Fulvestrant pharmaceutical composition with excellent pharmacokinetic characteristics and preparation method thereof

Abstract

The present invention relates to a pharmaceutical composition comprising fulvestrant and a method for preparing the same, and more particularly, to a pharmaceutical composition comprising fulvestrant as a poorly soluble drug, a nonionic surfactant, castor oil and a specific alcohol, and a method for preparing the same, the fulvestrant preparation does not contain lecithin or the content of lecithin is less than a specific content, so that the fulvestrant preparation has excellent pharmacokinetic characteristics, and has the same pharmacological treatment effect as that of the conventional fulvestrant preparation.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing fulvestrant and a preparation method thereof. More specifically, the present invention relates to a pharmaceutical composition and a preparation method thereof, the pharmaceutical composition combinatorially contains fulvestrant as a poorly soluble drug, a nonionic surfactant, castor oil, and a specific alcohol, does not contain lecithin or contains less than a specific content of lecithin, and thus exhibits excellent pharmacokinetic properties and shows the same pharmacological therapeutic effect as compared with existing fulvestrant preparations. Background Art

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

[0003]

[0004] Fulvestrant is a drug for treating hormone receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer, and is the only approved selective estrogen receptor degrader (SERD) drug. Fulvestrant is sold under the trade name Faslodex® (AstraZeneca), which is a preparation containing 250 mg of fulvestrant in a 5 mL injection solution. Basically, a dose of 500 mg (2 prefilled syringes) is intramuscularly injected every 2 weeks for the first month, and then the same dose is administered once a month thereafter.

[0005] When Faslodex is administered to a patient ® the administration method is set to intramuscularly inject it into both buttocks for 1 to 2 minutes respectively, which causes considerable pain to the person receiving the administration and brings considerable inconvenience to the provider performing the administration. The reason for setting the therapy in this way is that the total volume of the injection solution is 10 mL, which greatly exceeds the maximum volume (about 5 mL) that can be administered at one time during intramuscular administration.

[0006] Fulvestrant has extremely low solubility in aqueous solution. According to FDA data, it is known to be "practically insoluble" in pure water (after investigation, Faslodex ®In the formulation of the preparation, the saturated solubility of fulvestrant is approximately 90 mg / mL at room temperature and approximately 65 mg / mL under refrigerated storage conditions. The concentration of the product is 50 mg / mL in terms of fulvestrant). Therefore, solubilizers must be used when formulating fulvestrant. In Faslodex ® In the case of the injection, ethanol and benzyl alcohol are used as the main solubilizers, and these solubilizers all correspond to organic solvents. However, when organic solvents are used in excess, the solubility of the drug in the formulation can be increased, but the amount used in the human body is limited, and since it rapidly releases after administration and rapidly increases the initial release of the drug, it will not only cause C 最大 to rise excessively, but also increase the risk of residual precipitation of the drug in the formulation after rapid release. Therefore, it is not preferred. Therefore, in order to improve the solubility of fulvestrant, in addition to an appropriate amount of organic solvent, it is urgently necessary to use other additives to improve the solubility.

[0007] Faslodex ® The injection is an oil depot formulation, and the castor oil component accounts for the largest part among the additives. The oil depot is a common formulation in sustained-release injections, and most of its matrix is composed of oil. Different from in situ forming gels or in situ polymer precipitations, polymeric implants, etc. which are sustained-release formulations using polymers, the characteristic of the oil depot is that it remains in a liquid phase in the body. The oil depot is a formulation that can be administered both subcutaneously and intramuscularly, while Faslodex ® injection is only used for intramuscular injection.

[0008] When formulating fulvestrant, the type and amount of oil, the type and proportion of organic solvents, the type and proportion of additives, etc. are very important because they not only determine the solubility of fulvestrant in the matrix, but also become the main determinants of its sustained-release characteristics (release rate, initial release amount, etc.). In particular, for formulations with improved solubility, the pharmacokinetic characteristics are usually different from those of existing formulations, and in this case, the pharmacodynamic effects or side effects may be different. Summary of the Invention

[0009] Technical Problems to be Solved

[0010] The object of the present invention is to provide a composition containing fulvestrant and a preparation method thereof. Compared with existing fulvestrant formulations, the composition has improved solubility, the volume of the preparation to be injected is reduced, but it shows the same content, the same pharmacokinetic characteristics, and the same pharmacological therapeutic effects.

