In situ gel formulation and preparation method therefor

Abstract

Provided are an in situ gel formulation and a preparation method therefor. The in situ gel formulation comprises a component A and a component B, wherein the component A comprises an active pharmaceutical ingredient and a solvent A, the component B comprises a biodegradable polymer and a solvent B, and the component A and the component B are separately dispensed in two containers. The formulation is easily mixed well during clinical use, and the active pharmaceutical ingredient has good content uniformity, exhibits good stability during storage, and can stably and persistently exert efficacy.

Description

An in-situ gel formulation and its preparation method

[0001] Citation of relevant applications

[0002] This disclosure claims priority to Chinese Patent Application No. 202510108454.9, filed on January 23, 2025, entitled "An In-situ Gel Formulation and Its Preparation Method", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the field of pharmaceutical formulations, specifically relating to an in-situ gel formulation and a method for preparing the formulation. Background Technology

[0004] In-situ gel formulations are solutions or semi-solid preparations composed of active pharmaceutical ingredients, biodegradable polymers, and other components. They can solidify / gel at the injection site to form a drug reservoir, slowly releasing the drug to achieve long-term drug administration.

[0005] Currently available in-situ gel formulations, such as These products are packaged in pairs of syringes. One syringe contains the solid active pharmaceutical ingredient, while the other contains a solution of a biodegradable polymer. Before clinical use, the two syringes are connected, and multiple cycles of pushing and pulling are performed to uniformly disperse the bioactive substance in the polymer solution, forming a suspension. According to the product instructions, to obtain a uniformly dispersed suspension, 100 cycles need to be completed at a rate of one cycle per second. 60 cycles are required. Sixty mixing cycles are required. When the above-mentioned in-situ gel formulation is administered, the active pharmaceutical ingredient exists in the form of microparticles. The dispersion of the active pharmaceutical ingredient is highly dependent on the degree of mixing. Insufficient mixing may affect the efficacy and safety of the drug, and also increase the workload of medical staff in clinical administration and the risk to drug quality assurance.

[0006] Therefore, improving the safety and efficacy of in-situ gel formulations in clinical use and providing an in-situ gel formulation that is easy to operate and has controllable quality are urgent problems to be solved. Summary of the Invention

[0007] To address the problems existing in the prior art, this disclosure provides an in-situ gel formulation that is easy to mix evenly. The formulation can reduce the number of mixing steps and the difficulty of mixing before clinical use, thereby reducing the administration burden on medical staff. The in-situ gel formulation used for administration is a homogeneous solution with good uniformity of active pharmaceutical ingredients, ensuring product safety and enabling stable and sustained efficacy.

[0008] A first aspect of this disclosure provides an in-situ gel formulation comprising component A and component B;

[0009] Component A contains the active pharmaceutical ingredient and solvent A;

[0010] Component B contains a biodegradable polymer and solvent B;

[0011] Component A and component B are packaged separately in two containers.

[0012] In some embodiments of this disclosure, component A and / or component B further comprise hydrophobic additives.

[0013] In some embodiments of this disclosure, the mass of component A accounts for 5%-50% of the total mass of the in-situ gel formulation, preferably 10%-40%, and more preferably 15%-35%.

[0014] In some embodiments of this disclosure, the mass of component B accounts for 50%-95% of the total mass of the in-situ gel formulation, preferably 60%-90%, and more preferably 65%-85%.

[0015] In some embodiments of this disclosure, the “pharmaceutical active ingredient” refers to any single substance or mixture of substances in the in-situ gel formulation that has pharmacological activity or other direct effects in the diagnosis, treatment, symptom relief, management, or prevention of disease, or that can affect the function or structure of the body.

[0016] In some embodiments of this disclosure, the active pharmaceutical ingredient may be selected from drugs for treating schizophrenia or hormonal drugs. In some specific embodiments, the active pharmaceutical ingredient of this disclosure includes, but is not limited to, risperidone, paliperidone, bupivacaine, ropivacaine, leuprorelin, triptorelin, octreotide, rotigotine, pramipexole, rumepiride, or pharmaceutically acceptable salts thereof. In some specific embodiments, the active pharmaceutical ingredient of this disclosure is selected from rotigotine, pramipexole, rumepiride, or pharmaceutically acceptable salts thereof. In some specific embodiments, the active pharmaceutical ingredient of this disclosure is selected from rotigotine.

