FULVESTRANT COMPOSITIONS

Abstract

The subject matter provides ready to inject fulvestrant compositions with improved solubility and stability, and methods for preparing the same. Contemplated compositions include fulvestrant at a concentration of greater than 100 mg/ml, that exhibit degradation of the fulvestrant at a level of less than 5 wt % when stored over at least three months at 25 C.

Claims

1.-23. (canceled)

24. A ready to inject fulvestrant composition, comprising: (a) fulvestrant at a concentration of equal to or greater than 100 mg/ml; (b) at least 10 v/v % diethylene glycol monoethyl ether or an alkyl derivative thereof as a solvent; and (c) 1-10 v/v % of a co-solvent; and wherein the composition maintains a degradation of fulvestrant at a level of less than 5 wt % when stored over at least three months at 25 C.

25. The composition of claim 24, wherein the co-solvent is benzyl alcohol.

26. The composition of claim 24, wherein fulvestrant is present at a concentration of at least 125 mg/ml.

27. The composition of claim 26, wherein fulvestrant is present at a concentration of at least 150 mg/ml.

28. The composition of claim 24, further comprising second co-solvent present in the composition in the range of 1 to 75 v/v %.

29. The composition of claim 28, wherein the second co-solvent comprises castor oil and acts as a release rate modifier.

30. The composition of claim 24, wherein the composition is formulated to maintain degradation of fulvestrant at a level of less than 2 wt % when stored over at least three months at 25 C.

31. The composition of claim 24, wherein the composition is formulated to maintain degradation of fulvestrant at a level of less than 5 wt % when stored over at least three months at 2-8 C.

32. The composition of claim 24, wherein the composition is provided in a multi-use container.

33. The composition of claim 24, wherein the diethylene glycol monoethyl ether or the alkyl derivative thereof is present in the composition at more than 40 v/v %.

34. A method of manufacturing a ready to inject fulvestrant composition containing article, comprising: formulating a liquid composition including fulvestrant such that the formulation pexhibits less than 5 wt % degradation of the fulvestrant when stored over at least three months at 25 C.; wherein the liquid composition comprises diethylene glycol monoethyl ether or an alkyl derivative thereof as a solvent, fulvestrant at a concentration equal to or greater than 100 mg/ml, and between 1-10 v/v % of a co-solvent; and packaging the liquid formulation in the article.

35. The method of claim 34, wherein the co-solvent is benzyl alcohol.

36. The method of claim 34, wherein fulvestrant is present at a concentration of at least 125 mg/ml.

37. The method of claim 36, wherein fulvestrant is present at a concentration of at least 150 mg/ml.

38. The method of claim 34, wherein the liquid composition further comprises second co-solvent present in the in the range of 1 to 75v/v %.

39. The method of claim 38, wherein the second co-solvent comprises castor oil and acts as a release rate modifier.

40. The method of claim 34, wherein formulating comprises formulating the liquid composition such that the formulation exhibits less than 2 wt % degradation when stored over at least three months at 25 C.

41. The method of claim 34, wherein formulating comprises formulating the liquid composition such that the formulation remains clear and colorless when stored over at least three months at 25 C.

42. The method of claim 34, wherein the article is a multi-use container, and wherein packaging comprises packaging the liquid formulation in an amount that includes at least 500 mg fulvestrant.

43. The method of claim 34, wherein diethylene glycol monoethyl ether or the alkyl derivative thereof is present in the composition at more than 40 v/v %.

44. A ready to inject fulvestrant composition, comprising: (a) fulvestrant in a concentration of equal to or greater than 100 mg/ml; and (b) at least 10 v/v % diethylene glycol monoethyl ether or an alkyl derivative thereof as a solvent; wherein the composition has a viscosity of less than 80 centipoise; and wherein the composition maintains a degradation of the fulvestrant at a level of less than 5 wt % when stored over at least three months at 25 C.

