Method for preparing sterile in-situ gel based on solvent removal technology and product thereof

Abstract

The invention discloses a method for preparing sterile in-situ gel based on a solvent removal technology and a product thereof. Compared with a traditional sterile production mode of an in-situ gel preparation, the preparation method of the in-situ gel has the advantages that the viscosity of a preparation solution is reduced by adding the volatile solvent in the production process, so that filtration and sterilization can be conveniently carried out, the volatile solvent in the preparation can be removed in multiple modes subsequently, and the production efficiency is improved. And the finally prepared in-situ gel preparation has no adverse effect. Research data shows that volatile solvent residues in the in-situ gel preparation prepared by the preparation method conform to safety standards, and compared with a preparation prepared by a traditional preparation method of irradiation sterilization, the in-situ gel preparation has the advantages that the types and contents of degraded impurities of polymers and active pharmaceutical ingredients are reduced, and the in-situ gel preparation is suitable for industrial production. Therefore, the safety of the preparation is improved.

Description

A method for preparing sterile in-situ gel based on solvent removal technology and its product

[0001] Citation of Related Applications

[0002] This disclosure claims priority to an invention patent application filed with the Patent Office of China on January 10, 2023, with application number 202310035221.1 and titled “A method for preparing sterile in-situ gel based on solvent removal technology and its product,” and the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure belongs to the field of pharmaceutical preparations, and particularly relates to a method for preparing a sterile in-situ gel based on a solvent removal technology, and a sterile in-situ gel prepared by the method. Background Art

[0004] In situ forming implants (ISFIs) are novel drug delivery systems composed of biodegradable polymer solutions or semisolids that solidify / gel at the site of introduction to form a reservoir. Depending on the formulation, ISFIs are formed primarily through different mechanisms, including in situ precipitation, organic gelation, or polymer cross-linking. Among these, the in situ precipitation-induced by solvent diffusion is the most common method. The system is currently the most commercialized and widely used technology, with several commercial products already on the market. Advanced prostate cancer Opioid use disorder and schizophrenia Widely used in fields such as

[0005] Dunn et al. first proposed the Technical Concepts. This technology primarily involves mixing a biodegradable polymer carrier (e.g., poly(lactic-co-glycolic acid) copolymer (PLGA, polylactic acid, PLA)) with an organic solvent (e.g., N-methylpyrrolidone (NMP)) to form a carrier system. Small molecules, peptides, or macromolecules are then dissolved or dispersed within the carrier system to form a solution or suspension that can be delivered into the body. Under prolonged high temperature conditions, the polymer carrier (e.g., PLGA) and the active pharmaceutical ingredient in these in situ gel formulations are susceptible to degradation and potential interactions, making them impractical to sterilize using terminal dry or wet heat. Furthermore, due to the high polymer concentration and high gel viscosity, sterilization by filtration is difficult to achieve for delivery into the body. Therefore, irradiation, primarily gamma ray irradiation, is commonly used internationally for sterilization of these in situ gel formulations.

[0006] The principle of irradiation sterilization is to release high-energy radiation through the transition of atoms from a high-energy state to a low-energy state. These radiations are high in energy and have strong penetrating power, which can induce a series of biophysical and biochemical reactions in microorganisms in pharmaceuticals, inhibiting and disrupting their metabolism and growth, thereby killing them. However, they can also accelerate the degradation of the polymer carrier and active pharmaceutical ingredient in the in situ gel, as well as the interaction between the polymer and the drug, resulting in the generation of some undesirable impurities. Therefore, under normal circumstances, the carrier and drug components of such preparations need to be packaged separately and prepared before use. This makes it easy for medical staff to make inaccurate dosages due to improper preparation or use during use. In addition, because irradiation-related factories must undergo strict qualification review and site selection, the irradiation sterilization process usually requires pharmaceutical manufacturers to entrust professional irradiation factories to carry out this process. From product packaging to transportation and then to irradiation, all stages are completed outside the GMP or cGMP system, which poses high management and quality assurance risks.

[0007] Therefore, it is of great significance to develop a simple aseptic preparation method for in situ gel formulation.

[0008] Summary of the Invention

[0009] Problems to be solved by the invention

[0010] In response to existing problems in the prior art, such as the current aseptic production method of in situ gel preparations, which accelerates the degradation of drugs and polymer carriers, generates additional impurities, and causes inconvenience in use, the present disclosure provides a method for preparing an in situ gel preparation. By adding a volatile solvent during the traditional in situ gel preparation process to reduce the viscosity of the gel solution so that filtration and sterilization can be performed, and the volatile solvent is removed through subsequent operations, the problems existing in the aseptic production method of traditional in situ gel preparations are solved.

[0011] Solutions for solving problems

[0012] A first aspect of the present disclosure provides a method for preparing an in situ gel preparation, the method comprising the following steps:

[0013] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with part or all of the components in the optional remaining preparation raw materials until uniform, to obtain a feed solution I;

[0014] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0015] iii: removing the volatile solvent from the sterile feed solution I;

[0016] Furthermore, when the feed solution I does not contain all the preparation raw materials, the preparation method further comprises the following steps:

[0017] iv: mixing the product obtained in iii with the sterile raw materials not contained in the feed solution I under sterile conditions until uniform;

[0018] The preparation raw materials also include active pharmaceutical ingredients, non-volatile solvents and optionally release regulators.

