Baricitinib sustained-release gel preparation

Abstract

The invention provides a baricitinib in-situ sustained-release gel preparation. The baricitinib in-situ sustained-release gel preparation comprises an active component, a gel carrier, an organic solvent and other optional pharmaceutically acceptable auxiliary materials. The in-situ sustained-release gel preparation disclosed by the invention can realize long-term stable release, reduce the administration frequency, reduce the treatment risk caused by blood concentration fluctuation, reduce the toxic and side effects and improve the medication compliance of patients; the local concentration of the medicine is improved, and the bioavailability is improved, so that the medicine effect is better played, and the application value is high.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a baricitinib sustained-release gel preparation. Background Art

[0002] Baricitinib is a selective JAK1 and JAK2 inhibitor, which has a strong inhibitory effect on JAK1 and JAK2. The currently marketed dosage form is tablets, which are mainly used for moderate to severe active rheumatoid arthritis in adults and severe adult alopecia areata. Rheumatoid arthritis (RA) is a common chronic, systemic autoimmune disease, characterized by chronic synovitis and cartilage destruction. Patients often have persistent joint pain, swelling, and stiffness. In severe cases, it can cause cardiovascular, pulmonary, and bone complications. RA is recurrent and difficult to cure, and the treatment cycle is long. The treatment cycle of patients using baricitinib is generally 12 weeks, and 2 mg is taken orally daily. The effective relief of symptoms depends to a certain extent on the patient's adherence to medication. Alopecia areata is the most common type of hair loss after androgenic alopecia. It has a significant impact on external image, social interaction, and mental stress, and is often accompanied by symptoms such as reduced quality of life and sleep, generalized anxiety disorder, and severe depression. After taking 2 mg of baricitinib orally daily for up to one year, 22.6% of patients achieved significant scalp hair regrowth, with 67.5% of patients achieving 90% or greater hair coverage.

[0003] For the above two diseases that require long-term medication, whether patients can adhere to medication for a long time is a major challenge to the development of the disease; patients forgetting to take or missing medication has a significant adverse effect on the control of the disease. At present, there are no reports on the in situ sustained-release gel preparation of baricitinib, and it still needs to be studied. Summary of the invention

[0004] The present invention aims to solve the technical problems existing in the prior art at least to a certain extent. To this end, the present invention proposes an in situ sustained-release gel preparation and a preparation method thereof, and a method for using and preventing or treating alopecia areata or rheumatoid arthritis. The in situ sustained-release gel preparation of the present invention is clear and has flowability, can achieve long-term stable release, reduce the frequency of administration, reduce the treatment risk caused by fluctuations in blood drug concentration, reduce toxic and side effects, improve patients' medication compliance, increase local drug concentration, and improve bioavailability, so as to better exert the efficacy of the drug, and has high application value.

[0005] In one aspect of the present invention, the present invention provides an in situ sustained-release gel formulation. According to an embodiment of the present invention, the in situ sustained-release gel formulation comprises: an active ingredient, the active ingredient comprises baricitinib and / or a pharmaceutically acceptable salt thereof; and a gel carrier, the gel carrier comprises: at least one biodegradable polymer; an organic solvent; and optionally other pharmaceutically acceptable excipients.

[0006] Biodegradable polymers have good biocompatibility and biodegradability. The in situ sustained-release gel preparations made by embedding baricitinib and / or its pharmaceutically acceptable salts can achieve long-term stable release, reduce the frequency of administration, reduce the treatment risks caused by fluctuations in blood drug concentrations, reduce toxic side effects, improve patients' medication compliance, increase local drug concentrations, and improve bioavailability, so as to better exert the efficacy of the drug, and have high application value.

[0007] According to an embodiment of the present invention, the above-mentioned in situ sustained-release gel preparation may also have the following additional technical features:

[0008] According to an embodiment of the present invention, based on the total weight of the in situ sustained-release gel preparation, the content of the active ingredient is 5-20wt%, the content of the gel carrier is 20-50wt%, the content of the organic solvent is 35-65wt%, and the content of the excipient is 0-40wt%.

[0009] According to an embodiment of the present invention, the biodegradable polymer is selected from polyester or polyester copolymer.

[0010] According to an embodiment of the present invention, the biodegradable polymer is selected from polylactide or lactide-glycolide copolymer, preferably lactide-glycolide copolymer.