45. The composition of claim 44, further comprising between one or more co-solvent.

46. The composition of claim 44, wherein the co-solvent is benzyl alcohol.

47. The composition of claim 24, wherein the co-solvent is selected from the group consisting of benzyl alcohol, castor oil, benzyl benzoate, ethanol, tween 80, PLX-188 (poloxamer-188), PVP K-17 (polyvinyl pyrrolidone K-17), ethyl oleate, PVP K-30 (polyvinyl pyrrolidone K-30), glycofurol and Transcutol HP or combination thereof.

48. The composition of claim 24, wherein the co-solvent is selected from the group consisting of benzyl alcohol, ethanol, dimethyl sulfoxide, glycofurol, n-methyl pyrrolidone, propylene glycol, polyethylene glycols, solketal, glycerol formal, and acetone or combination thereof.

49. The composition of claim 44 further comprising a co-solvent, wherein the co-solvent is selected from the group consisting of benzyl alcohol, castor oil, benzyl benzoate, ethanol, tween 80, PLX-188 (poloxamer-188), PVP K-17 (polyvinyl pyrrolidone K-17), ethyl oleate, PVP K-30 (polyvinyl pyrrolidone K-30), glycofurol and Transcutol HP or combination thereof.

50. The composition of claim 44 further comprising a co-solvent, wherein the co-solvent is selected from the group consisting of benzyl alcohol, ethanol, dimethyl sulfoxide, glycofurol, n-methyl pyrrolidone, propylene glycol, polyethylene glycols, solketal, glycerol formal, and acetone or combination thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0024] FIG. 1 depicts the change in fulvestrant plasma concentration over time upon administration of a reference composition (similar to Faslodex) or compositions of the inventive subject matter in rats.

DETAILED DESCRIPTION OF THE INVENTION

[0025] The inventive subject matter provides ready to inject compositions with improved solubility and stability. In particular, compositions comprising fulvestrant or other hormone therapy drug at a concentration of greater than 100 mg/ml are provided, which include DEGEE-containing solvent systems, and maintain degradation of the fulvestrant at a level of less than 5 wt % when stored over at least three months at 25 C.

[0026] For example, in experiments showing the solubility and stability of compositions of the inventive subject matter as further discussed below, a ready to inject fulvestrant composition was formulated, including 300 mg fulvestrant, 4 v/v % benzyl alcohol, and DEGEE in a quantity sufficient to make up 1.7 ml. The fulvestrant solubility achieved was 176 mg/ml.

[0027] However, as shown in the following examples, it should be appreciated that high solubility and stability fulvestrant compositions do not need to be limited to formulations having solvent systems consisting of DEGEE and benzyl alcohol. Contemplated formulations can include various concentrations and combinations of DEGEE, a benzyl alcohol co-solvent, one or more other co-solvents, and one or more release rate modifiers.

Example 1: Solubility

[0028] Solubility studies of fulvestrant were performed using various combinations of solvent, co-solvents, oils and release rate modifiers. The resultant data are shown herein below Table 1.

TABLE-US-00001 TABLE 1 Sr. Fulvestrant solubility No. Solvent/Mixture of solvents and release rate modifiers achieved 1. N-methyl Pyrolidone 250 mg/ml 2. TCLS-101 (DMI) 30.76 mg/ml 3. Polyethylene Glycol 400 11.11 mg/ml 4. Benzyl alcohol (2 v/v %):Diethylene glycol monoethyl 200 mg/mL ether ((q.s. to 1 mL) 5. Benzyl alcohol (2 v/v %):MCT oil (1 v/v %):Diethylene 200 mg/mL glycol monoethyl ether ((q.s. to 1 mL) 6. Benzyl alcohol (4 v/v %):Diethylene glycol monoethyl 300 mg/1.7 mL ether ((q.s. to 1.7 mL) 176 mg/ml 7. Benzyl alcohol (5 v/v %):Diethylene glycol monoethyl 500 mg/3.3 mL ether ((q.s. to 3.3 mL) 151 mg/ml 8. Benzyl alcohol (4 v/v %):Diethylene glycol monoethyl 125 mg/mL ether (46 v/v %):Castor oil (q.s. to 1 mL) 9. Benzyl alcohol (4 v/v %):Diethylene glycol monoethyl 30 mg/mL ether (31 v/v %):Castor oil (q.s. to 1 mL) 10. Benzyl alcohol (10 w/v %):Ethanol (10 w/v %):Benzyl 50 mg/mL benzoate (15 w/v %):Castor oil (q.s. to 1 mL) 11. Benzyl alcohol (10 v/v %):Castor oil (50 v/v %): 151 mg/mL Diethylene glycol monoethyl ether (q.s. to 1 mL) 12. Benzyl alcohol (4 v/v %):Benzyl benzoate (10 w/v %): 56 mg/mL Castor oil (50 v/v %):Diethylene glycol monoethyl ether (q.s. to 1 mL)