[0019] Furthermore, when the feed liquid I does not contain all the preparation raw materials, the product obtained in iii is mixed with the preparation raw materials not contained in the feed liquid I in step iv by any one or more of the following methods (a) to (g):

[0020] (a) adding the sterile active pharmaceutical ingredient through a sterile feeding device;

[0021] (b) adding the solution of the pharmaceutical active ingredient and the non-volatile solvent after filtering and sterilizing;

[0022] (c) if present, filter sterilize the solution of the pharmaceutically active ingredient and the release modifier before adding;

[0023] (d) if present, adding a filter sterilized solution of the pharmaceutically active ingredient, the non-volatile solvent, and the release-modifying agent;

[0024] (e) adding the non-volatile solvent after filtering and sterilizing;

[0025] (f) if present, filter sterilize the solution of the non-volatile solvent and the release modifier before adding;

[0026] (g) If present, the release modifier is filter sterilized prior to addition.

[0027] Preferably, when the feed liquid I does not contain all the preparation raw materials, the feed liquid I satisfies any one of the following conditions (j) to (p):

[0028] (j) the feed solution I contains the pharmaceutical active ingredient and the non-volatile solvent but does not contain the release modifier;

[0029] (k) the feed solution I contains the pharmaceutically active ingredient and the release modifier and does not contain the non-volatile solvent;

[0030] (1) the feed liquid I contains the pharmaceutical active ingredient and does not contain the non-volatile solvent and the release modifier;

[0031] (m) the feed liquid I contains the non-volatile solvent and the release modifier but does not contain the pharmaceutical active ingredient;

[0032] (n) the feed liquid I contains the non-volatile solvent but does not contain the pharmaceutical active ingredient and the release modifier;

[0033] (o) the feed solution I contains the release modifier but does not contain the pharmaceutically active ingredient and the non-volatile solvent;

[0034] (p) The feed solution I does not contain the pharmaceutical active ingredient, the non-volatile solvent and the release regulator.

[0035] Furthermore, the volatile solvent is selected from volatile alkanes, volatile halogenated alkanes, volatile alcohols, volatile ketones, volatile esters, volatile organic cyanides or volatile ethers.

[0036] Preferably, in the preparation raw materials, the mass ratio of the volatile solvent to the biodegradable polymer is 10:1 to 1:1.

[0037] Furthermore, the volatile solvent is selected from dichloromethane, chloroform or acetone.

[0038] Furthermore, in the step iii, the method for removing the volatile solvent in the sterile liquid I is selected from one or more of pressure reduction, temperature control, ventilation and stirring.

[0039] Furthermore, the biodegradable polymer is selected from polyester, polyester copolymer or block copolymer.

[0040] Furthermore, the biodegradable polymer is selected from PLGA, PLA, PCL, POE, PEG-PLA, PLA-PEG-PLA, PEG-PLGA, PEG-PLGA-PEG, TPGS-PLGA or TEG-POE.

[0041] Furthermore, the non-volatile solvent is N-methylpyrrolidone and / or dimethyl sulfoxide.

[0042] Furthermore, the optional release modifier is selected from one or more of ethyl acetate, medium chain triglycerides, triacetin, tricaprylin, benzyl benzoate and benzyl alcohol.

[0043] Preferably, the optional release modifier is benzyl benzoate and / or glyceryl triacetate.

[0044] A second aspect of the present disclosure provides an in situ gel preparation prepared according to the preparation method described in the first aspect of the present disclosure.

[0045] Effects of the Invention

[0046] The present disclosure provides a method for preparing an in situ gel. Compared with the traditional aseptic production method of in situ gel preparations, the present disclosure reduces the viscosity of the preparation solution by adding a volatile solvent during the production process, so as to facilitate filtration and sterilization. The volatile solvent in the preparation can be subsequently removed by various methods without any adverse effects on the final prepared in situ gel preparation.

[0047] Research data show that the in situ gel preparations prepared using the preparation method provided by the present invention have volatile solvent residues that meet safety standards, and compared with preparations prepared by traditional preparation methods using irradiation sterilization, the types and contents of degradation impurities of polymers and active pharmaceutical ingredients are reduced, thereby improving the safety of the preparations.

[0048] At the same time, the sterile in situ gel preparation prepared by the preparation method provided by the present invention already contains the active ingredient of the drug, which solves the problems of inconvenience in use and inaccurate dosage caused by separate packaging of the carrier part and the active ingredient of the drug in the prior art, and greatly improves the convenience and accuracy of the preparation use.

[0049] Furthermore, the in situ gel preparation method provided herein is simple to operate, enabling pharmaceutical manufacturers to independently produce sterile pharmaceuticals while ensuring product quality, thus facilitating better management of the production process and ensuring quality. Furthermore, the in situ gel preparation method provided herein has lower requirements for the sterility quality of raw materials and sterile feeding space and equipment, thus reducing production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG1 is a curve showing the change in drug concentration over time of the rotigotine in situ gel formulations in rats in Example 1 and Example 4. DETAILED DESCRIPTION

[0051] The following describes the embodiments of the present disclosure, but the present disclosure is not limited thereto. The present disclosure is not limited to the various structures described below, and various modifications can be made within the scope of the disclosure. Embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples are also included in the technical scope of the present disclosure.

[0052] <Definition>

[0053] In the present disclosure, a numerical range expressed using "a value A to a value B" or "a value A - a value B" means a range including the endpoints A and B.

[0054] In the present disclosure, the use of “may” includes both the meanings of performing a certain process and the meaning of not performing a certain process.

[0055] In this disclosure, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0056] In the present disclosure, the term “a” or “an” or “the” may mean “one”, and may also mean “one or more”, “at least one” and “one or more than one”.

[0057] In this disclosure, the term "about" may mean that a value includes the standard deviation of the error of the device or method used to determine the value. The numerical ranges and parameters used to define the present disclosure are all approximate values, and the relevant numerical values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations caused by the aforementioned testing devices or methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "about" generally means that the actual value is within ±10%, ±5%, ±1% or ±0.5% of a particular value or range.