[0011] Technical solution

[0012] One aspect of the present invention provides a pharmaceutical composition, which is a pharmaceutical composition for treating cancer. The pharmaceutical composition comprises: fulvestrant as an active ingredient; a non-ionic surfactant; castor oil; and a C2-C5 alcohol, wherein the pharmaceutical composition does not contain lecithin or, based on 100% by weight of the total composition, the content of lecithin is less than 0.4% by weight.

[0013] Another aspect of the present invention provides a method for preparing a pharmaceutical composition, which is a method for preparing a pharmaceutical composition for treating cancer. The preparation method comprises the following steps: (1) dissolving fulvestrant in a C2-C5 alcohol; and (2) adding a non-ionic surfactant and castor oil to the product of step (1), wherein the prepared composition does not contain lecithin or, based on 100% by weight of the total composition, the content of lecithin is less than 0.4% by weight.

[0014] Beneficial effects

[0015] The pharmaceutical composition of fulvestrant provided by the present invention has excellent pharmacokinetic properties, that is, in its plasma concentration profile, the initial peak plasma concentration (C 最大1 ) is adjusted to the same level as that of the existing preparation (Faslodex ® ), the secondary peak plasma concentration (C 最大2 ) does not appear or is significantly reduced in the middle stage, showing a substantially single-phase absorption profile, and a stable sustained-release plasma concentration profile is presented in the second half. Compared with the existing fulvestrant preparations, it shows an equivalent pharmacokinetic curve and pharmacological treatment effect. In the present invention, the injection volume is reduced by improving solubility, but the pharmacokinetic properties are adjusted to be comparable through precise formulation design. Detailed implementation manners

[0016] Throughout this specification, unless otherwise specified, "comprising" or "containing" means including a certain constituent element (or component) without other limitations, and should not be construed as excluding the addition of other constituent elements (or components).

[0017] Hereinafter, the present invention will be described in more detail.

[0018] One aspect of the present invention relates to a pharmaceutical composition, which is a pharmaceutical composition for treating cancer. The pharmaceutical composition comprises: fulvestrant as an active ingredient; a non-ionic surfactant; castor oil; and a C2-C5 alcohol. The pharmaceutical composition does not contain lecithin or, based on 100% by weight of the total composition, the content of lecithin is less than 0.4% by weight.

[0019] In a specific embodiment, based on the total composition of 100% by weight, the content of fulvestrant contained in the pharmaceutical composition can 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, and can be 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, but is not limited thereto.

[0020] In a specific embodiment, based on the total composition of 100% by weight, the content of the nonionic surfactant contained in the pharmaceutical composition can be from 0.01 to 0.75% by weight. If the content of the nonionic surfactant in the composition is below the above level, the solubility of the drug decreases, and the blood drug concentration of the drug may decrease compared with the control drug. On the other hand, when the content of the nonionic surfactant exceeds the above level, the secondary blood drug peak concentration (C 最大2 ) may show a high level.

[0021] More specifically, based on the total composition of 100% by weight, the content of the nonionic surfactant contained in the pharmaceutical composition can 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, and can 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 thereto.

[0022] In a specific embodiment, the nonionic surfactant can be selected from polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, or combinations thereof.

[0023] In a specific embodiment, the polyoxyethylene castor oil derivative can be polyoxyethylene castor oil (for example, polyoxyethylene castor oil EL (cremophor EL), polyoxyethylene castor oil ELP (cremophor ELP), polyoxyethylene-35 castor oil, polyoxyethylene-40 castor oil, or combinations thereof), more specifically, polyoxyethylene castor oil EL (cremophor EL), polyoxyethylene castor oil ELP (cremophor ELP), polyoxyethylene-35 castor oil, or combinations thereof, and further specifically, polyoxyethylene castor oil EL (cremophor EL), polyoxyethylene castor oil ELP (cremophor ELP), or combinations thereof, but is not limited thereto.

[0024] In a specific embodiment, polyoxyethylene sorbitan fatty acid esters can use polysorbates (e.g., Tween 80, Tween 60, Tween 20, etc.), and more specifically, Tween 80 can be used, but it is not limited thereto.

[0025] In a specific embodiment, in addition to the above polyoxyethylene castor oil derivatives and polyoxyethylene sorbitan fatty acid esters, the pharmaceutical composition can further contain other nonionic surfactants.

[0026] In a specific embodiment, the other nonionic surfactants can use polyoxyethylene alkyl or aryl ethers, sorbitan esters, or combinations thereof.

[0027] In a specific embodiment, the polyoxyethylene alkyl or aryl ethers can use polyoxyethylene alkyl phenyl ethers (e.g., Triton X-100, etc.), but it is not limited thereto.

