Field of the invention

The present invention relates to a novel stable injectable composition for intramuscular administration comprising 7-alpha-[9-(4,4,5,5,5-penta fluoropentyl sulphinyl) nonyl]estra-l,3,5-(10)- triene-3,17-beta-diol (Fulvestrant) as active pharmaceutical ingredient. More specifically, the present invention discloses compositions that exhibit superior stability of the formulation and in-vivo release characteristics at steady state than the formulation known in the art.

BACKGROUND OF THE INVENTION

Fulvestrant is an estrogen receptor antagonist used in the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. As the growth of this type of tumor is dependent on the presence of hormones which stimulate tumor growth by binding to cellular hormone receptors, it is desirable to administer hormone receptor antagonists to block the growth signaling pathway. The recommended dose of Fulvestrant is 500 mg and is administered intramuscularly at intervals of 1, 15, 29 days and once monthly thereafter as two 5 mL injections. Intramuscular formulations need to have a high concentration of active as only relatively low volumes can be injected. Fulvestrant has very high lipophilicity and extremely low solubility in many pharmaceutically acceptable solvents and accordingly is difficult to formulate at appropriate concentrations. Fulvestrant is very soluble in alcohols (>200 mg/mL in benzyl alcohol and ethanol) and glycols (70 mg/mL in propylene glycol) and poorly soluble in fixed oils except castor oil in which solubility is 13 mg/mL. US6774122 and US7456160 disclosed formulations comprising alcohol 10% w/v, benzyl alcohol 10% w/v, benzyl benzoate 15% w/v as co-solvents, made up to 100% w/v with castor oil as co-solvent and release rate modifier.

It is observed that formulations of prior art utilize an organic ester and castor oil for release rate modification and vehicle thus leading to potential issues with local tissue irritation. However, it is also noted that due to high lipophilicity and insolubility of the drug, it is extremely difficult to achieve an acceptable release rate utilizing the approve excipents that are generally recognized as safe and non-irritating while simultaneously achieving acceptable solubility, stability.

Therefore it is surprisingly found that the release of composition comprising Fulvestrant of the present invention on administration is substantially stable and improved than formulation in the art without any local tissue irritation.
Further, composition of the present invention is provided with better stability, syringeability and better release profile of the formulation thus providing an alternative for better patient compliance and therapeutic outcome.

SUMMARY OF THE INVENTION

A stable sustained release pharmaceutical composition comprising Fulvestrant as active, mixture of one or more alcohols and /glycols as co-solvent, castor oil as an adjuvant for prevention of injection site precipitation, medium chain triglycerides as a vehicle and release rate modifier.

One aspect of the invention is to provide once a month sustained release composition for a patient with positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy.

In another aspect of the present invention, castor oil is provided in the composition to prevent injection site precipitation due to its hydrogen bonding capability with the active owing to its hydroxyl fatty acid composition.

Further aspect of the present invention includes the composition that exhibits a superior release profile in comparison with the products known in the art and offers better patient compliance.

Sustained release composition of the present invention comprises more specifically Fulvestrant; pharmaceutically acceptable co-solvents such as ethanol, benzyl alcohol, propylene glycol, polyethylene glycol or a mixture thereof; hydroxyl fatty acids including castor oil or any such oils to prevent injection site precipitation; and medium chain triglycerides (MCT) as a release rate modifier.

Still another aspect of the invention is a method of treatment of a patient with positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy by administering once a month therapeutically effective amount of Fulvestrant substantially free of Fulvestrant Sulfone analogue.

Use of composition comprising administering once a month therapeutically effective amount of Fulvestrant with pharmaceutically acceptable excipients for a patient with positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy wherein the injection is substantially free of Fulvestrant Sulfone analogue.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are intended to provide further understanding of invention and are incorporated in and constitute a part of invention. The drawings illustrate an embodiment of invention and together with the description illustrate principle of invention. The drawings should not be taken as implying any necessary limitation on the essential scope of invention. The drawings are given by way of non-limitative example to explain the nature of the invention. For a more complete understanding of the invention reference is now made to the following description taken in conjunction with accompanying drawings.

