A long-acting immunomodulator composition and its preparation method and application

Abstract

The present invention discloses a pomalidomide long-acting sustained-release delivery system. Specifically, the pomalidomide long-acting sustained-release delivery system comprises: an active ingredient and a flowable composition; wherein the active ingredient is pomalidomide, or a pharmaceutically acceptable salt thereof or a hydrate thereof; and the flowable composition comprises a biodegradable polymer and a biocompatible polar non-protonated organic solvent. The pomalidomide long-acting sustained-release delivery system has a small drug burst release and a stable blood drug concentration, so it has a significant therapeutic effect and high safety.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a long-acting immunomodulator composition and a preparation method and application thereof. Background Art

[0002] Pomalidomide is a type of immunomodulatory drug (IMID) containing an imide group. It is a third-generation product after thalidomide and lenalidomide. The U.S. FDA first approved pomalidomide capsules for marketing in 2013 under the trade name POMALYST, which is mainly used to treat patients with multiple myeloma (MM). Due to its significant efficacy, it has gained a huge market share of nearly US$3 billion per year.

[0003] Pomalidomide, like other IMIDs, has a variety of adverse reactions. Domestic multicenter phase II clinical trials have shown that common adverse reactions in patients with relapsed and refractory MM treated with pomalidomide are leukopenia (86%), neutropenia (86%), thrombocytopenia (78%), anemia (68%), lymphopenia (50%), hyperglycemia (46%), pneumonia (28%), etc.; common grade 3-4 adverse reactions are neutropenia (64%), leukopenia (38%), anemia (31%), thrombocytopenia (28%), pneumonia (27%). Among them, long-term use of pomalidomide will significantly increase the frequency of asymptomatic and asymptomatic neutropenia. In addition, there are adverse reactions such as bone marrow suppression, infection, rash, neuropathy, and thromboembolism.

[0004] Therefore, the original product has made clear regulations on the use of the drug: take it orally once a day, 4 mg / day, take it continuously for 21 days, stop taking it for 7 days to let the blood indicators (neutrophils, etc.) return to normal levels, and then proceed to the next course of treatment. At the same time, if adverse reactions occur during medication, the dosage will be reduced to 1 mg / day. Because the half-life of pomalidomide is 6 hours, under the 1 mg / day dosing regimen, too long a dosing interval (24 hours) will cause significant blood drug fluctuations. Excessive blood drug concentration is the main cause of adverse reactions.

[0005] WO2022029429 discloses a long-acting injection preparation of pomalidomide using micron crystal technology, but it uses expensive media grinding equipment, which makes mass production difficult. In addition, the solubility of the drug in water, the size and uniformity of the crystal particle size (PDI) significantly affect the drug release rate and release period. The "top-down" method of media grinding will result in the particle size and PDI fluctuating within a certain range, which may cause release differences, resulting in large differences between product batches and unstable product efficacy.

[0006] CN116669767 A provides a pharmaceutical composition, in which an in situ gel system is used to load the drug components, thereby preparing a pharmaceutical composition for in situ injection into a tumor. However, the prior art does not suggest any technical solution for preparing a drug delivery preparation for pomalidomide using a gel system.

[0007] Therefore, there is an urgent need to develop a drug that is safe and can be released stably for a long time. Summary of the invention

[0008] The purpose of the present invention is to solve the problems of the prior art and to provide a pomalidomide long-acting release system with low burst release and good safety, as well as a preparation method and application thereof.

[0009] In a first aspect of the present invention, there is provided a long-acting sustained-release delivery system of pomalidomide, comprising an active ingredient and a flowable composition;

[0010] Wherein, the active ingredient is pomalidomide, or a pharmaceutically acceptable salt or hydrate thereof;

[0011] The flowable composition includes: a biodegradable polymer, and a biocompatible polar non-protonated organic solvent;

[0012] Wherein, the biodegradable polymer is a polymer selected from the following groups (a), (b), (c) or (d):

[0013] (a) polylactide, polyglycolide, polylactic acid, polycaprolactone, or a combination thereof;

[0014] (b) binary or ternary copolymers of the following polymers: polylactide, polyglycolide, polylactic acid, polycaprolactone;

[0015] (c) a combination of the copolymers described in (b);

[0016] (d) a combination of the polymer described in (a) and the copolymer described in (b);

[0017] Preferably, the biodegradable polymer is a lactide-glycolide copolymer.

[0018] In a preferred example, the intrinsic viscosity of the biodegradable polymer is 0.12-0.42 dl / g, preferably 0.15-0.38 dl / g, further preferably 0.17-0.36 dl / g, more preferably 0.17-0.30 dl / g, and most preferably 0.18-0.26 dl / g.

[0019] In a preferred embodiment, the biodegradable polymer accounts for 10%-50% of the total mass of the pomalidomide long-acting sustained-release delivery system, preferably 20-50%, more preferably 25-46%; and / or

[0020] The active ingredient accounts for 2%-50% of the total mass of the pomalidomide long-acting sustained-release delivery system, preferably 4%-30%, more preferably 8%-20%, and most preferably 12%-18%.

[0021] In another preferred example, the active ingredient accounts for 4%-9% of the total mass of the pomalidomide long-acting sustained-release delivery system.

[0022] In another preferred embodiment, the biodegradable polymer accounts for 10-90% of the total mass of the flowable composition, preferably 20-70%, more preferably 30-60%, and most preferably 30-50%.

