Sustained-release pharmaceutical composition capable of forming an in-situ implant and manufacturing the same

Abstract

The present invention relates to a sustained-release pharmaceutical composition capable of forming an in-situ implant and a method for manufacturing the same, wherein goserelin and a biodegradable polymer are each prepared in a sol state dissolved in a pharmaceutically acceptable solvent, and the composition rapidly converts to a solid state on the spot after administration, thereby suppressing initial drug release and simultaneously forming an in-situ implant capable of maintaining a long-term effect of at least one month with a single injection.

Description

Technology Field

[0001] The present invention relates to a sustained-release pharmaceutical composition capable of forming an in-situ implant and a method for manufacturing the same, wherein goserelin and a biodegradable polymer are each prepared in a sol state dissolved in a pharmaceutically acceptable solvent, and the composition rapidly converts to a solid state on the spot after administration, thereby suppressing initial drug release and simultaneously forming an in-situ implant capable of maintaining a long-term effect of at least one month with a single injection. Background Technology

[0002] Goserelin is a peptide drug that inhibits the production of sex hormones as a GnRH agonist (gonadotropin releasing hormone agonist). It inhibits the production of testosterone in the testes in men and estrogen in the ovaries in women, thereby inhibiting the growth of prostate cancer cells and breast cancer cells. Consequently, it is used as a treatment for patients with prostate cancer and breast cancer who require hormone therapy.

[0003] Biopharmaceuticals, including peptide drugs such as goserelin, are mostly administered via injectable formulations because they are broken down by digestive enzymes in the digestive system when administered orally, rendering them ineffective. Injectable formulations have the advantages of having no absorption barrier, rapid efficacy, and avoiding the hepatic first-pass effect associated with oral administration. However, conventional general injectables (fluids, emulsions, solvents, etc.) are rapidly eliminated from the body after intramuscular or subcutaneous injection, and because drug elimination is very fast, repeated administration at short intervals is essential to maintain effective blood concentrations. In particular, when treating chronic diseases such as hormone-dependent disorders, there is a disadvantage in that patient compliance decreases due to frequent repeated administration.

[0004] Therefore, to improve these disadvantages, the development of controlled-release injectable formulations is required, and to this end, active development is underway for sustained-release injectable formulations that can release the drug for a long period with a single injection to extend the duration of efficacy and reduce side effects and patient discomfort.

[0005] Drug delivery systems (DDS) for the development of sustained-release injectable formulations include microparticles, nanoparticles, liposomes, and microparticle manufacturing technologies derived from polymers or lipids. In addition, research on active targeted drug delivery systems utilizing ligand modification and pegylation is currently being actively conducted. In particular, the development of sustained-release injectable formulations using biodegradable polymers is attracting interest from various pharmaceutical companies worldwide, and research in this area is actively underway.

[0006] For example, Korean Registered Patent No. 10-1411349 discloses a microparticle composition containing a physiologically active peptide including goserelin and a method for manufacturing the same. Microparticles can be administered via intramuscular or subcutaneous injection, and by controlling the drug release rate, the duration of drug delivery can be controlled, allowing for the maintenance of an effective therapeutic drug concentration for an extended period with a single administration and improving patient compliance with drug treatment. However, such biodegradable polymer microparticles generally have a high initial burst release, which has the limitation that this initial drug release can cause side effects such as toxic reactions. Furthermore, manufacturing microparticles requires the use of an excessive amount of organic solvent to dissolve the polymer, and incurs costs and time due to processes such as volatilization, washing, and freeze-drying. Additionally, there are disadvantages such as difficulty in scaling up, reduced structural stability of the active ingredient or polymer, or reduced encapsulation efficiency of pharmacologically active substances depending on the freeze-drying conditions.

[0007] Meanwhile, among the currently marketed sustained-release goserelin injectables, there is 'Zoladex®', developed and sold by AstraZeneca as an implantable formulation. This implantable formulation was developed in two types containing 3.6 mg and 10.8 mg of goserelin, characterized by sustained efficacy for 1 month and 3 months, respectively. At this time, due to the characteristics of the implantable formulation, a very thick needle is required to implant the conical depot subcutaneously into the anterior abdominal wall. In the case of the 1-month sustained-release goserelin 3.6 mg formulation, a 1 cm long implant is contained within a 16G needle (OD 1.651 mm), and in the case of the 3-month sustained-release goserelin 10.8 mg formulation, a 1.7 cm implant is contained within a 14G needle (OD 2.108 mm). In other words, because a needle with a thickness of 1.6 to 2.1 mm is used, the pain caused by subcutaneous injection into the anterior abdominal wall is very severe, so local anesthesia must be administered before administration, and there are disadvantages such as bleeding after administration, which significantly lowers patient compliance.

[0008] As a technology to improve the low medication adherence of such implant formulations, Korean Registered Patent No. 10-0831113 discloses ATRIGEL™ technology, a type of biodegradable polymer delivery system that can be injected as a liquid. In ATRIGEL™, the polymer encapsulates the drug and solidifies within the body upon injection of the formulation, and the solidified implant biodegrades within the body to release the drug. In this type of delivery system, the drug release rate is controlled by the polymer's form and molecular weight. The ATRIGEL™ drug delivery system has been approved by the U.S. FDA as ELIGARD® (leuprolide 1, 3, and 4-month subcutaneous depot) and ATRIDOX® (doxycycline applied to periodontal pockets) and is currently on the market. Clinical studies and post-marketing experience using these products have demonstrated that the ATRIGEL™ drug delivery system provides sustained drug release over a specified dosing period. However, the aforementioned formulation failed to improve the high initial drug release phenomenon, which is a general disadvantage of PLGA formulations; on the contrary, it is known to exhibit higher initial drug concentrations than Lupron® Depot, a PLGA microparticle formulation. Furthermore, n-methyl-2-pyrrolidinone (NMP), a biocompatible polar aprotic solvent used in the aforementioned formulation, is known as a biocompatible organic solvent; however, safety concerns regarding excessive use have been raised, with the EU recently announcing restrictions on its usage due to reproductive toxicity and irritation to the eyes and skin. Additionally, there are issues with ease of use due to the complex process of preparing the final mixed solution for administration, which involves more than 10 detailed steps.