[0017] In some embodiments of this disclosure, the pharmaceutically acceptable salt may be selected from inorganic acid salts or organic acid salts. In some specific embodiments, the inorganic acid may be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and the organic acid may be selected from acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0018] In some embodiments of this disclosure, the content of the active pharmaceutical ingredient can be adjusted within a certain range according to specific needs. In some specific embodiments, the content of the active pharmaceutical ingredient is calculated in its free base form. In other specific embodiments, the content of the active pharmaceutical ingredient is calculated in its acid addition salt form.

[0019] In some embodiments of this disclosure, the mass of the active pharmaceutical ingredient accounts for 2%-40% of the total mass of the in-situ gel formulation, preferably 2%-30%, more preferably 3%-30%, further preferably 6%-20%, even more preferably 8%-15%, and most preferably 8%-10%.

[0020] In some embodiments of this disclosure, the content of the active pharmaceutical ingredient, calculated in its free base form, accounts for 2%-40% of the total mass of the in-situ gel formulation, preferably 2%-30%, more preferably 3%-30%, further preferably 6%-20%, even more preferably 8%-15%, and most preferably 8%-10%.

[0021] In some embodiments of this disclosure, the term "biodegradable polymer" refers to a polymer that, upon interaction with the physiological environment, can be degraded by chemical or physical methods, such as at an implantation site within a subject, eroding, decomposing, or dissolving over a period of time, such as days, weeks, or months. Biodegradable polymers can degrade into fragments and be metabolized or excreted by the host. Biodegradable polymers play a temporary role in the subject, such as storing and releasing active pharmaceutical ingredients.

[0022] In some embodiments of this disclosure, the biodegradable polymer may be a polyester, which refers to a polymer 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. Polyesters can also be formed by ring-opening polymerization of cyclic ester monomers.

[0023] In some embodiments of this disclosure, the biodegradable polymer is selected from polyesters, preferably polylactide, poly(ε-caprolactone), polyorthoester, lactide / glycolic acid copolymer, ε-caprolactone / glycolic acid copolymer, or lactide / trimethylene carbonate copolymer, more preferably polylactide, poly(ε-caprolactone), polyorthoester, or lactide / glycolic acid copolymer, and even more preferably lactide / glycolic acid copolymer.

[0024] In some embodiments of this disclosure, "lactide / glycolic acid copolymer" and "PLGA" may be used interchangeably. In some more specific embodiments, the molar ratio of lactide to glycolide in the lactide / glycolic acid copolymer is 5:95-95:5, preferably 50:50-95:5, such as 50:50, 75:25, 85:15 or 95:5.

[0025] This disclosure does not impose a particular limitation on the molecular weight of the biodegradable polymer, which can be determined by those skilled in the art according to actual needs. In some specific embodiments, the molecular weight of the biodegradable polymer is 5000-100000 Da, preferably 5000-70000 Da, more preferably 10000-50000 Da, and even more preferably 10000-30000 Da.

[0026] In some embodiments of this disclosure, the designation of the lactide / glycolic acid copolymer has the following meanings: Taking "7525 2A" as an example, "7525" indicates that the molar ratio of lactide to glycolide is 75:25; "2" represents the intrinsic viscosity, 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, 3.5 indicates an intrinsic viscosity of 0.30-0.40 dL / g, and 4 indicates an intrinsic viscosity of... 0.35-0.45 dL / g, 4.5 indicates an intrinsic viscosity of 0.40-0.50 dL / g, 5 indicates an intrinsic viscosity of 0.45-0.55 dL / g, 6 indicates an intrinsic viscosity of 0.50-0.70 dL / g, 7 indicates an intrinsic viscosity of 0.60-0.80 dL / g, 8 indicates an intrinsic viscosity of 0.70-0.90 dL / g, and 9 indicates an intrinsic viscosity of 0.80-1.00 dL / g; the intrinsic viscosity of PLGA with a molecular weight of 100,000 Da is 1 dL / g; "A" indicates that the terminal group is a carboxyl group.

[0027] In some embodiments of this disclosure, the biodegradable polymer accounts for 10%-80% of the total mass of the in-situ gel formulation, preferably 10%-60%, more preferably 20%-50%, and even more preferably 30%-50%.

[0028] In some embodiments of this disclosure, the mass ratio of the biodegradable polymer to the active pharmaceutical ingredient is 1:1-20:1, preferably 1:1-15:1, more preferably 2:1-15:1, further preferably 2:1-10:1, and even more preferably 2:1-5:1.