[0011] According to an embodiment of the present invention, the lactide-glycolide copolymer has a carboxyl terminal or an ester terminal.

[0012] According to an embodiment of the present invention, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is 30:70 to 95:5.

[0013] According to an embodiment of the present invention, the viscosity of the biodegradable polymer is 0.1-0.7 dl / g.

[0014] According to an embodiment of the present invention, the weight ratio of the biodegradable polymer to the organic solvent is 20:80 to 50:50.

[0015] According to an embodiment of the present invention, the organic solvent is selected from N-methyl-2-pyrrolidone and / or dimethyl sulfoxide.

[0016] According to an embodiment of the present invention, the other pharmaceutically acceptable excipients are selected from at least one of the following: benzyl benzoate, triacetin, poloxamer, carbomer, glycerol, ethyl acetate, benzyl alcohol, ethanol and Tween 80.

[0017] According to an embodiment of the present invention, the viscosity of the in situ sustained-release gel preparation is 0.05-20 Pa·s.

[0018] According to an embodiment of the present invention, the dosage form of the in situ sustained-release gel preparation is an injection.

[0019] In another aspect of the present invention, the present invention proposes a method for preparing the aforementioned in situ sustained-release gel preparation. According to an embodiment of the present invention, the method comprises: mixing the active ingredient, gel carrier, organic solvent and other optional pharmaceutically acceptable excipients to obtain the in situ sustained-release gel preparation. Thus, the in situ sustained-release gel preparation prepared according to the method of the present invention can achieve long-term stable release, reduce the frequency of administration, reduce the treatment risk caused by fluctuations in blood drug concentration, reduce toxic and side effects, improve patients' medication compliance, increase local drug concentration, and improve bioavailability, so as to better exert the efficacy of the drug, and has high application value. In addition, the preparation method of the present invention is simple to operate, highly efficient, and low in cost, and is suitable for large-scale production.

[0020] According to an embodiment of the present invention, the method comprises: dissolving the active ingredient in the organic solvent to obtain a drug solution; and mixing the gel carrier, the drug solution and optionally other pharmaceutically acceptable excipients to obtain the gel preparation.

[0021] According to an embodiment of the present invention, the concentration of the active ingredient in the drug solution is not less than 15 wt %.

[0022] According to an embodiment of the present invention, the mixing temperature is room temperature.

[0023] In another aspect of the present invention, the present invention proposes the use of the above-mentioned in situ sustained-release gel preparation or the above-mentioned in situ sustained-release gel preparation prepared by the method in the preparation of medicine. According to an embodiment of the present invention, the medicine is used to prevent or treat alopecia areata or rheumatoid arthritis. Thus, the medicine of the present invention can achieve long-term stable release, reduce the frequency of administration, reduce the treatment risk caused by fluctuations in blood drug concentration, reduce toxic and side effects, improve patients' medication compliance, increase local drug concentration, and improve bioavailability, so as to better exert the efficacy, and has high application value.

[0024] In another aspect of the present invention, the present invention provides a method for preventing or treating alopecia areata or rheumatoid arthritis. According to an embodiment of the present invention, the method comprises: administering the above-mentioned in situ sustained-release gel preparation or the in situ sustained-release gel preparation prepared by the above-mentioned method to a subject. Thus, the method of the present invention can achieve long-term stable release, reduce the frequency of administration, reduce the treatment risk caused by fluctuations in blood drug concentration, reduce toxic and side effects, improve patients' medication compliance, increase local drug concentration, and improve bioavailability, so as to better exert the efficacy of the drug, and has high application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0026] Figure 1 The in vitro release curve of the corresponding preparation in Example 1;

[0027] Figure 2 The in vitro release curve of the corresponding preparation prescription of Example 2;

[0028] Figure 3 The gelation phenomenon of the baricitinib gel prepared in Example 3 after being added to the release medium;

[0029] Figure 4 The in vitro release curve of the corresponding preparation prescription of Example 3;

[0030] Figure 5 The in vitro release curve of the corresponding preparation prescription of Example 4;

[0031] Figure 6 The baricitinib gel solution prepared in Example 5 and Example 6;

[0032] Figure 7 is the in vitro release curve of the corresponding preparation prescription of Example 5;