[0023] In a preferred example, in the lactide-glycolide copolymer, the molar ratio of lactide to glycolide is 50:50 to 85:15, preferably 50:50, 65:35, 75:25 or 85:15, and more preferably 50:50 or 75:25.

[0024] In another preferred embodiment, the weight average molecular weight of the lactide-glycolide copolymer is 8000Da to 45000Da, preferably 10000Da to 40000Da.

[0025] In another preferred example, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is 50:50-75:25, and the intrinsic viscosity of the lactide-glycolide copolymer is 0.07-0.36 dl / g.

[0026] In another preferred example, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is 50:50-75:25, and the intrinsic viscosity of the lactide-glycolide copolymer is 0.17-0.36 dl / g.

[0027] In a preferred embodiment, the biocompatible polar non-protonated organic solvent is selected from the following group: N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin, triacetin, triethyl citrate, medium chain triglycerides, or a combination thereof.

[0028] In another preferred embodiment, the biocompatible polar non-protonated organic solvent is N-methyl-2-pyrrolidone or dimethyl sulfoxide.

[0029] In another preferred embodiment, the biocompatible polar non-protonated organic solvent is N-methyl-2-pyrrolidone.

[0030] In another preferred embodiment, the biocompatible polar non-protonated organic solvent accounts for 10%-90% of the total mass of the flowable phase composition, preferably 30%-80%, and more preferably 40%-70%.

[0031] In a preferred example, the mass ratio of the flowable composition to the active ingredient is 1:(0.001-0.70), preferably 1:(0.005-0.50), and more preferably 1:(0.01-0.45).

[0032] In a preferred example, the average dynamic viscosity of the long-acting sustained-release delivery system is 0.1-50000 cP, preferably 10-45000 cP, more preferably 30-43000 cP, and most preferably 300-30000 cP.

[0033] In another preferred embodiment, the average dynamic viscosity of the long-acting sustained-release delivery system is 1000-100000 cP.

[0034] In another preferred embodiment, the pomalidomide long-acting sustained-release delivery system further comprises a plasticizer.

[0035] In another preferred embodiment, the plasticizer is selected from the following group: poloxamer P188, triacetin, triethyl citrate, or a combination thereof.

[0036] In another preferred embodiment, the plasticizer is triacetin.

[0037] In another preferred embodiment, the pomalidomide long-acting sustained-release delivery system does not contain a plasticizer.

[0038] In another preferred embodiment, the pomalidomide long-acting sustained-release delivery system is a clear and transparent gel-like liquid.

[0039] In another preferred embodiment, the pomalidomide long-acting sustained-release delivery system is a non-transparent gel suspension liquid.

[0040] In another preferred embodiment, the pomalidomide long-acting sustained-release delivery system is a pomalidomide sustained-release in situ gel.

[0041] A second aspect of the present invention provides a pomalidomide drug combination, the combination comprising:

[0042] Pomalidomide, or a pharmaceutically acceptable salt thereof, or a hydrate thereof placed in a first container;

[0043] a flowable composition disposed in a second container, comprising a biodegradable polymer and a biocompatible polar nonprotonated organic solvent;

[0044] Wherein, the biodegradable polymer is a polymer selected from the following groups (a), (b), (c) or (d):

[0045] (a) polylactide, polyglycolide, polylactic acid, polycaprolactone, or a combination thereof;

[0046] (b) binary or ternary copolymers of the following polymers: polylactide, polyglycolide, polylactic acid, polycaprolactone;

[0047] (c) a combination of the copolymers described in (b);

[0048] (d) a combination of the polymer described in (a) and the copolymer described in (b);

[0049] Preferably, the biodegradable polymer is a lactide-glycolide copolymer.

[0050] In another preferred embodiment, the drug combination further includes an instruction manual, and the instruction manual records the following content: the components in the first container and the second container are fully mixed and then injected into the desired administration site to complete the administration.

[0051] In another preferred embodiment, the first container and the second container may be connected via threads.

[0052] The third aspect of the present invention provides a pomalidomide sustained-release in situ gel for injection, which comprises the pomalidomide long-acting sustained-release delivery system as described in the first aspect of the present invention, or the pomalidomide drug combination as described in the second aspect of the present invention.

[0053] The fourth aspect of the present invention provides a use of the pomalidomide long-acting sustained-release delivery system as described in the first aspect of the present invention, or the pomalidomide drug combination as described in the second aspect of the present invention, or the pomalidomide sustained-release in situ gel for injection as described in the third aspect of the present invention in the preparation of a drug for treating multiple myeloma.

[0054] The fifth aspect of the present invention provides a method for preparing the pomalidomide long-acting sustained-release delivery system according to the first aspect of the present invention, the method comprising mixing an active ingredient with a flowable composition to obtain the pomalidomide long-acting sustained-release delivery system.

[0055] In another preferred embodiment, the method comprises the following steps:

[0056] (A) mixing a biodegradable polymer and a biocompatible polar non-protonated organic solvent to obtain a gel solution;

[0057] (B) mixing the active ingredient with the gel solution of step (A) to obtain a pomalidomide long-acting sustained-release delivery system.

[0058] The sixth aspect of the present invention provides a method for treating multiple myeloma, the method comprising administering the pomalidomide long-acting sustained-release delivery system as described in the first aspect of the present invention, or the pomalidomide drug combination as described in the second aspect of the present invention, or the pomalidomide sustained-release in situ gel for injection as described in the third aspect of the present invention to a subject in need of treatment.