[0009] Meanwhile, U.S. Patent 9,364,518 discloses a pharmaceutical composition for an in-situ implant containing goserelin. To overcome the pain at the injection site associated with solid implants such as Zoladex®, the invention provides a first component consisting of goserelin acetate in the form of a freeze-dried powder and a second component consisting of a solution containing a biodegradable polymer, each dissolved in a biocompatible solvent, preferably NMP, to form an in-situ implant comprising goserelin or a pharmaceutically acceptable salt thereof, a biodegradable polymer, and a biocompatible organic solvent, and fills a vial. However, there are disadvantages in that the structural stability of the active ingredient may be compromised because the raw material preparation process requires a freeze-drying process, and the time and cost associated with the process increase, as well as scaling up is difficult. In addition, as can be seen from the in-vitro release profile of the above formulation, high initial drug release was not effectively prevented, and 20% of the drug was released on the first day of administration, so the initial drug release was not effectively controlled.

[0010] Therefore, there is a need to develop a sustained-release injectable that can form an in-situ implant with improved ease of use, which simplifies the process by eliminating special pretreatment of active ingredients such as freeze-drying, ensures safety by suppressing initial drug release and reducing the use of toxic solvents compared to conventional products, and allows for easy injection into the body using a small needle due to the simple manufacturing process of the final mixed solution. Prior art literature

[0011] (0001) Republic of Korea Registered Patent No. 10-1411349 (0002) Republic of Korea Registered Patent No. 10-0831113 (0003) United States Registered Patent No. 9,364,518 The problem to be solved

[0012] To solve the aforementioned problems, the present invention aims to provide a sustained-release pharmaceutical composition and a method for manufacturing the same, wherein goserelin and a biodegradable polymer are each prepared in a sol state dissolved in a pharmaceutically acceptable solvent, and the composition is rapidly converted into a solid state on the spot after administration, thereby suppressing initial drug release and forming an in-situ implant capable of maintaining a long-term therapeutic effect of more than one month with a single injection. means of solving the problem

[0013] To solve the above-mentioned problem, the present invention provides a sustained-release pharmaceutical composition capable of forming an in-situ implant, comprising: a drug comprising goserelin or a pharmaceutically acceptable salt thereof; a biodegradable polymer; and a pharmaceutically acceptable organic solvent, wherein the organic solvent is a mixture of a first solvent selected from N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO); and a second solvent selected from the group consisting of benzyl alcohol (BA), benzyl benzoate, polyethylene glycol, and sucrose acetate isobutyrate, wherein the goserelin or the pharmaceutically acceptable salt thereof and the biodegradable polymer are dissolved in the organic solvent.

[0014] In one embodiment, the biodegradable polymer may comprise one or more selected from the group consisting of polylactide, polyglycolide and poly(lactide-co-glycolide), polycaprolactone, etc.

[0015] In one embodiment, the sustained-release pharmaceutical composition may comprise a first component comprising the drug; and a second component comprising the biodegradable polymer.

[0016] In one embodiment, the first component may include one or more selected from the group consisting of NMP and DMSO, and the second component may include one or more selected from the group consisting of NMP, DMSO and BA.

[0017] In one embodiment, the biodegradable polymer may comprise one or more selected from the group consisting of poly(DL-lactide-co-glycolide) having a weight ratio of lactide to glycolide of 40:60 to 60:40 and poly(DL-lactide-co-glycolide) having a weight ratio of lactide to glycolide of 70:30 to 80:20.

[0018] In one embodiment, the sustained-release pharmaceutical composition forms a sol phase, and the sustained-release pharmaceutical composition sol may not use separate water for injection, have a total dosing volume of less than 1 mL, and have an infusion power of 30 N or less at 20°C.

[0019] In one embodiment, the sustained-release pharmaceutical composition may comprise, based on the total weight, 1 to 10 parts by weight of the drug, 10 to 30 parts by weight of the biodegradable polymer, 9 to 40 parts by weight of the first solvent, and 15 to 70 parts by weight of the second solvent.

[0020] The present invention also provides a kit containing a sustained-release pharmaceutical composition capable of forming an in-situ implant, comprising: a container containing a first component including a drug including goserelin or a pharmaceutically acceptable salt thereof; and a container containing a second component including a biodegradable polymer and said biodegradable polymer, wherein the first component and said second component each include different solvents, and said solvent is one or more biocompatible organic solvents selected from the group consisting of N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), benzyl alcohol (BA), benzyl benzoate, polyethylene glycol, and sucrose acetate isobutyrate.

[0021] In one embodiment, the kit is characterized in that the sustained-release pharmaceutical composition comprises an injectable, and the injectable is capable of subcutaneous injection with a thin needle having a diameter of 20 G or less, and the total dosage volume may be less than 1 mL without the use of separate water for injection. Effects of the invention

[0022] The in-situ implant sustained-release pharmaceutical composition containing goserelin according to the present invention can ensure product safety by reducing the amount of solvents that cause side effects and initial excessive drug release compared to conventional biodegradable polymer microparticles and in-situ implant systems. Additionally, the manufacturing process is simple and can be administered with an injection force of 30 N or less using a needle with a diameter of 20 G or less, which significantly reduces patient pain during product use. Furthermore, since it exhibits sustained drug release for more than one month after a single injection, it can improve convenience of use and patient compliance.