[0033] Figure 8 is the in vitro release curve of the corresponding preparation prescription of Example 6;

[0034] Fig. 9 The baricitinib gel solution prepared in Example 7;

[0035] Fig.10 The in vitro release curve of the corresponding preparation prescription of Example 7;

[0036] Fig.11 This is the in vitro release curve of the corresponding formulation of Example 8. DETAILED DESCRIPTION

[0037] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0038] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0039] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0040] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0041] NMP represents N-methyl-2-pyrrolidone; DMSO represents dimethyl sulfoxide; PLGA represents poly(lactide-co-glycolide), specifically poly(lactic acid-co-glycolic acid); API represents baricitinib raw material; dl / g represents intrinsic viscosity; Pa·s represents dynamic viscosity.

[0042] The present invention provides an in-situ sustained-release gel preparation and a preparation method, application and method for preventing or treating alopecia areata or rheumatoid arthritis, which will be described in detail below.

[0043] In situ sustained release gel preparation

[0044] In one aspect of the present invention, the present invention provides an in situ sustained-release gel formulation. According to an embodiment of the present invention, the in situ sustained-release gel formulation comprises: an active ingredient, the active ingredient comprises baricitinib and / or a pharmaceutically acceptable salt thereof; and a gel carrier, the gel carrier comprises: at least one biodegradable polymer; an organic solvent; and optionally other pharmaceutically acceptable excipients.

[0045] Biodegradable polymers have good biocompatibility and biodegradability. By embedding baricitinib and / or its pharmaceutically acceptable salts into in situ sustained-release gel preparations, long-term stable release can be achieved, the frequency of administration can be reduced, the treatment risks caused by fluctuations in blood drug concentrations can be reduced, toxic side effects can be reduced, patient compliance with medication can be improved, local drug concentrations can be increased, and bioavailability can be improved so as to better exert the efficacy of the drug, which has high application value.

[0046] In this article, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammals treated therewith. Preferably, the "pharmaceutically acceptable" of the present invention refers to the use in animals, especially humans, approved by the national government or listed in the Chinese Pharmacopoeia or other generally recognized pharmacopoeias.

[0047] As used herein, the term "pharmaceutically acceptable salt" refers to both organic and inorganic salts of baricitinib of the present invention.

[0048] According to an embodiment of the present invention, the other pharmaceutically acceptable excipients are selected from at least one of the following: benzyl benzoate, triacetin, poloxamer, carbomer, glycerol, ethyl acetate, benzyl alcohol, ethanol and Tween 80.

[0049] According to an embodiment of the present invention, based on the total weight of the in-situ sustained-release gel preparation, the content of the active ingredient is 5-20wt%. In some embodiments, the content of the active ingredient is 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%, 16wt%, 17wt%, 18wt%, 19wt%, 20wt% or any two of them as the range value between the endpoint values, for example, 8wt% to 20wt%. Thus, the drug effect can be better exerted.

[0050] According to an embodiment of the present invention, based on the total weight of the in-situ sustained-release gel preparation, the content of the gel carrier is 20-50wt%. In some embodiments, the content of the gel carrier is 20wt%, 21wt%, 22wt%, 23wt%, 24wt%, 25wt%, 26wt%, 27wt%, 28wt%, 29wt%, 30wt%, 31wt%, 32wt%, 33wt%, 34wt%, 35wt%, 36wt%, 37wt%, 38wt%, 39wt%, 40wt%, 41wt%, 42wt%, 43wt%, 44wt%, 45wt%, 46wt%, 47wt%, 48wt%, 49wt%, 50wt% or any two of them as the range value between the endpoint values, for example 30-45wt%, 35-40wt%. In this way, the sustained-release effect can be better exerted, which can not only realize the long-term release of active ingredients, but also achieve a better local drug concentration and better exert the drug efficacy.