[0029] In some embodiments of the present invention, solvent A and solvent B are biocompatible organic solvents that can diffuse within a living organism and be metabolized or absorbed by the organism. In some embodiments of the present invention, solvent A and solvent B do not have volatile properties at room temperature and pressure.

[0030] In some embodiments of this disclosure, solvent A and solvent B are each independently selected from N-methyl pyrrolidone (NMP) and / or dimethyl sulfoxide (DMSO), preferably N-methyl pyrrolidone.

[0031] In some embodiments of this disclosure, the solvent content can be adjusted within a certain range according to specific needs. In some specific embodiments, the sum of the masses of solvent A and solvent B accounts for 20%-80% of the total mass of the in-situ gel formulation, preferably 30%-70%, more preferably 30%-50%, and even more preferably 30%-40%.

[0032] In some embodiments of this disclosure, the mass ratio of solvent A to solvent B is 1:1-1:8, preferably 1:1-1:6, more preferably 1:1-1:5, even more preferably 1:2-1:5, and even more preferably 1:3-1:5.

[0033] In some embodiments of this disclosure, the mass ratio of solvent A to the active pharmaceutical ingredient is 0.5:1-5:1, preferably 0.5:1-3:1, more preferably 0.5:1-2:1, and even more preferably 0.5:1-1.5:1.

[0034] In some embodiments of this disclosure, the mass ratio of solvent B to the biodegradable polymer is 0.5:1-5:1, preferably 0.5:1-3:1, more preferably 0.5:1-2.5:1, and even more preferably 0.5:1-1:1.

[0035] In some embodiments of this disclosure, component A and / or component B further comprise hydrophobic additives.

[0036] In some embodiments of this disclosure, component A contains a hydrophobic additive, and component B does not contain a hydrophobic additive.

[0037] In some embodiments of this disclosure, component A does not contain hydrophobic additives, and component B contains hydrophobic additives.

[0038] In some embodiments of this disclosure, component A comprises a hydrophobic additive, and component B comprises a hydrophobic additive.

[0039] In some embodiments of this disclosure, neither component A nor component B contains hydrophobic additives.

[0040] In some embodiments of this disclosure, the "hydrophobic additive" may be a pharmaceutically acceptable additive that is hydrophobic and plays a role in regulating the release rate of the active pharmaceutical ingredient in the in-situ gel formulation of this disclosure.

[0041] In some embodiments of this disclosure, the hydrophobic additive is selected from one or more of ethyl acetate, medium-chain triglycerides, triacetylglycerol, tricaprylic acid glyceride, benzyl benzoate, and benzyl alcohol, preferably one or more of benzyl benzoate, triacetylglycerol, and tricaprylic acid glyceride, and more preferably benzyl benzoate.

[0042] In some embodiments of this disclosure, the total mass of the hydrophobic additives accounts for 2%-30% of the total mass of the in-situ gel formulation, preferably 5%-20%, more preferably 8%-20%, and even more preferably 10%-18%.

[0043] In some embodiments of this disclosure, the mass ratio of the hydrophobic additive in component A to the hydrophobic additive in component B is 5:0 to 0:5, for example, 5:0, 5:1, 5:2, 5:3, 5:4, 5:5, 4:5, 3:5, 2:5, 1:5, 0:5 or any two of the above ratios.

[0044] In some embodiments of this disclosure, the container is selected from vials, ampoules, and syringes, preferably syringes, and more preferably pre-filled syringes.

[0045] In some embodiments of this disclosure, component A and component B are mixed before clinical use to obtain a homogeneous solution, wherein the relative standard deviation of the content of the active pharmaceutical ingredient in the homogeneous solution is not more than 5%, preferably not more than 2.2%, more preferably not more than 1.6%, and even more preferably not more than 1%.

[0046] In some embodiments of this disclosure, the container is a syringe. In some specific embodiments, the mixing of component A and component B is carried out by connecting two syringes containing component A and component B respectively, and pushing the syringe plunger back and forth, with the number of back-and-forth cycles not exceeding 100 times, preferably not exceeding 80 times, more preferably not exceeding 60 times, for example 40-60 times, 60 times, 40 times, or 20 times.

[0047] A second aspect of this disclosure provides a method for preparing an in-situ gel formulation, comprising the following steps:

[0048] (1) Dissolve the active pharmaceutical ingredient and optional hydrophobic additive in solvent A to obtain component A, and fill it into a container;

[0049] (2) Dissolve the biodegradable polymer and optional hydrophobic additives in solvent B to obtain component B, which is then filled into a container.

