Pharmaceutical composition of fulvestrant having excellent pharmacokinetic properties and its manufacturing method

Abstract

The present invention relates to a pharmaceutical composition containing fulvestrant and a method for producing the same. More specifically, the present invention relates to a pharmaceutical composition containing the poorly soluble drug fulvestrant in combination with a nonionic surfactant, castor oil, and a specific alcohol, and which does not contain lecithin or whose lecithin content is less than a specific amount, thereby exhibiting an excellent pharmacokinetic profile and pharmacological therapeutic effect equivalent to that of conventional fulvestrant formulations, and a method for producing the same.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing fulvestrant and a method for producing the same. More specifically, the present invention relates to a pharmaceutical composition containing the poorly soluble drug fulvestrant in combination with a nonionic surfactant, castor oil, and a specific alcohol, and which does not contain lecithin or whose lecithin content is less than a specific amount, thereby exhibiting an excellent pharmacokinetic profile and pharmacological therapeutic effect equivalent to that of conventional fulvestrant formulations, and a method for producing the same. [Background technology]

[0002] The chemical name of fulvestrant (fulvestrant) is 7-α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5-(10)-triene-3,17β-diol and has the following chemical structure: [ka]

[0003] Fulvestrant is used to treat hormone receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer and is the only approved selective estrogen receptor degrader (SERD). Fulvestrant is marketed under the trade name Faslodex® Intramuscular Injection (manufactured by AstraZeneca) and contains 250 mg of fulvestrant per 5 mL injection. The standard dosing regimen is 500 mg (two prefilled syringes) administered intramuscularly every two weeks for the first month, followed by the same amount once a month.

[0004] When administering Faslodex® intramuscular injection to a patient, it is administered by injecting it into each buttock muscle over a period of 1-2 minutes, which causes considerable pain for the patient receiving the injection and discomfort for the medical staff administering the injection.The reason for this dosage is believed to be that the total volume of the injection is 10 mL, which significantly exceeds the maximum single dose possible for intramuscular administration (approximately 5 mL).

[0005] Fulvestrant has very low solubility in aqueous solutions, and according to FDA data, it is "practically insoluble" in pure water. (In the formulation of Faslodex® intramuscular injection, the saturated solubility of fulvestrant was measured at approximately 90 mg / mL at room temperature and approximately 65 mg / mL when stored refrigerated, resulting in a product concentration of 50 mg / mL of fulvestrant.) Therefore, the use of solubilizers is necessary when formulating fulvestrant. In the case of Faslodex® intramuscular injection, ethanol and benzyl alcohol are the primary solubilizers, both of which are organic solvents. However, while excessive use of organic solvents can increase the solubility of the drug in the formulation, their use in humans is limited. Excessive use of organic solvents not only increases the drug's initial release rate, resulting in an excessive increase in Cmax, but also increases the risk of precipitation of the drug remaining in the formulation after rapid release. Therefore, to improve the solubility of fulvestrant, it is urgent to use an appropriate amount of organic solvents as well as other additives to improve solubility.

[0006] Faslodex® intramuscular injection is an oil depot formulation, and its additive component is castor oil. Depot formulations are a common type of sustained-release injection, and their matrix is ​​mostly composed of oil. Unlike sustained-release formulations that use polymers, such as in situ-forming gels, in situ polymer precipitates, and polymer implants, depot formulations maintain a liquid state in the body. Depot formulations can be injected subcutaneously or intramuscularly, and Faslodex® intramuscular injection is only available for intramuscular injection.

[0007] When formulating fulvestrant, the type and amount of oil, the type and ratio of organic solvent, and the type and ratio of additives are very important factors, and these factors determine not only the solubility of fulvestrant in the matrix but also its sustained-release characteristics (release rate, initial release amount, etc.). In particular, formulations with improved solubility often have different pharmacokinetic profiles from conventional formulations, raising concerns that their efficacy and side effects may differ. Summary of the Invention [Problem to be solved by the invention]

[0008] The object of the present invention is to provide a fulvestrant-containing composition and a method for producing the same, which has improved solubility and reduces the amount of the formulation to be injected compared to conventional fulvestrant formulations, while exhibiting the same content, pharmacokinetic profile, and pharmacological therapeutic effect. [Means for solving the problem]

[0009] A first aspect of the present invention provides a pharmaceutical composition for cancer treatment, comprising fulvestrant as active ingredients; a nonionic surfactant; castor oil; and a C2-C5 alcohol; wherein the composition does not contain lecithin or the content of lecithin is less than 0.4% by weight relative to 100% by weight of the total weight of the composition.