[0051] According to an embodiment of the present invention, based on the total weight of the in-situ sustained-release gel preparation, the content of the organic solvent is 35-65wt%. In some embodiments, the content of the organic solvent is 35wt%, 36wt%, 37wt%, 38wt%, 39wt%, 40wt%, 41wt%, 42wt%, 43wt%, 44wt%, 45wt%, 46wt%, 47wt%, 48wt%, 49wt%, 50wt%, 51wt%, 52wt%, 53wt%, 54wt%, 55wt%, 56wt%, 57wt%, 58wt%, 59wt%, 60wt%, 61wt%, 62wt%, 63wt%, 64wt%, 65wt% or any two of them as the range value between the endpoint values, for example, 40-65wt%. Thus, the in-situ sustained-release gel preparation has strong stability, can be long-term stable sustained release, and better exerts the drug effect.

[0052] According to an embodiment of the present invention, based on the total weight of the in-situ sustained-release gel preparation, the excipient content is 0-40wt%. In certain embodiments, the excipient content is 0wt%, 2wt%, 5wt%, 8wt%, 10wt%, 12wt%, 15wt%, 18wt%, 20wt%, 22wt%, 25wt%, 28wt%, 30wt%, 32wt%, 35wt%, 38wt%, 40wt% or any two of them as the range value between the endpoint values. Thus, the in-situ sustained-release gel preparation has strong stability, can be long-term stable sustained release, and better play the drug effect.

[0053] According to an embodiment of the present invention, the biodegradable polymer is selected from polyester or polyester copolymer.

[0054] According to an embodiment of the present invention, the biodegradable polymer is selected from polylactide or lactide-glycolide copolymer, preferably lactide-glycolide copolymer.

[0055] In this article, "poly(lactide-glycolide)" is referred to as "PLGA", which is a high molecular copolymer formed by the polymerization of two monomers, lactide (LA) and glycolide (GA), under the action of a catalyst. It can be degraded into lactic acid, water and carbon dioxide in the body.

[0056] According to an embodiment of the present invention, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is 30:70 to 95:5. In some embodiments, the molar ratio of lactide to glycolide in the lactide-glycolide copolymer is 30:70, 40:60, 50:50, 60:40, 70:30, 75:25, 80:20, 90:10, 95:5 or any two of them as the range value between the endpoint values. Thus, the in-situ sustained-release gel preparation has strong stability, is not prone to crystallization, and can be stably sustained-released for a long time.

[0057] According to an embodiment of the present invention, the viscosity of the biodegradable polymer is 0.1 to 0.7 dl / g. In some embodiments, the viscosity of the biodegradable polymer is 0.1 dl / g, 0.2 dl / g, 0.3 dl / g, 0.4 dl / g, 0.5 dl / g, 0.6 dl / g, 0.7 dl / g, or a range between any two of them as endpoint values, preferably 0.2 to 0.6 dl / g. Thus, the in situ sustained-release gel preparation has strong stability, is not prone to crystallization, and can be stably sustained-released for a long time.

[0058] According to an embodiment of the present invention, the weight ratio of the biodegradable polymer to the organic solvent is 20:80 to 50:50. In some embodiments, the weight ratio of the biodegradable polymer to the organic solvent is 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50 or a range value between any two of them as endpoint values, preferably 20:80 to 38:62, more preferably 25:75 to 50:50. Thus, the in situ sustained-release gel preparation has strong stability, is not prone to crystallization, and can be stably sustained-released for a long time.

[0059] According to an embodiment of the present invention, the organic solvent is selected from N-methyl-2-pyrrolidone and / or dimethyl sulfoxide. Thus, the in-situ sustained-release gel preparation has strong stability, is not prone to crystallization, and can achieve long-term stable sustained release.

[0060] According to an embodiment of the present invention, the viscosity of the in situ sustained-release gel preparation is 0.05 to 20 Pa·s. In some embodiments, the viscosity of the in situ sustained-release gel preparation is 0.05 Pa·s, 0.1 Pa·s, 1 Pa·s, 5 Pa·s, 10 Pa·s, 15 Pa·s, 20 Pa·s, or a range value between any two of them as endpoint values. Thus, the needle-passing property is good and the injection difficulty is low.

[0061] According to an embodiment of the present invention, the dosage form of the in situ sustained-release gel preparation is an injection.