[0058] In the present disclosure, the following explanation is given regarding the parameters of PLGA: Taking PLGA (7525DLG 2A) as an example, "7525" indicates that the molar ratio of lactide to glycolide is 75:25; "DLG" indicates lactide / glycolide copolymer, and "DL" indicates polylactide; "2" is the intrinsic viscosity identifier, where 1 indicates an intrinsic viscosity of 0.05-0.15 dL / g, 1.5 indicates an intrinsic viscosity of 0.10-0.20 dL / g, 2 indicates an intrinsic viscosity of 0.15-0.25 dL / g, 2.5 indicates an intrinsic viscosity of 0.20-0.30 dL / g, 3 indicates an intrinsic viscosity of 0.25-0.35 dL / g, and 3.5 indicates an intrinsic viscosity of 0.30-0.40 dL / g, 4 means the intrinsic viscosity is 0.35-0.45dL / g, 4.5 means the intrinsic viscosity is 0.40-0.50dL / g, 5 means the intrinsic viscosity is 0.45-0.55dL / g, 6 means the intrinsic viscosity is 0.50-0.70dL / g, 7 means the intrinsic viscosity is 0.60-0.80dL / g, 8 means the intrinsic viscosity is 0.70-0.90dL / g, and 9 means the intrinsic viscosity is 0.80-1.00dL / g; the intrinsic viscosity of PLGA with a molecular weight of 100,000Da is 1dL / g; "A" means the end group is an acid, and "E" means the end group is an ester.

[0059] In the present disclosure, the “water” includes any feasible water that can be used in the art, such as deionized water, distilled water, ion-exchanged water, double-distilled water, high-purity water, and purified water.

[0060] In the present disclosure, the "normal temperature" refers to 25±2°C.

[0061] In the present disclosure, the “normal pressure” refers to one standard atmospheric pressure.

[0062] Furthermore, unless otherwise defined, other technical and scientific terms used in the present disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs.

[0063] This disclosure is mainly based on the following insights:

[0064] In order to develop a simple aseptic preparation method for in situ gel, the inventors of the present disclosure conducted in-depth research and provided a method for preparing sterile in situ gel based on solvent removal technology, by adding volatile solvents (such as chloroform, dichloromethane, acetone, etc.) during the traditional in situ gel preparation process to reduce the viscosity of the gel solution, and then filtering and sterilizing it through a 0.22μm filter membrane, and then removing the volatile solvent, and finally filling it under a sterile environment.

[0065] The technical solution of the present disclosure is further described below:

[0066] <Method for Preparing In Situ Gel Preparation>

[0067] The present disclosure provides a method for preparing an in situ gel preparation, the method comprising the following steps:

[0068] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with part or all of the components in the optional remaining preparation raw materials until uniform, to obtain a feed solution I;

[0069] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0070] iii: removing the volatile solvent from the sterile feed solution I;

[0071] Furthermore, when the feed solution I does not contain all the preparation raw materials, the preparation method further comprises the following steps:

[0072] iv: mixing the product obtained in iii with the sterile raw materials not contained in the feed solution I under sterile conditions until uniform;

[0073] The preparation raw materials also include active pharmaceutical ingredients, non-volatile solvents and optionally release regulators.

[0074] [Raw materials for preparation of in situ gel preparations]

[0075] The preparation materials described in the present disclosure include a volatile solvent, a biodegradable polymer, a non-volatile solvent, a pharmaceutically active ingredient, and an optional release modifier.

[0076] In some embodiments, the preparation materials described in the present disclosure include a volatile solvent, a biodegradable polymer, a non-volatile solvent, and a pharmaceutically active ingredient.

[0077] In other embodiments, the preparation materials described in the present disclosure include a volatile solvent, a biodegradable polymer, a non-volatile solvent, a pharmaceutically active ingredient, and a release modifier.

[0078] Volatile solvents

[0079] In this disclosure, "volatile solvent" refers to a liquid substance that is volatile at room temperature and pressure. This disclosure does not specifically limit the specific type of volatile solvent, which can be determined by those skilled in the art based on actual needs.

[0080] In some embodiments, the volatile solvent of the present disclosure is selected from volatile halogenated alkanes, volatile alcohols, volatile ketones, or volatile ethers. Suitable volatile alkanes include, but are not limited to, pentane, cyclopentane, cyclohexane, n-hexane, n-octane, isooctane, and heptane; suitable volatile halogenated alkanes include, but are not limited to, dichloromethane, chloroform, and carbon tetrachloride; suitable volatile alcohols include, but are not limited to, methanol, ethanol, propanol, and butanol; suitable volatile ketones include, but are not limited to, acetone and cyclohexanone; suitable volatile esters include, but are not limited to, ethyl acetate; suitable volatile organic cyanides include, but are not limited to, acetonitrile; and suitable volatile ethers include, but are not limited to, diethyl ether.

[0081] In some embodiments, the volatile solvents described herein have a boiling point of less than 150°C, preferably less than 100°C, and more preferably less than 70°C.

[0082] In some specific embodiments, the volatile solvent disclosed herein is selected from dichloromethane, chloroform or acetone. The boiling points of the three volatile solvents are relatively low, with dichloromethane boiling point of about 39°C, chloroform boiling point of about 61°C, and acetone boiling point of about 53°C, which is significantly different from the boiling point of the non-volatile solvent N-methylpyrrolidone in the preparation (about 202-204°C), which is conducive to removing the volatile solvent without volatilizing the non-volatile solvent. Moreover, the three volatile solvents can dissolve biodegradable polymers (such as PLGA) well, and can effectively reduce the viscosity of the biodegradable polymer to facilitate filtration and sterilization operations.

[0083] The present disclosure does not impose any particular limitation on the amount of the volatile solvent, and those skilled in the art can adjust the amount according to actual production conditions, as long as it is sufficient to reduce the viscosity of the solution containing the biodegradable polymer so that filtration and sterilization can be performed.

