GnRH antagonist injectable composition as well as preparation method and application thereof

Abstract

The invention discloses a GnRH antagonist injectable composition as well as a preparation method and application thereof. The pharmaceutical composition comprises an active ingredient, a polymer and an organic solvent, the active component is selected from cetrorelix, cetrorelix acetate or cetrorelix pamoate; the polymer is selected from a biodegradable thermoplastic polymer; the organic solvent is selected from a biocompatible polar aprotic organic solvent. The pharmaceutical composition and the cetrorelix injection emulsion have good stability and uniformity, the preparation process is simple, the sterile control difficulty is low, and the cetrorelix injection emulsion can be released for a long time.

Description

A GnRH antagonist injectable composition and its preparation method and application

[0001] This application claims the benefit of priority of the following two prior applications: Patent Application No. 202211669089.1, filed with the State Intellectual Property Office of China on December 23, 2022, entitled “A GnRH Antagonist Injectable Composition, Preparation Method, and Use Thereof”; and Patent Application No. 202311614183.1, filed with the State Intellectual Property Office of China on November 29, 2023, entitled “A GnRH Antagonist Injectable Composition, Preparation Method, and Use Thereof”. The entire contents of each of the prior applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical compositions, and in particular relates to a GnRH antagonist injectable composition, a preparation method and an application thereof. Background Art

[0003] Gonadotropin-releasing hormone (GnRH) is a decapeptide hormone synthesized by the hypothalamus. Its primary function is to control the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), playing an important regulatory role in sex differentiation, gonadal development, and reproduction. GnRH analogs, obtained by replacing or removing pharmacologically active amino acids in GnRH and altering its chemical structure, include GnRH agonists and antagonists. GnRH agonists reduce the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by downregulating GnRH receptors, thereby feedback-blocking androgen secretion and lowering testosterone levels. Representative drugs include leuprorelin, goserelin, and triptorelin. However, due to their mechanism of action, these drugs can cause a testosterone surge, which can worsen bone pain and cause adverse cardiovascular reactions during clinical use. GnRH antagonists directly inhibit GnRH receptors, rapidly inhibit the excitatory effect of endogenous GnRH on the pituitary gland, and directly block the secretion of LH and FSH, thereby reducing testosterone levels. Representative drugs include abarelix, degarelix, ganirelix, cetrorelix, etc. They will not initially cause a surge in testosterone, have stable effects, and have good overall safety in clinical application.

[0004] The clinical studies and medical applications of the aforementioned GnRH antagonist analogs have been successful or attempted in the fields of assisted reproductive technology, ovarian cancer, benign prostatic hyperplasia, and prostate cancer. The major limitation to the successful application of GnRH antagonist analogs is that they are only available in short-acting formulations, whereas longer-acting depot formulations are more advantageous.

[0005] Currently listed It is a GnRH antagonist that is taken once a month. The initial loading dose of FIRMAGON is two 3mL subcutaneous injections, followed by a monthly maintenance dose of 4mL subcutaneous injection. Due to the initial loading dose and the large volume of injection, patient compliance is poor and the pain is strong. Oral GnRH antagonist (relugolix tablets) may lead to poor compliance due to patients' unwillingness or inability to take the medication orally as prescribed. There are no commercially approved long-acting formulations of GnRH antagonists with a duration exceeding one month. US 2018 / 0250354 A1 describes loading a GnRH antagonist into a multi-block copolymer. The product is in the form of a microsphere formulation with a release period of up to 90 days. However, the microsphere formulation has a complicated preparation process, and the raw materials and auxiliary materials require sterility control. The entire preparation process is sterile, which increases the difficulty of controlling the sterility of the finished product. In the initial stage of microsphere release, the drug adsorbed on the microsphere surface is rapidly released by diffusion, causing a rapid increase in local drug concentration in a short period of time, which is very likely to cause side effects. In addition, the clinical administration of microsphere formulations is difficult, and the lyophilized powder needs to be reconstituted and suspended, which poses a high risk of contamination. The particle size is relatively large, and there are disadvantages such as pain during administration. At the same time, stability has always been a key indicator of concern in formulation development, but US 2018 / 0250354 A1 does not focus on the stability of microsphere formulations.