[0059] In another preferred embodiment, the administration method is subcutaneous injection.

[0060] In another preferred embodiment, the administered dose is 0.2 mL / dose to 2 mL / dose, preferably 0.3 mL / dose to 1.5 mL / dose.

[0061] In another preferred embodiment, the administration cycle is once a month, once every three months, or once every six months.

[0062] In another preferred embodiment, the subject is a human or non-human mammal, such as rats, mice, dogs, rabbits, pigs, sheep, and cows.

[0063] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 The relationship between the average dynamic viscosity of pomalidomide gel preparations and 3h blood drug concentration is shown.

[0065] Figure 2 The blood drug concentration-time curves of rats in Examples 1, 2, 4, and 5 from day 1 to day 28 are shown.

[0066] Figure 3 The blood drug concentration-time curves of rats in Examples 6, 7, 8, 9 and 25 from day 1 to day 28 are shown.

[0067] Figure 4 The blood drug concentration-time curves of rats in Examples 11 to 16 from day 1 to day 28 are shown.

[0068] Figure 5 The blood drug concentration-time curves of rats in Examples 17, 18 and 19 from day 1 to day 28 are shown.

[0069] Figure 6 The blood drug concentration-time curves of rats in Examples 20 to 24 from day 1 to day 28 are shown.

[0070] Figure 7The blood drug concentration-time curves of rats in Examples 3, 14, 25 and 26 from day 1 to day 28 are shown.

[0071] Figure 8 Shown is the 28-day plasma concentration-time curve of pomalidomide in situ gel formulation in cynomolgus monkeys.

[0072] Fig. 9 Shown are changes in tumor volume after administration of the in situ gel formulation of pomalidomide.

[0073] Fig.10 Shown are the changes in body weight of tumor-bearing mice after administration of the in situ gel formulation of pomalidomide. DETAILED DESCRIPTION

[0074] After long-term and in-depth research, the inventor unexpectedly found that a long-acting sustained-release delivery system of pomalidomide composed of a flowable composition and an active ingredient effectively solves the burst release problem of the sustained-release delivery system, and the long-acting sustained-release delivery system has good safety and low toxicity, wherein the active ingredient is pomalidomide, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and the flowable composition includes a biodegradable polymer and a biocompatible polar non-protonated organic solvent. Based on the above findings, the inventor has completed the present invention.

[0075] the term

[0076] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0077] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamate, pyroglutamate, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginate, ascorbate, salicylates, 4-aminosalicylates, naphthalene disulfonates, and the like. These salts may be prepared by methods known in the art.

[0078] "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. The salt derived from organic base includes but is not limited to the following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the profession.

[0079] As used herein, the term "hydrate" refers to a complex in which pomalidomide or a pharmaceutically acceptable salt thereof is coordinated with water molecules to form a specific ratio.

[0080] As used herein, the term "weight average molecular weight" refers to the average mass of all molecules in a polymer.

[0081] The PLGH described in the present invention is a carboxyl-terminated lactide-glycolide copolymer, which comprises a lactide-glycolide copolymer with a carboxyl terminal.

[0082] The PLGA described in the present invention is a lactide-glycolide copolymer.

[0083] The NMP described in the present invention is N-methylpyrrolidone.

[0084] The DMSO described in the present invention is dimethyl sulfoxide.

[0085] The Triacetin or TC described in the present invention is triacetin.

[0086] The Triethyl citrate or TEC described in the present invention is triethyl citrate.

[0087] The medium chain triglycerides or MCT described in the present invention are medium chain triglycerides.

[0088] Pomalidomide long-acting sustained-release delivery system and its preparation

[0089] Common long-acting preparations are generally PLGA-based preparations (microspheres, in situ gels, solid implants) and nanocrystal and micron crystal technologies, of which more than 50% of long-acting injections on the market are based on PLGA microspheres. However, during our research, we found that due to the special solubility properties of pomalidomide (poorly soluble in dichloromethane, benzyl alcohol, and water), it is difficult to develop it using the conventional water-in-oil (O / W) emulsification preparation process. Although pomalidomide microspheres can be prepared using the oil-in-solid (S / O) method, their drug loading is low (8w / w%) and have a high burst release (50w / w%).

[0090] Surprisingly, the ATRIGEL in situ gel technology used in this study not only developed a sustained-release reservoir with a high encapsulation rate (100% W / W), which allows the drug to be released for 1 month or more, but also the burst release of the gel can be controlled within 4%; at the same time, the pomalidomide long-acting gel preparation has better efficacy and safety, and its anti-tumor effect is significantly better than oral pomalidomide and lenalidomide.

[0091] The preparation of the present invention adopts in situ gelation technology. Specifically, the preparation comprises:

[0092] Active ingredient, wherein the active ingredient is pomalidomide, or a pharmaceutically acceptable salt or hydrate thereof;

[0093] A flowable composition, wherein the flowable composition comprises a biodegradable polymer and a biocompatible polar non-protonated organic solvent;

[0094] Wherein, the biodegradable polymer is a polymer selected from the following groups (a), (b), (c) or (d):

[0095] (a) polylactide, polyglycolide, polylactic acid, polycaprolactone, or a combination thereof;

[0096] (b) binary or ternary polymers of the following polymers: polylactide, polyglycolide, polylactic acid, polycaprolactone;

[0097] (c) a combination of the copolymers described in (b) above;

[0098] (d) a combination of the polymer described in (a) and the copolymer described in (b);

[0099] The "binary polymer" or "ternary polymer" refers to a block polymer or a random polymer formed by two or three polymers in the group. Preferably, the biodegradable polymer is a lactide-glycolide copolymer.