[0010] Another aspect of the present invention provides a method for producing a pharmaceutical composition for cancer treatment, comprising: (1) dissolving fulvestrant in a C2 to C5 alcohol; and (2) adding a nonionic surfactant and castor oil to the product obtained in step (1); wherein the prepared composition does not contain lecithin or has a lecithin content of less than 0.4 wt% relative to the total weight of the composition (100%). [Effects of the Invention]

[0011] The pharmaceutical composition of fulvestrant provided by the present invention has a blood concentration pattern that exhibits a first maximum blood concentration (C max1 ) is controlled to the same level as the existing formulation (Faslodex®), and the second maximum blood concentration (C max2 ), exhibiting an excellent pharmacokinetic profile in which no or significantly low absorption peaks are observed, a substantially single-phase absorption profile, and a stable sustained-release blood concentration pattern in the later phase, and exhibiting an equivalent pharmacokinetic profile and pharmacological therapeutic effect compared to conventional fulvestrant formulations. In the present invention, the pharmacokinetic profile has been made equivalent by precise formulation design while improving solubility to reduce the dosage. DETAILED DESCRIPTION OF THE INVENTION

[0012] Throughout this specification, unless otherwise specified, the words "comprise" or "contain" mean the inclusion of a certain component (or ingredients) without specific limitation, and are not to be construed as excluding the addition of other components (or ingredients).

[0013] The present invention will now be described in further detail.

[0014] One aspect of the present invention relates to a pharmaceutical composition for cancer treatment, comprising as active ingredients fulvestrant; a nonionic surfactant; castor oil; and a C2-C5 alcohol, wherein the composition does not contain lecithin or the content of lecithin is less than 0.4 wt% relative to the total weight of the composition (100%).

[0015] In one embodiment, the content of fulvestrant in the pharmaceutical composition may be, for example, 5% by weight or more, 6% by weight or more, 7% by weight or more, 8% by weight or more, or 9% by weight or more, relative to the total weight of the composition (100%), and may be, but is not limited to, 20% by weight or less, 18% by weight or less, 15% by weight or less, 13% by weight or less, or 11% by weight or less.

[0016] In one embodiment, the content of the nonionic surfactant in the pharmaceutical composition may be 0.01 to 0.75 wt % relative to the total weight of the composition (100%). If the content of the nonionic surfactant in the composition is less than the above level, the solubility of the drug may be reduced, and the blood concentration of the drug may be lower than that of the control drug. Conversely, if the content of the nonionic surfactant in the composition is greater than the above level, the second maximum blood concentration (C max2 ) may appear at high levels. More specifically, the content of the nonionic surfactant in the pharmaceutical composition may be, for example, 0.01% by weight or more, 0.05% by weight or more, 0.1% by weight or more, 0.15% by weight or more, 0.2% by weight or more, or 0.25% by weight or more, relative to the total weight of the composition (100%), and may be 0.75% by weight or less, 0.7% by weight or less, 0.6% by weight or less, 0.5% by weight or less, or 0.4% by weight or less, but is not limited to these.

[0017] In one embodiment, the non-ionic surfactant may be selected from the group consisting of polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, or combinations thereof.

[0018] In one embodiment, the polyoxyethylene castor oil derivative may be a polyoxyl castor oil (e.g., Cremophor EL, Cremophor ELP, polyoxyl-35 castor oil, polyoxyl-40 castor oil, or a combination thereof), more specifically, Cremophor EL, Cremophor ELP, polyoxyl-35 castor oil, or a combination thereof, more specifically, Cremophor EL, Cremophor ELP, or a combination thereof, but is not limited to these.

[0019] In one embodiment, the polyoxyethylene sorbitan fatty acid ester is a polysorbate (e.g., Tween 80, Tween 60, Tween 20, etc.), more specifically, Tween 80, but is not limited thereto.

[0020] In one embodiment, the pharmaceutical composition may further comprise an additional non-ionic surfactant in addition to the polyoxyethylene castor oil derivative and polyoxyethylene sorbitan fatty acid ester.

[0021] In one embodiment, the additional non-ionic surfactant may be a polyoxyethylene alkyl or aryl ether, a sorbitan ester, or a combination thereof.

[0022] In one embodiment, the polyoxyethylene alkyl or aryl ether may be, but is not limited to, polyoxyethylene alkyl phenyl ether (for example, Triton X-100).