[0006] Therefore, there is an urgent need to develop a cetrorelix-type pharmaceutical composition with good stability, simple preparation process, low difficulty in aseptic control, and long-term release.

[0007] Summary of the Invention

[0008] In order to improve the technical problems existing in the prior art, the present invention provides a pharmaceutical composition comprising: an active ingredient, a polymer and an organic solvent;

[0009] The active ingredient is selected from cetrorelix, cetrorelix acetate or cetrorelix pamoate, preferably cetrorelix pamoate;

[0010] The polymer is selected from biodegradable thermoplastic polymers, for example, one or more selected from polyglycolide (PLG), polylactide (PLA), polycaprolactone (PCL) and poly(lactide-co-glycolide) (PLGA);

[0011] The organic solvent is selected from biocompatible polar aprotic organic solvents, such as one or more of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), 2-pyrrolidone, N,N-dimethylformamide and caprolactam.

[0012] According to an embodiment of the present invention, the pharmaceutical composition contains 5-25 parts of active ingredient, such as 8-20 parts, exemplified by 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, and 19 parts, based on the weight of cetrorelix.

[0013] According to an embodiment of the present invention, the pharmaceutical composition contains 15-55 parts of polymer, preferably 30-55 parts of polymer, for example 35-52 parts, and exemplified by 20 parts, 25 parts, 36 parts, 37 parts, 38 parts, 39 parts, 40 parts, 41 parts, 42 parts, 43 parts, 44 parts, 45 parts, 46 parts, 47 parts, 48 ​​parts, 49 parts, 50 parts, and 51 parts by weight.

[0014] According to an embodiment of the present invention, the pharmaceutical composition contains 30-65 parts of organic solvent by weight, for example 40-55 parts, exemplified by 41 parts, 42 parts, 43 parts, 44 parts, 45 parts, 46 parts, 47 parts, 48 ​​parts, 49 parts, 50 parts, 51 parts, 52 parts, 53 parts, 54 parts, 60 parts, and 64 parts.

[0015] According to an embodiment of the present invention, the pharmaceutical composition comprises cetrorelix pamoate, polylactide and N-methylpyrrolidone.

[0016] In one embodiment, the pharmaceutical composition comprises the following components in parts by weight: 13 parts of cetrorelix pamoate (calculated as cetrorelix), 42 parts of polylactide, and 55 parts of N-methylpyrrolidone.

[0017] In another embodiment, the pharmaceutical composition comprises the following components in parts by weight: 15 parts of cetrorelix pamoate (calculated as cetrorelix), 52 parts of polylactide, and 45 parts of N-methylpyrrolidone.

[0018] In yet another embodiment, the pharmaceutical composition comprises the following components in parts by weight: 13 parts of cetrorelix pamoate (calculated as cetrorelix), 40 parts of polylactide, and 45 parts of N-methylpyrrolidone.

[0019] In yet another embodiment, the pharmaceutical composition comprises the following components in parts by weight: 9 parts of cetrorelix pamoate (calculated as cetrorelix), 42 parts of polylactide, and 49 parts of N-methylpyrrolidone.

[0020] In yet another embodiment, the pharmaceutical composition comprises the following components in parts by weight: 16 parts of cetrorelix pamoate (calculated as cetrorelix), 20 parts of polylactide, and 64 parts of N-methylpyrrolidone.

[0021] The present invention also provides use of the above-mentioned pharmaceutical composition in preparing a pharmaceutical preparation, preferably the pharmaceutical preparation is an injectable emulsion.

[0022] According to an embodiment of the present invention, the pharmaceutical preparation is used for the treatment of hormone-dependent diseases such as prostate cancer, prostatic hyperplasia, uterine fibroids, breast cancer, ovarian cancer, endometriosis, central precocious puberty, and assisted reproduction.

[0023] The present invention also provides a pharmaceutical preparation, preferably an injectable emulsion, which is prepared from the above pharmaceutical composition.

[0024] According to an embodiment of the present invention, the cumulative release of the pharmaceutical preparation within 24 hours does not exceed 20%, preferably does not exceed 15%.

[0025] According to an embodiment of the present invention, the pharmaceutical preparation is in a flowable state in vitro and becomes solid after contacting with aqueous fluid or after being injected into the body and contacting with body fluid.