[0100] The in situ gel preparation prepared by the present invention has fluidity at room temperature, so it can be administered by a syringe. In a preferred embodiment of the present invention, the intrinsic viscosity of the biodegradable polymer is 0.12-0.42 dl / g, preferably 0.15-0.38 dl / g, more preferably 0.17-0.36 dl / g, more preferably 0.17-0.30 dl / g, and most preferably 0.18-0.26 dl / g. When the flowable composition is injected into the body, the preparation undergoes a phase transition to form a solid or gel implant.

[0101] In the present invention, a sustained-release delivery system is provided by in situ gel technology, and the delivery system comprises a flowable composition and an active ingredient. The flowable composition comprises a biodegradable polymer and a biocompatible polar non-protonated organic solvent, the active ingredient is pomalidomide or a pharmaceutically acceptable salt thereof, an analogue or a derivative thereof, and the biodegradable polymer can be a single polymer or a binary copolymer or a ternary copolymer, or a combination thereof, wherein the binary copolymer or the ternary copolymer can be a linear polymer molecule, or a star-shaped molecule with multiple branches branched by a polyol polyester. The flowable composition can be phase-transformed into a solid reservoir by contact with water, body fluid or other aqueous media.

[0102] In a preferred embodiment of the present invention, the biodegradable polymer accounts for 10-90% of the total mass of the flowable composition, preferably 20-70%, more preferably 30-60%, most preferably 30-50%.

[0103] In a preferred embodiment of the present invention, the active ingredient accounts for 2%-50% of the total mass of the pomalidomide long-acting sustained-release delivery system (i.e., the drug loading of the long-acting sustained-release delivery system), preferably 4%-30%, more preferably 8%-20%, and most preferably 12%-18%.

[0104] In a preferred embodiment of the present invention, the biodegradable polymer accounts for 10-50% of the total mass of the pomalidomide long-acting sustained-release delivery system, preferably 20-50%, more preferably 25-46%.

[0105] In a preferred embodiment, the molar ratio of lactide to glycolide in the copolymer is 50:50-85:15, preferably 50:50, 65:35, 75:25 or 85:15, and more preferably 50:50 or 75:25.

[0106] In another preferred embodiment, the weight average molecular weight of the lactide-glycolide copolymer is 8000Da to 45000Da, preferably 10000Da to 40000Da.

[0107] In another preferred example, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is 50:50-75:25, and the intrinsic viscosity of the lactide-glycolide copolymer is 0.07-0.36 dl / g.

[0108] In addition to the biodegradable polymer, the flowable composition also includes a biocompatible polar non-protonated organic solvent. In a preferred embodiment, the organic solvent is selected from the following group: N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin, triacetin, triethyl citrate, medium chain triglycerides, or a combination thereof; preferably, the biocompatible polar non-protonated organic solvent is N-methyl-2-pyrrolidone or dimethyl sulfoxide; more preferably, the biocompatible polar non-protonated organic solvent is N-methyl-2-pyrrolidone.

[0109] In another preferred embodiment, the biocompatible polar non-protonated organic solvent accounts for 10%-90% of the total mass of the flowable phase composition, preferably 30%-80%, and more preferably 40%-70%.

[0110] In a preferred embodiment of the present invention, the mass ratio of the flowable composition to the active ingredient is 1:(0.001-0.70), preferably 1:(0.005-0.50), and more preferably 1:(0.01-0.45).

[0111] In another preferred embodiment, the average dynamic viscosity of the long-acting sustained-release delivery system is 0.1-50000 cP, preferably 10-45000 cP, more preferably 30-43000 cP, and most preferably 300-30000 cP.

[0112] The inventors found that the long-acting gel preparation of pomalidomide has higher safety than the oral pomalidomide preparation. max The level is lower than that of oral pomalidomide, and the blood concentration of the drug in 1 to 28 days has no drug peak and valley effect, and can be stably maintained at a therapeutically effective dose, which is conducive to eliminating the C max and causing adverse reactions.

[0113] The present invention provides a sustained-release delivery system, which can deliver pomalidomide or its pharmaceutically acceptable salt or hydrate thereof, its analogs (lenalidomide or its pharmaceutically acceptable salt or hydrate thereof, thalidomide or its pharmaceutically acceptable salt or hydrate thereof) or derivatives (iberdomide or its pharmaceutically acceptable salt or hydrate thereof), and maintain treatment for a period of 14 days to 6 months. The sustained-release delivery system includes a flowable gel composition or solid implant for sustained release of pomalidomide, pomalidomide analogs or pomalidomide derivatives, or pharmaceutically acceptable salts or hydrates of the above compounds. The sustained-release delivery system provides a release curve of 1 month to 6 months, which is characterized by a small burst of drug release, a stable blood drug concentration, and better efficacy and safety.

[0114] The applicant has also found in the research that when the biodegradable polymer is PLA, the pomalidomide in the pomalidomide sustained-release delivery system prepared therefrom can continuously release pomalidomide for 3 to 6 months.

[0115] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually carried out under normal conditions or under the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0116] The lactide / glycolide copolymer used in each example is carboxyl-terminated PLGA (ie, PLGH).

[0117] The “drug loading” in the examples refers to the total weight of the active ingredient in the pomalidomide long-acting sustained-release delivery system.