[0023] In addition, by dissolving goserelin, its pharmaceutically acceptable salt, and a biodegradable polymer in different pharmaceutically acceptable organic solvents without separate pretreatment and mixing them immediately before injection into the body, the preparation process is simplified compared to conventional technology. Furthermore, since special pretreatment of the active ingredient and the biodegradable polymer is omitted during the manufacturing process, the structural stability of the active ingredient or polymer can be prevented, the time and cost required for manufacturing are reduced, and the stability of the active ingredient can be ensured. Brief explanation of the drawing

[0024] Figure 1 illustrates the composition of a kit containing a sustained-release pharmaceutical composition capable of forming an in-situ implant of the present invention. Figure 2 shows whether precipitation occurs according to the solvent ratio mixing of goserelin acetate according to one embodiment of the present invention. Figure 3 shows a graph of long-term dissolution according to one embodiment of the present invention. Figure 4 shows a single subcutaneous pharmacokinetic profile using SD-Rat according to one embodiment of the present invention. Figure 5 shows a graph illustrating the change in blood testosterone concentration over time following a single subcutaneous administration using a Beagle dog according to one embodiment of the present invention. Specific details for implementing the invention

[0025] Preferred embodiments of the present invention are described in detail below. In describing the present invention, detailed descriptions of related prior art are omitted if it is determined that such detailed descriptions may obscure the essence of the invention. Throughout the specification, singular expressions should be understood to include plural expressions unless the context clearly indicates otherwise, and terms such as “comprising” or “having” are intended to specify the existence of the described features, numbers, steps, actions, components, parts, or combinations thereof, and should not be understood as precluding the existence or addition of one or more other features, numbers, steps, actions, components, parts, or combinations thereof. Furthermore, in carrying out the method or manufacturing method, each process constituting the method may occur differently from the specified order unless the context clearly indicates a specific order. That is, each process may occur in the same order as specified, may be performed substantially simultaneously, or may be performed in the reverse order.

[0026] The present invention is capable of various modifications and may have various embodiments, and specific embodiments are illustrated and described in detail in the detailed description. However, this is not intended to limit the present invention to specific embodiments, and it should be understood that it includes all modifications, equivalents, and substitutions that fall within the spirit and scope of the invention.

[0027] The technology disclosed in this specification is not limited to the embodiments described herein and may be embodied in other forms. The embodiments introduced herein are provided merely to ensure that the disclosed content is thorough and complete, and to ensure that the technical concept of the technology is sufficiently conveyed to those skilled in the art. In the drawings, the dimensions, such as the width or thickness of each component, have been shown slightly enlarged to clearly represent the components of each device. The description of the drawings is generally based on the observer's perspective, and where one element is described as being positioned above another element, this implies both that the element is positioned directly above the other element and that an additional element may be interposed between them. Furthermore, those skilled in the art may embody the concept of the invention in various other forms without departing from the technical concept of the invention. Also, in multiple drawings, the same reference numerals refer to substantially identical elements.

[0028] In this specification, the term "and / or" includes a combination of the plurality of described items or any one of the plurality of described items. In this specification, "A or B" may include "A," "B," or "both A and B."

[0030] The present invention relates to a sustained-release pharmaceutical composition capable of forming an in-situ implant, comprising a drug comprising goserelin or a pharmaceutically acceptable salt thereof; a biodegradable polymer; and a pharmaceutically acceptable organic solvent, wherein the organic solvent is a mixture of a first solvent selected from N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO); and a second solvent selected from the group consisting of benzyl alcohol (BA), benzyl benzoate, polyethylene glycol, and sucrose acetate isobutyrate, wherein the goserelin or the pharmaceutically acceptable salt thereof and the biodegradable polymer are dissolved in the organic solvent.

[0031] The present invention provides an in-situ gel composition in liquid form with improved administration convenience, which is prepared by mixing goserelin, a biodegradable polymer, and a pharmaceutically acceptable organic solvent to form a liquid sol state, and converts immediately after administration to a gel state, enabling 23G administration. It provides an injectable agent having long-acting properties for one month with a single injection.

[0032] The above-mentioned goserelin may include pharmaceutically acceptable salts such as goserelin or goserelin acetate, and may include pharmaceutically acceptable components in addition to the goserelin. For example, antibiotics, analgesics, antihistamines, etc. may be included.

[0033] By mixing the above-mentioned goserelin, a biodegradable polymer, and an organic solvent, a composition can be produced that is a viscous fluid having flowability while maintained in a sol state (for example, a composition with a viscosity of 200 cp to 2000 cp at 20°C and passing through an injection needle with a gauge diameter range of 18 to 23).

[0034] The above-mentioned fluid composition having flowability can transition to a gel state immediately after administration. The principle of transition from sol to gel is due to the precipitation phenomenon in which the solvent of the polymer solution rapidly diffuses into an aqueous medium.

[0035] At this time, the solvent may be a biocompatible organic solvent, and preferably, the organic solvent may be a mixture of a first solvent selected from N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO); and a second solvent selected from the group consisting of benzyl alcohol (BA), benzyl benzoate, polyethylene glycol, and sucrose acetate isobutyrate.