[0026] According to an embodiment of the present invention, the specification of the pharmaceutical preparation is less than 2 mL, such as 1 mL or 1.5 mL.

[0027] The present invention also provides a method for preparing the above-mentioned pharmaceutical preparation, comprising the following steps: filling a mixture of a polymer and an organic solvent into container one, filling an active ingredient into container two, both container one and container two being provided with a push-pull plunger, docking and fixing the two containers, and uniformly mixing the components by pushing and pulling the plunger back and forth in two directions to obtain the pharmaceutical preparation.

[0028] According to an embodiment of the present invention, the first container and the second container may be syringes.

[0029] According to an embodiment of the present invention, the active ingredient is in powder form.

[0030] Preferably, the mixture of polymer and organic solvent is sterilized before the components are mixed, for example by filtration sterilization or by terminal gamma irradiation or electron beam irradiation, for example to a maximum of 40 kGy.

[0031] Preferably, the active ingredients are sterilized before mixing, for example, by terminal sterilization by aseptic freeze-drying, gamma or beta irradiation, electron beam irradiation, etc.

[0032] The present invention also provides a method for treating a disease, comprising administering an effective amount or a therapeutically effective amount of the pharmaceutical composition or the pharmaceutical preparation to a patient; the disease is hormone-dependent diseases such as prostate cancer, prostatic hyperplasia, uterine fibroids, breast cancer, ovarian cancer, endometriosis, central precocious puberty, and assisted reproduction.

[0033] Definitions and Explanations of Terms

[0034] Unless otherwise indicated, the definitions of terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of this specification.

[0035] Term D 10 represents the particle size at which the cumulative distribution of particles is 10%, D 50 represents the particle size at which the cumulative distribution of particles is 50%, D 90 It represents the particle size at which the cumulative distribution of particles is 90%.

[0036] Terminology Dv 10 Represents the particle size at which the volume distribution is 10%, Dv 50 Represents the particle size at which the volume distribution is 50%, Dv 90 Represents the particle size at which the volume distribution is 90%.

[0037] The term "effective amount" or "therapeutically effective amount" refers to an amount of the compound or composition of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined above). The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by one of ordinary skill in the art. The specific dosage will vary depending on the specific compound selected, the dosage regimen used, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system carried.

[0038] The term "patient" refers to a patient in need of prevention or treatment of a hormone-dependent disease, wherein the patient is a mammal, for example, selected from rodents, cows, pigs, dogs, cats and primates, particularly humans. Beneficial effects

[0039] The pharmaceutical composition and cetrorelix injection emulsion of the present invention have the following advantages:

[0040] (1) The pharmaceutical composition and cetrorelix injection emulsion of the present invention have good stability and solubility of the active ingredient in the polymer solution system, ensuring product uniformity while avoiding the impact of differences in the particle size of the raw material on the release and efficacy of the final product;

[0041] (2) The injection volume is less than 2 mL, which is suitable for subcutaneous injection. The drug can be released continuously for three months or even longer without the need for an initial loading dose.

[0042] (3) As a GnRH antagonist, it can suppress testosterone immediately upon initial or repeated administration without causing a testosterone surge, thus avoiding the transient effects of agonists and reducing the occurrence of adverse cardiovascular events;

[0043] (4) Since cetrorelix injectable emulsion is a long-acting injectable depot formulation, there is no patient compliance issue during treatment;

[0044] (5) Compared with microsphere preparations, this product has a simple process, can achieve terminal sterilization, and has a high degree of sterility assurance. At the same time, the shortened mixing time greatly enhances the operability of clinical use and reduces the complexity of clinical operation. It can be injected subcutaneously, the injection volume is small, and the injection pain is also reduced.

[0045] The preparation of the present invention is mainly used for the treatment of hormone-dependent diseases such as prostate cancer, prostatic hyperplasia, uterine fibroids, breast cancer, ovarian cancer, endometriosis, central precocious puberty, and assisted reproduction. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1: Microscopic morphology of cetrorelix acetate injectable emulsion (A), microscopic morphology of cetrorelix pamoate injectable emulsion (B).