[0118] Example 1

[0119] Accurately weigh 240 mg of pomalidomide (POM) powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (50:50, intrinsic viscosity InV 0.17 dl / g), add 750 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0120] Example 2

[0121] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (50:50, InV 0.25 dl / g), add 750 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0122] Example 3

[0123] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (50:50, InV 0.20 dl / g), add 750 mg of DMSO and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0124] Example 4

[0125] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (50:50, InV 0.36 dl / g), add 750 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0126] Example 5

[0127] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 300 mg of PLGA (50:50, InV 0.20 dl / g) and 300 mg of PLGA (50:50, InV 0.36 dl / g), add 750 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, which is transferred to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0128] Example 6

[0129] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (65:35, InV 0.37 dl / g), add 750 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0130] Example 7

[0131] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (75:25, InV 0.17 dl / g), add 750 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0132] Example 8

[0133] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (75:25, InV 0.38 dl / g), add 750 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0134] Example 9

[0135] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (75:25, InV 0.38 dl / g), add 750 mg of NMP and 50 mg of PEG2000, stir and dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0136] Example 10

[0137] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 430 mg of PLGA (50:50, InV 0.24 dl / g), add 1145 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0138] Embodiment 11

[0139] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 650 mg of PLGA (50:50, InV 0.20 dl / g), add 2000 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0140] Example 12

[0141] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 750 mg of PLGA (50:50, InV 0.20 dl / g), add 2000 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0142] Embodiment 13

[0143] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 500 mg of PLGA (50:50, InV 0.20 dl / g), add 1335 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0144] Embodiment 14

[0145] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (50:50, InV 0.20 dl / g), add 750 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0146] Embodiment 15

[0147] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 335 mg of PLGA (50:50, InV 0.20 dl / g), add 1000 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0148] Example 16

[0149] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 335 mg of PLGA (50:50, InV 0.20 dl / g), add 835 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0150] Embodiment 17

[0151] Accurately weigh 125 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 750 mg of PLGA (75:25, InV 0.19 dl / g), add 2000 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0152] Embodiment 18

[0153] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 750 mg of PLGA (75:25, InV 0.19 dl / g), add 2000 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0154] Embodiment 19

[0155] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 400 mg of PLGA (75:25, InV 0.19 dl / g), add 2000 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0156] Embodiment 20

[0157] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 400 mg of PLGA (75:25, InV 0.19 dl / g) and 82.5 mg of poloxamer P188, add 2000 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, which is transferred to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0158] Embodiment 21

[0159] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 500 mg of PLGA (75:25, InV 0.19 dl / g), add 665 mg of NMP and 665 mg of triacetin, stir and dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0160] Embodiment 22

[0161] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 750 mg of PLGA (75:25, InV 0.19 dl / g), add 1000 mg of NMP and 1000 mg of triacetin, stir and dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0162] Embodiment 23

[0163] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 750 mg of PLGA (75:25, InV 0.19 dl / g), add 1880 mg of NMP and 120 mg of triacetin, stir and dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0164] Embodiment 24

[0165] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 750 mg of PLGA (75:25, InV 0.19 dl / g), add 1720 mg of NMP and 300 mg of triethyl citrate, stir and dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0166] Embodiment 25

[0167] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (75:25, InV 0.19 dl / g), add 750 mg of NMP and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0168] Embodiment 26

[0169] Accurately weigh 240 mg of pomalidomide powder and transfer it to syringe A; accurately weigh 600 mg of PLGA (75:25, InV 0.19 dl / g), add 750 mg DMSO and stir to dissolve to obtain a clear and transparent gel solution, and transfer it to syringe B; connect syringes A and B with a PEEK adapter, and push the two syringes back and forth for more than 90 times to obtain a uniformly mixed gel.

[0170] Experimental Example 1 Relationship between blood concentration and average dynamic viscosity of pomalidomide gel preparation

[0171] The average dynamic viscosity of the samples prepared in the embodiment was measured at 25°C using a Brookfield viscometer. The specific method is as follows: open the thermostat, set the temperature to 25°C and maintain it for 20 minutes, remove the viscometer sample tank, accurately measure 4.2 ml of the sample solution, select a No. 16 rotor, adjust the speed so that the torque is between 25% and 80%, measure each sample twice in parallel, and the average value of the dynamic viscosity is shown in Table 1.

[0172] The average blood drug concentration of the sample prepared in the example was detected in rats at 3 hours. The specific method was as follows: SD male rats (n=3) with a body weight of 234-302 g were selected. The dosage of the pomalidomide gel preparation was 24 mg / rat. The administration method was subcutaneous injection. Blood was collected from the tail vein 3 hours after administration. After the plasma sample was pretreated, the concentration of pomalidomide was determined by LC-MS / MS. The results are shown in Table 1. The relationship between the 3-hour blood drug concentration and the average dynamic viscosity of the pomalidomide gel preparation is shown in Table 1. Figure 1 shown.

[0173] Table 1. Average dynamic viscosity of pomalidomide gel preparations and 3h blood concentration in rats

[0174]

[0175]

[0176] From the above results, it can be seen that when the average dynamic viscosity of pomalidomide gel preparation is in the range of 10 cP to 1000 cP, its average dynamic viscosity and 3h blood drug concentration are negatively correlated, that is, the larger the average dynamic viscosity, the smaller the burst release of the drug (the more gradual the change in blood drug concentration);

[0177] When the average dynamic viscosity of the pomalidomide gel preparation is between 1000 cP and 100000 cP, the 3-hour blood drug concentration is maintained within 500 ng / mL, that is, the blood drug concentration will not change with the increase in viscosity.