[0023] In one embodiment, the sorbitan ester may be, but is not limited to, a sorbitan fatty acid ester (for example, Span 20, Span 80, etc.).

[0024] In one embodiment, when the pharmaceutical composition contains the additional nonionic surfactant, the content of the additional nonionic surfactant in the composition may be, for example, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 2% by weight or more, or 3% by weight or more, relative to the total weight of the composition (100%), but is not limited to these.

[0025] In one embodiment, the pharmaceutical composition may further comprise polyethylene glycol.

[0026] The polyethylene glycol may have a weight average molecular weight of, for example, 200 to 1,000 g / mol, but is not limited thereto. In one embodiment, when the pharmaceutical composition further comprises polyethylene glycol, the content of polyethylene glycol in the composition may be, for example, 0.1% by weight or more, 0.3% by weight or more, or 0.5% by weight or more, based on the total weight of the composition (100%), and may be, but is not limited to, 10% by weight or less, 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, or 5% by weight or less.

[0027] In another embodiment, when the pharmaceutical composition further comprises polyethylene glycol, the content of polyethylene glycol in the composition may be, for example, 0.1 parts by weight or more, 0.3 parts by weight or more, or 0.5 parts by weight or more, or 5 parts by weight or less, 4 parts by weight or less, 3 parts by weight or less, or 2 parts by weight or less, per 100 parts by weight of all ingredients other than fulvestrant, but is not limited thereto.

[0028] In one embodiment, the pharmaceutical composition may further comprise an additional vegetable oil other than the castor oil. In one embodiment, the additional vegetable oil may be sesame oil, soybean oil, sunflower oil, coconut oil, olive oil, canola oil, peanut oil, palm oil, grapeseed oil, safflower oil, almond oil, linseed oil, cottonseed oil, or a combination thereof. Specifically, the additional vegetable oil may be sesame oil.

[0029] In one embodiment, when the pharmaceutical composition comprises the additional vegetable oil, the content of the additional vegetable oil in the composition may be, for example, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 2% by weight or more, or 3% by weight or more, and may be 15% by weight or less, 14% by weight or less, 13% by weight or less, 12% by weight or less, 11% by weight or less, or 10% by weight or less, relative to 100% by weight of the total weight of the composition, but is not limited to these.

[0030] In one embodiment, the C2 to C5 alcohol may be ethanol. In one embodiment, the content of the C2 to C5 alcohol in the pharmaceutical composition may be, for example, 1 wt % or more, 3 wt % or more, 5 wt % or more, 7 wt % or more, 10 wt % or more, or 15 wt % or more, relative to 100% total weight of the composition, and may be, but is not limited to, 40 wt % or less, 35 wt % or less, 30 wt % or less, 25 wt % or less, or 20 wt % or less.

[0031] In one embodiment, the content of the castor oil in the pharmaceutical composition may be, for example, 1% by weight or more, 10% by weight or more, 20% by weight or more, 30% by weight or more, 40% by weight or more, or 50% by weight or more, and may be 95% by weight or less, 90% by weight or less, 85% by weight or less, 80% by weight or less, or 75% by weight or less, relative to 100% by weight of the total weight of the composition, but is not limited to these.

[0032] In one embodiment, the weight ratio of castor oil to C2-C5 alcohol in the pharmaceutical composition may be, for example, but is not limited to, 1-10:1, or 1-5:1, or 2-4:1, or 2.5-3:1.

[0033] In one embodiment, the pharmaceutical composition comprises a C max It may further comprise benzyl benzoate (BB), which helps prevent a significant increase in blood cholesterol levels, thereby reducing unexpected side effects of the drug.

[0034] In one embodiment, when the pharmaceutical composition further contains benzyl benzoate, the content thereof may be, for example, but is not limited to, 0.01% by weight or more, or 0.05% by weight or more, or 1% by weight or less, or 0.5% by weight or less, relative to 100% by weight of the total weight of the composition.

[0035] The pharmaceutical composition of the present invention does not contain lecithin, or the content of lecithin is less than 0.4% by weight based on the total weight of the composition (100%). When the pharmaceutical composition contains 0.4% by weight or more of lecithin, the blood concentration pattern shows a first maximum blood concentration (C max1 ) may be excessively high.

[0036] In one embodiment, when the pharmaceutical composition contains lecithin (i.e., when the content thereof is greater than 0% by weight), the lecithin is contained in an amount, for example, but not limited to, less than 0.4% by weight, 0.35% by weight or less, 0.3% by weight or less, 0.2% by weight or less, 0.1% by weight or less, 0.05% by weight or less, or 0.01% by weight or less, based on 100% by weight of the total composition.