[0050] In some embodiments of this disclosure, the preparation method is carried out under aseptic production conditions.

[0051] In some embodiments of this disclosure, the preparation method further includes the step of filtering and sterilizing component A and / or component B.

[0052] In some embodiments of this disclosure, the step of filtering and sterilizing component B is to directly filter and sterilize component B.

[0053] In some embodiments of this disclosure, the preparation method includes the following steps:

[0054] (1) Under aseptic production conditions, the active pharmaceutical ingredient and optional hydrophobic additives are dissolved in solvent A to obtain component A, which is then filtered through a 0.22μm filter for sterilization and filled into containers.

[0055] (2) Dissolve the biodegradable polymer and optional hydrophobic additives in solvent B to obtain component B, filter it through a 0.22 μm filter for sterilization, and fill it into a container.

[0056] In some embodiments of this disclosure, the step of filtering and sterilizing component B is as follows: adding a volatile solvent to component B, filtering and sterilizing, and removing the volatile solvent.

[0057] In some embodiments of this disclosure, the preparation method includes the following steps:

[0058] (1) Under aseptic production conditions, the active pharmaceutical ingredient and optional hydrophobic additives are dissolved in solvent A to obtain component A, which is then filtered through a 0.22μm filter for sterilization and filled into containers.

[0059] (2) Dissolve the biodegradable polymer, volatile solvent and optional hydrophobic additive in solvent B to obtain component B, filter it through a 0.22μm filter to remove volatile solvent, and fill it into a container.

[0060] In some embodiments of this disclosure, "volatile solvent" refers to a liquid substance that is easily volatile at room temperature and pressure. This invention does not specifically limit the type of volatile solvent, which can be determined by those skilled in the art based on actual needs.

[0061] In some embodiments of this disclosure, the boiling point of the volatile solvent is less than 150°C, preferably less than 100°C, more preferably less than 80°C, even more preferably less than 70°C, and even more preferably less than 65°C.

[0062] In some embodiments of this disclosure, the volatile solvent is selected from volatile alkanes, volatile haloalkanes, volatile alcohols, volatile ketones, volatile esters, volatile organic cyanides, or volatile ethers, preferably dichloromethane, trichloromethane, or acetone, and more preferably acetone.

[0063] In some embodiments of this disclosure, the mass ratio of the volatile solvent to the biodegradable polymer is 1:1-10:1, preferably 1:1-5:1, more preferably 1:1-3:1, and even more preferably 1.5:1-2.5:1.

[0064] In some embodiments of this disclosure, the method for removing volatile solvents is not particularly limited, and those skilled in the art can choose according to actual needs. In some specific embodiments, the method for removing volatile solvents is selected from one or more of reduced pressure, temperature control, aeration, and stirring, preferably rotary evaporation.

[0065] The beneficial effects of this disclosure are as follows:

[0066] (1) The in-situ gel formulation provided in this disclosure is a homogeneous solution before clinical administration, and the active pharmaceutical ingredient has good uniformity in content, ensuring the safety of the product and enabling it to exert a stable and sustained effect. Compared with commercially available products, it can reduce the number of mixing times and the difficulty of mixing before clinical use, and reduce the administration burden on medical staff.

[0067] (2) The in-situ gel formulation provided in this disclosure has a high drug loading capacity, and can achieve a long-term continuous release for drug delivery methods with limited injection volume, such as subcutaneous injection and intramuscular injection, with a small burst release.

[0068] (3) The in-situ gel formulation provided in this disclosure has good stability of the active pharmaceutical ingredient during storage, low levels of related substances, and is safe and controllable.

[0069] (4) The in-situ gel formulation provided in this disclosure has good stability of biodegradable polymer during storage, which can ensure the stable and sustained release of active pharmaceutical ingredients after administration.

[0070] (5) The in-situ gel preparation method provided in this disclosure is simple and easy to scale up industrially. The active pharmaceutical ingredient is dispensed in solution form into containers, especially syringes, which is simpler than dispensing the active pharmaceutical ingredient in solid powder form and has better accessibility to filling equipment.

[0071] (6) The method for preparing in-situ gel formulations provided in this disclosure is suitable for filtration sterilization, which can ensure the production of sterile formulations and can better control the generation of related substances compared with irradiation sterilization. Attached Figure Description

[0072] Figure 1 shows the curve of drug concentration change over time in SD rats for the in situ gel formulation of Example 6. Detailed Implementation

[0073] The following describes the embodiments of this disclosure, but the disclosure is not limited thereto. This disclosure is not limited to the above embodiments, and various modifications can be made within the scope of protection claimed in this disclosure. Embodiments and embodiments obtained by appropriately combining different embodiments and the technical means disclosed in the embodiments are also included in the technical scope of this disclosure.