[0028] In a specific embodiment, the sorbitan esters can use sorbitan fatty acid esters (e.g., Span 20, Span 80, etc.), but it is not limited thereto.

[0029] In a specific embodiment, when the pharmaceutical composition contains the other nonionic surfactants, based on the total 100% by weight of the composition, the content of the other nonionic surfactants in the composition can 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 can be 30% by weight or less, 25% by weight or less, 20% by weight or less, or 15% by weight or less, but it is not limited thereto.

[0030] In a specific embodiment, the pharmaceutical composition can further contain polyethylene glycol.

[0031] The polyethylene glycol can have a weight average molecular weight of, for example, 200 to 1000 g / mol, but it is not limited thereto.

[0032] In a specific embodiment, when the pharmaceutical composition further contains polyethylene glycol, based on the total 100% by weight of the composition, the content of polyethylene glycol in the composition can be, for example, 0.1% by weight or more, 0.3% by weight or more, or 0.5% by weight or more, and can be 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, but it is not limited thereto.

[0033] In another specific embodiment, when the pharmaceutical composition further comprises polyethylene glycol, based on the total of 100 parts by weight of the components other than fulvestrant, the content of polyethylene glycol in the composition can be, for example, 0.1 part by weight or more, 0.3 part by weight or more, or 0.5 part by weight or more, and can be 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, but is not limited thereto.

[0034] In one specific embodiment, the pharmaceutical composition may further comprise other vegetable oils in addition to the castor oil.

[0035] In one specific embodiment, the other vegetable oils may be sesame oil, soybean oil, sunflower oil, coconut oil, olive oil, rapeseed oil, peanut oil, palm oil, grapeseed oil, safflower oil, almond oil, linseed oil, cottonseed oil, or a combination thereof. Specifically, the other vegetable oil may be sesame oil.

[0036] In one specific embodiment, when the pharmaceutical composition comprises the other vegetable oils, based on the total of 100% by weight of the composition, the content of the other vegetable oils in the composition can 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 can 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, but is not limited thereto.

[0037] In one specific embodiment, the C2-C5 alcohol can be ethanol.

[0038] In one specific embodiment, based on the total of 100% by weight of the composition, the content of the C2-C5 alcohol contained in the pharmaceutical composition can be, for example, 1% by weight or more, 3% by weight or more, 5% by weight or more, 7% by weight or more, 10% by weight or more, or 15% by weight or more, and can be 40% by weight or less, 35% by weight or less, 30% by weight or less, 25% by weight or less, or 20% by weight or less, but is not limited thereto.

[0039] In one specific embodiment, based on the total of 100% by weight of the composition, the content of the castor oil (i.e., castor seed oil) contained in the pharmaceutical composition can 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 can 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, but is not limited thereto.

[0040] In addition, in a specific embodiment, the weight ratio of castor oil to C2-C5 alcohol in the pharmaceutical composition can be, for example, 1 to 10:1, 1 to 5:1, 2 to 4:1, or 2.5 to 3:1, but is not limited thereto.

[0041] In a specific embodiment, the pharmaceutical composition may further comprise benzyl benzoate (BB) to prevent the phenomenon of a significant increase in the C value of the composition, thereby helping to reduce unexpected side effects of the drug. 最大 value, thus helping to reduce unexpected side effects of the drug.

[0042] In a specific embodiment, when the pharmaceutical composition contains benzyl benzoate, based on the total 100% by weight of the composition, the content of benzyl benzoate can be, for example, 0.01% by weight or more, or 0.05% by weight or more, and can be 1% by weight or less, or 0.5% by weight or less, but is not limited thereto.

[0043] The pharmaceutical composition of the present invention does not contain lecithin, or even if it contains lecithin, based on the total 100% by weight of the composition, the content of lecithin is less than 0.4% by weight. When the pharmaceutical composition contains 0.4% by weight or more of lecithin, the primary blood drug peak concentration (C 最大1 ) in the blood drug concentration profile may be too high.

[0044] In a specific embodiment, when the pharmaceutical composition contains lecithin (i.e., when the content of lecithin exceeds 0% by weight), based on the total 100% by weight of the composition, for example, the content of lecithin can be 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, but is not limited thereto.

[0045] In a specific embodiment, the pharmaceutical composition is an injection, more specifically an intramuscular injection.

[0046] In a specific embodiment, the injection force of the injection can be 0.5 - 10 kgf (kilogram-force).

[0047] In a specific embodiment, the concentration of fulvestrant in the injection can be 90 - 300 mg / mL.