Figure 1, illustrates the drug release rate in plasma level of two compositions of the present invention along with reference composition. It is observed that the evaluated compositions I, II III and IV attained a faster steady state while maintaining the similar plasma concentrations as that of the Reference Composition. This improved unforeseen steady and fast release of the compositions along with prevention of injection site precipitation is due to synergistic effect of the components present in the composition.

Figure 2 and 3, illustrates the presence of major degradation product sulfone in the proposed composition along with reference composition. It is evident from Figures 2 and

3 with respect to the data as shown in Table 1 and 2 that the major degradation product Sulfone analogue of Fulvestrant is significantly lower in the present compositions in both accelerated and stress stability condition. The enhanced stability at elevated temperatures will enable storage/transportation at room temperature and will not impact the potency of the product in case of temperature excursions.

The foregoing description outlined is rather broadly preferred and alternative feature of the present invention so that those skilled in the art may better understand the detailed description of the intention that follows. Additional features of the invention will be described hereinafter that form the subject of claims of the invention. Those skilled in the art should appreciate that they can readily use the disclosed conception and specific embodiment as a basis for designing and modifying other structures for carrying out the same purposes of the present invention. Those skilled in the art should realize such equivalent conception do not depart from the spirit and scope of the invention in its broadest form.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is related to sustained release composition of Fulvestrant. The composition within the scope of present invention may include carriers or excipients for formulating Fulvestrant into suitable pharmaceutical dosage form for therapeutic use. Fulvestrant synthesized using the method disclosed in Indian Patent Application number 1643/CHE/2010 for the purpose of preparing composition of the present invention which is incorporated herein by reference.

The present invention comprising Fulvestrant and pharmaceutically acceptable excipients such as mixture of one or more alcohols and /glycols as co-solvent, castor oil as an adjuvant for prevention of injection site precipitation and medium chain triglycerides as a vehicle and release rate modifier. Alcohols are monohydric alcohol, dihydric alcohol or aromatic alcohol, more specifically ethanol, propylene glycol, polyethylene glycol, benzyl alcohol or a mixture thereof. Further the invention employs medium chain triglycerides as a vehicle and also to modulate the steady state release characteristics of the depot injection. Castor oil is used as an adjuvant prevents the injection site precipitation of the active ingredient. Surprisingly the composition enables the depot to achieve a faster steady state with minimum fluctuations in the plasma concentration of the active.

The compositions containing Fulvestrant as active ingredient were prepared using different combinations of ethanol, benzyl alcohol, propylene glycol, polyethylene glycol, castor oil, and using a vehicle of Medium chain triglyceride oil. The samples were evaluated for stability, chromatographic profile and release characteristics in comparison with currently marketed formulation. The evaluation also includes the prior art formulation for comparison purposes.

Administration of sustained release composition of the present invention as an Injectable dosage form results in release of the drug for at least one month. This composition can be administered to a patient in the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy.

The formulations that were evaluated for stability of the product and release characteristics included compositions containing one or a mixture of the following ingredients: Benzyl alcohol, Ethanol, Propylene Glycol, Polyethylene glycol, Medium chain triglycerides, Castor oil. Composition contains a mixture of two or more co-solvents in the proposed ratio either alone or along with Castor oil.

Composition comprising Fulvestrant between 3% w/v to 7% w/v, ethanol between 5% w/v and 20% w/v; benzyl alcohol is between 5% w/v and 20% w/v; propylene glycol is between 0.5% w/v and 20% w/v; polyethylene glycol is between 0.5% w/v and 10% w/v; and castor oil is between 10% w/v and 75% w/v.

The composition of the present invention is prepared according to the following method or any other method known to those skilled in the art of synthesizing steroids.

Example 1

Process for preparing Fulvestrant

To a stirred solution of 17p-acetoxy-7a -(9-acetoxynonyl) oestra-l,3,5(10)-triene-3-ol [Diacetate VIII (10 g, 20.08 mmol)] in methanol (100 mL) 6N-sodium hydroxide solution (20.1 mL, 120.5 mmol) was added and the mixture was stirred at room temperature for 120 minutes. After completion of reaction, the reaction mixture was neutralized with aqueous 2N-hydrochloric acid. The product obtained after distilling out methanol was extracted in to dichloromethane, washed with water up to neutral, evaporated and dried to yield a compound (8g, 97%).