[0074] Unless otherwise defined, the technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0075] In this disclosure, the word "may" has both the meaning of performing a certain process and the meaning of not performing a certain process.

[0076] In this disclosure, "optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes both the scenario in which the event occurs and the scenario in which the event does not occur.

[0077] In this disclosure, the term "drug loading" refers to the percentage of the active pharmaceutical ingredient by mass of the in-situ gel formulation.

[0078] Unless otherwise specified, percentages in this disclosure refer to weight percentages.

[0079] Whether explicitly stated or not, all numerical values ​​in this disclosure are modified by the term “about”. The term “about” means within ±10%, ±5%, or ±2% of the stated value.

[0080] All technical features disclosed herein, or all steps in all methods or processes disclosed herein, may be combined in any way, except for mutually exclusive technical features and / or steps.

[0081] To more clearly illustrate the technical solution of this disclosure, specific embodiments are described below, but these should not be construed as limiting the scope of this disclosure. Unless otherwise stated, the instruments, reagents, materials, laboratory animals, etc., used in this disclosure can all be obtained through conventional commercial means. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer should be followed.

[0082] Example 1

[0083] Mix 4g of rotigotine and 6g of NMP, dissolve them completely, and fill the first pre-filled syringe.

[0084] Mix 10g of PLGA (5050 4.5A) and 24g of NMP, dissolve them completely, and fill them into the second pre-filled syringe.

[0085] Example 2

[0086] Mix 4g of rotigotine and 6g of NMP, dissolve them completely, and fill the first pre-filled syringe.

[0087] Mix 10g of PLGA (5050 4.5A), 21g of NMP, and 3g of benzyl benzoate, dissolve completely, and fill into the second pre-filled syringe.

[0088] Example 3

[0089] Mix 4g of rotigotine, 6g of NMP, and 3g of benzyl benzoate, dissolve them completely, and fill them into the first pre-filled syringe.

[0090] Mix 10g of PLGA (5050 4.5A) and 21g of NMP, dissolve them completely, and fill them into the second pre-filled syringe.

[0091] Example 4

[0092] Mix 108g of rotigotine and 72g of NMP, dissolve them completely, filter them through a 0.22μm filter for sterilization, and fill them into the first pre-filled syringe in a sterile isolator.

[0093] Mix 441.6g of PLGA (7525 2A), 162g of benzyl benzoate, 306g of NMP, and 900g of acetone, dissolve completely, filter sterilize through a 0.22μm filter, remove acetone by rotary evaporation, and fill into a second pre-filled syringe in a sterile isolator.

[0094] Example 5

[0095] Mix 108g of rotigotine, 162g of benzyl benzoate, and 72g of NMP until completely dissolved. Filter the solution through a 0.22μm filter for sterilization and fill it into the first pre-filled syringe in a sterile isolator.

[0096] Mix 441.6g of PLGA (7525 2A), 306g of NMP, and 900g of acetone, dissolve completely, filter sterilize through a 0.22μm filter, remove acetone by rotary evaporation, and fill into a second pre-filled syringe in a sterile isolator.

[0097] Example 6

[0098] Mix 108g of rotigotine, 72g of benzyl benzoate, and 72g of NMP until completely dissolved. Filter the mixture through a 0.22μm filter for sterilization and fill it into the first pre-filled syringe in a sterile isolator.

[0099] Mix 441.6g of PLGA (7525 2A), 90g of benzyl benzoate, 306g of NMP, and 900g of acetone, dissolve completely, filter sterilize through a 0.22μm filter, remove acetone by rotary evaporation, and fill into a second pre-filled syringe in a sterile isolator.

[0100] Example 7

[0101] Mix 2.75g of rotigotine and 7.2g of NMP, dissolve completely, and fill into the first pre-filled syringe.

[0102] Mix 33.75g of PLGA (7525 2A), 12.4g of benzyl benzoate, and 21.7g of NMP, dissolve completely, and fill into the second pre-filled syringe.

[0103] Comparative Example 1

[0104] Mix 108g of rotigotine, 441.6g of PLGA (7525 2A), 162g of benzyl benzoate, 378g of NMP, and 900g of acetone, dissolve completely, filter sterilize through a 0.22μm filter, remove acetone by rotary evaporation, and fill into pre-filled syringes in a sterile isolator.