[0036] The biodegradable polymer of the present invention may include one or more selected from the group consisting of polylactide, polyglycolide, poly(lactide-co-glycolide), polycaprolactone, etc., and more preferably, the biodegradable polymer may include one or more selected from the group consisting of poly(DL-lactide-co-glycolide) in which the weight ratio of lactide to glycolide is 40:60 to 60:40 and poly(DL-lactide-co-glycolide) in which the weight ratio of lactide to glycolide is 70:30 to 80:20.

[0037] The concentration of the polymer used above may be 10 to 50% (w / w) depending on the solvent composition. In addition, the ratio (weight ratio) of the drug and polymer used in the pharmaceutical composition may be 1:3 to 1:30.

[0038] The above sustained-release pharmaceutical composition may comprise a first component containing the above drug; and a second component containing the above biodegradable polymer. That is, in the case of the present invention, it may be a two-component type composed of the above first component and the above second component, and may be mixed and used immediately before injection. At this time, the final mixture may be maintained in a viscous sol state having flowability so that it can be injected into the body with an injection needle having a diameter of 20 G or less. In addition, the final mixture in the sol state may not use separate water for injection, and the injection force of the mixture may be 30 N or less at 20°C. If the injection force exceeds the above, injection may be difficult without the use of water for injection.

[0039] The first component above may include one or more selected from the group consisting of NMP and DMSO, and the second component may include one or more selected from the group consisting of NMP, DMSO and BA.

[0040] The sustained-release pharmaceutical composition of the present invention may comprise, based on the total weight, 1 to 10 parts by weight of the drug, 10 to 30 parts by weight of the biodegradable polymer, 9 to 40 parts by weight of the first solvent, and 15 to 70 parts by weight of the second solvent. If the values ​​are above or below the above ranges, precipitation of the active ingredient occurs, making manufacturing difficult; furthermore, due to the increase in viscosity, the injection force becomes excessively high, resulting in reduced convenience of use by requiring a needle with a diameter of 20 gauge or larger, and continuous release for more than one month is difficult.

[0041] The present invention also provides a kit containing a sustained-release pharmaceutical composition capable of forming an in-situ implant, comprising: a container containing a first component including a drug including goserelin or a pharmaceutically acceptable salt thereof; and a container containing a second component including a biodegradable polymer and said biodegradable polymer, wherein the first component and said second component each include different solvents, and said solvent is one or more biocompatible organic solvents selected from the group consisting of N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), benzyl alcohol (BA), benzyl benzoate, polyethylene glycol, and sucrose acetate isobutyrate.

[0042] The solvent included in the first component of the present invention and the solvent included in the second component may be in a weight ratio of 1:0.2 to 1:3. Within the above range, normal sol formation is possible, but outside the above range, sol formation may be difficult.

[0043] The sum of the total volumes of the solvent included in the first component of the present invention and the solvent included in the second component may be 0.05 to 1 mL. If the volume is less than the above range, the injection force may be high, making normal injection difficult, and if the volume exceeds the above range, it may be difficult to form a sol.

[0044] By providing the goserelin and biodegradable polymer of the present invention dissolved in different solvents and mixing them immediately before injection, unlike conventional products, the amount of solvents that cause side effects, such as NMP, can be reduced. Additionally, the viscosity is reduced due to the dilution effect of the biodegradable polymer solution, so the injection force is lowered to 30N or less, thereby improving ease of use. Furthermore, although the active ingredient goserelin precipitates when mixed with BA, making formulation impossible, if goserelin is dissolved in the solvent included in the first upper part and then mixed with the second component in an appropriate ratio, no precipitation occurs. This suppresses the excessive initial drug release generally associated with poly(lactide-co-glycolide), thereby enabling sustained drug release for more than one month.

[0045] The present invention also provides a method for injecting a sustained-release pharmaceutical composition capable of forming an in-situ implant, comprising the steps of: providing a container containing a first component comprising a drug containing goserelin or a pharmaceutically acceptable salt thereof and a first solvent in which the drug is dissolved; providing a container containing a second component comprising a biodegradable polymer and a second solvent in which the biodegradable polymer is dissolved; preparing an injection solution by mixing the first component and the second component; and injecting the injection solution into the body through an injection needle having a diameter of 20 G (0.9 mm) or less.

[0046] To achieve the objective of the present invention, the present invention provides an in-situ implantable sustained-release pharmaceutical composition containing goserelin or a pharmaceutically acceptable salt thereof as an active ingredient.

[0047] The organic solvents used in the present invention are pharmaceutically acceptable, and only solvents suitable for use in injectable formulations are considered. Examples of suitable organic solvents may include N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin, benzyl benzoate, benzyl alcohol, polyethylene glycol, sucrose acetate isobutyrate, or combinations thereof. In this case, the organic solvent suitable for use in the in-situ implant formulation must be able to diffuse into body fluids to solidify the fluid composition, as disclosed in Korean Registered Patent 10-0831113, and must be a biocompatible solvent with low toxicity. As the water miscibility of such organic solvents increases, they diffuse rapidly into body fluids when the phase transitions from sol to implant, resulting in the excessive release of the initial drug. Therefore, the type and amount of solvent used affect the rate at which the active ingredient, goserelin acetate, is released from the in-situ implant.