[0037] In one embodiment, the pharmaceutical composition is an injection, more particularly an intramuscular injection. In one embodiment, the injection force of the injection may be 0.5 to 10 kgf. In one embodiment, the concentration of fulvestrant in the injection may be 90 to 300 mg / mL. In one embodiment, the in vitro release time of the injection using a dialysis bag may be 14 to 60 days.

[0038] The pharmaceutical composition is for the treatment of cancer, more particularly for the treatment of breast cancer, and even more particularly for the treatment of advanced breast cancer.

[0039] Another aspect of the present invention relates to a method for producing a pharmaceutical composition for cancer treatment, comprising: (1) dissolving fulvestrant in a C2 to C5 alcohol; and (2) adding a nonionic surfactant and castor oil to the product obtained in step (1); wherein the prepared composition does not contain lecithin or contains less than 0.4 wt% of lecithin relative to 100% of the total weight of the composition. In one embodiment, the composition prepared in step (2) may contain the nonionic surfactant in an amount of 0.01 to 0.75% by weight, relative to 100% by total weight of the composition.

[0040] In one embodiment, the method for producing the pharmaceutical composition may further comprise the step of adding polyethylene glycol to the product of step (1). In the method for producing the pharmaceutical composition, the fulvestrant, nonionic surfactant, castor oil, C2 to C5 alcohol, and polyethylene glycol are the same as those described above.

[0041] In one embodiment, the step (1) may further comprise removing a portion of the C2 to C5 alcohol from the mixture of fulvestrant and the C2 to C5 alcohol. The C2 to C5 alcohols can be removed using, for example, a rotary evaporator at 30 to 80° C., but the method is not limited thereto. In one embodiment, the product of step (1) may be a lecithin film containing fulvestrant.

[0042] In one embodiment, when the step (1) further comprises removing a portion of the alcohol from the mixture of fulvestrant and a C2-C5 alcohol, the method for producing the pharmaceutical composition may further comprise, after the step (2), a step of adding a C2-C5 alcohol to the product obtained in the step (2).

[0043] In one embodiment, the method for producing the pharmaceutical composition may further include one or more steps of simultaneously or sequentially adding a C2 to C5 alcohol and an additional vegetable oil other than castor oil to the product obtained in step (2).

[0044] The following examples are provided to facilitate understanding of the present invention, but are intended to be illustrative of the present invention and are not intended to limit the scope of the present invention in any way. [Example]

[0045] AC max1 evaluation 1. Preparation C of each example and comparative example max1 Test formulations for evaluating the above were produced using the types and amounts of ingredients shown in Table 1 below. The specific production method is as follows. Fulvestrant (and lecithin in the comparative example) was mixed and dissolved in a 50°C water bath for 30 minutes with stirring. Cremophor EL (C-EL) was added to the resulting solution, followed by benzyl benzoate (BB), and then castor oil was added to the solution.

[0046] 2.C max1 Evaluation (pharmacokinetic study) Each formulation of the Examples and Comparative Examples was administered to a laboratory animal (SD rat, female), and the profile was observed for 3 days. max1 The results are shown in Table 2 below.

[0047] [Table 1]

[0048] [Table 2]

[0049] From the results in Table 2, it can be seen that the comparative preparation containing lecithin has a higher C max1 The C max1 It is clear that they were unable to control the

[0050] B.C. max2 evaluation 1. Preparation C of each example and comparative example max2 To evaluate the above, test formulations were prepared using the types and amounts of ingredients shown in Table 3 below. The specific preparation method is as follows. Fulvestrant and ethanol were mixed and dissolved in a 50°C water bath for 30 minutes with stirring. Cremophor EL (C-EL) was added to the resulting solution, followed by benzyl benzoate (BB), and then castor oil.

[0051] 2.C max2 Evaluation (pharmacokinetic study) Each formulation of the Examples and Comparative Examples was administered to experimental animals (SD rats, female), and the profile was observed for 14 days, and the second maximum blood concentration (C max2 The results are shown in Table 4 below.

[0052] [Table 3]

[0053] [Table 4]

[0054] From the results in Table 4, it can be seen that the comparative preparation containing an excess amount of Cremophor EL has a higher C max2It can be seen that there was a significant increase.