[0105] Comparative Example 2

[0106] Mix 2.75g of rotigotine, 33.75g of PLGA (7525 2A), 12.4g of benzyl benzoate, 28.9g of NMP, and 110g of acetone, dissolve completely, filter through a 0.22μm filter for sterilization, remove acetone by rotary evaporation, and fill into pre-filled syringes in a sterile isolator.

[0107] Comparative Example 3

[0108] 4g of rotigotine was dispensed into the first pre-filled syringe.

[0109] Mix 10g of PLGA (5050 4.5A) and 30g of NMP, dissolve them completely, and fill them into the second pre-filled syringe.

[0110] Comparative Example 4

[0111] 4g of rotigotine was dispensed into the first pre-filled syringe.

[0112] Mix 10g of PLGA (5050 4.5A), 27g of NMP, and 3g of benzyl benzoate, dissolve completely, and fill into the second pre-filled syringe.

[0113] Comparative Example 5

[0114] 108g of rotigotine was dispensed into the first pre-filled syringe and sterilized by irradiation.

[0115] Mix 441.6g of PLGA (7525 2A), 162g of benzyl benzoate, 378g of NMP, and 900g of acetone, dissolve completely, filter sterilize through a 0.22μm filter, remove acetone by rotary evaporation, and fill into a second pre-filled syringe in a sterile isolator.

[0116] Comparative Example 6

[0117] 2.75g of rotigotine was dispensed into the first pre-filled syringe.

[0118] Mix 33.75g of PLGA (7525 2A), 12.4g of benzyl benzoate, and 28.9g of NMP, dissolve completely, and fill into the second pre-filled syringe.

[0119] Experimental Example 1: Performance Evaluation of Component A and Component B After Mixing

[0120] One pre-filled syringe (containing component A) and one pre-filled syringe (containing component B) from Examples 1-7 and Comparative Examples 3-6 were taken respectively. Matching pushers and plungers were installed, and the two pre-filled syringes were connected. The plungers were pushed back and forth to mix the components. Each back-and-forth push was counted as one mixing cycle. The number of mixing cycles and the corresponding sample characteristics were recorded. The characteristics and content uniformity of the mixed samples were examined. The specific results are shown in Table 1.

[0121] The specific method for detecting content uniformity is as follows: Divide the contents of the pre-filled syringe into 5 equal parts from the tip to the tail of the syringe, take a sample from each part, detect the content of the active pharmaceutical ingredient, and calculate the relative standard deviation (RSD).

[0122] Table 1. Investigation of mixing times and content uniformity

[0123] When the active pharmaceutical ingredient in the first pre-filled syringe is in solid form, mixing it with the components in the second pre-filled syringe involves a process of dissolving and dispersing the active pharmaceutical ingredient. The dissolution rate and content uniformity are affected by factors such as the content, solubility, and particle size of the active pharmaceutical ingredient, requiring a relatively large number of push-pull cycles for mixing and dissolution. When the active pharmaceutical ingredient in the first pre-filled syringe is in solution form, mixing it with the components in the second pre-filled syringe requires fewer push-pull cycles to achieve uniform sample mixing, making clinical operation simpler. In each embodiment, the content of each component in the mixed drug formulation is the same as that in the corresponding comparative example. The active pharmaceutical ingredient in the embodiments exists in solution form before mixing and becomes a homogeneous solution after mixing, resulting in good content uniformity of the active pharmaceutical ingredient, ensuring product quality during injection, and enabling stable efficacy.

[0124] Experimental Example 2: Investigation of the content of related substances

[0125] The samples were placed under accelerated (25℃, 40%RH±5%RH) and long-term (2-8℃) conditions, respectively. After a certain period of time, the samples were removed and the relevant substances were detected by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The results are detailed in Table 2.

[0126] Table 2. Results of related substances detection in rotigotin

[0127] The impurities listed in Table 2 are the corresponding impurities under the rotigotine entry in the European Pharmacopoeia. For example, impurity B is desthienylethyl rotigotine, impurity C is despropyl rotigotine, and impurity E is rotigotine N-oxide.

[0128] Example 6 and Comparative Example 1 had the same composition and content of in-situ gel formulation. In Example 6, components A and B were dispensed into two syringes. After 6 months of accelerated and long-term testing, the contents of impurities B, C, E, and total impurities were significantly lower than those in Comparative Example 1, where components A and B were dispensed into the same syringe. This demonstrates that dispensing components A and B into two syringes can effectively control the growth of related substances in the in-situ gel formulation during storage.