[0029] As shown, various high solubility fulvestrant formulations were formulated using a solvent system comprising or consisting of DEGEE and between 2-5 v/v % benzyl alcohol. A small concentration of oil (e.g., MCT oil) as a release rate modifier and second co-solvent did not substantially affect the fulvestrant solubility. Furthermore, a high solubility fulvestrant formulation was achieved even with higher concentrations of benzyl alcohol (e.g., 10 v/v %) where a high concentration of castor oil (e.g., 50 v/v %) was present. Where one or more of benzyl alcohol, ethanol and benzyl benzoate were present in larger concentrations (e.g., 14-35 v/v %), the fulvestrant solubility achieved was lower, for example, similar to Faslodex.

Example 2: Method of Manufacturing Ready to Inject High Solubility Fulvestrant Composition

[0030] Fulvestrant at a concentration of 1-20 w/v % is added to minimum quantity of DEGEE and stirred. 1% Benzyl alcohol is added while stirring. The ingredients are mixed well to dissolve. The solution is diluted further q.s. with DEGEE to make up the volume to 1 ml (See Table 2). The same is filtered aseptically and filled in ampoules or vials under nitrogen bubbling and blanketing.

TABLE-US-00002 TABLE 2 Sr. No. Name of Ingredients Quantity per ml 1. Fulvestrant 10-200 mg 2. Benzyl alcohol 1.0% v/v 3. Diethylene glycol monoethyl ether Q.s. to 1 ml

Example 3: Method of Manufacturing Ready to Inject High Solubility Fulvestrant Composition

[0031] Fulvestrant at a concentration of 10 w/v % is added to minimum quantity of DEGEE and stirred. 2% Benzyl alcohol is added while stirring. The ingredients are mixed well to dissolve. The solution is diluted further q.s. with DEGEE to make up the volume to 1 ml (See Table 3). The same is filtered aseptically and filled in ampoules or vials under nitrogen bubbling and blanketing.

TABLE-US-00003 TABLE 3 Sr. No. Name of Ingredients Quantity per ml 1. Fulvestrant 100 mg 2. Benzyl alcohol 2.0% v/v 3. Diethylene glycol monoethyl ether Q.s. to 1 ml

Example 4: Method of Manufacturing Ready to Inject High Solubility Fulvestrant Composition

[0032] Fulvestrant at a concentration of 15 w/v % is added to minimum quantity of DEGEE and stirred. 4% Benzyl alcohol is added while stirring. The ingredients are mixed well to dissolve. The solution is diluted further q.s. with DEGEE to make up the volume to 1 ml (See Table 4). The same is filtered aseptically and filled in ampoules or vials under nitrogen bubbling and blanketing. The solution viscosity of this formulation was found to be about 6.124 cps.