[0178] Therefore, the present application prefers a preparation with a larger average dynamic viscosity in order to obtain a pharmaceutical composition that overcomes the burst release phenomenon.

[0179] Experimental Example 2 Pharmacokinetic (PK) study of pomalidomide in situ gel preparation in rats for 1 to 28 days

[0180] SD male rats (n=3) were selected to investigate the in vivo pharmacokinetic behavior. The rats weighed 234-302 g. The dosage of pomalidomide gel preparation was 24 mg / rat. The administration method was subcutaneous injection. Blood was collected from the tail vein at predetermined time points (1, 7, 14, 21, 28 days). After pretreatment, the plasma samples were used to determine the concentration of pomalidomide by LC-MS / MS. The results are shown in Table 2.

[0181] Table 2 Pomalidomide gel preparation in rat blood concentration (Examples 1-26)

[0182]

[0183]

[0184]

[0185] 2.1 Effects of different PLGA on drug release

[0186] Examples (1, 2, 4, 5, 6, 7, 8, 9, 25) are intended to investigate the effect of different lactide:glycolide ratios in PLGA on drug release under the same formulation ratio.

[0187] Among them, the blood drug concentration-time curves of Examples 1, 2, 4, and 5 (the ratio of lactide: glycolide is 50:50) are as follows: Figure 2 As shown, the blood drug concentration-time curves of Examples 6, 7, 8, 9, and 25 (the ratio of lactide: glycolide is greater than 50:50) are as follows Figure 3 shown.

[0188] The experimental results show that different types of PLGA have a great influence on the stability of drug release. When the ratio of lactide: glycolide is 50:50 or the ratio of lactide: glycolide is greater than 50:50, a long-term stable release effect can be achieved.

[0189] 2.2 Effects of different formulation ratios on drug release

[0190] 2.2.1 Prescription ratio 1: lactide: glycolide = 50:50, InV 0.20

[0191] Examples (11-16) are intended to investigate the effects of different formulation ratios on drug release in the same PLGA (50:50, InV 0.20).

[0192] Among them, the drug loading of Examples (11-16) is 8-17w / w%, and the blood drug concentration-time curve is as follows Figure 4 shown.

[0193] The experimental results show that when the drug loading is 8-17w / w%, the blood drug concentration in rats can achieve a long-term stable release effect.

[0194] Especially when the drug loading is ≥15w / w%, the release of the preparation is smooth, and relatively high blood drug concentrations can be obtained on the 7th and 14th days, with good bioavailability.

[0195] Therefore, the present invention preferably has a drug loading of ≥15w / w%.

[0196] 2.2.2 Prescription ratio 2: lactide: glycolide = 75:25, InV 0.19

[0197] Examples (17, 18, 19) are intended to investigate the effects of different formulation ratios on drug release in the same PLGA (75:25, InV 0.19). The drug loading in Examples (17, 18, 19) is 4-9 w / w%, and the blood drug concentration-time curve is shown in FIG. Figure 5 shown.

[0198] The experimental results show that when the drug loading is 4-9w / w%, the blood drug concentration in rats can achieve a long-term stable release effect.

[0199] 2.3 Effect of plasticizers on drug release

[0200] Examples (20-24) are intended to investigate the effects of different plasticizers (poloxamer P188, triacetin, triethyl citrate) and their formulation ratios on drug release in the same PLGA (75:25, InV 0.19). The blood drug concentration-time curves of Examples (20-24) are shown in FIG. Figure 6 shown.

[0201] The experimental results of Examples (21 to 23) show that the addition of triacetin can reduce the burst release on the first day to a certain extent, and the experimental results of Examples (20 and 24) show that triethyl citrate and poloxamer P188 cannot reduce the burst release. However, according to the principle of the minimum number of types of injection excipients, no additional plasticizer is added in the preferred embodiment of the present invention.

[0202] 2.4 Effects of different solvents on drug release

[0203] Examples (3, 14, 25, 26) are intended to investigate the effects of different solvents (NMP, DMSO) on blood drug concentration in rats under the same PLGA (50:50, InV 0.20 or 75:25, InV 0.19) and the same formulation ratio. Among them, the blood drug concentration-time curves of Examples (20-24) are shown in Figure 7 shown.

[0204] The experimental results showed that compared with DMSO, NMP had a higher blood concentration from 1 to 28 days, especially in the PLGA (50:50, InV 0.20) formulation, where the difference in blood concentration between the two was more significant, indicating that using NMP as a solvent is more conducive to improving the bioavailability of the formulation.

[0205] Therefore, the present invention preferably uses NMP as the solvent.

[0206] Experimental Example 3 Pharmacokinetic (PK) and toxicological study of pomalidomide in situ gel preparation in monkeys for 1 to 28 days

[0207] The gel formulation (POM_ISI) of Example 14 was used to conduct an in vivo PK study in cynomolgus monkeys. The specific scheme is as follows: male eluted cynomolgus monkeys weighing about 4 kg were selected for the group experiment, and the administration method was a single, subcutaneous injection, the dosage was 24 mg / monkey, and the administration cycle was 30 days (equivalent to 0.2 mg / kg / day). Blood was collected from the vein at predetermined time points (1h, 3h, 6h, 12h, 1d, 2d, 3d, 7d, 14d, 21d, 28d). After the plasma samples were pretreated, the concentration of pomalidomide was determined by LC-MS / MS. The PK parameters are shown in Table 3; the blood drug concentration-time curve is shown in Table 3. Figure 8 shown.