[0129] Experimental Example 3: Polymer Stability Study

[0130] Examples 6 and Comparative Example 1 were placed under accelerated (25°C, 40%RH ± 5%RH) and long-term (2-8°C) test conditions, respectively. After a certain period of time, the samples were removed, and the molecular weight of the polymers was determined according to size exclusion chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0514). The results of the PLGA weight-average molecular weight determination are detailed in Table 3.

[0131] The specific method for determining the molecular weight of PLGA is as follows: Take appropriate amounts of multiple polystyrene molecular weight reference standards and prepare reference solutions. The molecular weight range should include the molecular weight of the test sample. Take an appropriate amount of the sample, dissolve it, and prepare a test solution. Use a size exclusion column and a differential refractive index detector for detection. The detection range should include the molecular weight of the test sample.

[0132] Table 3 Results of polymer weight-average molecular weight determination

[0133] Molecular weight change refers to the percentage change in molecular weight at the time of detection relative to the change in molecular weight at day 0.

[0134] Example 6 and Comparative Example 1 had the same composition and content of in-situ gel formulation. In Example 6, components A and B were dispensed into two syringes. After 6 months of accelerated and long-term testing, the change in polymer molecular weight was significantly lower than that of the Comparative Example 1 formulation where components A and B were dispensed into the same syringe. This demonstrates that dispensing components A and B into two syringes can significantly slow down the rate of decrease in polymer molecular weight and effectively control the degradation of PLGA in the in-situ gel formulation during storage.

[0135] Experimental Example 4: Drug Release Stability Study

[0136] Example 6 and Comparative Example 1 were placed under accelerated testing conditions (25°C, 40%RH ± 5%RH). After a certain period of time, the samples, which were dispensed into two containers, were removed, and components A and B were mixed before the in vitro release rate was measured. The results of the in vitro release study are detailed in Table 4.

[0137] The specific method for determining the in vitro release rate is as follows: A 20G needle is attached to the tip of a pre-filled syringe containing the test formulation. The sample is added dropwise to the release medium. The syringe is accurately weighed before and after sample addition, and the amount of sample injected is calculated by weight difference. The release medium is a 0.02M phosphate buffer solution with a volume of 50 ml. The sample vial containing the release medium is placed in a 45℃ water bath. Three replicates are prepared for each sample. At predetermined time points, 2 mL of the supernatant is collected, and 2 mL of the release medium at the same temperature is added simultaneously. The test solution is analyzed by HPLC, and the cumulative release is calculated using the external standard method.

[0138] Table 4. In vitro release study

[0139] Example 6 and Comparative Example 1 had the same composition and content of in-situ gel formulation. In Comparative Example 1, components A and B were packaged in the same syringe and stored under accelerated conditions for 3 months. The release at 0.5 hours was significantly increased compared to the day 0 sample, indicating a greater burst release. In Example 6, components A and B were dispensed into two syringes, and after 3 months of storage under accelerated conditions, there was no significant change in burst release. Therefore, dispensing components A and B into two syringes can avoid the safety risks caused by increased burst release after storage.

[0140] Experimental Example 5: Pharmacokinetic Study in Animals

[0141] The pharmacokinetic behavior of the in situ gel formulation was investigated using 12 male SD rats (half male and half female). After a single subcutaneous injection of 16 mg / kg of the in situ gel formulation described in Example 6, plasma samples were collected from each animal at predetermined time points. The concentration of rotigotine in rat plasma was determined by LC-MS / MS, and the drug concentration versus time curve is shown in Figure 1. The results showed that the effective concentration of rotigotine in rat plasma administered with the in situ gel formulation of Example 6 remained stable for at least 2 weeks, confirming the excellent sustained-release effect of the in situ gel formulation of this disclosure.

[0142] The embodiments described above are some, but not all, of the embodiments of this disclosure. The detailed description of the embodiments of this disclosure is not intended to limit the scope of the claimed disclosure, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this disclosure without inventive effort are within the scope of protection of this disclosure.

Claims

1. An in-situ gel formulation comprising component A and component B; Component A contains the active pharmaceutical ingredient and solvent A; Component B contains a biodegradable polymer and solvent B; Component A and component B are packaged separately in two containers.

2. The in situ gelling formulation according to claim 1, characterized in that, Component A and / or component B further contain hydrophobic additives.

