Saxagliptin oral preparation and preparation method thereof

Abstract

The invention relates to the technical field of pharmacy, in particular to a saxagliptin oral preparation and a preparation method thereof. The preparation is prepared from the following components in parts by weight: 5 to 15 parts of saxagliptin or salt thereof, 15 to 30 parts of sodium alginate, 10 to 20 parts of chitosan, 10 to 25 parts of polylactic acid-glycolic acid copolymer (PLGA), 5 to 15 parts of polyvinyl alcohol, 3 to 8 parts of N-acetylcysteine, 2 to 6 parts of vitamin E and 1 to 5 parts of sodium lauryl sulfate. According to the present invention, the drug stability is significantly improved, the chitosan and the sodium alginate are subjected to the polyelectrolyte composite reaction to form the stable gel so as to effectively protect the active components of the drug, and the freeze drying treatment ensures the uniform dispersion and the efficient dissolution of the drug, improves the bioavailability, and enables the drug to be rapidly and fully absorbed and utilized; according to the preparation method, the flexibility of the preparation is improved, the preparation can be easily processed into different dosage forms such as tablets and capsules, the requirements of different patients are met, all the components act synergistically, and the medicine performance is jointly improved.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceuticals, in particular to a saxagliptin oral preparation and a preparation method thereof. Background Art

[0002] Although certain progress has been made in the existing saxagliptin formulation technology, there are still some significant shortcomings. First, the lack of drug stability is a problem that needs to be solved urgently. Traditional saxagliptin preparations are easily affected by environmental factors such as temperature and humidity during storage and transportation, resulting in significant changes in the content of the drug's active ingredients, which in turn affects the drug's efficacy and safety. Especially in a high temperature and high humidity environment, the rate of drug degradation is accelerated, which greatly shortens the drug's shelf life, causing inconvenience to patients and increasing medical costs.

[0003] Secondly, the bioavailability of traditional saxagliptin preparations needs to be improved. Bioavailability is an important indicator to measure the degree of drug absorption and utilization by the body, which is directly related to the efficacy of the drug and the treatment effect of the patient. However, existing saxagliptin preparations often take a long time to reach the peak blood drug concentration after administration, and the bioavailability is relatively low, which causes patients to take larger doses to achieve the expected treatment effect, which not only increases the economic burden on patients, but may also cause more adverse reactions.

[0004] Therefore, in view of the deficiencies of existing saxagliptin preparations in terms of stability and bioavailability, a new saxagliptin preparation is developed to improve the stability and bioavailability of the drug, which has important clinical significance and application value. Summary of the invention

[0005] Technical issues solved

[0006] In view of the above-mentioned shortcomings of the prior art, the present invention provides an oral preparation of saxagliptin and a preparation method thereof. The present invention significantly improves the stability of the drug by reasonably combining multiple components such as sodium alginate, chitosan, PLGA, etc. Chitosan and sodium alginate undergo a polyelectrolyte complex reaction to form a stable gel, which effectively protects the active ingredients of the drug. At the same time, freeze-drying treatment ensures uniform dispersion and efficient dissolution of the drug, improves bioavailability, and enables the drug to be absorbed and utilized faster and more fully. In addition, the preparation method also improves the flexibility of the preparation, and is easy to process into different dosage forms, such as tablets and capsules, to meet the needs of different patients. The components work synergistically to jointly improve the performance of the drug.

[0007] Technical Solution

[0008] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0009] On the one hand, a saxagliptin preparation is composed of the following components in parts by weight: 5-15 parts of saxagliptin or its salt, 15-30 parts of sodium alginate, 10-20 parts of chitosan, 10-25 parts of polylactic acid-glycolic acid copolymer (PLGA), 5-15 parts of polyvinyl alcohol, 3-8 parts of N-acetylcysteine, 2-6 parts of vitamin E, and 1-5 parts of sodium lauryl sulfate.

[0010] Further, the chitosan is a low molecular weight chitosan with a deacetylation degree between 80% and 95%;

[0011] PLGA is a biodegradable polymer with a lactic acid to glycolic acid ratio of 75:25-50:50.

[0012] Furthermore, polyvinyl alcohol, as a hydrophilic polymer;

[0013] N-acetylcysteine ​​acts as an antioxidant.

[0014] Furthermore, vitamin E also has an antioxidant effect; sodium lauryl sulfate acts as a surfactant.