[0048] In a specific embodiment, the time required for in vitro release of the injection using a dialysis bag can be 14 - 60 days.

[0049] In a specific embodiment, the pharmaceutical composition is used for treating cancer, more specifically for treating breast cancer, and even more specifically for treating advanced breast cancer.

[0050] Another aspect of the present invention relates to a method for preparing a pharmaceutical composition, which is a method for preparing a pharmaceutical composition for treating cancer, and the preparation method comprises the following steps: (1) dissolving fulvestrant in an alcohol having 2 to 5 carbon atoms; and (2) adding a nonionic surfactant and castor oil to the product of step (1), wherein the prepared composition does not contain lecithin or, based on 100% by weight of the total composition, the content of lecithin is less than 0.4% by weight.

[0051] In a specific embodiment, based on 100% by weight of the total composition, the content of the nonionic surfactant in the composition prepared in step (2) may be 0.01 to 0.75% by weight.

[0052] In a specific embodiment, the method for preparing the pharmaceutical composition may further comprise the step of adding polyethylene glycol to the product of step (1).

[0053] In the method for preparing the pharmaceutical composition, fulvestrant, nonionic surfactant, castor oil, alcohol having 2 to 5 carbon atoms and polyethylene glycol are as described above.

[0054] In a specific embodiment, step (1) may further comprise removing a part of the alcohol having 2 to 5 carbon atoms from the mixture of fulvestrant and alcohol having 2 to 5 carbon atoms.

[0055] The removal of the alcohol having 2 to 5 carbon atoms can be carried out, for example, using a rotary evaporator at 30 - 80°C, but is not limited thereto.

[0056] In a specific embodiment, the product of step (1) may be a lecithin film containing fulvestrant.

[0057] In a specific embodiment, when step (1) further comprises removing a part of the alcohol from the mixture of fulvestrant and alcohol having 2 to 5 carbon atoms, after step (2) of the method for preparing the pharmaceutical composition, the method may further comprise the step of further adding alcohol having 2 to 5 carbon atoms to the product of step (2).

[0058] In a specific embodiment, the method for preparing the pharmaceutical composition may further comprise one or more steps of adding alcohol having 2 to 5 carbon atoms and one or more other vegetable oils except castor oil to the product of step (2) simultaneously or sequentially.

[0059] Hereinafter, preferred embodiments are presented to assist in understanding the present invention. However, the following embodiments are only used to illustrate the present invention, and the present invention is not limited thereto.

[0060] [Examples]

[0061] A.C 最大1 Evaluation of

[0062] 1. Preparation of the preparation

[0063] Prepare the C of each example and comparative example using the components of the types and contents shown in Table 1 below 最大1 Evaluation test preparation. The specific preparation method is as follows.

[0064] Mix fulvestrant and ethanol (and lecithin in the comparative example), then heat and stir for 30 minutes at 50 °C in a water bath until dissolved. Add polyoxyl castor oil (cremophor) EL (C-EL) to the obtained solution, add benzyl benzoate (BB) to the obtained solution, and then add castor oil.

[0065] 2. C 最大1 Evaluation (pharmacokinetic test)

[0066] Administer the preparations of each example and comparative example to experimental animals (SD rats, female), then observe their changes for 3 days, and measure the peak blood drug concentration (C 最大1 ). The results are shown in Table 2 below.

[0067] [Table 1]

[0068]

[0069] [Table 2]

[0070]

[0071] According to the results of Table 2 above, compared with the example preparations, the C of the comparative example preparations containing lecithin 最大1 increased significantly, and C can be controlled by adjusting the lecithin content 最大1 .

[0072] B.C 最大2 Evaluation of

[0073] 1. Preparation of the preparation

[0074] Use the components of the types and contents shown in Table 3 below to prepare the C of each example and comparative example 最大2 Evaluation test preparation. The specific preparation method is as follows.

[0075] After mixing fulvestrant and ethanol, heat and stir for 30 minutes at 50 °C in a water bath until dissolved, add polyoxyl castor oil (cremophor) EL (C-EL) to the obtained solution, add benzyl benzoate (BB) to the obtained solution, and then add castor oil.

[0076] 2.C 最大2 Evaluation (Pharmacokinetic Study)

[0077] The formulations of each example and comparative example were administered to experimental animals (female SD rats), and then their changes were observed for 14 days, and the secondary peak blood drug concentration (C 最大2 ) was measured. The results are shown in Table 4 below.