[0048] In response to this, the inventors of the present invention surprisingly discovered that when the active ingredient, goserelin acetate, and the biodegradable polymer are dissolved in different solvents and provided separately, and then mixed and administered immediately before injection, the initial excessive drug release typically associated with drug delivery systems utilizing biodegradable polymers is suppressed, and at the same time, drug release for more than one month is possible with a single injection. Preferably, when the product essentially contains at least one selected from NMP or DMSO for dissolving the above drug (first component) and at least one selected from the group consisting of NMP, DMSO, and BA for dissolving the biodegradable polymer (second component), more preferably when the solvent of the second component is BA, the precipitation of the drug caused by BA is prevented, making it possible to formulate it into an injectable form. Furthermore, the amount of side-effect-causing solvents such as NMP used is reduced, thereby improving the safety of the product. Additionally, due to the dilution effect of the polymer solution, the viscosity of the final mixture, the sol, is reduced, which improves the injectability even when using a thin needle with a diameter of 20G (0.9mm) or less, thereby improving the ease of use of the product and the convenience of the patient taking the medication.

[0049] The type, molecular weight, and quantity of biodegradable polymers vary depending on the desired controlled release characteristics. Typically, the strength and degradation characteristics differ according to the molar ratio and composition of the monomers constituting the biodegradable polymer; generally, low molecular weight polymers are more easily soluble in solvents and have lower viscosity compared to high molecular weight polymers. However, while high molecular weight polymer solutions aggregate immediately upon contact with water and undergo rapid phase transitions, low molecular weight polymer solutions aggregate slowly, affecting both initial and final drug release. In such an embodiment, the biodegradable polymer comprises one or more combinations selected from the group consisting of polylactide, polyglycolide, poly(lactide-co-glycolide), or polycaprolactone, and more preferably, when using one or more combinations selected from the group consisting of poly(DL-lactide-co-glycolide) with a weight ratio of the lactide to the glycolide of 40:60 to 60:40 and poly(DL-lactide-co-glycolide) with a weight ratio of the lactide to the glycolide of 70:30 to 80:20, it can be used to formulate a drug delivery of goserelin acetate for more than one month.

[0050] The sustained-release pharmaceutical composition of the present invention may comprise, based on the total weight, 1 to 10 parts by weight of the drug, 10 to 30 parts by weight of the biodegradable polymer, 9 to 40 parts by weight of the first solvent, and 15 to 70 parts by weight of the second solvent. If the values ​​are above or below the above ranges, precipitation of the active ingredient occurs, making manufacturing difficult; furthermore, due to the increase in viscosity, the injection force becomes excessively high, resulting in reduced convenience of use by requiring a needle with a diameter of 20 gauge or larger, and continuous release for more than one month is difficult.

[0051] The present invention also provides a method for preparing a final mixture. By dissolving goserelin and a biodegradable polymer in different solvents and filling them into separate syringes, and by directly connecting and arranging the first and second containers immediately before injection and then mixing them, the amount of side-effect-causing solvents such as NMP can be reduced, unlike conventional products. Additionally, the viscosity is reduced due to the dilution effect of the biodegradable polymer solution, so the injection force is lowered to 30N or less, thereby improving ease of use. Furthermore, although the active ingredient goserelin precipitates when mixed with BA, making formulation impossible, dissolving goserelin in the first solvent and mixing it with the second solvent in an appropriate ratio prevents precipitation. Moreover, it suppresses the excessive initial drug release typically associated with poly(lactide-co-glycolide), thereby enabling sustained drug release for more than one month.

[0053] Hereinafter, preferred embodiments of the present invention will be described with reference to the accompanying drawings so that those skilled in the art can easily implement them. Furthermore, in describing the present invention, if it is determined that a detailed description of related known functions or known configurations may unnecessarily obscure the essence of the invention, such detailed description will be omitted. Also, some features presented in the drawings have been enlarged, reduced, or simplified for ease of explanation, and the drawings and their components are not necessarily depicted in appropriate proportions. However, those skilled in the art will easily understand these details.

[0055] Confirmation of the solubility of goserelin acetate in biocompatible organic solvents

[0056] 10 mg of goserelin acetate was mixed with organic solvents according to the weight ratios in [Table 1] below, added, and then thoroughly mixed by stirring at room temperature using a vortex mixer. Subsequently, changes in appearance were observed visually, and the results are shown in [Table 1] and [Figure 1].

[0057] Goserelin acetate organic solvent Mixing ratio (w / w) Saint 10 mg BA Precipitation O BA DMSO 1:5 Precipitation X 1:3 Precipitation X 1:1 Precipitation X 1:0.5 Precipitation X 1:0.33 Precipitation X 1:0.2 Precipitation O BA NMP 1:5 Precipitation X 1:3 Precipitation X 1:1 Precipitation X 1:0.5 Precipitation X 1:0.33 Precipitation O 1:0.2 Precipitation O

[0059] Based on the results in Table 1 above, when the active ingredient goserelin acetate is mixed with benzyl alcohol (BA), precipitation of the active ingredient occurs, making it impossible to formulate it into an in-situ implantable injectable. However, it was confirmed that precipitation is prevented from a certain ratio, making formulation into an injectable possible.

[0061] Preparation of a sustained-release in-situ implant using a first component (NMP, goserelin acetate) and a second component (BA, polymer)

[0062] Pharmaceutically acceptable goserelin acetate (Manufacturer: Bachem, Switzerland) was used as the bioactive substance, and lactide / glycolide (50:50) copolymer (Manufacturer: Evonik, Germany) was used as the biodegradable polymer. As shown in [Table 2] below, Examples 1 to 3 were prepared by sufficiently dissolving 3.78 mg of goserelin acetate (3.6 mg as goserelin) in N-methyl-2-pyrrolidone (NMP) solvent using a vortex mixer, and by sufficiently dissolving the biodegradable polymer in Benzyl alcohol (BA) solvent using a vortex mixer to prepare the drug solution. At this time, the weight ratio of the drug to the polymer was set to 1:5, and the total weight of the two solvents was designed to be equal.