3. An in situ gelling formulation according to claim 1 or 2, characterised in that, The mass of component A accounts for 5%-50% of the total mass of the in-situ gel formulation, preferably 10%-40%, and more preferably 15%-35%.

4. An in situ gelling formulation according to any one of claims 1 to 3, wherein, The formulation meets one or more of the following conditions: (1) The biodegradable polymer is selected from polyester, preferably polylactide, poly(ε-caprolactone), polyorthoester, lactide / glycolic acid copolymer, ε-caprolactone / glycolic acid copolymer, or lactide / trimethylene carbonate copolymer, more preferably polylactide, poly(ε-caprolactone), polyorthoester, or lactide / glycolic acid copolymer, and even more preferably lactide / glycolic acid copolymer; (2) Solvent A and solvent B are each independently selected from N-methylpyrrolidone and / or dimethyl sulfoxide, preferably N-methylpyrrolidone; (3) The hydrophobic additive is selected from one or more of ethyl acetate, medium-chain triglycerides, triacetylglycerol, tricaprylic acid glycerides, benzyl benzoate and benzyl alcohol, preferably one or more of benzyl benzoate, triacetylglycerol and tricaprylic acid glycerides, and more preferably benzyl benzoate.

5. An in situ gelling formulation according to any one of claims 1 to 4, wherein, The formulation meets one or more of the following conditions: (1) The mass of the active pharmaceutical ingredient accounts for 2%-40% of the total mass of the in-situ gel preparation, preferably 2%-30%, more preferably 3%-30%, further preferably 6%-20%, even more preferably 8%-15%, and most preferably 8%-10%; (2) The biodegradable polymer accounts for 10%-80% of the total mass of the in-situ gel formulation, preferably 10%-60%, more preferably 20%-50%, and even more preferably 30%-50%; (3) The mass ratio of the biodegradable polymer to the active pharmaceutical ingredient is 1:1-20:1, preferably 1:1-15:1, more preferably 2:1-15:1, even more preferably 2:1-10:1, and even more preferably 2:1-5:1; (4) The sum of the masses of solvent A and solvent B accounts for 20%-80% of the total mass of the in-situ gel preparation, preferably 30%-70%, more preferably 30%-50%, and even more preferably 30%-40%; (5) The mass ratio of solvent A to solvent B is 1:1-1:8, preferably 1:1-1:6, more preferably 1:1-1:5, further preferably 1:2-1:5, and even more preferably 1:3-1:5; (6) The mass ratio of the solvent A to the active pharmaceutical ingredient is 0.5:1-5:1, preferably 0.5:1-3:1, more preferably 0.5:1-2:1, and even more preferably 0.5:1-1.5:1; (7) The mass ratio of the solvent B to the biodegradable polymer is 0.5:1-5:1, preferably 0.5:1-3:1, more preferably 0.5:1-2.5:1, and even more preferably 0.5:1-1:1; (8) The hydrophobic additive accounts for 2%-30% of the total mass of the in-situ gel formulation, preferably 5%-20%, more preferably 8%-20%, and even more preferably 10%-18%; (9) The mass ratio of the hydrophobic additive in component A to the hydrophobic additive in component B is 5:0-0:5, for example, 5:0, 5:1, 5:2, 5:3, 5:4, 5:5, 4:5, 3:5, 2:5, 1:5, 0:

5.

6. An in situ gelling formulation according to any one of claims 1 to 5, wherein, The container is selected from vials, ampoules, and syringes, preferably syringes, and more preferably pre-filled syringes.

7. An in situ gelling formulation according to any one of claims 1 to 6, wherein, Before clinical use, component A and component B are mixed to obtain a homogeneous solution, wherein the relative standard deviation of the content of the active pharmaceutical ingredient in the homogeneous solution does not exceed 5%, preferably not more than 2.2%, more preferably not more than 1.6%, and even more preferably not more than 1%.

8. A method for preparing an in-situ gel formulation according to any one of claims 1-7, comprising the following steps: (1) Dissolve the active pharmaceutical ingredient and optional hydrophobic additive in solvent A to obtain component A, and fill it into a container; (2) Dissolve the biodegradable polymer and optional hydrophobic additives in solvent B to obtain component B, which is then filled into a container.

9. A production method according to claim 8, characterized in that, It also includes the step of filtering and sterilizing component A and / or component B.

10. The production method according to claim 9, characterized in that, The step of filtering and sterilizing component B is selected from... (i) Component B is directly filtered for sterilization; or (ii) Add the volatile solvent to component B, filter to remove the volatile solvent.

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