[0062] Method for preparing gel formulation

[0063] In another aspect of the present invention, the present invention proposes a method for preparing the aforementioned in situ sustained-release gel preparation. According to an embodiment of the present invention, the method comprises: mixing the active ingredient, gel carrier, organic solvent and other optional pharmaceutically acceptable excipients to obtain the in situ sustained-release gel preparation. Thus, the in situ sustained-release gel preparation prepared according to the method of the present invention can achieve long-term stable release, reduce the frequency of administration, reduce the treatment risk caused by fluctuations in blood drug concentration, reduce toxic and side effects, improve patients' medication compliance, increase local drug concentration, and improve bioavailability, so as to better exert the efficacy of the drug, and has high application value. In addition, the preparation method of the present invention is simple to operate, highly efficient, and low in cost, and is suitable for large-scale production.

[0064] According to an embodiment of the present invention, the method comprises: dissolving the active ingredient in the organic solvent to obtain a drug solution; and mixing the gel carrier, the drug solution and other optional pharmaceutically acceptable excipients to obtain the gel preparation. Thus, a uniform gel preparation can be better formed by stepwise addition and dissolution.

[0065] According to an embodiment of the present invention, the concentration of the active ingredient in the drug solution is not less than 15wt%. In some embodiments, the concentration of the active ingredient in the drug solution is 15wt%, 18wt%, 20wt%, 25wt% or 30wt% or a range value between any two of them as endpoint values. Thus, the sustained release effect is better.

[0066] It should be noted that the features and advantages described above for the in situ sustained-release gel preparation are also applicable to this method and will not be described in detail here.

[0067] application

[0068] In another aspect of the present invention, the present invention proposes the use of the above-mentioned in situ sustained-release gel preparation or the above-mentioned in situ sustained-release gel preparation prepared by the method in the preparation of medicine. According to an embodiment of the present invention, the medicine is used to prevent or treat alopecia areata or rheumatoid arthritis. Thus, the medicine of the present invention can achieve long-term stable release, reduce the frequency of administration, reduce the treatment risk caused by fluctuations in blood drug concentration, reduce toxic and side effects, improve patients' medication compliance, increase local drug concentration, and improve bioavailability, so as to better exert the efficacy, and has high application value.

[0069] As used herein, the term "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or may be therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, such as blocking the progression of the disease; or (c) alleviating the disease, such as alleviating symptoms associated with the disease. "Treatment" as used herein covers any medication that administers a drug to an individual to treat, cure, alleviate, improve, mitigate or inhibit an individual's disease, including but not limited to administering a drug described herein to an individual in need.

[0070] It should be noted that the features and advantages described above for the in situ sustained-release gel preparation are also applicable to this application and will not be described in detail here.

[0071] Method for preventing or treating alopecia areata or rheumatoid arthritis

[0072] In another aspect of the present invention, the present invention provides a method for preventing or treating alopecia areata or rheumatoid arthritis. According to an embodiment of the present invention, the method comprises: administering the above-mentioned in situ sustained-release gel preparation or the in situ sustained-release gel preparation prepared by the above-mentioned method to a subject. Thus, the method of the present invention can achieve long-term stable release of drugs, reduce the frequency of administration, reduce the treatment risk caused by fluctuations in blood drug concentration, reduce toxic and side effects, improve patients' medication compliance, increase local drug concentration, and improve bioavailability, so as to better exert the efficacy of the drug, and has high application value.

[0073] The term "subject" refers to any animal being examined, studied or treated, and it is not intended that the present invention be limited to any particular type of subject. In some embodiments of the present invention, humans are preferred subjects, while in other embodiments, non-human animals are preferred subjects, including but not limited to mice, monkeys, ferrets, cattle, sheep, goats, pigs, chickens, turkeys, dogs, cats, horses, and reptiles.

[0074] It should be noted that the features and advantages described above for the in situ sustained-release gel preparation are also applicable to this method and will not be described in detail here.

[0075] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0076] Experimental methods

[0077] (1) Preparation of in situ gel

[0078] Accurately weigh the prescribed amount of the drug, add it to a quantitative organic solvent, stir and dissolve it at room temperature to obtain a clear and transparent drug solution. Then add the prescribed amount of polymer and other optional pharmaceutically acceptable excipients to the drug solution, stir and dissolve them, and the product is obtained.

[0079] (2) Viscosity measurement of in situ gel

[0080] The viscosity of baricitinib gel was measured using a Thermo Fisher TYP003-7370 rheometer at a frequency of 5 Hz and a measurement temperature of 25°C.