[0084] In some embodiments, the mass ratio of the volatile solvent used in the present disclosure to the biodegradable polymer is 10:1 to 1:1, preferably 5:1 to 1:1; for example, 5:1, 4:1, 3:1, 2:1, 1:1, or any value within the above range. The amount of volatile solvent used within the above range not only meets the requirement of reducing the solution viscosity but also facilitates subsequent removal of the volatile solvent.

[0085] Biodegradable polymers

[0086] In this disclosure, the terms "biodegradable polymer," "bioabsorbable polymer," and "absorbable polymer" are used interchangeably to refer to polymers that can be decomposed by chemical or physical methods upon interaction with the physiological environment, such as by erosion, decomposition, or dissolution at an implantation site within a subject over a period of time, such as days, weeks, or months. Biodegradable polymers serve a temporary purpose in a subject, such as delivering a bioactive agent such as a drug. Biodegradable polymers can degrade into fragments and be metabolized or excreted by the host. This disclosure does not specifically limit the specific type of biodegradable polymer, which can be determined by a person skilled in the art based on actual needs.

[0087] In some embodiments, the biodegradable polymers described herein are selected from polyesters or polyester copolymers. Polyesters refer to polymers in which all or substantially all repeating units are linked together by ester groups. Polyesters can be formed by reacting monomers having carboxyl and hydroxyl groups to form ester groups. Suitable polyesters include, but are not limited to, polyglycolide, polylactide, polycaprolactone, and polyorthoesters; suitable polyester copolymers include, but are not limited to, lactide / glycolide copolymers, ε-caprolactone / glycolide copolymers, lactide / trimethylene carbonate copolymers, lactide / glycolide / caprolactone terpolymers, lactide / glycolide / trimethylene carbonate terpolymers, lactide / caprolactone / trimethylene carbonate terpolymers, glycolide / caprolactone / trimethylene carbonate terpolymers, and lactide / glycolide / caprolactone / trimethylene carbonate tetrapolymers. In other embodiments, the biodegradable polymers disclosed herein may be selected from block copolymers. For example, they may be block copolymers based on PLGA and / or PLA, such as PEG-PLA, PLA-PEG-PLA, PEG-PLGA, PEG-PLGA-PEG, and TPGS-PLGA, etc.; or they may be block copolymers based on polyorthoesters, such as TEG-POE, etc.

[0088] In some specific embodiments, the biodegradable polymer described in the present disclosure is selected from lactide / glycolide copolymer, polycaprolactone or polyorthoester.

[0089] In some more specific embodiments, the biodegradable polymer described herein is a lactide / glycolide copolymer. The present disclosure does not specifically limit the molar ratio of lactide to glycolide in the lactide / glycolide copolymer; this ratio can be determined by one skilled in the art based on practical needs. For example, the molar ratio of lactide to glycolide in the lactide / glycolide copolymer is 50:50 to 95:5; for example, it can be 50:50, 75:25, 85:15, or 95:5.

[0090] The present disclosure does not particularly limit the molecular weight of the biodegradable polymer, and those skilled in the art can determine it according to actual needs. For example, the molecular weight of the biodegradable polymer described in the present invention can be 5000-70000 Da, for example, 5000 Da, 10000 Da, 15000 Da, 20000 Da, 25000 Da, 30000 Da, 35000 Da, 40000 Da, 45000 Da, 50000 Da, 55000 Da, 60000 Da, 65000 Da, 70000 Da, or any value within the range.

[0091] Non-volatile solvents

[0092] In this disclosure, a "non-volatile solvent" is one that is not volatile at room temperature and pressure and can diffuse within a living organism and be metabolized or absorbed by the organism. This disclosure does not specifically limit the specific type of non-volatile solvent, and can be determined by those skilled in the art based on actual needs.

[0093] In some embodiments, the non-volatile solvent described in the present disclosure is N-methylpyrrolidone and / or dimethyl sulfoxide.

[0094] In some specific embodiments, the non-volatile solvent described in the present disclosure is N-methylpyrrolidone.

[0095] Release modifiers

[0096] In this disclosure, a "release modifier" is used to regulate the time-dependent release of the active pharmaceutical ingredient in an in situ gel formulation in vitro and in vivo. This disclosure does not specifically limit the specific type of release modifier, which can be determined by those skilled in the art based on actual needs.

[0097] In some embodiments, the release modifiers described herein are selected from one or more of ethyl acetate, medium chain triglycerides, triacetin, tricaprylin, benzyl benzoate, and benzyl alcohol.

[0098] In some specific embodiments, the release modifiers described herein are benzyl benzoate and / or glyceryl triacetate.

[0099] In some more specific embodiments, the release-modifying agent of the present disclosure is benzyl benzoate.

[0100] Active pharmaceutical ingredients

[0101] The present disclosure does not particularly limit the specific types of pharmaceutical active ingredients in the in situ gel preparation, and those skilled in the art can select them according to actual needs.

[0102] In some embodiments, the pharmaceutically active ingredient described herein is a poorly soluble drug.

[0103] In some embodiments, the pharmaceutically active ingredient described herein is rotigotine or pramipexole hydrochloride.

[0104] [Method for preparing in situ gel]

[0105] The preparation method of the in situ gel provided by the present disclosure is based on solvent removal technology. By adding a volatile solvent during the preparation process, the viscosity of the solution containing the biodegradable polymer is reduced so that sterilization can be performed by filtration. The volatile solvent is removed from the preparation by utilizing the volatility of the volatile solvent, thereby improving the convenience of preparing the sterile in situ gel preparation.