[0208] Among them, the PK data of pomalidomide (CC-4047) in cynomolgus monkeys published by the FDA were used for comparative study. Oral pomalidomide (POM_ORAL) was administered continuously for 28 days at a dose of 0.2 mg / kg. The PK parameters on day 1 (day 1) and day 28 (day 28) are shown in Table 3.

[0209] Table 3 PK parameters of pomalidomide gel preparation and oral preparation

[0210]

[0211] The experimental results show that at a dosage of 0.2 mg / kg / day, the C max (50.3 ng / mL) is much lower than the C of commercially available oral pomalidomide. max(79-113 ng / mL), and the 24-hour burst rate of the long-acting gel preparation of the present invention is only 3.96%, indicating that the long-acting preparation of pomalidomide has higher safety.

[0212] In addition, oral pomalidomide has a serious accumulation phenomenon. At a dose of 0.2 mg / kg / day, the AUC on day 28 is 0～24 (2258hr*ng / mL) is 11.6 times that of day 1 (195hr*ng / mL), and C max It also increased by 1.4 times, so there is a risk of increased toxicity in the later treatment process. This is why the original product POMALYST needs to be discontinued for 7 days after continuous medication for 21 days, and the medication can only be continued after the body clears the excess drugs. However, the blood drug release of the pomalidomide long-acting gel preparation of the present invention is stable and safer. Continuous medication for 30 days will not cause serious accumulation, so there is no need to stop the medication, avoiding the problem of decreased efficacy caused by discontinuation of medication.

[0213] In addition, the oral preparation has a peak-valley effect in blood drug concentration, resulting in a significant fluctuation in blood drug concentration (0-113 ng / mL, SD=58.0); while the long-acting gel preparation of the present invention does not have a peak-valley effect in blood drug concentration within 1-28 days, and its blood drug fluctuation is relatively small (10-30 ng / mL, SD=5.4), indicating that the preparation of the present invention can achieve a long-term and stable release effect, with higher efficacy and better safety.

[0214] Experimental Example 4: Study on the anti-tumor efficacy (PD) of pomalidomide in situ gel preparation in mice

[0215] This study aimed to investigate the anti-tumor efficacy of pomalidomide in situ gel preparation (ISI), and used oral pomalidomide (POM), lenalidomide (LEN) and oral new molecule drug iberdomide (CC-220, IBER) which is currently in clinical trials as comparisons.

[0216] The specific experimental plan is as follows: 6-8 weeks old NOD-SCID female mice weighing about 19-23g were used for subcutaneous tumor transplantation modeling. The model cells were selected from the NCI-H929 tumor cell line. The tumor volume was selected to be 100mm 3 Model mice were enrolled in the experiment, with 5 mice in each group.

[0217] This experiment used the gel formulation of Example 14 for research. The administration method of the gel preparation was a single subcutaneous injection of 6.3 mg / mouse (equivalent to 10 mg / kg per day for 30 days); the oral administration methods of pomalidomide, lenalidomide and iberdrolin were all once a day (PO / QD), and the dosages were 10 mg / kg, 25 mg / kg and 10 mg / kg respectively. After administration, the tumor volume and body weight changes were detected twice a week. The results are as follows: Fig. 9 and 10 shown.

[0218] Surprisingly, the therapeutic effect of the pomalidomide in situ gel of the present invention is significant, far superior to the same dose of oral pomalidomide and a higher dose of oral lenalidomide; even more gratifying is that, with 30 days as the treatment endpoint, the anti-tumor efficacy of the long-acting pomalidomide in situ gel preparation is consistent with that of the new molecule iberdomide, and in experiments at the cellular level, the anti-tumor activity of the iberdomide molecule is 20 times higher than that of pomalidomide.

[0219] This result indicates that the in situ gel long-acting preparation of the present invention significantly enhances the anti-tumor effect of pomalidomide and achieves very significant benefits in anti-tumor efficacy.

[0220] Test Example 5 Toxicological study of pomalidomide in situ gel preparation in monkeys

[0221] This experiment uses the gel prescription (POM_ISI) of Example 14 to carry out safety studies in cynomolgus monkeys. The experimental method is as follows: male eluted cynomolgus monkeys weighing about 4 kg are selected for group entry experiments. The administration method is a single, subcutaneous injection, the dosage is 72 mg / monkey, and the administration cycle is 30 days (equivalent to 0.6 mg / kg / day); and oral pomalidomide (0.6 mg / kg / day, OP / QD) is used as a control group. Within the specified time after administration, the activity level and mental state of the eluted cynomolgus monkeys are observed; and blood is collected from the animals within the specified time to examine the blood indicators of all animals. The results are shown in Table 4. The blood indicators include:

[0222] A. Hematological test indicators: WBC, NEUT, LYMP, MONO, EOS, BASO, RBC, HGB, HCT, MCV, MCH, MCHC, RDW, PLT, MPV, PCT, PDW;

[0223] B. Blood biochemical test indicators: ALT, AST, ALP, CK, TBIL, GLU, UREA, CREA, TG, CHOL, TP, ALB, GLOB, A / G, GGT, Na, Ca, K, Cl, P, CRP;

[0224] C. Blood coagulation test indicators: PT, APTT, TT, FIB.