[0055] C. Bioequivalence of Formulations 1. Preparation The formulations for pharmacokinetic testing in each of the Examples and Comparative Examples were produced using the types and amounts of ingredients shown in Table 5 below. The specific production method is as follows. Fulvestrant and ethanol were mixed and dissolved in a 50°C water bath for 30 minutes with stirring. Cremophor EL (C-EL) and benzyl benzoate (BB) were added to the resulting solution, and then castor oil was added to the solution. Comparative Example C1 used the commercially available control drug, Faslodex® intramuscular injection.

[0056] 2. Pharmacokinetic studies Each formulation of the Examples and Comparative Examples was administered to laboratory animals (rabbits), and the blood concentrations were measured for 28 days, and the profiles were observed. The results are shown in Table 6 below. The results for the commercially available control drug, Faslodex (registered trademark) intramuscular injection (Comparative Example C1), were set at 100%, and the AUC 14d is the relative area under the curve (%) of the drug's blood concentration profile over 14 days, and AUC 28d is the relative area under the curve (%) of the 28-day drug blood concentration profile, and C max is the relative maximum blood concentration (%) of the drug. In nonclinical studies, the AUC 14d , AUC 28 d and C max A drug was assessed as bioequivalent to the comparator if it showed 80-125% of the target activity.

[0057] [Table 5]

[0058] [Table 6] From the results in Table 4, the preparations of Examples C1 to C4 had a C maxwas 85.3-121.3%, AUC 14d was 86.7-119.6%, and AUC 28d The efficacy was 90.9-120.0%, indicating that the drug was evaluated as bioequivalent to the control drug.

Claims

1. A pharmaceutical composition for treating cancer, comprising: Fulvestrant as the active ingredient; nonionic surfactants; Castor oil; and C2 to C5 alcohols; Including, A pharmaceutical composition which does not contain lecithin or which contains less than 0.4% by weight of lecithin relative to 100% of the total weight of the composition.

2. 2. The pharmaceutical composition according to claim 1, wherein the amount of said nonionic surfactant is 0.01 to 0.75% by weight, based on 100% by weight of the total weight of the composition.

3. 2. The pharmaceutical composition of claim 1, wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, or combinations thereof.

4. 4. The pharmaceutical composition according to claim 3, wherein the polyoxyethylene castor oil derivative is polyoxyl castor oil.

5. 4. The pharmaceutical composition according to claim 3, wherein the polyoxyethylene sorbitan fatty acid ester is a polysorbate.

6. 4. The pharmaceutical composition of claim 3, further comprising an additional non-ionic surfactant other than the polyoxyethylene castor oil derivative and the polyoxyethylene sorbitan fatty acid ester.

7. 7. The pharmaceutical composition of claim 6, wherein the additional non-ionic surfactant is a polyoxyethylene alkyl or aryl ether, a sorbitan ester, or a combination thereof.

8. 10. The pharmaceutical composition of claim 1, further comprising polyethylene glycol.

9. 10. The pharmaceutical composition of claim 1, further comprising an additional vegetable oil other than castor oil.

10. 10. The pharmaceutical composition of claim 9, wherein the additional vegetable oil is sesame oil, soybean oil, sunflower oil, coconut oil, olive oil, canola oil, peanut oil, palm oil, grapeseed oil, safflower oil, almond oil, linseed oil, cottonseed oil, or a combination thereof.

11. 2. The pharmaceutical composition according to claim 1, wherein the C2 to C5 alcohol is ethanol.

12. 8. The pharmaceutical composition according to claim 7, wherein the weight ratio of the vegetable oil to the C2-C5 alcohol in the composition is 1-10:

1.

13. 10. The pharmaceutical composition of claim 1, further comprising benzyl benzoate.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the composition is an intramuscular injection.

15. A method for producing a pharmaceutical composition for cancer treatment, comprising: (1) dissolving fulvestrant in a C2-C5 alcohol; and (2) adding a nonionic surfactant and castor oil to the product obtained in step (1); Including, A method for producing a pharmaceutical composition, wherein the prepared composition does not contain lecithin or the lecithin content is less than 0.4% by weight based on 100% of the total weight of the composition.

16. The method for producing a pharmaceutical composition according to claim 15, wherein the composition prepared in step (2) contains the nonionic surfactant in an amount of 0.01 to 0.75% by weight, based on 100% by weight of the total weight of the composition.

17. The method for producing a pharmaceutical composition for cancer treatment according to claim 15, further comprising the step of adding polyethylene glycol to the product obtained in step (1).

18. The method for producing a pharmaceutical composition according to claim 15, further comprising one or more steps of simultaneously or sequentially adding a C2-C5 alcohol and an additional vegetable oil other than castor oil to the product obtained in step (2).

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