[0106] In some embodiments, the present disclosure provides a method for preparing an in situ gel formulation comprising the following steps:

[0107] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with all the components in the remaining preparation raw materials until uniform, to obtain a feed solution I;

[0108] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0109] iii: removing the volatile solvent from the sterile feed solution I.

[0110] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0111] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with the active pharmaceutical ingredient, non-volatile solvent and optional release modifier until uniformity is achieved to obtain a feed solution I;

[0112] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0113] iii: removing the volatile solvent from the sterile feed solution I.

[0114] In the above scheme, all raw materials can be filtered and sterilized at one time, which greatly improves the convenience of preparation of the preparation. Experimental data confirm that the above scheme has no adverse effects on the active ingredients of the drug and their pharmacokinetic behavior, and compared with the irradiation sterilization method, the types and quantities of impurities generated during the preparation process are greatly reduced.

[0115] In other embodiments, the present disclosure provides a method for preparing an in situ gel formulation comprising the following steps:

[0116] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with some of the optional components in the remaining preparation raw materials until uniform, to obtain a feed solution I;

[0117] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0118] iii: removing the volatile solvent from the sterile feed solution I;

[0119] iv: The product obtained in iii is mixed with the sterile raw materials not contained in the feed solution I under sterile conditions until uniformity is achieved.

[0120] In some specific embodiments, when the feed solution I does not contain all the preparation raw materials, the feed solution I satisfies any one of the following conditions (j) to (p):

[0121] (j) the feed solution I contains the pharmaceutically active ingredient and the non-volatile solvent but does not contain the optional release modifier;

[0122] (k) the feed solution I contains the pharmaceutically active ingredient and the release modifier and does not contain the non-volatile solvent;

[0123] (1) the feed liquid I contains the pharmaceutical active ingredient and does not contain the non-volatile solvent and the release modifier;

[0124] (m) the feed liquid I contains the non-volatile solvent and the release modifier but does not contain the pharmaceutical active ingredient;

[0125] (n) the feed liquid I contains the non-volatile solvent but does not contain the pharmaceutical active ingredient and the release modifier;

[0126] (o) the feed solution I contains the release modifier but does not contain the pharmaceutically active ingredient and the non-volatile solvent;

[0127] (p) The feed solution I does not contain the pharmaceutical active ingredient, the non-volatile solvent and the release regulator.

[0128] For step iv, when the raw materials not included in the feed liquid I are all solid components, the sterile raw materials not included in the feed liquid I can be added to the product obtained in step iii using a sterile feeding device or the like and mixed until uniform. When the raw materials not included in the feed liquid I are all liquid components, it is preferred to sterilize the raw materials not included in the feed liquid I by filtration sterilization, and add the sterilized sterile components to the product obtained in step iii and mix until uniform. When the raw materials not included in the feed liquid I contain both solid components and liquid components, the sterile solid components can be added to the product obtained in step iii and mixed until uniform. The liquid components can be sterilized by filtration sterilization, and the sterilized sterile liquid components can be added to the product obtained in step iii and mixed until uniform. Alternatively, the solid components and liquid components can be mixed until uniform and then filtered and sterilized, and then the sterilized sterile components can be added to the product obtained in step iii and mixed until uniform.

[0129] In some preferred embodiments, when the feed liquid I does not contain all the preparation raw materials, the preparation raw materials not contained in the feed liquid I are mixed with the product obtained in iii in iv by any one or more of the following methods (a) to (g):

[0130] (a) adding the sterile active pharmaceutical ingredient through a sterile feeding device;

[0131] (b) adding the solution of the pharmaceutical active ingredient and the non-volatile solvent after filtering and sterilizing;

[0132] (c) if present, filter sterilize the solution of the pharmaceutically active ingredient and the release modifier before adding;

[0133] (d) if present, adding a filter sterilized solution of the pharmaceutically active ingredient, the non-volatile solvent, and the release-modifying agent;

[0134] (e) adding the non-volatile solvent after filtering and sterilizing;

[0135] (f) if present, filter sterilize the solution of the non-volatile solvent and the release modifier before adding;

[0136] (g) If present, the release modifier is filter sterilized prior to addition.

[0137] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0138] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with the active pharmaceutical ingredient and non-volatile solvent until uniform, to obtain liquid I;

[0139] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0140] iii: removing the volatile solvent from the sterile feed solution I;

[0141] Furthermore, when a release modifier is present in the raw materials, the preparation method further comprises the following steps:

[0142] iv: The product obtained in iii is mixed with the release modifier that has been sterilized by filtration under aseptic conditions until homogeneity.

[0143] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0144] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with the active pharmaceutical ingredient and the release modifier until uniform, to obtain a feed solution I;

[0145] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0146] iii: removing the volatile solvent from the sterile feed solution I;

[0147] Furthermore, the preparation method further comprises the following steps:

[0148] iv: The product obtained in iii is mixed with a non-volatile solvent that has been sterilized by filtration under sterile conditions until homogeneity occurs.

[0149] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0150] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with the active pharmaceutical ingredient until uniform, to obtain liquid I;

[0151] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0152] iii: removing the volatile solvent from the sterile feed solution I;

[0153] Furthermore, when the release modifier is not present in the raw materials, the preparation method further comprises the following steps:

[0154] iv: The product obtained in iii is mixed with a non-volatile solvent that has been sterilized by filtration under sterile conditions until homogeneity occurs.

[0155] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0156] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with the active pharmaceutical ingredient until uniform, to obtain liquid I;

[0157] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0158] iii: removing the volatile solvent from the sterile feed solution I;

[0159] Furthermore, when a release modifier is present in the raw materials, the preparation method further comprises the following steps:

[0160] iv: Mix the non-volatile solvent and the release modifier until uniform, filter and sterilize, and then mix with the product obtained in iii under sterile conditions until uniform.