To a solution of the above compound (10 g, 24.15 mmol) in tetrahydrofuran (200 mL) was added 7.24 mL of 6N-sodium hydroxide solution followed by trityl chloride (12.12 g, 43.47 mmol) and the reaction mixture was stirred for 4 hours at room temperature. After completion of reaction the reaction mixture poured in to saturated sodium bicarbonate solution. The product was extracted with dichloromethane and the organic layer washed to neutral with water, evaporated and dried to yield a crude material which was purified by chromatography to yield a gummy Trityl ether (12.64g, 80%).

To a stirred solution of above Trityl ether (10 g, 15.2 mmol) in dichloromethane(100 mL) at -10°C was added triethylamine (4.25 mL, 30.4 mmol) followed by p-toluene sulphonyl chloride (4.36 g, 22.8 mmol). The reaction mixture was stirred at -10°C for 24 hours.After completion of reaction, the mixture was concentrated, diluted with methanol and poured in to saturated sodium bicarbonate solution, stirred vigorously for one hour and the product was extracted with dichloromethane, the organic phase washed with water until neutral and evaporated to yield the Tosylate compound (12g,97%).

A solution of sodium 4,4,5,5,5-pentafluorothiopentoxide [generated from 4,4,5,5,5-pentafluoropentane thiol (2.8 g 14.4 mmol) and a 60 % dispersion of sodium hydride in mineral oil (0.74 g , 18 mmol)] in tetrahydrofuran (60 mL) was added to a solution of the above Tosylate compound (10 g, 0.012 mol) in tetrahydrofuran (60 mL) and the reaction mixture was stirred at laboratory temperature for 2 hours. After completion of reaction, the reaction mixture was concentrated under reduced pressure and poured into water. The oil separated was extracted into dichloromethane, washed until neutral with water and organic layer was concentrated to yield the Sulphide compound (7g, 68%).

A solution of sodium metaperiodate (3.085 g, 14.4 mmol) in water (10 mL) was added to a solution of the above Sulphide compound (10 g, 12 mmol) in methanol(200 mL) and the mixture was stirred at laboratory temperature for 24 hours and completion of reaction was checked by TLC. The reaction mixture was concentrated and poured in to sodium bicarbonate solution. The product was extracted with dichloromethane and the organic layer washed with water to neutral and evaporated to yield the Sulphoxide compound (9.8g, 96%).

To a stirred solution of the above Sulphoxide compound (10 g, 11.79 mmol) in 100 mL methanol was added concentrated hydrochloric add (2.08 mL, 23.58 mmol) and the solution was stirred at laboratory temperature for 2 hours and reaction completion checked by TLC. Reaction solution concentrated completely and a residue dissolved in dichloromethane, washed with water to neutral, dichloromethane solution concentrated completely and dried to yield a pale yellow gummy solid, which on crystallization from petroleum ether-ethyl acetate mixture yields pure Fulvestrant (5.36g, 75%).

Following compositions are prepared using the Fulvestrant obtained from Example-1.

Method of Preparation of Formulations described in Examples from 2 to 8:
To the accurately weighed mixture of alcohol and/ glycols, Fulvestrant was added and dissolved. To this solution the oils are added and made up to volume with the vehicle medium chain triglycerides. The formulation bulk is aseptically filtered with a 0.22 micron filter into a pre-sterilized vessel and filled into a suitable administration device like vials/ pre-filled syringes/ampoules, stoppered and sealed.

Method of treating for patients with positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy by administering once a month therapeutically effective amount of Fulvestrant with other pharmaceutically acceptable excipients, which is substantially free of Fulvestrant Sulfone analogue.

Use of composition comprising administering once a month therapeutically effective amount of Fulvestrant with pharmaceutically acceptable excipients for a patient with positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy wherein the injection is substantially free of Fulvestrant Sulfone analogue.