[0081] (3) In vitro release assay of in situ gel

[0082] The in vitro release of baricitinib gel was investigated by direct addition of samples using the USP-Ⅱ method, and the release medium was a pH 7.4 buffer system. Samples were taken at predetermined time points and detected using a Thermo Fisher U3000 liquid chromatograph HPLC, with a C18 column, a pH 6.5 phosphate buffer-acetonitrile (70:30) mobile phase, and a detection wavelength of 220 nm.

[0083] Release calculation formula:

[0084]

[0085] Example 1: Investigation of polymer terminal groups

[0086] (1) Prescription composition

[0087] In the table, the viscosity of PLGA is 0.20 dl / g, the molar ratio of lactide to glycolide is 50:50, and the organic solvent is NMP.

[0088] Table 1 Prescription composition

[0089] prescription API dosage (g) PLGA dosage (g) Terminal Group Amount of organic solvent (g) Prescription 1 12 30.4 Carboxyl terminal 37.6 Prescription 2 12 30.4 Ester terminal 37.6

[0090] (2) Viscosity measurement

[0091] Table 2 Viscosity

[0092]

[0093]

[0094] (3) In vitro release study

[0095] Table 3 In vitro release

[0096]

[0097] The gel prepared by prescription 1-2 was clear and transparent, without drug crystal precipitation. The viscosity test results showed that the gel prepared by prescription 1-2 had low viscosity, good needle permeability, and low injection difficulty. Figure 1 As shown, when the polymer terminal group is an ester group, the release amount of the gel in the early stage is slightly higher than that of the carboxyl terminal, but the subsequent release behavior of the gel under each formulation is basically the same.

[0098] Example 2: Investigation of the molar ratio of lactide to glycolide in lactide-glycolide copolymers

[0099] (1) Prescription composition

[0100] In the table, the viscosity of PLGA is 0.20 dl / g, the terminal group is carboxyl, and the organic solvent is NMP.

[0101] Table 4 Prescription

[0102]

[0103] (2) In vitro release study

[0104] Table 5 In vitro release

[0105]

[0106] The gels prepared by Prescription 1 and Prescription 3 were clear and transparent, without precipitation of drug crystals. Figure 2 As shown, it is shown that the gel with a molar ratio of lactide to glycolide of 50:50 and 75:25 in the polymer has better burst release and sustained release effects.

[0107] Example 3: Investigation of polymer viscosity

[0108] (1) Prescription composition

[0109] In the table, the molar ratio of lactide to glycolide in the PLGA copolymer is 50:50, the terminal group is carboxyl, and the organic solvent is NMP.

[0110] Table 6 Prescription

[0111] prescription API dosage (g) PLGA dosage (g) Viscosity Amount of organic solvent (g) Prescription 4 12 12.5 0.20dl / g 37.6 Prescription 5 12 12.5 0.51dl / g 37.6

[0112] (2) In vitro release study

[0113] Table 7 In vitro release

[0114]

[0115] The gel prepared by prescription 4-5 was clear and transparent, without drug crystal precipitation. The gelation phenomenon after adding to the release medium was as follows: Figure 3 As shown in the figure (prescription 4 on the left and prescription 5 on the right), the gel solidifies from a flowing liquid into a white or off-white solid irregular spherical gel drug reservoir. Figure 4 As shown, the results show that as the polymer viscosity increases, it is beneficial to reduce the burst release of baricitinib gel in 1 hour, but has little effect on the subsequent release behavior.

[0116] Example 4: Investigation of the weight ratio of polymer to organic solvent

[0117] (1) Prescription composition

[0118] In the table, the viscosity of PLGA is 0.20 dl / g, the molar ratio of lactide to glycolide is 75:25, the terminal group is carboxyl, and the organic solvent is NMP.

[0119] Table 8 Prescription

[0120]

[0121]

[0122] (2) Viscosity measurement results

[0123] Table 9 Viscosity

[0124] Viscosity Viscosity Pa·s Prescription 6 2.03 Prescription 7 1.45 Prescription 8 0.56 Prescription 9 0.32 Prescription 10 0.20

[0125] (3) In vitro release study results

[0126] Table 10 In vitro release

[0127]

[0128] The results showed that the gels prepared by prescriptions 6-10 were clear and transparent, with no drug crystals precipitated. The viscosity measurement results showed that as the proportion of organic solvent increased, the viscosity of the in-situ gel decreased. The gel viscosity under each formulation was relatively low, with good needle permeability and low injection difficulty.

