Dexamethasone polymeric micelle and preparation method thereof

Abstract

The invention discloses a dexamethasone preparation and a preparation method thereof. The preparation comprises dexamethasone polymeric micelles, polyamino acid copolymers, and hydrophilic excipients. By screening the types and dosages of polyamino acid copolymers and hydrophilic excipients, the dexamethasone micelle preparation prepared by the invention effectively reduces the dosage of other excipients, has a more uniform particle size, significantly improves the drug loading and stability of the product, and has good uniformity of preparation content.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and in particular relates to dexamethasone polymerized micelles, and also provides a preparation method of the micelles. Background Art

[0002] Dexamethasone is a glucocorticoid with a wide range of clinical applications. It can be used for allergic and autoimmune inflammatory diseases, including connective tissue diseases, severe bronchial asthma, dermatitis and other allergic diseases, ulcerative colitis, acute leukemia, malignant lymphoma, etc.

[0003] Dexamethasone has poor solubility and is almost insoluble in water, chloroform, ether, and acetone. It is also sensitive to temperature and humidity and is easily hydrolyzed in high temperature and high humidity environments. Long-term storage will cause discoloration of the drug solution and excessive impurities, which will reduce the quality of the drug, increase toxic side effects, and pose a hidden danger to the safe use of the drug.

[0004] In recent years, polymeric micelles have become ideal carriers for poorly soluble drugs due to their small particle size, high solubility, and controllable drug release. However, in practical applications, the use of polymeric micelles as drug carriers has not achieved better results in drug experiments. There are still defects such as poor targeting, insufficient stability, and harsh production conditions, which greatly limit the application of polymeric micelles in dexamethasone preparations.

[0005] Based on this, developing a new dexamethasone preparation with larger drug loading, higher stability and better efficacy to meet clinical use is an urgent problem to be solved. Summary of the invention

[0006] The present invention aims at the deficiencies of the prior art and provides a novel dexamethasone preparation, in particular to a dexamethasone polymer micelle. The prepared dexamethasone nano micelle effectively increases the drug loading amount, and the obtained product has higher stability and better efficacy.

[0007] One of the purposes of the present invention is to provide a dexamethasone polymer micelle, wherein the micelle comprises dexamethasone, a polyamino acid copolymer and a hydrophilic excipient.

[0008] The present invention also provides the distribution ratio of each component of the dexamethasone polymer micelle, wherein the polyamino acid copolymer: hydrophilic excipient = 1-0.8:1.88.

[0009] Furthermore, the hydrophilic excipient in the dexamethasone polymer micelle is a water-soluble polyol.

[0010] Preferably, the polyol is one of propylene glycol, ethylene glycol and propylene alcohol. To ensure better effect, the polyol is propylene glycol.

[0011] The present invention also provides a method for preparing the polyamino acid copolymer, which specifically comprises: mixing serine, methionine and bis(trichloromethyl)carbonate respectively, adding tetrahydrofuran, and separating in excess cyclohexanone after the reaction is complete to obtain L-serine-N-internal carboxylic acid anhydride and L-methionine-N-internal carboxylic acid anhydride respectively; adding toluene to the above compounds to remove water by azeotropic azeotropy, adding anhydrous N,N-dimethylformamide containing dimethylaminopyridine, heating and stirring until the reaction is completed, washing with cyclohexanone, filtering, and freeze-drying to obtain the poly(L-methionine:L-serine) copolymer.

[0012] Furthermore, the weight parts of each component are:

[0013]

[0014] Preferably, the weight parts of each component are:

[0015]

[0016] Further preferably, the weight parts of each component are:

[0017]

[0018] The second object of the present invention is to provide a method for preparing the dexamethasone polymer micelles, comprising the following steps:

[0019] (1) dissolving dexamethasone in an appropriate amount of an organic solvent to obtain an oil phase;

[0020] (2) adding the polyamino acid copolymer and the hydrophilic auxiliary material into deionized water, adjusting the pH to 4.5-5.5, and stirring to obtain an aqueous phase;

[0021] (3) Under stirring, the aqueous phase in step (2) is added to the oil phase in step (1), and the organic solvent is removed by stirring. The resulting solution is filtered through a 0.22 μm filter membrane to obtain a dexamethasone polymer micelle solution.