TABLE-US-00004 TABLE 4 Sr. No. Name of Ingredients Quantity per ml 1. Fulvestrant 150.0 mg 2. Benzyl alcohol 4.0% v/v 3. Diethylene glycol monoethyl ether Q.s. to 1 ml

Example 5: Impurities

[0033] A fulvestrant composition was prepared as taught herein in Example 4 (150 mg fulvestrant, 4 v/v % benzyl alcohol, and DEGEE q.s. to 1 ml), and was filtered aseptically and filled in ampoules or vials under nitrogen bubbling and blanketing. The composition was tested for 6 months stability studies to assess drug degradation patterns. The impurities levels were calculated using area normalization method (USP 39). 6 months total impurities results was found to be encouraging as 0.25% (at 2-8 C.), 0.25% (at 25 C./60% RH.) and 0.17% (at 30 C./65% RH.), respectively, which are each less than 0.5 wt %.

Example 6: Effect of Oxygen Content on Stability of Fulvestrant Injection Compositions

[0034] Upon achieving success in the initial experiments set forth above, further trials were taken to establish the stability of the formulation of Example 4 for up to 180 days. The fulvestrant composition was prepared and filtered aseptically and filled in vials under nitrogen bubbling and blanketing. The vials were exposed to various percentages of oxygen to determine the degradation of the composition. The composition was tested for Related Compounds as per USP 39 API method (by Area normalization method in HPLC). The following experiments were performed to determine the impact of ambient oxygen content (in the head space of vials) on the stability of inventive formulations with respect to the content of impurities: [0035] 1. Effect of approximately 10% oxygen content (11.50% by volume according to gas chromatography testing) in head space of filled vials. [0036] 2. Effect of approximately 15% oxygen content (16.53% by volume according to gas chromatography testing) in head space of filled vials; and [0037] 3. Effect of approximately 20% oxygen content (20.70% by volume according to gas chromatography testing) in head space of filled vials.

[0038] The results obtained are presented in Tables 5-7 below. *OC: Oxygen content; **ND: Not detected. The analytical variations in 30 and 180 days stability data could be attributed to adopted Area normalization method. The results below clearly indicate that the composition is physically and chemically stable for up to 180 days at all ICH conditions in the presence of a high oxygen concentration environment.

TABLE-US-00005 TABLE 5 Sr. Test 2-8 C. No. Formulation Parameters Initial 30 Days 180 Days 1 Formulation Description Clear colorless Clear colorless Clear colorless of Example 4 liquid liquid liquid (with 11.50% Total 0.06% 0.118% ND** OC*) Impurities (NMT 1.0%) Assay 100.69% 101.80% 100.50% 2 Formulation Description Clear colorless Clear colorless Clear colorless of Example 4 liquid liquid liquid (with 16.53% Total 0.06% 0.101% ND** OC*) Impurities (NMT 1.0%) Assay 101.31% 102.11% 98.72% 3 Formulation Description Clear colorless Clear colorless Clear colorless of Example 4 liquid liquid liquid (with 20.70% Total 0.06% 0.087% 0.088% OC*) Impurities (NMT 1.0%) Assay 104.20% 102.36% 99.99%

TABLE-US-00006 TABLE 6 Sr. Test 25 C./60% R.H. No. Formulation Parameters Initial 30 Days 180 Days 1 Formulation Description Clear colorless Clear colorless Clear colorless of Example 4 liquid liquid liquid (with 11.50% Total 0.06% 0.106% ND** OC*) Impurities (NMT 1.0%) Assay 100.69% 100.21% 99.79% 2 Formulation Description Clear colorless Clear colorless Clear colorless of Example 4 liquid liquid liquid (with 16.53% Total 0.06% 0.091% ND** OC*) Impurities (NMT 1.0%) Assay 101.31% 101.82% 97.88% 3 Formulation Description Clear colorless Clear colorless Clear colorless of Example 4 liquid liquid liquid (with 20.70% Total 0.06% 0.108% ND** OC*) Impurities (NMT 1.0%) Assay 104.20% 101.42% 100.10%