[0015] On the other hand, a method for preparing a saxagliptin preparation comprises the following steps:

[0016] S100: dissolving sodium alginate in an appropriate amount of water to prepare a sodium alginate solution with a concentration of 5%-10% (w / v), and dissolving chitosan in a dilute acetic acid solution to prepare a chitosan solution with a concentration of 3%-6% (w / v);

[0017] S200: slowly adding saxagliptin or its salt to the sodium alginate solution under stirring, and continuing stirring until completely dissolved to obtain a drug-sodium alginate mixed solution;

[0018] S300: adding the chitosan solution dropwise into the drug-sodium alginate mixed solution, and adjusting the pH value to between 5.0 and 6.5, so that the sodium alginate and the chitosan undergo a polyelectrolyte complex reaction to form a gel-like substance;

[0019] S400: dissolving PLGA in an organic solvent to prepare a PLGA solution with a concentration of 10%-20% (w / v), adding the solution to the gel-like substance, and stirring and mixing thoroughly;

[0020] S500: Add polyvinyl alcohol to the above mixture, heat to 60-80°C, and continue stirring until the polyvinyl alcohol is completely dissolved to form a uniform dispersion system;

[0021] S600: Dissolve N-acetylcysteine, vitamin E and sodium lauryl sulfate in a small amount of water respectively, add them into the dispersion system in sequence, and continue to stir evenly;

[0022] S700: freeze-drying the obtained mixture at a freezing temperature of -40--20°C, a vacuum degree of 0.1-0.5 mbar, and a drying time of 24-48 hours to obtain a dry saxagliptin preparation powder.

[0023] Furthermore, if the saxagliptin preparation powder prepared in step S700 is to be prepared into a specific dosage form, if it is a tablet, the powder can be added with an appropriate amount of auxiliary materials, mixed evenly and then tableted;

[0024] If it is a capsule, the powder is directly filled into the capsule shell. The pressure during tableting is controlled at 80-120MPa, and the tablet weight difference is within ±5%. When filling the capsule, the filling amount difference is controlled within ±10%.

[0025] Furthermore, before the freeze-drying treatment in step S700, the mixture is filtered using a filter membrane with a pore size of 0.22-0.45 μm to ensure the removal of possible insoluble impurities, and the filtration process is carried out at a constant temperature of 25-30° C. to maintain the stability of the formulation ingredients.

[0026] Furthermore, when adding polyvinyl alcohol in step S500, glycerol accounting for 5%-10% of the weight of polyvinyl alcohol is added as a plasticizer, and high-speed stirring is performed for 30-60 minutes, wherein the rotation speed is 800-1200 rpm to ensure that the plasticizer is fully mixed with the mixture to improve the flexibility of the preparation.

[0027] Furthermore, for the prepared tablets, a mixed solution of hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG) is used for coating treatment, wherein the mass ratio of HPMC to PEG is 3:1-2:1, and the coating weight gain is 3%-5% of the tablet weight. The coating operation is carried out at a temperature of 40-50°C and a relative humidity of 40%-60% to improve the stability and aesthetics of the preparation.

[0028] Furthermore, during the capsule filling process, the capsule shell is pre-treated with plasma treatment technology, with a treatment power of 80-120 W and a treatment time of 10-20 seconds, so that the surface roughness of the capsule shell is reduced to 0.1-0.2 μm to improve its compatibility with the powder.

[0029] Beneficial Effects

[0030] Compared with the known public technology, the technical solution provided by the present invention has the following beneficial effects:

[0031] 1. The present invention reasonably combines multiple components such as sodium alginate, chitosan, polylactic acid-glycolic acid copolymer (PLGA), etc., which produce synergistic effects and jointly improve the stability of the drug. Each component plays a different function in the preparation. Chitosan, as a low molecular weight chitosan with a deacetylation degree between 80% and 95%, undergoes a polyelectrolyte complex reaction with sodium alginate to form a stable gel-like substance, which effectively protects the active ingredients of the drug.

[0032] 2. The present invention ensures uniform dispersion and efficient dissolution of the drug through freeze-drying. This preparation method not only improves the bioavailability of the drug, allowing the drug to be absorbed and utilized faster and more fully in the body, but also improves the flexibility of the preparation, making it easier to process into different dosage forms, such as tablets and capsules, thereby meeting the medication needs of different patients. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] The present invention will be further described below in conjunction with the embodiments.

[0035] 1. Preparation composition:

[0036] The saxagliptin preparation of the present invention is composed of the following components in parts by weight: 5-15 parts of saxagliptin or its salt, 15-30 parts of sodium alginate, 10-20 parts of chitosan, 10-25 parts of polylactic acid-glycolic acid copolymer (PLGA), 5-15 parts of polyvinyl alcohol, 3-8 parts of N-acetylcysteine, 2-6 parts of vitamin E and 1-5 parts of sodium lauryl sulfate.

[0037] (1) Characteristics of each component

[0038] Chitosan: low molecular weight chitosan with a deacetylation degree between 80% and 95% is used.

[0039] PLGA: It is a biodegradable polymer with a ratio of lactic acid to glycolic acid of 75:25-50:50.

[0040] Polyvinyl alcohol: as a hydrophilic polymer.

[0041] N-Acetylcysteine: acts as an antioxidant.

[0042] Vitamin E: has antioxidant effect.

[0043] Sodium Lauryl Sulfate: acts as a surfactant.

[0044] 2. Preparation method:

[0045] (I) Solution preparation:

[0046] Sodium alginate solution:

[0047] Accurately weigh sodium alginate, dissolve it in an appropriate amount of water, and prepare a sodium alginate solution with a concentration of 5%-10% (w / v). For example, take 20 parts of sodium alginate (assuming 1 part is 1 g, i.e. 20 g), add 200-400 mL of water, and stir to dissolve it. The stirring speed can be set to 200-300 rpm, and the stirring time is about 15-25 minutes.