[0022] The organic solvent in step (1) is one or more of acetone, methanol, ethanol, dioxane and chloroform. Preferably, the solvent is a mixture of acetone and dioxane.

[0023] In one embodiment, the method for removing ethanol in step (3) of the method for preparing dexamethasone polymer micelles is vigorous stirring at a temperature of 40 to 60° C. The stirring speed is higher than 10,000 r / min, and the stirring time is longer than 30 min.

[0024] In another embodiment, the method for removing ethanol in step (3) of the method for preparing dexamethasone polymer micelles is vacuum rotary evaporation at a controlled temperature of 40 to 60°C.

[0025] The third object of the present invention is to provide the use of the dexamethasone polymer micelles in pharmaceutical preparations. The dexamethasone polymer micelles prepared by the present invention can be further prepared into pharmaceutically acceptable dosage forms, preferably tablets, capsules, and lyophilized powder injections, by conventional preparation methods.

[0026] A fourth object of the present invention is to provide a new use of the dexamethasone polymer micelles, specifically the use of the micelles in drugs for treating and / or preventing allergic and autoimmune inflammatory diseases.

[0027] The beneficial effects of the present invention are:

[0028] (1) The present invention effectively reduces the amount of other excipients used and increases the drug loading of the product by optimizing the polymer materials and proportions. The prepared micelles have a higher encapsulation rate, a more uniform particle size, and a higher stability.

[0029] (2) The preparation method provided by the present invention is simple and easy to operate, and is suitable for industrial promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Example 1 Dexamethasone copolymer micelle formulation design diagram

[0031] Figure 2 Example 1 Particle size distribution of dexamethasone copolymer micelles

[0032] Figure 3 Particle size distribution of dexamethasone copolymer micelles in comparative example 2

[0033] Figure 4 Particle size distribution of dexamethasone copolymer micelles in comparative example 3

[0034] Figure 5 The drug loading and encapsulation efficiency results of dexamethasone copolymer micelles in each group (A1 is the result of Example 1; A2 is the result of Example 2; A3 is the result of Example 3; A4 is the result of Example 4; C1 is the result of Comparative Example 1; C2 is the result of Comparative Example 2; C3 is the result of Comparative Example 3.)

[0035] Figure 6 The drug loading and encapsulation efficiency results of dexamethasone copolymer micelles in each group (A1 is the result of Example 1; A2 is the result of Example 2; A3 is the result of Example 3; A4 is the result of Example 4; C1 is the result of Comparative Example 1; C2 is the result of Comparative Example 3; C3 is the result of Comparative Example 4.) DETAILED DESCRIPTION

[0036] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0037] The materials used in the embodiments of the present invention are all of pharmaceutical grade and are conventionally commercially available.

[0038] 1. Preparation of poly(L-methionine:L-serine):

[0039] Equal amounts of serine, methionine and bis(trichloromethyl)carbonate are mixed in a ratio of 1:3, 1 volume of tetrahydrofuran is added, and the mixture is heated to 60°C until the reaction is complete, and separated in excess cyclohexanone to obtain L-serine-N-internal carboxylic acid anhydride and L-methionine-N-internal carboxylic acid anhydride, respectively; 2 times the amount of toluene is added to the above compounds for azeotropic dehydration, and anhydrous N,N-dimethylformamide containing 5% dimethylaminopyridine is added according to 2 times the molar amount of the original serine, and the mixture is heated to 60°C with stirring until the reaction is completed, and the mixture is washed with excess cyclohexanone, filtered, and freeze-dried at -15°C to obtain a poly(L-methionine:L-serine) copolymer.

[0040] 2. The following are preparation examples and comparative examples of dexamethasone polymeric micelles and preparations.

[0041] Example 1 Preparation of dexamethasone polymeric micelles

[0042] Formula:

[0043] Components content Dexamethasone 10 servings Poly(L-methionine:L-serine) 85 copies Propylene glycol 100 copies water Moderate

[0044] Preparation process:

[0045] (1) dissolving dexamethasone in a proper amount of a mixed solvent of acetone and dioxane to obtain an oil phase;

[0046] (2) adding the polyamino acid copolymer and the hydrophilic auxiliary material into deionized water, adjusting the pH to 4.5-5.5, and stirring to obtain an aqueous phase;

[0047] (3) Add the aqueous phase in step (2) to the oil phase in step (1) under stirring, vigorously stir at a temperature of 40 to 60° C., at a stirring speed of more than 10,000 r / min, stir for 5 h to remove the organic solvent, and filter the resulting solution through a 0.22 μm filter membrane to obtain a dexamethasone polymer micelle solution.