[0078] [Table 3]

[0079]

[0080] [Table 4]

[0081]

[0082] According to the results in Table 4 above, compared with the formulation of the example, the C of the comparative example formulation containing excessive polyoxyl castor oil EL (cremophor EL) 最大2 increased significantly.

[0083] C. Bioequivalence of Formulations

[0084] 1. Preparation of Formulations

[0085] Using the components of the types and contents shown in Table 5 below, the formulations for the pharmacokinetic study of each example were prepared. The specific preparation method is as follows.

[0086] Fulvestrant and ethanol were mixed, and then heated and stirred at 50 °C in a water bath for 30 minutes and dissolved. Polyoxyl castor oil (cremophor) EL (C-EL) was added to the obtained solution, benzyl benzoate (BB) was added to the resulting solution, and then castor oil was added.

[0087] Comparative Example C1 used the commercially available reference drug Faslodex ® injection.

[0088] 2. Pharmacokinetic Study

[0089] The formulations of each example and comparative example were administered to experimental animals (rabbits), and then the blood drug concentrations were measured for 28 days to observe their changes. The results are shown in Table 6 below.

[0090] Commercially available reference drug Faslodex ® For the results of the injection (Comparative Example C1), taking 100% as the reference, AUC 14d is the relative area under the curve (%) of the blood drug concentration curve of the drug for 14 days, AUC 28d is the relative area under the curve (%) of the blood drug concentration curve of the drug for 28 days, C最大 is the relative peak plasma concentration (%) of the drug. In non-clinical studies, if the test formulation exhibits 80 - 125% of the AUC of the reference drug 14d , AUC 28d and C 最大 , it is evaluated to be bioequivalent to the reference drug.

[0091] [Table 5]

[0092]

[0093] [Table 6]

[0094]

[0095] According to the results of Table 4 above, the formulations of Examples C1 to C4 exhibited 85.3 - 121.3% of C 最大 , 86.7 - 119.6% of AUC 14d and 90.9 - 120.0% of AUC 28d . Thus, it was evaluated to be bioequivalent.

Claims

1. A pharmaceutical composition for treating cancer, the pharmaceutical composition comprising: Fulvestrant as an active ingredient; A non-ionic surfactant; Castor oil; and C2-C5 alcohol, Among them, The pharmaceutical composition does not contain lecithin or, based on the total 100% by weight of the composition, the content of lecithin is less than 0.4% by weight.

2. The pharmaceutical composition according to claim 1, wherein, Based on the total 100% by weight of the composition, the content of the non-ionic surfactant is 0.01 to 0.75% by weight.

3. The pharmaceutical composition according to claim 1, wherein, The non-ionic surfactant is selected from polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters or combinations thereof.

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

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

6. The pharmaceutical composition according to claim 3, wherein In addition to polyoxyethylene castor oil derivatives and polyoxyethylene sorbitan fatty acid esters, the pharmaceutical composition further comprises other non-ionic surfactants.

7. The pharmaceutical composition according to claim 6, wherein, The other non-ionic surfactants are polyoxyethylene alkyl or aryl ethers, sorbitan esters or combinations thereof.

8. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition further comprises polyethylene glycol.

9. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition further comprises other vegetable oils in addition to castor oil.

10. The pharmaceutical composition according to claim 9, wherein, The other vegetable oils are sesame oil, soybean oil, sunflower oil, coconut oil, olive oil, rapeseed oil, peanut oil, palm oil, grapeseed oil, safflower oil, almond oil, linseed oil, cottonseed oil or combinations thereof.

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

12. 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 to 10:

1.

13. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition further comprises 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 preparing a pharmaceutical composition for treating cancer, the preparation method comprising the following steps: (1) Dissolving fulvestrant in C2-C5 alcohol; And (2) Adding a non-ionic surfactant and castor oil to the product of step (1), wherein the prepared composition does not contain lecithin or, based on the total 100% by weight of the composition, the content of lecithin is less than 0.4% by weight.

16. The preparation method of the pharmaceutical composition according to claim 15, wherein, Based on the total 100% by weight of the composition, the content of the non-ionic surfactant in the composition prepared in step (2) is 0.01 to 0.75% by weight.

17. The preparation method of the pharmaceutical composition for treating cancer according to claim 15, wherein, The preparation method further comprises the step of adding polyethylene glycol to the product of step (1).

18. The preparation method of the pharmaceutical composition according to claim 15, wherein, The preparation method further comprises one or more steps of adding C2-C5 alcohol and other vegetable oils in addition to castor oil to the product of step (2) simultaneously or sequentially.

Images