[0129] In vitro release results Figure 5As shown, the results showed that with the increase of organic solvent ratio, the in situ gel burst release and 1d release increased, but the subsequent release behavior under each formulation was basically the same.

[0130] Example 5 Investigation of preparing gel by mixing various polymers

[0131] (1) Prescription composition

[0132] In the table, the organic solvent is NMP, and two PLGAs with different composition ratios or viscosities are mixed.

[0133] Table 11 Prescription

[0134]

[0135]

[0136] (2) Viscosity measurement

[0137] Table 12 Viscosity

[0138] prescription Viscosity Pa·s Prescription 11 4.17 Prescription 12 3.89 Prescription 13 4.00 Prescription 14 3.08 Prescription 15 3.85

[0139] (3) In vitro release assay

[0140] Table 13 In vitro release

[0141]

[0142] The results are as follows Figure 6 As shown in the figure, the gels prepared by formula 11-15 (sample numbers 1-5 on the bottle) are clear and transparent, with no drug crystals precipitated. The viscosity measurement results show that the prepared gels have low viscosity, good needle permeability, and low injection difficulty. The in vitro release results are shown in the figure. Figure 7 As shown, the results showed that the release behaviors of baricitinib gels prepared from formulations 11-15 were basically the same.

[0143] Example 6: Dosage Study

[0144] (1) Prescription composition

[0145] In the table, the viscosity of PLGA is 0.20 dl / g, the molar ratio of lactide to glycolide is 50:50, the terminal group is carboxyl, and the organic solvent is NMP.

[0146] Table 14 Prescription

[0147] prescription API dosage (g) PLGA dosage (g) Amount of organic solvent (g) Prescription 16 12 30.4 37.6 Prescription 17 15 30.4 37.6

[0148] (2) Gel state

[0149] Table 15 Gel state

[0150] prescription Gel state Prescription 16 Clear solution Prescription 17 Clear solution

[0151] (3) Viscosity measurement

[0152] Table 16 Viscosity

[0153] prescription Viscosity Pa·s Prescription 16 4.17 Prescription 17 5.36

[0154] (4) In vitro release assay

[0155] Table 17 In vitro release

[0156]

[0157] The results are as follows Figure 6 As shown, the results of prescriptions 16-17 (sample numbers 6-7 on the bottle) showed that when the dosage was increased to 15 g, the resulting gel solution remained clear and transparent, and no drug crystals were precipitated. Figure 8 As shown, the results show that the in vitro release behaviors of the gels prepared by prescriptions 16-17 are basically the same, which indicates that the gel release effect is good within this prescription range.

[0158] Example 7: Investigation of organic solvents

[0159] (1) Prescription composition

[0160] In the table, the viscosity of PLGA is 0.20 dl / g, the molar ratio of lactide to glycolide is 50:50, and the terminal group is carboxyl.

[0161] Table 18 Prescription

[0162]

[0163] (2) Gel state

[0164] Table 19 Gel state

[0165] prescription Gel state Prescription 18 Clear solution Prescription 19 Clear solution Prescription 20 Drug crystallization Prescription 21 Drug crystallization Prescription 22 Clear solution

[0166] (2) In vitro release assay

[0167] Table 20 In vitro release

[0168]

[0169]

[0170] The results are as follows Fig. 9 As shown in the figure (sample number 8 corresponds to prescription 20, sample number 9 corresponds to prescription 21), baricitinib has low solubility and only has good solubility in DMSO and NMP. When 1 / 10 ethanol or benzyl alcohol is mixed into the organic solvent, the drug is easy to crystallize, which is not conducive to the stability of the preparation. Fig.10As shown, the results show that when the organic solvent is DMSO or a small amount of DMSO is mixed into the NMP solution, the burst release amount of the prepared in situ gel at 1 h is slightly reduced compared to when the organic solvent is NMP, but it has no significant effect on the sustained release behavior of the in situ gel.

[0171] Example 8: Investigation of release modifiers

[0172] (1) Prescription composition

[0173] In the table, the viscosity of PLGA is 0.20 dl / g, the molar ratio of lactide to glycolide is 50:50, the terminal group is carboxyl, and the organic solvent is NMP.