[0161] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0162] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with the non-volatile solvent and release modifier until uniform, to obtain a feed solution I;

[0163] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0164] iii: removing the volatile solvent from the sterile feed solution I;

[0165] Furthermore, the preparation method further comprises the following steps:

[0166] iv: Add the sterile active pharmaceutical ingredient to the product obtained in iii through a sterile feeding device and mix until uniform.

[0167] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0168] i: mixing the biodegradable polymer and volatile solvent in the preparation raw materials with the non-volatile solvent and release modifier until uniform, to obtain a feed solution I;

[0169] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0170] iii: removing the volatile solvent from the sterile feed solution I;

[0171] Furthermore, the preparation method further comprises the following steps:

[0172] iv: The active pharmaceutical ingredient is mixed with a non-volatile solvent until uniform, filtered and sterilized, and then mixed with the product obtained in iii under sterile conditions until uniform.

[0173] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0174] i: mixing the biodegradable polymer, volatile solvent and non-volatile solvent in the preparation raw materials until uniform, to obtain feed solution I;

[0175] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0176] iii: removing the volatile solvent from the sterile feed solution I;

[0177] Furthermore, when the release modifier is not present in the raw materials, the preparation method further comprises the following steps:

[0178] iv: Add the sterile active pharmaceutical ingredient to the product obtained in iii through a sterile feeding device and mix until uniform.

[0179] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0180] i: mixing the biodegradable polymer, volatile solvent and non-volatile solvent in the preparation raw materials until uniform, to obtain feed solution I;

[0181] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0182] iii: removing the volatile solvent from the sterile feed solution I;

[0183] Furthermore, when a release modifier is present in the raw materials, the preparation method further comprises the following steps:

[0184] iv: The active pharmaceutical ingredient and the release modifier are mixed until uniform, filtered and sterilized, and then mixed with the product obtained in iii under sterile conditions until uniform.

[0185] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0186] i: mixing the biodegradable polymer and the volatile solvent in the preparation raw materials with the release modifier until uniform, to obtain a feed solution I;

[0187] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0188] iii: removing the volatile solvent from the sterile feed solution I;

[0189] Furthermore, the preparation method further comprises the following steps:

[0190] iv: The active pharmaceutical ingredient is mixed with a non-volatile solvent until uniform, filtered and sterilized, and then mixed with the product obtained in iii under sterile conditions until uniform.

[0191] In some specific embodiments, the method for preparing the in situ gel formulation provided by the present disclosure comprises the following steps:

[0192] i: mixing the biodegradable polymer and the volatile solvent in the preparation raw materials until uniform, to obtain a feed solution I;

[0193] ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I;

[0194] iii: removing the volatile solvent from the sterile feed solution I;

[0195] Furthermore, the preparation method further comprises the following steps:

[0196] iv: The active pharmaceutical ingredient, the non-volatile solvent and the optional release modifier are mixed until uniform, filtered and sterilized, and then mixed with the product obtained in iii under sterile conditions until uniform.

[0197] For the filtration sterilization operation in the preparation method of the in situ gel preparation provided by the present disclosure, it is preferred to use a microporous filter membrane, more preferably a 0.22 μm filter membrane.

[0198] The present disclosure does not specifically limit the method for removing volatile solvents in the preparation method of the in situ gel formulation, and those skilled in the art may select a method based on actual needs. In some embodiments, the method for removing volatile solvents described in the present disclosure is selected from one or more of pressure reduction, temperature control, ventilation, and stirring. Furthermore, suitable equipment can be used to remove volatile solvents. Exemplary equipment includes, but is not limited to, a thin film evaporator, a rotary evaporator, or an air blowing device.

[0199] After the steps included in the preparation method of the in situ gel preparation provided by the present disclosure, the steps of adding other ingredients and the steps of filling etc. may also be included; preferably, the other ingredients added are sterile; preferably, the other ingredients added are non-drug active ingredients.

[0200] Example

[0201] To more clearly illustrate the technical solutions of the present disclosure, the following examples are provided for further explanation. However, these examples are not intended to limit the present disclosure and are merely partial examples. Unless otherwise specified, the instruments, reagents, materials, and experimental animals used in the present disclosure were all commercially available. Where specific conditions are not specified in the examples, conventional conditions or those recommended by the manufacturer were used.

[0202] Example 1 (Comparative Example)

[0203] Accurately weigh 33.75 g of PLGA (7525DLG 2A), 28.9 g of NMP, 2.75 g of rotigotine, and 12.4 g of benzyl benzoate, mix and dissolve until homogeneous, and dispense into 1 mL prefilled syringes. Sterilize by 25 kGy gamma irradiation.

[0204] Example 2

[0205] Accurately weigh 33.75 g of PLGA (7525DLG 2A), 28.9 g of NMP, 110 g of dichloromethane, 2.75 g of rotigotine, and 12.4 g of benzyl benzoate, mix and dissolve. Sterile filter through a 0.22 μm filter, and remove the dichloromethane by rotary evaporation. Dispense into 1 mL prefilled syringes in a sterile isolator.

[0206] Example 3

[0207] Accurately weigh 33.75 g of PLGA (7525DLG 2A), 28.9 g of NMP, 110 g of chloroform, 2.75 g of rotigotine, and 12.4 g of benzyl benzoate, mix and dissolve. Sterile filter the mixture through a 0.22 μm filter and remove the chloroform by rotary evaporation. Dispense the mixture into 1 mL prefilled syringes in a sterile isolator.

[0208] Example 4

[0209] Accurately weigh 33.75 g of PLGA (7525DLG 2A), 28.9 g of NMP, 110 g of acetone, 2.75 g of rotigotine, and 12.4 g of benzyl benzoate, mix and dissolve, then sterilize by filtering through a 0.22 μm filter and removing the acetone by rotary evaporation. Dispense into 1 mL prefilled syringes in a sterile isolator.