[0063] Comparative Examples 1 to 3 were prepared using only NMP solvent without using BA, in the same manner as Examples 1 to 3. Comparative Example 4 reduced only the amount of NMP solvent in the composition of Comparative Example 3.

[0064] After filling the corresponding amounts of the prepared 1st and 2nd components into 0.5 mL syringes (Manufacturer: BD), connect the two syringes with a connector and alternately press the syringe plungers on both sides to thoroughly mix the two components. Attach a 23G needle to the 0.5 mL syringe, draw an equivalent amount of 3.6 mg of goserelin, and slowly inject it with the tip of the needle submerged in the dissolution test solution. The total volume per syringe does not exceed 0.5 mL.

[0065] division Drug:Molecular weight ratio NMP (weight%) BA (weight%) Example 1 1:5 23 46 Example 2 1:5 34 34 Example 3 1:5 52 17 Comparative Example 1 1:10 56 0 Comparative Example 2 1:16 66 0 Comparative Example 3 1:22 63 0 Comparative Example 4 1:22 59 0

[0066] Preparation of a sustained-release in-situ implant using a first component (DMSO, goserelin acetate) and a second component (BA, two types of polymers)

[0067] Pharmaceutically acceptable goserelin acetate (Manufacturer: Bachem, Switzerland) was used as the physiologically active substance, and a lactide / glycolide (50:50) copolymer (Manufacturer: Evonik, Germany) was used as the biodegradable polymer. As shown in [Table 3] below, Examples 4 to 15 were prepared by sufficiently dissolving 3.78 mg of goserelin acetate (3.6 mg as goserelin) in a dimethyl sulfoxide (DMSO) solvent using a vortex mixer, and by sufficiently dissolving the biodegradable polymer in a benzyl alcohol (BA) solvent using a vortex mixer to prepare the drug solution. At this time, the weight ratio of the drug to the polymer was set to 1:4 to 1:5.

[0068] Examples 16 and 17 were prepared by varying the ratio of lactide / glycolide (50:50) copolymer (manufacturer: Evonik, Germany) and lactide / glycolide (75:25) copolymer (manufacturer: Evonik, Germany) in the same manner as Examples 4 to 15. In Example 16, only a single type of lactide / glycolide (50:50) copolymer (manufacturer: Evonik, Germany) was used, and in Example 17, 0.25 parts by weight of lactide / glycolide (75:25) copolymer (manufacturer: Evonik, Germany) was added to 1 part by weight of lactide / glycolide (50:50) copolymer (manufacturer: Evonik, Germany).

[0069] Comparative Examples 4 to 6 were prepared using only DMSO solvent without using BA, in the same manner as Examples 4 to 15.

[0070] After filling the corresponding amounts of the prepared 1st and 2nd components into 0.5 mL syringes (Manufacturer: BD), connect the two syringes with a connector and alternately press the syringe plungers on both sides to thoroughly mix the two components. Attach a 23G needle to the 0.5 mL syringe, draw an equivalent amount of 3.6 mg of goserelin, and slowly inject it with the tip of the needle submerged in the dissolution test solution. The total volume per syringe does not exceed 0.5 mL.

[0071] division Drug:Molecular weight ratio DMSO (weight%) BA (weight%) Example 4 1:4 24 59 Example 5 1:4 20 62 Example 6 1:4 19 60 Example 7 1:4 11 68 Example 8 1:4.5 23 59 Example 9 1:4.5 21 59 Example 10 1:4.5 15 65 Example 11 1:4.5 10 69 Example 12 1:5 23 58 Example 13 1:5 24 56 Example 14 1:5 19 60 Example 15 1:5 18 57 Example 16 1:3.3 15 68 Example 17 1:4 23 58 Comparative Example 5 1:10 100 0 Comparative Example 6 1:16 100 0 Comparative Example 7 1:22 100 0

[0072] Single-dose subcutaneous pharmacokinetic study using SD rats

[0073] Pharmacokinetic studies were conducted using SD Rat to evaluate the in vivo pharmacokinetics according to the composition of the in-situ implant containing goserelin according to the present invention. As test drugs, the formulations prepared in Example 2, Example 17, and Comparative Example 3 were used.

[0074] The dosage of the test drug was 3.6 mg / head equivalent of goserelin, dispensed into a syringe, and then a 23G needle was used to create a space between the skin and muscle by pulling the skin of the dorsal and cervical region of SD rats with the thumb and index finger to perform a subcutaneous injection by inserting the needle into the subcutaneous space from the anterior part of the animal. 0.5 mL of blood was collected at scheduled times for 28 days, and the concentration of goserelin in the blood was measured using LC-MS / MS.

[0076] Single-dose subcutaneous efficacy test using Beagle dogs

[0077] To evaluate the potential of an in-situ implant containing goserelin according to the present invention as a sustained-release therapeutic agent, the testosterone secretion inhibitory effect of the in-situ implant containing goserelin and a control drug was compared in male Beagle dogs. AstraZeneca's Zoladex Depot Injection 3.6 mg was used as the control drug, and the formulations prepared in Examples 16 and 17 were used as the test substances.

[0078] The dose of the test drug was administered by dispensing an equivalent of 3.6 mg / head of goserelin into a syringe and administering it subcutaneously to the cervical-dorsal region of male Beagle dogs using a 23G needle, while the control drug was administered in the same manner as the test drug using a 16G needle fitted to the product. Approximately 3 mL of blood was collected at scheduled times for 28 days after administration, and blood testosterone concentrations were measured using LC-MS / MS.