TABLE-US-00007 TABLE 7 Sr. Test 40 C./75% R.H. No. Formulation Parameters Initial 30 Days 180 Days 1 Formulation Description Clear colorless Clear colorless Clear colorless of Example 4 liquid liquid liquid (with 11.50% Total 0.06% 0.124% ND** OC*) Impurities (NMT 1.0%) Assay 100.69% 100.99% 98.53% 2 Formulation Description Clear colorless Clear colorless Clear colorless of Example 4 liquid liquid liquid (with 16.53% Total 0.06% 0.130% ND** OC*) Impurities (NMT 1.0%) Assay 101.31% 100.81% 101.27% 3 Formulation Description Clear colorless Clear colorless Clear colorless of Example 4 liquid liquid liquid (with 20.70% Total 0.06% 0.151% ND** OC*) Impurities (NMT 1.0%) Assay 104.20% 102.27% 101.27%

Example 7-12: Fulvestrant Compositions with Benzyl Benzoate or Castor Oil

[0039] Fulvestrant compositions can be prepared based on the teachings herein, which include other excipients in variable concentration as shown below in Table 8. All of the following formulations were clear and physically stable when preserved in cold and at room temperature for a period of 15 days.

TABLE-US-00008 TABLE 8 Sr. Quantity per ml No. Ingredients 7 8 9 10 11 12 1. Fulvestrant 150 mg 150 mg 150 mg 150 mg 111.11 mg 125.0 mg 2. Benzyl benzoate 50% w/v 50% w/v 20% w/v 20% w/v 3. Benzyl alcohol 4% w/v 4% w/v 4% w/v 10% w/v 4. Diethylene q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 36% w/v 40% w/v glycol monoethyl ml ml ml ml ether 5. Castor oil q.s. to 1 q.s. to 1 ml ml

Example 13: Pharmacokinetic Study

[0040] A single dose comparative pharmacokinetic study of two test formulations prepared according to the present inventive subject matter was performed against a reference formulation similar to Faslodex (prepared based on patent publication WO 2001051056 A1 to Astrazeneca), in a female Sprague Dawley Rat model. See Table 9 for reference and test formulations.

TABLE-US-00009 TABLE 9 Quantity/ml Batch No.: FLV- Batch No.: FLV- Batch No.: FLV- 05 11 06 (Test (Test (Reference Formulation-1) Formulation-2) Formulation) S. No. Ingredients 500 mg/3.5 ml 500 mg/5 ml 250 mg/5 ml) 1 Fulvestrant USP 150.0 mg 100.0 mg 50.0 mg 2 Benzyl alcohol BP 4.0% v/v 10.0% v/v 10.0% w/v 3 Diethylene glycol Q.s. to 1 ml Q.s. to 1 ml monoethyl ether (Transcutol HP) 4 Ethanol BP 10.0% w/v 5 Benzyl benzoate 15.0% w/v 6 Castor oil BP 45.0% v/v Q.s. to 1 ml Viscosity 6.124 cps 40.778 cps 86.470 cps

[0041] 18 healthy rats were distributed into three different groups (6 rats each). The reference formulation was intramuscularly administered to a first group, a first test formulation was intramuscularly administered to a second group, and a second test formulation was intramuscularly administered to a third group. Each formulation was administered at a dose of 10 mg/kg body weight. Blood samples were collected from the retro orbital plexus over a 30 day period following dosing to analyze pharmacokinetic parameters. The blood samples were collected on days 1, 2, 3, 4, 5, 6, 7, 10, 15, 20 and 30 post-dosing for the analysis.

[0042] The mean log transformed C.sub.max, AUC.sub.0-t and AUC.sub.0- data observed during the study of the test and reference formulations are summarized in below Table 10.