[0174] Table 21 Prescription

[0175] prescription API dosage (g) PLGA dosage (g) Amount of organic solvent (g) Release modifier dosage (g) Prescription 23 12 30.4 37.6 / Prescription 24 12 30.4 37.6 Poloxamer 3.76 Prescription 25 12 30.4 37.6 Glycerol 3.76

[0176] (2) Viscosity measurement

[0177] Table 22 Viscosity

[0178] prescription Viscosity Pa·s Prescription 23 4.17 Prescription 24 14.33 Prescription 25 4.63

[0179] (3) In vitro release assay

[0180] Table 23 In vitro release

[0181]

[0182]

[0183] The results showed that the gels prepared by prescriptions 23-25 ​​were clear and transparent, with no drug crystals precipitated. The viscosity measurement results showed that the addition of poloxamer to baricitinib gel increased the viscosity of the gel matrix, but overall the gel viscosity was relatively low under each prescription, and the fluidity was good. Fig.11 As shown in the figure, the results show that although the addition of poloxamer significantly increases the viscosity of the gel, it does not significantly reduce the release amount of the gel. The addition of glycerol slightly reduces the burst release of baricitinib gel at 1 hour.

[0184] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. An in situ sustained-release gel preparation, characterized in that: include: An active ingredient, the active ingredient comprising baricitinib and / or a pharmaceutically acceptable salt thereof; as well as A gel carrier, the gel carrier comprising: at least one biodegradable polymer; Organic solvents; and / or, Other pharmaceutically acceptable excipients.

2. The in situ sustained-release gel preparation according to claim 1, characterized in that: Based on the total weight of the in situ sustained-release gel preparation, the content of the active ingredient is 5-20wt%, the content of the gel carrier is 20-50wt%, the content of the organic solvent is 35-65wt%, and the content of the auxiliary material is 0-40wt%.

3. The in situ sustained-release gel preparation according to claim 1, characterized in that: The biodegradable polymer is selected from polyester or polyester copolymer; The biodegradable polymer has a viscosity of 0.1 to 0.7 dl / g; The weight ratio of the biodegradable polymer to the organic solvent is 20:80 to 50:50; The biodegradable polymer is selected from polylactide or lactide-glycolide copolymer, preferably lactide-glycolide copolymer; The lactide-glycolide copolymer has a carboxyl terminal or an ester terminal; The molar ratio of lactide to glycolide in the lactide-glycolide copolymer is 30:70 to 95:5; The other pharmaceutically acceptable excipients are selected from at least one of the following: benzyl benzoate, triacetin, poloxamer, carbomer, glycerol, ethyl acetate, benzyl alcohol, ethanol and Tween 80.

4. The in situ sustained-release gel preparation according to claim 1, characterized in that: The organic solvent is selected from N-methyl-2-pyrrolidone and dimethyl sulfoxide.

5. The in situ sustained-release gel preparation according to claim 1, characterized in that: The other pharmaceutically acceptable excipients are selected from at least one of the following: benzyl benzoate, triacetin, poloxamer, carbomer, glycerol, ethyl acetate, benzyl alcohol, ethanol and Tween 80.

6. The in situ sustained-release gel preparation according to claim 1, characterized in that: The viscosity of the in-situ sustained-release gel preparation is 0.05-20 Pa·s.

7. A method for preparing the in situ sustained-release gel preparation according to any one of claims 1 to 6, characterized in that: The active ingredient, gel carrier, organic solvent and other optional pharmaceutically acceptable excipients are mixed to obtain the in situ sustained-release gel preparation.

8. The method according to claim 7, characterized in that include: dissolving the active ingredient in the organic solvent to obtain a drug solution; The gel carrier, the drug solution and other optional pharmaceutically acceptable excipients are mixed to obtain the in situ sustained-release gel preparation.

9. The method according to claim 8, characterized in that The concentration of the active ingredient in the drug solution is not less than 15 wt %.

10. Use of the in situ sustained-release gel preparation according to any one of claims 1 to 6 or the in situ sustained-release gel preparation prepared by the method according to any one of claims 7 to 9 in the preparation of a medicament for preventing or treating alopecia areata or rheumatoid arthritis.

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