[0080] Analysis method

[0081] 1. In-vitro long-term dissolution test of an in-situ implant containing goserelin

[0082] To measure the drug release behavior of the in-situ sustained-release compositions containing goserelin prepared according to Examples 1 to 14 and Comparative Examples 1 to 6, an in-vitro dissolution test was conducted in accordance with the dissolution item of the performance tests for Goserelin implants listed in the USP (United States Pharmacopeia) pharmacopoeia. The prepared in-situ implant compositions were weighed to obtain a drug amount of 3.6 mg as goserelin, placed in 50 mL of pH 7.4 phosphate / citrate buffer, and stored in an incubator at 39 ± 0.5°C. 1 mL was extracted at each time interval, and the amount of drug released was measured using HPLC. The concentration of the released drug was determined by converting the absorbance values, and a dissolution graph was plotted by calculating the cumulative percentage of the amount of drug released at each time interval relative to the total drug.

[0084] 2. Injectability test of an in-situ implant composition containing goserelin

[0085] For the in-situ sustained-release compositions containing goserelin prepared according to Examples 1 to 14 and Comparative Examples 1 to 6, a 1 mL liquid injection solution was loaded into a syringe at room temperature in the laboratory, and after attaching a 23 G needle, the injection force according to the drug / polymer ratio, polymer / solvent ratio, and solvent composition was measured using a Universal test machine (UTM, Testone).

[0087] Measurement results

[0088] 1. In-vitro long-term dissolution test of an in-situ implant containing goserelin

[0089] The initial drug release of Examples 1 to 14 and Comparative Examples 1 to 6 is shown in [Table 4] and [Table 5]. In addition, a graph of the 28-day long-term release for an example and a comparative example is shown in FIG. 3.

[0090] division Drug:Molecular weight ratio NMP (weight%) BA (weight%) Initial dissolution (2hr, %) Example 1 1:5 23 46 4.9 Example 2 1:5 34 34 14.2 Example 3 1:5 52 17 22.8 Comparative Example 1 1:10 56 0 32.8 Comparative Example 2 1:16 66 0 24.8 Comparative Example 3 1:22 63 0 13 Comparative Example 4 1:22 59 0 8.9

[0091] In the results of Examples 1 to 3, it was confirmed that when the drug:polymer ratio and the total amount of solvent are constant, the initial dissolution rate decreases from 22.8% to 4.9% as the proportion of BA increases. In the results of Comparative Examples 1 to 3, it was confirmed that when NMP is used alone without using BA, the initial dissolution rate decreases as the proportion of polymer increases. In the results of Comparative Examples 3 to 4, it was confirmed that when the molecular weight is the same, the initial dissolution rate decreases as the amount of solvent decreases.

[0092] However, it was confirmed that when NMP and BA are used separately as the first and second components, as in Examples 1 to 3, compared to when NMP is used alone, it is possible to formulate an injectable form even with a small amount of NMP, and the amount of NMP that can cause reproductive toxicity and irritation is reduced, thereby ensuring the relative safety of the product, and that even with the use of small amounts of polymers and solvents, the initial excessive release of the drug can be effectively prevented.

[0093] division Drug:Molecular weight ratio DMSO (weight%) BA (weight%) Initial dissolution (2hr, %) Example 4 1:4 24 59 11.6 Example 5 1:4 20 62 8.1 Example 6 1:4 19 60 6.5 Example 7 1:4 11 68 2.6 Example 8 1:4.5 23 59 8.9 Example 9 1:4.5 21 59 4.7 Example 10 1:4.5 15 65 3.1 Example 11 1:4.5 10 69 1.6 Example 12 1:5 23 58 9.6 Example 13 1:5 24 56 5.1 Example 14 1:5 19 60 3.9 Example 15 1:5 18 57 2.0 Example 16 1:3.3 15 68 12.2 Example 17 1:4 23 58 5.8 Comparative Example 5 1:10 100 0 38.2 Comparative Example 6 1:16 100 0 29.5 Comparative Example 7 1:22 100 0 17.8

[0094] In the results of Examples 4 to 17, it was confirmed that when DMSO and BA were used as the first and second components, respectively, the initial drug release decreased as the proportion of BA in the total solvent increased while the drug:polymer ratio remained constant. In the results of Comparative Examples 5 to 7, it was confirmed that when DMSO was used alone without BA, there was a limit to reducing the initial release even when the proportion of polymer increased. Furthermore, it was confirmed that when DMSO and BA were used together, the initial drug release could be effectively inhibited even with smaller amounts of polymer and solvent compared to when DMSO was used alone.

[0096] 2. Injectability test of an in-situ implant composition containing goserelin

[0097] Under room temperature conditions in the laboratory, a 1 mL liquid injection solution was loaded into a syringe, and a 23 G needle was attached. Then, a Universal test machine (UTM, Testone) was used to measure the drug / polymer ratio, polymer / solvent ratio, and injection force according to the solvent composition.