[0047] Figure 2: Initial microscopic morphology of the cetrorelix pamoate injectable emulsion after preparation (A), and laser confocal fluorescence microscopy image of the preparation after being placed at room temperature for 72 hours (B).

[0048] Figure 3: Initial microscopic morphology of the cetrorelix acetate injectable emulsion after preparation (A), and laser confocal fluorescence microscopy image of the preparation after being placed at room temperature for 72 hours (B).

[0049] Figure 4: In vitro accelerated release of cetrorelix injection emulsions with different formulations.

[0050] Figure 5: Concentration-time curve of cetrorelix injectable emulsion.

[0051] Figure 6: Testosterone concentration-time curve in rats. DETAILED DESCRIPTION

[0052] The above pharmaceutical preparation has good uniformity. Specifically,

[0053] In some embodiments, the relative standard deviation of the active ingredient content at different locations in the pharmaceutical preparation is no more than 1.5%, such as no more than 1%, and further such as no more than 0.6%.

[0054] In some embodiments, the D of the pharmaceutical formulation is 10The average value is 0.5-5 μm, for example 1-4 μm, exemplified by 1.5 μm, 1.8 μm, 2.0 μm, 2.5 μm, 2.9 μm, 3.0 μm, 3.5 μm.

[0055] In some embodiments, the D of the pharmaceutical formulation is 50 The average value is 4-10 μm, for example 5-9 μm, exemplified by 5.5 μm, 6.0 μm, 6.5 μm, 6.6 μm, 6.62 μm, 7.0 μm, 7.5 μm, 8.0 μm, 8.5 μm.

[0056] In some embodiments, the D of the pharmaceutical formulation is 90 The average value is 11-17 μm, for example 12-16 μm, and examples are 12.5 μm, 13.0 μm, 13.5 μm, 13.98 μm, 14.0 μm, 14.5 μm, 15.0 μm, and 15.5 μm.

[0057] In some embodiments, the Dv of the pharmaceutical formulation is 10 The average value is 7-16 μm, for example 8-15 μm, exemplified by 9 μm, 10 μm, 10.17 μm, 10.5 μm, 11 μm, 12 μm, 13 μm, and 14 μm.

[0058] In some embodiments, the Dv of the pharmaceutical formulation is 50 The average value is 25-40 μm, for example 27-38 μm, exemplified by 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 33.47 μm, 34 μm, 35 μm, 36 μm, 37 μm.

[0059] In some embodiments, the Dv of the pharmaceutical formulation is 90 The average value is 35-55μm, for example 30-50μm, and examples are 30μm, 35μm, 36μm, 37μm, 38μm, 39μm, 40μm, 41μm, 42μm, 42.34μm, 43μm, 44μm, 45μm, 46μm, 47μm, 48μm, and 49μm.

[0060] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0061] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0062] Example 1: Preparation of prefilled formulations

[0063] Dissolve polylactide in NMP solvent until the polymer solution is clear and transparent. Add the prescribed amount of a GnRH antagonist (cetrorelix acetate or cetrorelix pamoate) to the polymer solution and mix until the active ingredient is evenly distributed. Fill the product into a prefilled syringe. Remove the protective cap and connect the needle with a protective device for direct subcutaneous administration.

[0064] Example 2: Study on the Effect of Different Salt-Based Active Ingredients in the Formulation - Stability

[0065] The injectable composition in this embodiment is formulated as follows:

[0066] Prescription 1:

[0067] Prescription 2:

[0068] The two formulations were prepared according to the process of Example 1. The two formulations were placed in a stability test chamber at 25°C ± 2°C / 60% RH ± 5% RH. Samples were taken at 0, 5, and 10 days and the changes in related substances were measured. The related substances of cetrorelix acetate and cetrorelix pamoate drug substances were also measured. The stability results are shown in Table 1.

[0069] Table 1

[0070] The data in Table 1 demonstrate that the pamoate form of cetrorelix is ​​more stable than the acetate form in the delivery system, and the increase in total impurities after storage is relatively small. It is also noteworthy that once the cetrorelix acetate API is in this delivery system, the concentration of related substances rapidly increases, demonstrating that changing the salt form significantly improves the stability of the formulation.

[0071] Example 3: Preparation of composition formulation

[0072] Dissolve polylactide in NMP solvent until the polymer solution is clear and transparent, and fill the solution into a female syringe. The syringe can be sterilized by filtration or terminal irradiation with gamma or beta rays.