TABLE-US-00010 TABLE 10 C.sub.max AUC.sub.0-t AUC.sub.0- Parameters (ng/mL) (ng .Math. hr/mL) (ng .Math. hr/mL) Reference 18.0396 5986.0880 8986.3031 Formulation Test Formulation 1 23.2409 6907.3583 8797.8799 Test Formulation 2 17.5162 4608.9614 8094.2816

[0043] The above results indicate that C.sub.max (the maximum concentration available in the blood) of test formulation 1 is slightly higher than the reference product. The C.sub.max of test formulation 2 is similar to the C.sub.max of the reference product. The AUC.sub.0-t and the AUC.sub.0- results show that the maximum concentration of the drug is effectively available in plasma using the test formulations, and indicates that a better extent and rate of absorption of the drug can be achieved than that of the currently marketed Faslodex. FIG. 1 depicts fulvestrant plasma concentrations over time upon administration of each of the formulations to the rats. Each data point represents the mean plasma fulvestrant concentration of a group (n=6 rats per group). The results of this experiment show that the test formulations are safe, and do not appear to exceed the toxicity level of the reference product. This indicates that the test formulations can allow for rapid penetration and enhanced absorption as compared to the simultaneously prepared reference product when administered intramuscularly.

[0044] The two test formulations not only showed improved fulvestrant solubility (and higher mg/ml concentrations), but also showed significantly lower visocities and improved syringeability when compared to the reference formulation. Such formulations can advantageously reduce the pain and burden felt by the patient receiving the injection, while reducing the difficulties for healthcare professionals administering the drug by reducing the time and force required to deliver a suitable dose.

[0045] Therefore, various improved high solubility and stability fulvestrant compositions that can be administered in smaller volumes with reduced pain are provided, as well as methods for preparing such compositions, and methods for using such compositions to treat or prevent a disease or disorder.

[0046] It should be appreciated that it is an object of the inventive subject matter to provide a stable, physiologically effective composition comprising fulvestrant or other hormone therapy drug, alone or in combination with other pharmaceutically effective ingredients or drugs, which is suitable to be administered parenterally, particularly via intramuscular injection. It is also an object of the inventive subject matter to provide fulvestrant compositions with improved bioavailability and reduced toxicity (relative to known fulvestrant compositions), which are easily syringeable and administrable. It is yet another object of the invention to provide therapeutically effective amounts of fulvestrant in a fulvestrant composition that can be intramuscularly injected in smaller volumes and with reduced pain.

[0047] The optimum therapeutically effective amount of a drug is the amount of the drug in the composition that will yield the most effective results in terms of efficacy of treatment in a given subject. This amount can vary depending upon a variety of factors, including but not limited to the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration. One skilled in the clinical and pharmacological arts will be able to determine a therapeutically effective amount through routine experimentation, for instance, by monitoring a subject's response to administration of a compound and adjusting the dosage accordingly. For additional guidance, see Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

[0048] The formulations of the inventive subject matter can be administered according to any suitable dosing schedule. For example, it is contemplated that a dose of between 100-1,000 mg fulvestrant, more preferably between 150-750 mg fulvestrant, and even more preferably between 200-550 mg fulvestrant can be administered once, twice, or even three or more times per month.

[0049] Although some preferred compositions according to the inventive subject matter may be administered via intramuscular injection, it is contemplated that the formulations can be used to form a dosage form administered in any suitable manner, including for example, orally via capsules, powders, tablets, troches, elixirs, suspensions, syrups, wafers, chewing gums, aqueous suspensions or solutions. Oral pharmaceutical preparations can be made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When the dosage unit form is a capsule, it may additionally contain a pharmaceutically acceptable carrier, such as a liquid carrier (e.g., a fatty oil).

[0050] Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, such as, for example, a coating. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. Materials used in preparing these various compositions should be pharmaceutically or veterinarally pure and non-toxic in the amounts used. Pharmaceutically acceptable carrier as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be pharmaceutically acceptable in that it must be compatible with the other ingredients of the formulation.

[0051] Other suitable routes of administration may include parenteral, inhalation, topical, rectal, nasal, or via an implanted reservoir or trans-dermal patch, wherein the term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrathecal, intrahepatic, intralesional, and intracranial administration (typically injection or infusion).

[0052] Furthermore, the liquid compositions presented herein can have a viscosity such that they can be filled into a pump spray as a spray formulation or into a vaporizer such as nebulizer for use in oral or nasal administration. For example, the compositions prepared as described herein can have a viscosity from of between 1-45 centipoise (cps), or between 1-7 cps at room temperature.