[0048] Example 2 Preparation of dexamethasone polymeric micelles

[0049] Formula:

[0050] Components content Dexamethasone 10 servings Poly(L-methionine:L-serine) 80 servings Propylene glycol 120 servings water Moderate

[0051] The preparation process is the same as that of Example 1.

[0052] Example 3 Preparation of dexamethasone polymeric micelles

[0053] Formula:

[0054]

[0055]

[0056] The preparation process is the same as that of Example 1.

[0057] Example 4 Preparation of Dexamethasone Polymeric Micelle

[0058] Formula:

[0059] Components content Dexamethasone 10 servings Poly(L-methionine:L-serine) 120 servings Propylene glycol 110 copies water Moderate

[0060] The preparation process is the same as that of Example 1.

[0061] Example 5 Preparation of Dexamethasone Polymeric Micelle

[0062] Formula:

[0063] Components content Dexamethasone 10 servings Poly(L-methionine:L-serine) 80 servings Propylene glycol 80 servings water Moderate

[0064] The preparation process is the same as that of Example 1.

[0065] Example 6 Preparation of Dexamethasone Polymeric Micelle

[0066] Preparation of dexamethasone-containing polymeric micelle tablets: The dexamethasone micelles prepared in Example 1 were prepared into tablets according to conventional methods.

[0067] Comparative Example 1

[0068] Formula:

[0069]

[0070]

[0071] The preparation process is the same as that of Example 1.

[0072] Comparative Example 2

[0073] Formula:

[0074] Components content Dexamethasone 10 servings Poly(L-methionine:L-serine) 100 copies Propylene glycol 20 servings water Moderate

[0075] The preparation process is the same as that of Example 1.

[0076] Comparative Example 3

[0077] Formula:

[0078] Components content Dexamethasone 10 servings Poly(Glycine:L-Serine) 85 copies Propylene glycol 100 copies water Moderate

[0079] Preparation of poly(glycine:L-serine): Equal amounts of glycine, L-serine and bis(trichloromethyl) carbonate were mixed in a ratio of 1:3, 1 volume of tetrahydrofuran was added, and the mixture was heated to 60°C until the reaction was complete, and separated in excess cyclohexanone to obtain L-serine-N-internal carboxylic acid anhydride and glycine-N-internal carboxylic acid anhydride, respectively; 2 times the amount of toluene was added to the above compound for azeotropic dehydration, and anhydrous N,N-dimethylformamide containing 5% dimethylaminopyridine was added according to 2 times the molar amount of the original serine, and the mixture was heated to 60°C with stirring until the reaction was completed, and the mixture was washed with excess cyclohexanone, filtered, and freeze-dried at -15°C to obtain a poly(glycine:L-serine) copolymer.

[0080] The micelle preparation process is the same as that in Example 1.

[0081] Comparative Example 4

[0082] Formula:

[0083]

[0084]

[0085] Preparation of poly (L-theanine-DDPC) copolymer: L-theanine and DDPC were mixed evenly, and isopropanol was added to shake at 20-25°C for 5 hours, and dialyzed to obtain a crude product. The crude product was extracted with dichloromethane for 1-3 times, washed, and microfiltered to obtain L-theanine-DDPC copolymer micelles.

[0086] The micelle preparation process is the same as that in Example 1.

[0087] Comparative Example 5 Preparation of Dexamethasone Polymeric Micelle

[0088] Preparation of dexamethasone-containing polymeric micelle tablets: The dexamethasone micelles prepared in Comparative Examples 1, 2, 3, and 4 were prepared into tablets according to conventional methods.