[0073] The GnRH antagonist (cetrorelix acetate or cetrorelix pamoate) powder is filled into a male syringe. The powder is either sterile lyophilized or sterilized by irradiation after filling. Prior to injection, the product is reconstituted by connecting two syringes and mixing by reciprocating the plunger. After multiple cycles of mixing, the powder is completely dissolved in the polymer solution. After thorough mixing, the formulation is withdrawn into the female syringe, connected to a protected needle, and the final subcutaneous injection is completed, with an injection volume of <2 mL.

[0074] Example 4: Study on the Effect of Different Salt-Based Active Ingredients in the Formulation - Solubility and Clinical Operability

[0075] The effects of different salt forms of cetrorelix in formulations were evaluated using the following compositions:

[0076] Prescription three:

[0077] Prescription 4:

[0078] Following the preparation process of Example 3, a male and female syringe were connected and injected back and forth to mix. After multiple cycles of mixing, the powder was completely dissolved in the polymer solution. After thorough mixing, the formulation was withdrawn into the female syringe and connected to a needle with a protective device. Samples were taken from different locations in the female syringe and the active ingredient content was measured to assess the uniformity of the formulation. The data are shown in Table 2.

[0079] Table 2

[0080] The microscopic morphologies of cetrorelix acetate and cetrorelix pamoate injectable emulsions are shown in Figure 1, A and B, respectively. Injectable compositions prepared using the acetate salt of cetrorelix exhibit insoluble particles after reconstitution, whereas the pamoate salt of cetrorelix is ​​completely soluble in the injectable composition system. Because particle size differentially influences the release phases of the composition, namely initial burst release, subsequent diffusion release, and erosion release, controlling the API particle size increases formulation and process complexity, and the impact on in vivo release behavior is unpredictable. Furthermore, the content results in Table 2 demonstrate that injectable compositions prepared using cetrorelix pamoate significantly improve product content uniformity and reduce the number of mixing steps required during clinical operation.

[0081] Example 5: Particle size characterization of injectable compositions

[0082] Cetrorelix pamoate and PLA are soluble in NMP. However, when a clear solution of cetrorelix pamoate dissolved in NMP and a clear solution of PLA dissolved in NMP are mixed, the mixture becomes opaque. Numerous small oily droplets were observed under a microscope. Cetrorelix is ​​fluorescent, and in this example, the particle size and size distribution of Prescription 1, described in Example 2, were characterized using a laser confocal microscope. The preparation was injected into a small dish with a needle and imaged using a 405 nm fluorescent laser beam. The results are shown in Figure 2 and analyzed using data FIJI software. The specific results are shown in Table 3.

[0083] Table 3

[0084] Cetrorelix pamoate injectable emulsion consists of a narrower distribution with no large droplets (Figure 2, B). No solid particles were observed in the formulation, ensuring uniformity and preventing the impact of particle size differences on release. Furthermore, the microscopic morphology of the cetrorelix pamoate injectable emulsion remained unchanged after placement (see Figure 2, A and B), further demonstrating the excellent stability of cetrorelix pamoate.

[0085] The same characterization method as above was used to characterize the particle size of the formulation 2 mentioned in Example 2. However, after standing, the cetrorelix acetate injection emulsion changed from the form of A in FIG3 to the form of B in FIG3 , and the formulation demulsified, making particle size characterization impossible.

[0086] Example 6: Injectable emulsion containing cetrorelix pamoate

[0087] Several long-acting composition formulations using different polymers and concentrations were prepared for testing the in vitro accelerated release (IVR) of cetrorelix. The formulations tested are shown in Table 4.

[0088] Table 4

[0089] To rapidly evaluate the in vitro release of cetrorelix pamoate injectable emulsions, 30-40 mg of the formulations listed in the table above were placed in 100 mL of release medium containing 0.4% polyvinyl alcohol, 0.1% polysorbate 80, and 0.18% lactic acid. The release of the cetrorelix pamoate formulations was tested using a temperature-programmed approach. The release medium was preheated to 37°C ± 0.5°C and shaken at 120 rpm. The temperature was then increased by 0.5°C every hour and maintained at this temperature for 1 hour, from 37°C to 61°C. The results, shown in Table 5 and Figure 4, show that the polymer PLA significantly reduced the initial release of the cetrorelix formulations. Furthermore, increasing the PLA concentration within a certain range did not significantly reduce the release rate.