[0098] division Drug:Molecular weight ratio NMP (weight%) DMSO (weight%) BA (weight%) Injection power (N) Comparative Example 1 1:10 56 - 0 12.7±1.2 Comparative Example 2 1:16 66 - 0 19.4±1.5 Comparative Example 3 1:22 63 - 0 25.7±0.8 Comparative Example 4 1:22 59 - 0 31.6±0.3 Comparative Example 5 1:10 - 100 0 13.5±0.7 Comparative Example 6 1:16 - 100 0 18.6±1.2 Comparative Example 7 1:22 - 100 0 24.2±1.1 Example 1 1:5 23 46 4.2±0.7 Example 2 1:5 34 34 3.3±0.8 Example 3 1:5 52 17 2.5±1.1 Example 4 1:4 - 24 59 2.1±0.7 Example 5 1:4 - 20 62 3.5±0.3 Example 6 1:4 - 19 60 4.9±0.5 Example 7 1:4 - 11 68 6.3±1.0 Example 8 1:4.5 - 23 59 2.4±0.5 Example 9 1:4.5 - 21 59 3.5±0.2 Example 10 1:4.5 - 15 65 5.3±0.7 Example 11 1:4.5 - 10 69 7.2±1.4 Example 12 1:5 - 23 58 4.5±0.5 Example 13 1:5 - 24 56 6.0±0.2 Example 14 1:5 - 19 60 7.9±1.8 Example 15 1:5 18 57 9.8±1.1 Example 16 1:3.3 15 68 2.8±1.7 Example 17 1:4 23 58 2.3±1.2

[0099] In the results of Comparative Examples 1 to 7, it was confirmed that when the first solvent and the second solvent are provided as a single solvent, the injection power increases as the polymer ratio increases in order to reduce the initial elution rate. In particular, in the results of Comparative Example 4 and Example 8, it was confirmed that even though the initial elution rate is similar, the injection power shows a difference of more than 13 times. Therefore, it can be confirmed that when the first solvent is NMP or DMSO and the second solvent is BA, the improvement in the initial elution rate as well as the improvement in injection power is evident.

[0101] 3. Single-dose subcutaneous pharmacokinetic study using SD rats

[0102] As can be seen in Fig. 4, the initial blood concentration of goserelin in Examples 2 and 17, which used different first and second solvents, is lower than the initial blood concentration of goserelin in Comparative Example 4, which used only a single solvent for the first and second solvents. Furthermore, although Comparative Example 4 showed a lower initial dissolution rate than Example 2 in the in-vitro long-term dissolution test, it was confirmed to show more than twice the initial drug release in-vivo.

[0103] In addition, Examples 2 and 7 have a sustained-release effect in which the drug is effectively released into the bloodstream over a period of 28 days, whereas in the case of Comparative Example 4, due to the initial over-release of the drug, all of the drug is lost after 17 days from injection, and it was confirmed that the drug effect cannot be maintained for a long period of more than 1 month with a single injection.

[0106] 4. Single-dose subcutaneous efficacy test using Beagle dogs

[0107] Goserelin, a GnRH agonist, acts on the pituitary gland to inhibit the production of testosterone by suppressing the secretion of luteinizing hormone, thereby lowering the blood testosterone concentration to the castration threshold and preventing the cell proliferation mechanism from proceeding.

[0108] As can be seen in Figure 5, it was confirmed that the concentration of testosterone in Examples 16, 17 and the control drug reached a castration level on day 10 and maintained a stable castration level until day 17.

[0109] However, in the case of the reference drug, the blood testosterone concentration began to increase after 17 days of administration and exceeded the castration level on 24 days, whereas in Examples 16 and 17, the blood testosterone concentration gradually increased after 17 days and maintained the castration level until 24 days, and since the pattern of increase in blood testosterone thereafter showed an improved effect compared to the reference drug, it was confirmed that the formulation according to one example showed a superior testosterone inhibitory effect compared to the reference drug.

[0111] Foregoing, specific parts of the present invention have been described in detail. It will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.

Claims

Claim 1 A sustained-release pharmaceutical composition capable of forming an in-situ implant, comprising: a drug comprising goserelin or a pharmaceutically acceptable salt thereof; a biodegradable polymer; and a pharmaceutically acceptable organic solvent; wherein the sustained-release pharmaceutical composition comprises a first component comprising the drug; and a second component comprising the biodegradable polymer, wherein the first component comprises, as a first solvent, one or more selected from the group consisting of N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), and the second component comprises benzyl alcohol (BA) as a second solvent, and the biodegradable polymer is poly(lactide-co-glycolide). Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 A sustained-release pharmaceutical composition according to claim 1, wherein the biodegradable polymer comprises one or more selected from the group consisting of poly(DL-lactide-co-glycolide) having a weight ratio of lactide to glycolide of 40:60 to 60:40 and poly(DL-lactide-co-glycolide) having a weight ratio of lactide to glycolide of 70:30 to 80:

20. Claim 6 The sustained-release pharmaceutical composition according to claim 1, wherein the sustained-release pharmaceutical composition forms a sol phase, and the sol of the sustained-release pharmaceutical composition does not use separate water for injection, has a total dosing volume of less than 1 mL, and the infusion power of the mixture is 30 N or less at 20°C. Claim 7 The sustained-release pharmaceutical composition according to claim 1 comprises, based on the total weight, 1 to 10 parts by weight of the drug, 10 to 30 parts by weight of the biodegradable polymer, 9 to 40 parts by weight of the first solvent, and 15 to 70 parts by weight of the second solvent. Claim 8 A kit containing a sustained-release pharmaceutical composition capable of forming an in-situ implant, comprising: a container containing a first component comprising a drug including goserelin or a pharmaceutically acceptable salt thereof; and a container containing a second component including a biodegradable polymer and said biodegradable polymer; wherein the first component and said second component each comprise different solvents, the first component comprises, as a first solvent, one or more selected from the group consisting of N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), the second component comprises benzyl alcohol (BA) as a second solvent, and said biodegradable polymer is poly(lactide-co-glycolide). Claim 9 In claim 8, the kit comprises an injectable of the sustained-release pharmaceutical composition, wherein the injectable is capable of subcutaneous injection with a thin needle having a diameter of 20 G or less, and the kit has a total dosing volume of less than 1 mL without the use of separate water for injection.

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