[0089] 3. Determination of relevant parameters

[0090] 1. Particle size detection of dexamethasone polymeric micelles prepared in Example 3, Comparative Example 3 and Comparative Example 4;

[0091] 2. Calculation of drug loading and encapsulation efficiency of dexamethasone polymeric micelles prepared in Examples 3 and 5;

[0092] 3. Tablet content uniformity inspection

[0093] The content uniformity of dexamethasone in the tablets prepared in Example 6 and Comparative Example 6 was checked according to the 0941 content uniformity test method in Part IV of the Chinese Pharmacopoeia (2020 Edition).

[0094] Chromatographic conditions: octadecylsilane bonded silica gel as filler; acetonitrile-water (28:72) as mobile phase; detection wavelength at 240 nm; injection volume 50 μl.

[0095] Take an appropriate amount of the tablets prepared in Example 6 and Comparative Example 6, place them in a mortar, add 2 ml of mobile phase, grind, transfer to a 25 ml volumetric flask with the mobile phase in batches, dissolve the dexamethasone with ultrasound, cool, dilute to scale with the mobile phase, shake well, filter, and take the filtrate as the test solution. Dissolve in methanol and quantitatively dilute to make a solution containing about 50 μg per 1 ml, and inject for detection.

[0096] 4. Investigation of related substances and stability

[0097] Chromatographic conditions: HPLC detection method was adopted, octadecylsilane bonded silica gel was used as filler, acetonitrile-water (28:72) was used as mobile phase, and the detection wavelength was 240 nm.

[0098] Determination of related substances in the embodiments: According to commercial packaging, the temperature is 40±2°C, and the tablets prepared in Example 6 and Comparative Example 6 are placed under a relative humidity of 75%±5% for 6 months. Samples are taken at the 0th month, 1st month, 2nd month, 3rd month, and 6th month during the test period, and dissolved in methanol and quantitatively diluted to prepare a solution containing about 0.5 mg per 1 ml; 20 μl is injected into a liquid chromatograph to calculate the percentage of related substances in each group.

[0099] The results are shown in Table 1.

[0100] Table 1 Stability study data of dexamethasone micellar preparation

[0101]

[0102]

[0103] It can be seen from the data in Table 1 that the preparation obtained by the present invention has a low impurity content and better stability performance in the accelerated experiment. Compared with the comparative experiment, the shelf life of the drug can be significantly improved.

Claims

1. A dexamethasone polymer micelle, characterized in that The weight parts of each component in the micelle are: Dexamethasone 10 parts Poly(L-methionine:L-serine) 85 parts Propylene glycol 100 parts Water Equal amounts of serine, methionine and bis(trichloromethyl) carbonate were mixed in a ratio of 1:3, 1 volume of tetrahydrofuran was added, and the mixture was heated to 60°C until the reaction was complete, and separated in excess cyclohexanone to obtain L-serine-N-internal carboxylic acid anhydride and L-methionine-N-internal carboxylic acid anhydride, respectively; 2 times the amount of toluene was added to the above compounds for azeotropic dehydration, and anhydrous N,N-dimethylformamide containing 5% dimethylaminopyridine was added according to 2 times the molar amount of the original serine, and the mixture was heated to 60°C with stirring until the reaction was completed, and the mixture was washed with excess cyclohexanone, filtered, and freeze-dried at -15°C to obtain a poly(L-methionine:L-serine) copolymer; The preparation method of the micelle comprises the following steps: (1) dissolving dexamethasone in a proper amount of a mixed solvent of acetone and dioxane to obtain an oil phase; (2) adding a polyamino acid copolymer and a hydrophilic auxiliary material into deionized water, adjusting the pH to 4.5-5.5, and stirring to obtain an aqueous phase; (3) adding the aqueous phase in step (2) into the oil phase in step (1) under stirring, vigorously stirring at a temperature of 40-60° C., with a stirring speed of more than 10,000 r / min, stirring for 5 hours to remove the organic solvent, and filtering the obtained solution through a 0.22 μm filter membrane to obtain a dexamethasone polymer micelle solution.

2. The dexamethasone polymer micelle according to claim 1, characterized in that The micelle is further prepared into a pharmaceutically acceptable dosage form selected from tablets, capsules or lyophilized powder injections.

3. The dexamethasone polymer micelle according to claim 1, characterized in that The micelle is used in preparing drugs for treating and / or preventing allergic and autoimmune inflammatory diseases.

Images