[0210] Example 5

[0211] Accurately weigh 67.5 g of PLGA (7525DLG 2A), 57.8 g of NMP, 220 g of acetone, 5.5 g of rotigotine, and 24.8 g of benzyl benzoate, mix and dissolve, then sterilize by filtration through a 0.22 μm filter. Remove the acetone by thin-film evaporation at 15 mL / min at 40°C. Dispense into 1 mL prefilled syringes in a sterile isolator.

[0212] Example 6

[0213] Accurately weigh 33.75 g of PLGA (7525DLG 2A), 110 g of acetone, 21.7 g of NMP, and 12.4 g of benzyl benzoate, mix and dissolve, then sterilize and filter through a 0.22 μm filter. Remove the acetone by rotary evaporation to obtain Solution A. Weigh 7.2 g of NMP and 2.75 g of rotigotine, mix and dissolve, then sterilize and filter through a 0.22 μm filter into Solution A and mix thoroughly. Then, dispense into 1 mL prefilled syringes in a sterile isolator.

[0214] Example 7 (Comparative Example)

[0215] Accurately weigh 33.75g of PLGA (5050DLG 2E), 38.8g of NMP, and 6.5g of sterile pramipexole hydrochloride, stir until uniformly dispersed, and then dispense into 1ml prefilled syringes. Finally, sterilize by 25kGy gamma irradiation.

[0216] Example 8

[0217] Accurately weigh 33.75g of PLGA (5050DLG 2E), 38.8g of NMP, and 110g of acetone, mix and dissolve, then filter through a 0.22μm filter membrane. Remove the acetone by rotary evaporation to obtain Liquid A. Add 6.5g of sterile pramipexole hydrochloride to Liquid A via a sterile dosing device (αβ valve) and stir until uniformly dispersed. Dispense into 1mL prefilled syringes in a sterile isolator.

[0218] Results of the investigation of the embodiment

[0219] Experimental Example 1: Investigation of Solvent Residue

[0220] Approximately 0.1-0.5 g of each sample from Examples 1-8 was accurately weighed and placed in an empty headspace vial. Dimethyl sulfoxide and 0.5-5 mL of water were accurately added and immediately sealed to obtain the test solution. The test solution and the reference solution were analyzed by gas chromatography, and the residual solvent content was calculated using the peak area using the external standard method. The results are shown in Table 1.

[0221] Table 1 Solvent residue results

[0222] [注1] :The concentration limit is based on the concentration limit specified in ICH Q3C and chp2020 Part IV 0861, and the calculation base is the total daily dose (the sum of all raw materials and excipients in the finished preparation).

[0223] The results in Table 1 show that the residual volatile solvents in the samples of Examples 2 to 6 and Example 8 all meet the limit standards and satisfy the safety requirements of the preparations.

[0224] Experimental Example 2: Investigation of in vitro release of in situ gel preparations

[0225] (1) In vitro burst release study of rotigotine in situ gel preparation

[0226] Use a 1mL syringe connected to a 21G needle (outer diameter 0.8mm), draw about 0.1mL, and accurately weigh. Slowly inject the sample dropwise into 50mL of release medium (0.01M phosphate buffer solution (0.2% SDS, pH adjusted to 7.40)), accurately weigh the syringe again, and calculate the amount of injected sample by weight loss. Place the sample bottle in a constant temperature oscillating water bath at 25±0.5℃ to keep warm. Prepare three replicates for each sample. Take 2mL of the supernatant at the predetermined time point and add 2mL of the release medium at the same temperature. Take the above test solution and test it by HPLC, and calculate the cumulative release amount by the external standard method. The in vitro release test results of rotigotine in Examples 1-6 are detailed in Table 2. The in vitro release rate is the mass percentage of the released drug to the total active pharmaceutical ingredients in the preparation.

[0227] (2) In vitro release study of pramipexole in situ gel preparation

[0228] Use a 1mL syringe connected to a 21G needle (outer diameter 0.8mm), draw 0.1mL, and accurately weigh. Slowly push the preparation into 100mL of release medium (0.01M phosphate buffer solution (0.2% SDS, pH adjusted to 7.40)), accurately weigh the syringe again, and calculate the amount of injected sample by weight loss method. Place the sample bottle in a 37±0.5℃ constant temperature oscillating water tank and oscillate at 50rpm. Prepare three replicates for each sample. Take 2mL of supernatant at the predetermined time point and supplement 2mL of release medium at the same temperature. Take the above test solution and detect it by HPLC, and calculate the cumulative release amount by the external standard method. The results of the in vitro release test of pramipexole in Examples 7-8 are detailed in Table 3.

[0229] Table 2 Rotigotine in vitro release test results

[0230] The results in Table 2 show that there is no significant difference in the in vitro release within 48 hours between Examples 2 to 6 and Example 1, indicating that the sterile rotigotine in situ gel prepared by solvent removal technology does not affect the release characteristics of the preparation.

[0231] Table 3 Pramipexole in vitro release results

[0232] The results in Table 3 show that there is no significant difference in the in vitro release within 48 hours between Example 8 and Example 7, indicating that the sterile pramipexole in situ gel prepared by solvent removal technology does not affect the release characteristics of the preparation.

[0233] Experimental Example 3: Investigation of Related Substances in Rotigotine In Situ Gel Formulation

[0234] After 6 months of storage at 2-8°C in the dark, 180 mg of the sample was weighed and placed in a 2 mL volumetric flask. 0.4 mL of the impurity reference substance stock solution was added, and the sample was dissolved and diluted to the mark with a diluent. After shaking well, the content of the related substances of rotigotine was determined by HPLC. The related substance content test results for Examples 1-4 and Example 6 are detailed in Table 4. The related substance content is the mass percentage of each related substance in the in situ gel formulation.