[0090] Table 5

[0091] Example 7: Pharmacokinetics of Cetrorelix Pamoate Injection Emulsion in Rats

[0092] To characterize the pharmacokinetic characteristics of a single subcutaneous (SC) dose of a depot formulation containing cetrorelix in male rats and to evaluate its pharmacokinetic characteristics in rats. The release cycle of a cetrorelix pamoate injection emulsion formulation in male rats was investigated by comparing testosterone suppression with a control (leuprorelin acetate microspheres for injection, 11.25 mg, 3 months / vial). The enataton group was subcutaneously injected into rats at a dose of 1.1256 mg / kg. Sample 2 of Example 6, cetrorelix pamoate injection emulsion, was subcutaneously injected into rats at single doses of 42 mg / kg and 84 mg / kg. Plasma cetrorelix and testosterone levels were monitored over a three-month period. The results are summarized in Table 6 and Figure 5. The data show that compared to the 40.34% cumulative release of the enataton formulation within 24 hours, the initial burst release of the tested formulation within 24 hours was lower, ranging from 9.36% to 14.20%. The tested formulation reached maximum plasma drug concentration within the first day, with detectable plasma cetrorelix persisting until day 84. On day 84, quantifiable concentrations of cetrorelix were present in all tested rats, and all animals exhibited linear kinetic characteristics within the dosage range.

[0093] Table 6

[0094] The pharmacodynamics of cetrorelix pamoate injectable emulsion was evaluated by monitoring testosterone levels in rats. This formulation reduced testosterone to normal levels 15 minutes after injection and significantly decreased serum testosterone levels 24 hours later (Figure 6). These levels were lower than those in the enantone group at all time points. These low testosterone levels were maintained in all rats for at least 84 days.

[0095] Example 8: Irradiation Study of Cetrorelix Pamoate Injection Emulsion

[0096] The formulations shown in Table 7 were prepared and sterilized by irradiation with cobalt-60 gamma rays. The content, related substances, molecular weight, and accelerated release of the formulations before and after irradiation were investigated to evaluate the effect of the irradiation process on the critical quality attributes of the formulations.

[0097] Table 7

[0098] Test results showed that the active ingredient content of the above-mentioned preparations decreased slightly before and after irradiation, but remained between 98% and 102%, meeting the requirements. There was no significant increase in related substances. Due to the high temperature caused by irradiation, the polymer degraded, and the Mw value decreased by approximately 2000 (results are shown in Table 8). Changes in molecular weight may affect the release behavior of the preparation. However, the preparations before and after irradiation were tested according to the in vitro release method of Example 6. The release data are shown in Table 9. Both release curves have an f2 factor greater than 50. This indicates that the preparation can be sterilized by irradiation and that irradiation does not cause changes in the critical quality attributes of the preparation.

[0099] Table 8

[0100] Table 9

[0101] Example 9: Effect of mixing times on the particle size of the composition

[0102] Prior to injection, the product can be reconstituted by connecting a syringe containing the polymer solution to a syringe containing the active ingredient powder. This example primarily examines whether the number of bolus mixing injections affects the particle size of the formulation, thereby avoiding the impact of the mixing number on the formulation quality. The formulation containing the injectable composition of cetrorelix pamoate is shown in Table 10 below.

[0103] Table 10

[0104] The composition was mixed for 50 cycles, 100 cycles, 150 cycles, and 200 cycles, respectively. The results were measured using a laser confocal microscope using the same method as in Example 5. The results are shown in Table 11. The results show that the number of mixing times has no significant effect on the particle size of the preparation (P>0.05).

[0105] Table 11

[0106] The cetrorelix pamoate injection emulsion of the present invention is in a flowable state in vitro and forms a solid subcutaneous reservoir with therapeutic effect after contact with aqueous fluids or after injection into the body and contact with body fluids. The injection volume of the reservoir is less than 2 mL. After injection, the active drug entrapped therein is slowly and continuously released as the high molecular weight polymer slowly degrades. The drug release rate and cycle can be controlled by adjusting the prescription to meet the clinical needs of patients with different clinical needs, and the release cycle can reach up to three months or even longer.