[0053] The administration of the suitable dose can be administered with a single administration, or can be spread out over the course of a day through multiple administrations. For example, an effective dose of the composition can be divided and separately packaged in a pre-filled syringe or vial, or in a set of syringes or vials (e.g., 2, 3, 4, 5 syringes or vials). Additionally or alternatively, the suitable dose can be divided and separately packaged in one or more capsules, tablets, powders or oral dissolve strips, and separately administered one to five or more times a day. Alternate day dosing or dosing once every several days may also be utilized.

[0054] Contemplated formulations may also include one or more anti-oxidants. For example, hydrophobic anti-oxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, and -tocopherol, DL-tocopherol, -tocopherol acetate, Tocopherol Polyethylene Glycol Succinate (Vitamin E TPGS), L-cysteine, or hydrophilic anti-oxidants, including sodium EDTA and thioglycerol. Most typically, the concentration of the anti-oxidant can be between 0.005% and 10% w/v of the total composition. Additionally, or alternatively, contemplated formulations may include a preservative (e.g., phenol, thimerosal, chlorobutanol, m-cresol, phenoxyethanol, methylparaben and propylparaben), typically at a concentration of between 0.001% w/v and less than 10% w/v of the total composition. For example, contemplated compositions can include ethanol at 1-4 w/v % (although some preferred compositions are free or essentially free of ethanol), chlorobutanol at 0.1-2 w/v %, parabens such as methyl paraben 0.1-0.18 w/v % or propyl paraben 0.01-0.2 w/v %, isosorbide dimethyl ether, glycerol, thioglycerol, phenol at 0.1-1 w/v %, meta cresol or chlorocresol at 0.1-0.3%, methylhydroxy benzoate 0.1-0.2 w/v %, or a phenyl mercuric salt such as acetate, borate or nitrate 0.1-0.2 w/v %.

[0055] The carrier may also contain adjuvants such as preserving stabilizing, wetting, emulsifying agents and the like together with the penetration enhancer. In some embodiments, the fulvestrant composition can include additional excipients e.g. preservatives for multi-dose containers, including for example, phenol, phenoxyethanol, methylparabens and propylparabens.

[0056] The pharmaceutical forms suitable for injectable use include sterile solutions, dispersions, emulsions, and sterile powders. The final form should be stable under conditions of manufacture and storage. Furthermore, the final pharmaceutical form should be protected against contamination and should, therefore, be able to inhibit the growth of microorganisms such as bacteria or fungi. The ready to inject formulations should also be able to pass readily through an injection device such as a hollow needle.

[0057] It should further be appreciated that contemplated formulations can be sterilized and all known manners of sterilization are deemed suitable for use herein, including filtration through 0.22 micron filters, heat sterilization, radiation (e.g., gamma, electron beam, microwave), or ethylene oxide sterilization to render the formulations sterile. Where contemplated formulations are lyophilized, they may be prepared as lyophilized cake, lyophilized powder, etc.

[0058] Depending on the particular purpose, it should also be recognized that contemplated compositions may be combined (in vivo, or in a therapeutic formulation or administration regimen) with at least one other therapeutically active agent to additively or synergistically provide a therapeutic or prophylactic effect. The additional ingredients could include, for example, other anticancer agents such as palbociclib or letrozole in suitable dosage form to achieve therapeutically effective blood concentration for the treatment of breast cancer.

[0059] As used in the description herein and throughout the claims that follow, the meaning of a, an, and the includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of in includes in and on unless the context clearly dictates otherwise.

[0060] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term about. Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0061] The discussion herein provides example fulvestrant compositions and methods of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

[0062] It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the disclosure. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Indeed, the present invention is in no way limited to the methods and materials described.

[0063] Moreover, in interpreting the disclosure all terms should be interpreted in the broadest possible manner consistent with the context. In particular the terms comprises and comprising should be interpreted as referring to the elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps can be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced.