solid dispersion was obtained by adding a low amount of vitamin E TPGS as an antioxidant agent.

Vitamin E derivatives are obtained from natural sources and are themselves pharmacologically active in nature. Use of vitamin E derivatives in oral dosage forms is not widely studied. Therefore, vitamin E derivatives may pose a problem to the patients when used as an auxiliary in dosage forms containing other actives used to treat different diseases.

SUMMARY

The present application relates to pharmaceutical formulations with improved stability, comprising exemestane and antioxidants or chelating agents. More specifically, the application includes pharmaceutical compositions with improved stability comprising exemestane and antioxidants or chelating agents for oral administration. Also included are processes for preparing such compositions and methods of using such compositions for treating hormone-dependent cancers in mammals.

An aspect of the present invention provides methods for inhibiting oxidative degradation of pharmaceutical formulations containing exemestane as an active ingredient, which methods comprise adding antioxidants or chelating agents to the formulation for oral administration.

Another aspect of the present invention provides simple, rapid and inexpensive manufacturing processes for preparing a stable solid dosage form for oral administration of exemestane, which processes comprise granulating the oxidation-susceptible and poorly water-soluble drug and other pharmaceutically acceptable excipients with a binder solution comprising antioxidants or chelating agents.

Another aspect of the present invention provides includes stable film coated pharmaceutical compositions of exemestane.

In one aspect of the invention, antioxidants or chelating agents can be blended along with exemestane and then granulated using a binder solution.

In another aspect of the invention, antioxidants or chelating agents can be added into a binder solution and then used for granulating mixtures of exemestane and other conventional excipients.

In another aspect of the invention, antioxidants or chelating agents can be added at the lubrication stage of a process of preparation of formulations.

Another aspect of the invention includes improved stability of pharmaceutical compositions of oxidation susceptible and poorly water-soluble drugs with antioxidants or chelating agents in the composition.

Another aspect of the present invention provides therapeutically beneficial and stable pharmaceutical compositions of exemestane comprising antioxidants or chelating agents.

DETAILED DESCRIPTION

The present invention relates to pharmaceutical formulations with improved stability comprising exemestane and antioxidants or chelating agents. More specifically, the invention includes pharmaceutical compositions with improved stability comprising exemestane and antioxidants or chelating agents for oral administration. Also included are processes for preparing such compositions and methods of using such compositions for treating hormone-dependent cancers in mammals.

Exemestane is an irreversible aromatase inactivator that works on the aromatase enzyme inhibiting the conversion of androgens to estrogens. This compound has low water solubility, about 80 μ g/mL, that could affect the oral administration and absorption of this active drug. In addition, exemestane exhibits poor chemical stability properties due to oxidative reactions under stress conditions.

The pharmaceutical compositions of the present invention further comprise other excipients used in formulation of oral dosage forms, along with an antioxidant or chelating agent.

Useful antioxidants or chelating agents include one or more of ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), ethylenediaminetetraaceticacid (EDTA), sodium metabisulphate, sodium thiosulphate, malic acid and its derivatives, amino acids and their salts, and the like.

The pharmaceutical compositions of the invention can be prepared following conventional methods and are administered in pharmaceutically suitable forms such as solid compositions for oral administration, e.g. tablets, capsules and liquid compositions for oral administration, e.g., syrups, emulsions and suspensions.

In the context of the present invention, the desired in vitro and/or in vivo drug release of exemestane contained in the pharmaceutical formulation can be achieved by various means, such as, but not limited to, use of surfactants and solubilizers, altering the hardness of the granules/tablets, use of suitable binders in desired concentrations, use of hydrophobic and/or hydrophilic pharmaceutical excipients, altering the particle sizes and/or polymorphic form of the active, use of pharmaceutically acceptable coating excipients, and the like, or combinations thereof.

In one aspect of the invention, film coated tablets of exemestane are physically more stable than sugar coated tablets. When exposed to room temperature conditions for a period of time, sugar coated tablets tend to became sticky, while film coated tablets remain intact.

In one aspect of the invention, formulations are prepared using exemestane particles having mean particle sizes of about 1 urn to about 200 urn, about 3 urn to about 100 urn, or about 5 urn to about 50 urn. Such particles of the active ingredient exhibit desired micromeritic properties such as, but not limited to, bulk density, tapped density, angle of repose, Carr index, compressibility ratio, and the like.

In another aspect of the invention, mean average particle sizes of exemestane are less than about 30 microns.

As used herein, the term "mean particle size" refers to a distribution of particles wherein about 50 volume percent of all particles measured have particle sizes less than the defined mean particle size value, and about 50 volume percent of all measurable particles measured have particle sizes greater than the defined mean particle size value; this can be denoted by the term "D50." Similarly, a particle size distribution parameter where 90 volume percent of the particles have sizes less than a specified size is referred to as "D90" and a distribution parameter where 10 volume percent of particles have sizes less than a specified size is referred to as "D10." A desired particle size range material can be obtained directly from a synthesis process or any known particle size reduction processes can be used, such as but not limited to sifting, milling, micronization, fluid energy milling, ball milling, and the like. Methods for determining D10, D50 and D90 include laser light diffraction, such as using equipment from Malvern Instruments Ltd. (Malvern, Worcestershire, United Kingdom), as well as other techniques known to those having skill in the art.

Therapeutically effective amounts of active ingredient can be provided in the form of pharmaceutical formulations in the form of tablets, capsules, granules (synonymously, "beads" or "particles" or "pellets"), suspensions, emulsions, powders, dry syrups, and the like. All such formulations are included herein without limitation.

Granules can be formed by any processes, using operations such as one or more of dry granulation, wet granulation, extrusion-spheronization, and the like. In an embodiment, the granulation of the active ingredient, optionally with one or more pharmaceutically acceptable excipients like diluents or fillers, is carried out in equipment such as planetary mixers, rapid mixer granulators (RMG), fluid bed processors and the like. The granules obtained may further be compressed into tablets or filled into capsules using techniques known in the art. Alternatively, powder blends can be compacted using a roller compactor and then milled to produce granules that are suitable for compression. Alternatively, tablets can be prepared by a direct compression technique, using powder blends.

In one aspect of the invention, the granules formed by a wet granulation process have bulk densities ranging from about 0.4 to 0.6 g/mL, tapped densities ranging from about 0.6 to 0.8 g/mL, and Carr indexes ranging from about 20 to 40%.

In the context of the present invention, during the processing of the pharmaceutical formulations into finished dosage forms, one or more pharmaceutically acceptable excipients may optionally be included, such as but not limited to one or more diluents, binders, disintegrants, lubricants, glidants, coloring agents, film-forming agents, and others.

Diluents:

Various useful fillers or diluents include, but are not limited to, starches, lactose, mannitol (Pearlitol™ SD200), cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV) and others. Different starches include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation) and starch 1500, starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products) and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose.

Examples of crystalline cellulose products include, but are not limited to, CEOLUS™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, PH-112 microcrystalline cellulose 114, microcrystalline cellulose 112, and silicified microcrystalline cellulose (e.g., Prosolv™ supplied by JRS Pharma). Other useful diluents include, but are not limited to, carmellose, sugar alcohols such as mannitol (Pearlitol™ SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Binders:

Various useful binders include, but are not limited to, hydroxypropyl celluloses, also called HPC (Klucel™ LF, Klucel EXF) and useful in various grades, hydroxypropyl methylcelluloses, also called hypromelloses or HPMC (Methocel™) and useful in various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP-K29, PVP-K30, and PVP-K90), Plasdone™ S 630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (Carbopol™), methylcelluloses, polymethacrylates, and starches.

Disintegrants:

Various useful disintegrants include, but are not limited to, carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (Ac-di-sol™ from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, Kollidon™ CL [manufactured by BASF (Germany)], Polyplasdone™ XL, XI-10, and INF-10 [manufactured by ISP Inc. (USA)], and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcelluloses include, but are not limited to, low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches.

Lubricants:

An effective amount of any pharmaceutically acceptable tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and combinations thereof.

Glidants:

One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variation can be used. Useful glidants include, but are not limited to, silicon dioxide, talc and combinations thereof.

Coloring Agents:

Coloring agents can be used to color code the compositions, for example, to indicate the type and dosage of the therapeutic agent therein. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, iron oxides, silicon dioxide, and zinc oxide, combinations thereof, and the like.

Film-forming Agents:

Various film-forming agents that are useful for coating dosage forms include, but are not limited to, cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methyl celluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc., insoluble cellulose derivative such as ethyl celluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polymethacrylates and derivatives thereof (Eudragit™ products), chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances. Useful enteric coating materials include, but are not limited to, materials such as cellulosic polymers like cellulose acetate phthalates, cellulose acetate trimellitates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, etc., methacrylic acid polymers and copolymers (Eudragit™), and the like, and mixtures thereof.

Some excipients are frequently used as adjuvants for the coating processes, including plasticizers, opacifiers, antiadhesives, polishing agents, etc. Various useful plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, and mixtures thereof. An opacifier like titanium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating.

Antiadhesives are frequently used in the film coating process to avoid sticking effects during film formation and drying. An example of a useful antiadhesive for this purpose is talc. The antiadhesive is frequently present in the film coating in an amount of about 5% (w/w) to 15% (w/w) based upon the total weight of the coating.

Suitable polishing agents include polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., camauba wax, candelilla wax and white wax).

In addition to the above coating ingredients, sometimes pre-formulated coating products such as OPADRY™ products (supplied by Colorcon) or TABCOAT™ products can be used. OPADRY compositions generally comprise polymer, plasticizer and, if desired, pigment in a dry concentrate. OPADRY products produce attractive, elegant coatings on a variety of tablet cores and can be used in both aqueous and organic coating procedures. Products sold in a dry form generally require only dispersion in a liquid before use.

Other useful additives for coating include but are not limited to plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents.

Various useful plasticizers include, but are not limited to, substances such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. An opacifier like titanium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating.

When coloured tablets are desired, the colour is normally applied in the coating. Consequently, colouring agents and pigments may be present in the film coating. Various colouring agents include, but are not limited to, iron oxides, which can be red, yellow, black or blends thereof.

Polymers that can be used in the present invention include hydrophilic and hydrophobic substances, and combinations thereof. Suitable polymers include, but are not limited to, cellulose ethers, e.g., hydroxypropyl methylcelluloses or hypromelloses (HPMC), ethylcelluloses, hydroxypropylcelluloses (HPC), hydroxyethylcelluloses and carboxymethylcellulose sodium, polyvinylpyrrolidones, including noncross-linked polyvinylpyrrolidones, carboxymethylstarch, polyethylene glycols, polyoxyethylenes, poloxamers (polyoxyethylene-polyoxypropylene copolymers), polyvinylalcohols, glucanes (glucans), carrageenans, scleroglucanes (scleroglucans), mannans, galactomannans, gellans, alginic acid and derivatives (e.g., sodium or calcium alginate, propylene glycol alginate), polyaminoacids (e.g., gelatin), methyl vinyl ether/maleic anhydride copolymers, polysaccharides (e.g., carageenan, guar gum, xanthan gum, tragacanth and ceratonia); alpha, beta or gamma cyclodextrins, and dextrin derivatives (e.g., dextrin), polymethacrylates (e.g., copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups); cellulose esters (e.g. cellulose acetate); acrylic acid polymers (e.g., carbomers); chitosan and derivatives thereof, shellac and derivatives thereof.

Sugar coating can be performed using any process and excipients as are known to the person skilled in the art.

In other embodiments, the invention includes methods of preparing the pharmaceutical compositions of the present invention.

Equipment suitable for processing the pharmaceutical compositions of the present invention include rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, homogenizers, blenders, roller compacters, extrusion-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans, tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multimills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like, equipped with a suitable screen.

Dosage forms can be subjected to in vitro dissolution evaluation such as that according to Test 711 "Dissolution" in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP") to determine the rate at which the active substance is released from the dosage forms, and content of active substance can be determined in dissolution solutions by techniques such as high performance liquid chromatography.

In some embodiments, the invention includes use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, glassine foil, aluminium pouches, and blisters or strips composed of aluminium or high-density polypropylene, polyvinyl chloride, polyvinylidene dichloride, etc.

The pharmaceutical dosage forms of the present invention are intended for oral administration to a patient in need thereof.

Mention of exemestane is intended to include any of the alternative forms in which the exemestane can be administered, such as salts, esters, hydrates, solvates, crystalline or amorphous polymorphs, racemic mixtures, enantiomeric isomers, etc.

The following examples further describe certain specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

In the examples, impurity percentages are calculated based on the label drug content of a formulation.

COMPARATIVE EXAMPLE:

Formulation comprising exemestane without an antioxidant.

Evaporates during processing.

Manufacturing process:

1. Sift exemestane, mannitol and crospovidone through an ASTM #40 mesh sieve and mix well.

2. Prepare a binder solution by dissolving HPMC 3 cps in Isopropyl alcohol water mixture. Then add polysorbate 80 to the solution. Stir the solution well.

3. Granulate the sifted ingredients of step 1 with binder solution.

4. Dry the granules 60 ± 5°C until the loss on drying is 2-3% w/w.
5. Mill the dried granules.

6. Sift microcrystalline cellulose, crospovidone, colloidal silicon dioxide through an ASTM #40 mesh sieve and mix well.

7. Load the granules of step 5 and the step 6 mixture into a blender and blend for 10 minutes.

8. Sift magnesium stearate through an ASTM #60 mesh sieve.

9. Load the mixture of step 7 and the step 8 material into a blender and blend for 5 minutes.

10. Compress the blend using 5.90 mm deep concave punches.
After tablets of the Comparative Example without any antioxidant are subjected to storage under accelerated stability testing conditions at 60°C for 2 weeks, in closed HDPE and PVDC packages, the impurity levels are as follows:
EXAMPLE 1: Formulation comprising exemestane with butylated hydroxytoluene

CLAIMS:

1. A stable pharmaceutical formulation for oral administration comprising exemestane as an active ingredient, wherein the formulation further comprises at least one antioxidant or chelating agent and optionally other pharmaceutically acceptable excipients.

2. A stable pharmaceutical formulation comprising exemestane and at least one antioxidant or chelating agent, wherein the total drug-related impurities content is less than about 1 percent by weight of the label exemestane content.

3. A stable pharmaceutical formulation according to either of claims 1 or 2, wherein the antioxidant or chelating agent is selected from the group consisting of ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), ethylenediaminetetraaceticacid (EDTA), sodium thiosulphate, malic acid and its derivatives.

4. A stable pharmaceutical formulation of either of claims 1 or 2, wherein the formulation is in the form of tablet.

5. A stable pharmaceutical tablet formulation of claim 4, wherein the tablet is coated or uncoated.

6. A stable pharmaceutical coated tablet formulation of claim 4, wherein the tablet is coated with a film-coating or sugar coating.

7. A stable pharmaceutical formulation of any of claims 1-6, wherein the tablet is prepared by wet granulation, dry granulation, or direct compression.

8. A stable pharmaceutical formulation of exemestane of any of claims 1-7, prepared using exemestane having mean particle sizes less than about 50 urn.