[0107] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: an active ingredient, a polymer and an organic solvent; The active ingredient is selected from cetrorelix, cetrorelix acetate or cetrorelix pamoate; The polymer is selected from biodegradable thermoplastic polymers; The organic solvent is selected from biocompatible polar aprotic organic solvents.

2. The pharmaceutical composition according to claim 1, characterized in that The active ingredient is cetrorelix pamoate; and / or, the polymer is selected from one or more of polyglycolide, polylactide, polycaprolactone and lactide-glycolide copolymer; And / or, the organic solvent is selected from one or more of N-methylpyrrolidone, dimethyl sulfoxide, 2-pyrrolidone, N,N-dimethylformamide and caprolactam.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The pharmaceutical composition contains 5-25 parts of active ingredient based on the weight of cetrorelix; and / or, the pharmaceutical composition contains 15-55 parts of polymer or 30-55 parts of polymer in parts by weight; And / or, the pharmaceutical composition contains 30-65 parts of organic solvent by weight.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition comprises cetrorelix pamoate, polylactide and N-methylpyrrolidone.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The pharmaceutical composition comprises the following components in parts by weight: 13 parts of cetrorelix pamoate (calculated as cetrorelix), 42 parts of polylactide and 55 parts of N-methylpyrrolidone; Alternatively, the pharmaceutical composition comprises the following components in parts by weight: 15 parts of cetrorelix pamoate (calculated as cetrorelix), 52 parts of polylactide and 45 parts of N-methylpyrrolidone; Alternatively, the pharmaceutical composition comprises the following components in parts by weight: 13 parts of cetrorelix pamoate (calculated as cetrorelix), 40 parts of polylactide and 45 parts of N-methylpyrrolidone; Alternatively, the pharmaceutical composition comprises the following components in parts by weight: 9 parts of cetrorelix pamoate (calculated as cetrorelix), 42 parts of polylactide and 49 parts of N-methylpyrrolidone; Alternatively, the pharmaceutical composition comprises the following components in parts by weight: 16 parts of cetrorelix pamoate (calculated as cetrorelix), 20 parts of polylactide and 64 parts of N-methylpyrrolidone.

6. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a pharmaceutical preparation, preferably the pharmaceutical preparation is an injectable emulsion.

7. The use according to claim 6, characterized in that The pharmaceutical preparation is used for the treatment of hormone-dependent diseases such as prostate cancer, prostatic hyperplasia, uterine fibroids, breast cancer, ovarian cancer, endometriosis, central precocious puberty, and assisted reproduction.

8. A pharmaceutical preparation, characterized in that The pharmaceutical preparation is prepared from the pharmaceutical composition according to any one of claims 1 to 5; preferably, the pharmaceutical preparation is an injectable emulsion.

9. The pharmaceutical preparation according to claim 8, characterized in that The cumulative release of the drug preparation does not exceed 20% within 24 hours; Preferably, the pharmaceutical preparation is in a flowable state in vitro and forms a solid after contacting with an aqueous fluid or after being injected into the body and contacting with body fluids; Preferably, the specification of the pharmaceutical preparation is less than 2 mL.

10. The method for preparing the pharmaceutical preparation according to claim 8 or 9, characterized in that: The preparation method comprises the following steps: a mixture of a polymer and an organic solvent is filled into a first container, an active ingredient is filled into a second container, both the first container and the second container are provided with push-pull plungers, the two containers are docked and fixed, and the components are mixed uniformly by pushing and pulling the plungers in two directions to obtain the pharmaceutical preparation; Preferably, the mixture of polymer and organic solvent is sterilized before the components are mixed; Preferably, the active ingredient is sterilized before the components are mixed.

11. A method for treating a disease, characterized in that: The method comprises administering to the patient an effective amount or a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 5 or the pharmaceutical preparation according to any one of claims 8 to 9; the disease is hormone-dependent diseases such as prostate cancer, prostatic hyperplasia, uterine fibroids, breast cancer, ovarian cancer, endometriosis, central precocious puberty, and assisted reproduction.

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