[0235] Table 4 Detection results of related substances in rotigotine

[0236] The results in Table 4 show that after gamma-ray sterilization, the formulation in Example 1 showed a significant increase in impurities B and C, and the presence of a large unknown single impurity. Compared to Example 6, Examples 2-4 showed a slight increase in impurity E, while other impurities showed no significant changes. The results for related substances indicate that the impurities in the formulations significantly increased after irradiation, failing to meet the impurity limits. However, the formulations prepared using the solvent removal technique showed no significant increase in impurities, meeting the impurity limits.

[0237] Experimental Example 4: Investigation of blood concentration of rotigotine in situ gel formulation in rats

[0238] SD male rats (N=6) were used to investigate in vivo pharmacokinetic (PK) behavior. The formulations described in some of the aforementioned examples were administered subcutaneously at a dose of 5 mg / kg (as rotigotine). Blood was collected from the tail vein at predetermined time points. Plasma samples were processed by SPE (Solid-Phase Extraction), and rotigotine concentrations were determined using LC-MS / MS. The drug concentration results for the formulations in Examples 1 and 4 in rats are shown in Table 5, and the drug concentration curves over time are shown in Figure 1.

[0239] Table 5 Blood drug concentration test results of rotigotine in situ gel preparation in rats

[0240] The results in Table 5 and Figure 1 show that the kinetic behavior of the drugs in the preparations of Example 4 and Example 1 in rats is consistent, indicating that the preparation of sterile rotigotine in situ gel by solvent removal technology does not affect the in vivo release characteristics of the preparations.

Claims

1. A method for preparing an in situ gel preparation, the method comprising the following steps: i: mixing the biodegradable polymer and the volatile solvent in the raw materials with part or all of the components in the remaining raw materials until they are uniform, to obtain a feed solution I; ii: filtering and sterilizing the feed solution I to obtain a sterile feed solution I; iii: removing the volatile solvent in the sterile feed solution I; Furthermore, when the feed solution I does not contain all the preparation raw materials, the preparation method further comprises the following steps: iv: mixing the product obtained in iii with the sterile raw materials not contained in the feed solution I under sterile conditions until uniform; The preparation raw materials also include active pharmaceutical ingredients, non-volatile solvents and optionally release regulators.

2. The preparation method according to claim 1, characterized in that: When the feed liquid I does not contain all the raw materials for preparation, the product obtained in iii is mixed with the raw materials for preparation not contained in the feed liquid I in step iv until uniform by any one or more of the following methods (a) to (g): (a) adding the sterile active pharmaceutical ingredient through a sterile feeding device; (b) adding the solution of the pharmaceutical active ingredient and the non-volatile solvent after filtering and sterilizing; (c) if present, adding the solution of the pharmaceutically active ingredient and the release modifier after sterilization by filtration; (d) if present, adding a sterile filtered solution of the pharmaceutically active ingredient, the non-volatile solvent and the release modifier; (e) adding the non-volatile solvent after filtering and sterilizing; (f) if present, adding a solution of the non-volatile solvent and the release modifier after sterilization by filtration; (g) if present, adding the release modifier after filter sterilization; Preferably, when the feed liquid I does not contain all the preparation raw materials, the feed liquid I satisfies any one of the following conditions (j) to (p): (j) the feed liquid I contains the pharmaceutically active ingredient and the non-volatile solvent but does not contain the release modifier; (k) the feed liquid I contains the pharmaceutically active ingredient and the release modifier but does not contain the non-volatile solvent; (1) the feed liquid I contains the pharmaceutical active ingredient and does not contain the non-volatile solvent and the release regulator; (m) the liquid I contains the non-volatile solvent and the release regulator and does not contain the drug active Element; (n) the feed liquid I contains the non-volatile solvent but does not contain the pharmaceutical active ingredient and the release modifier; (o) the feed liquid I contains the release regulator but does not contain the active pharmaceutical ingredient and the non-volatile solvent; (p) The liquid I does not contain the pharmaceutically active ingredient, the non-volatile solvent and the release regulator.

3. The preparation method according to claim 1 or 2, characterized in that: The volatile solvent is selected from volatile alkanes, volatile halogenated alkanes, volatile alcohols, volatile ketones, volatile esters, volatile organic cyanides or volatile ethers; Preferably, in the preparation raw material, the mass ratio of the volatile solvent to the biodegradable polymer is 10:1 to 1:

1.

4. The preparation method according to any one of claims 1 to 3, characterized in that The volatile solvent is selected from dichloromethane, chloroform or acetone.

5. The preparation method according to any one of claims 1 to 4, characterized in that: In the step iii, the method for removing the volatile solvent in the sterile liquid I is selected from one or more of decompression, temperature control, ventilation and stirring.

6. The preparation method according to any one of claims 1 to 5, characterized in that The biodegradable polymer is selected from polyesters, polyester copolymers or block copolymers.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The biodegradable polymer is selected from PLGA, PLA, PCL, POE, PEG-PLA, PLA-PEG-PLA, PEG-PLGA, PEG-PLGA-PEG, TPGS-PLGA or TEG-POE.

8. The preparation method according to any one of claims 1 to 7, characterized in that The non-volatile solvent is N-methylpyrrolidone and / or dimethyl sulfoxide.

9. The preparation method according to any one of claims 1 to 8, characterized in that The optional release modifier is selected from one or more of ethyl acetate, medium chain triglycerides, triacetin, tricaprylin, benzyl benzoate and benzyl alcohol; Preferably, the optional release modifier is benzyl benzoate and / or glyceryl triacetate.

10. An in situ gel preparation prepared by the preparation method according to any one of claims 1 to 9.

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