PHARMACOKINETIC in vivo STUDY OF FULVESTRANT INJECTION:

The following compositions of the present invention and composition known in the art as reference composition were used for the pharmacokinetic in vivo study

The compositions were evaluated for pharmacokinetic release studies in New Zealand rabbit animal model. The animals were injected intramuscularly with 50 mg dose of Injection and the drug release was studied for a minimum of 3 to 5 weeks. Post steady state the animals were sacrificed and the injection site was observed for precipitation of the active, any signs of irritation or necrosis or any other apparent changes.
The studies showed that castor oil played a significant role in preventing the injection site precipitation while the co-solvents increased the solubility. Propylene glycol and PEG also acted as release rate modifiers in addition to being co-solvents. Figure-1 shows drug release rate in plasma level of two compositions of the present invention along with reference composition. It is observed that the evaluated compositions I, II III and IV attained a faster steady state while maintaining the similar plasma concentrations as that of the Reference Composition. This improved unforeseen steady and fast release of the compositions along with prevention of injection site precipitation is due to synergistic effect of the components present in the composition.
Stability study of the composition:

The compositions prepared using the above method were evaluated for chromatographic profile, release characteristics in comparison with marketed formulation and showing no local site precipitation when evaluated in-vivo. For the purpose of testing the stability of two compositions of the present invention and prior art composition were used for HPLC. This no way restricts the scope of the present invention.

To analyze the level of Fulvestrant sulfone in the above Fulvestrant formulations by HPLC, the formulations have been stored at 25°C with relative humidity 60% for 6 months. HPLC analysis was carried out for both prior art and formulation of present invention initial, thereafter end of first, second and third month. Peak values of HPLC analysis is provided hereunder in Table 1.

In stress exerted conditions, the formulations have been stored at 40°C with relative humidity 75% for a month. HPLC analysis was carried out for both prior art and formulation of present invention initial, thereafter end of two weeks, and first month. Peak values of HPLC analysis is provided hereunder in Table 2.

Further, the proposed formulation has less viscosity and is expected to reduce pain on injection while facilitating easy syringeability when filled in a prefilled syringe device or other administration devices. Stability of the compositions of the present invention was studied at accelerated conditions of storage and stress condition according to ICH guidelines. It is evident from Figures 2 and 3 with respect to the data as shown in Table 1 and 2 that the major degradation product sulfone analogue of Fulvestrant is significantly lower in the present compositions in both accelerated and stress stability condition. The enhanced stability at elevated temperatures will enable storage/transportation at room temperature and will not impact the potency of the product in case of temperature excursions.

We claim:

1. A stable sustained release composition for treating patients with positive metastatic breast cancer comprising therapeutically effective amount of Fulvestrant or salt and pharmaceutically acceptable excipients substantially free of Fulvestrant Sulfone analogue.

2. The composition as claimed in claim 1 wherin Fulvestrant or a pharmaceutically acceptable salt, alcohol as co-solvent, Castor oil or other hydroxyl fatty acid containing oil as an adjuvant for preventing the injection site precipitation of the active and medium chain triglyceride oil as a release rate modifier and vehicle.

3. The composition according to claim 2, wherein Fulvestrant is between 3% w/v to 7% w/v, ethanol between 5% w/v and 20% w/v; benzyl alcohol is between 5% w/v and 20% w/v; castor oil is between 10% w/v and 75% w/v.

4. The composition as claimed in any preceding claim, wherein the composition further comprising preferably propylene glycol between 0.5% w/v and/or 20% w/v; polyethylene glycol is between 0.5% w/v and 10% w/v; and

5. A composition according to claim 1-3, wherein the composition contains a mixture of two or more co-solvents in the proposed ratio of 5 to 20% either alone or along with Castor oil.

6. The composition according to claiml, wherein alcohol is ethanol, benzyl alcohol, propylene glycol, polyethylene glycol or a mixture thereof as co-solvent.

7. The composition of the preceding claims, wherein castor oil or any other hydroxyl fatty acid containing oils acts as an adjuvant for preventing the injection site precipitation of the active.

8. Method for treatment of a patient with positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy by administering once a month therapeutically effective amount of Fulvestrant substantially free of Fulvestrant sulfone analogue and pharmaceutically acceptable excipients.

9. The method of claim 7, wherein the composition is administered preferably weekly, more preferably bi-weekly, most preferably monthly.

10. Use of composition comprising administering once a month therapeutically effective amount of Fulvestrant with pharmaceutically acceptable excipients for a patient with positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy wherein the composition is substantially free of Fulvestrant Sulfone analogue.