[0225] Table 4 Blood parameters of pomalidomide gel preparation and oral preparation

[0226]

[0227]

[0228] Domestic multicenter phase II clinical trials have shown that common adverse reactions in patients with relapsed and refractory MM treated with pomalidomide are leukopenia (86%), neutropenia (86%), thrombocytopenia (78%), anemia (68%), lymphopenia (50%), hyperglycemia (46%), pneumonia (28%), etc.; common grade 3-4 adverse reactions are neutropenia (64%), leukopenia (38%), anemia (31%), thrombocytopenia (28%), pneumonia (27%). Among them, long-term use of pomalidomide will significantly increase the frequency of asymptomatic and asymptomatic neutropenia. In addition, adverse reactions such as bone marrow suppression, infection, rash, neuropathy, and thromboembolism may also occur.

[0229] The toxicological experiment results of the present application show that in the oral pomalidomide group (POM_ORAL), four indicators were abnormal due to drug toxicity, namely: white blood cells (WBC), neutrophils (NEUT), monocytes (MONO), C-reactive protein (CRP) and coagulation factor I (FIB).

[0230] The above abnormal data are consistent with the adverse reactions of pomalidomide during clinical treatment, and the maximum abnormal deviation % (+increase↑, -decrease↓) of blood indicators at each time point (3rd, 7th, 28th day) compared with day 0 are: WBC (-62.71%↓), NEUT (-75.41%↓), CRP (93.39%↑), FIB (345.44%↑); however, there are no abnormal blood indicators in the pomalidomide gel preparation group (POM_ISI), and all blood indicators are within the reference range. This evidence strongly proves that pomalidomide in situ gel has higher safety.

[0231] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A pomalidomide long-acting sustained-release delivery system, characterized in that: A composition comprising an active ingredient and a flowable; Wherein, the active ingredient is pomalidomide or a pharmaceutically acceptable salt thereof; The flowable composition includes: a biodegradable polymer, and a biocompatible polar non-protonated organic solvent; Wherein, the biodegradable polymer is a lactide-glycolide copolymer; in the lactide-glycolide copolymer, the molar ratio of lactide to glycolide is 50:50 to 75:25; The intrinsic viscosity of the biodegradable polymer is 0.17-0.30 dl / g; The biocompatible polar non-protonated organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone, dimethyl sulfoxide, or a combination thereof.

2. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: The intrinsic viscosity of the biodegradable polymer is 0.18-0.26 dl / g.

3. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: The biodegradable polymer accounts for 10%-50% of the total mass of the pomalidomide long-acting sustained-release delivery system; and / or The active ingredient accounts for 2%-50% of the total weight of the pomalidomide long-acting sustained-release delivery system.

4. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: The biodegradable polymer accounts for 20-50% of the total mass of the pomalidomide long-acting sustained-release delivery system; and / or The active ingredient accounts for 4%-30% of the total weight of the pomalidomide long-acting sustained-release delivery system.

5. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: The biodegradable polymer accounts for 25-46% of the total mass of the pomalidomide long-acting sustained-release delivery system; and / or The active ingredient accounts for 8%-20% of the total weight of the pomalidomide long-acting sustained-release delivery system.

6. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: The biodegradable polymer accounts for 25-46% of the total mass of the pomalidomide long-acting sustained-release delivery system; and / or The active ingredient accounts for 12%-18% of the total weight of the pomalidomide long-acting sustained-release delivery system.

7. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: In the lactide-glycolide copolymer, the molar ratio of lactide to glycolide is 50:50, 65:35 or 75:

25.

8. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: In the lactide-glycolide copolymer, the molar ratio of lactide to glycolide is 50:50 or 75:

25.

9. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: The biocompatible polar non-protonated organic solvent is N-methyl-2-pyrrolidone.

10. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: The mass ratio of the flowable composition to the active ingredient is 1:(0.001-0.70).

11. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: The mass ratio of the flowable composition to the active ingredient is 1:(0.005-0.50).

12. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: The mass ratio of the flowable composition to the active ingredient is 1:(0.01-0.45).

13. The pomalidomide long-acting sustained-release delivery system according to claim 1, characterized in that: The average dynamic viscosity of the long-acting sustained-release delivery system is 300-30000 cP.

14. A pomalidomide drug combination product, characterized in that: The combination product comprises: Pomalidomide or a pharmaceutically acceptable salt thereof placed in a first container; A flowable composition placed in a second container, comprising a biodegradable polymer and a biocompatible polar non-protonated organic solvent; wherein the biodegradable polymer is a lactide-glycolide copolymer; and in the lactide-glycolide copolymer, the molar ratio of lactide to glycolide is 50:50 to 75:25; The intrinsic viscosity of the biodegradable polymer is 0.17-0.30 dl / g; The biocompatible polar non-protonated organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone, dimethyl sulfoxide, or a combination thereof.

15. A pomalidomide sustained-release in-situ gel for injection, characterized in that: A pomalidomide long-acting sustained-release delivery system comprising any one of claims 1 to 13, or a pomalidomide drug combination product according to claim 14.

16. Use of the pomalidomide long-acting sustained-release delivery system according to any one of claims 1 to 13, or the pomalidomide drug combination product according to claim 14, or the pomalidomide sustained-release in-situ gel for injection according to claim 15 in the preparation of a drug for treating multiple myeloma.

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