[0048] Chitosan solution:

[0049] Dissolve chitosan in dilute acetic acid solution to prepare a chitosan solution with a concentration of 3%-6% (w / v). For example, take 15 parts of chitosan (15 g), add 250-500 mL of dilute acetic acid solution, and stir to dissolve at a stirring speed of about 150-250 rpm for about 20-30 minutes.

[0050] PLGA solution:

[0051] Dissolve PLGA in an organic solvent (such as dichloromethane) to prepare a PLGA solution with a concentration of 10%-20% (w / v). For example, take 18 parts of PLGA (18 g), add 90-180 mL of organic solvent, and stir until completely dissolved. The stirring speed can be set to 300-400 rpm, and the stirring time is about 25-35 minutes.

[0052] (II) Drug mixing:

[0053] Drug-sodium alginate mixed solution:

[0054] Under stirring conditions, saxagliptin or its salt is slowly added to the sodium alginate solution. For example, 8 portions of saxagliptin salt (8 g) are taken, the stirring speed is set to 300-400 rpm, and stirring is continued until completely dissolved to obtain a drug-sodium alginate mixed solution. The stirring time is about 20-30 minutes.

[0055] Gel-like substance formation:

[0056] The chitosan solution is added dropwise to the drug-sodium alginate mixed solution, and the pH value is adjusted to between 5.0 and 6.5. For example, the pH value is adjusted using 1 mol / L hydrochloric acid or sodium hydroxide solution and accurately measured using a pH meter to allow the sodium alginate and chitosan to undergo a polyelectrolyte complex reaction to form a gel-like substance.

[0057] PLGA Mixing:

[0058] The PLGA solution is added to the gel-like substance, and the mixture is stirred thoroughly at a stirring speed of 400-500 rpm for about 30-40 minutes.

[0059] (III) Addition of additives:

[0060] Polyvinyl alcohol added:

[0061] Add polyvinyl alcohol to the above mixture, heat to 60-80°C, and continue stirring until the polyvinyl alcohol is completely dissolved to form a uniform dispersion system. For example, take 10 parts of polyvinyl alcohol (10g), stir at 70°C, the stirring speed is 400-500 rpm, and the stirring time is about 30-40 minutes. At the same time, add glycerol accounting for 5%-10% of the weight of polyvinyl alcohol as a plasticizer, and stir at high speed for 30-60 minutes, wherein the rotation speed is 800-1200 rpm. For example, take 10g of polyvinyl alcohol, add 0.5-1g of glycerol, and stir at high speed for 40-50 minutes.

[0062] Other additives added:

[0063] Dissolve N-acetylcysteine, vitamin E and sodium lauryl sulfate in a small amount of water respectively, add them to the dispersed system in turn, and continue to stir evenly. For example, take 5 parts of N-acetylcysteine ​​(5g) and dissolve them in 10-20mL of water, take 4 parts of vitamin E (4g) in a container (it is speculated that the statement here is incomplete), take 3 parts of sodium lauryl sulfate (3g) and dissolve them in 6-12mL of water and then add them, set the stirring speed to 300-400 rpm, and the stirring time is about 15-25 minutes.

[0064] (IV) Filtration and drying:

[0065] Filter operation:

[0066] Before freeze-drying, the mixture is filtered using a filter membrane with a pore size of 0.22-0.45 μm. The filtration process is carried out at a constant temperature of 25-30°C to maintain the stability of the formulation ingredients. For example, the filtration pressure is set at 0.1-0.2 MPa, and the filtration time is determined according to the amount of the mixture, generally 10-20 minutes.

[0067] Freeze drying:

[0068] The obtained mixture is freeze-dried at a freezing temperature of -40--20°C, a vacuum degree of 0.1-0.5 mbar, and a drying time of 24-48 hours, for example, at -30°C and a vacuum degree of 0.3 mbar for 36 hours.

[0069] (V) Preparation of dosage forms:

[0070] Tablet preparation:

[0071] If tablets are to be prepared, appropriate amounts of auxiliary materials (such as microcrystalline cellulose, lactose, etc.) are added to the powder, mixed evenly and then tableted. During the tableting process, the pressure is controlled to be 80-120 MPa, and the tablet weight difference is within ±5%. For example, the target tablet weight of the prepared tablet is 0.5 g, and the actual tablet weight range should be between 0.475-0.525 g. At the same time, a mixed solution of hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG) is used for coating, wherein the mass ratio of HPMC to PEG is 3:1-2:1, and the coating weight gain is 3%-5% of the tablet weight. For example, for a 0.5 g tablet, the coating weight gain is 0.015-0.025 g, and the coating operation is carried out at a temperature of 40-50°C and a relative humidity of 40%-60%.

[0072] Capsule preparation:

[0073] If it is a capsule, the powder is directly filled into the capsule shell, and the filling amount difference is controlled within ±10%. For example, the standard filling amount of the capsule is 0.3g, and the actual filling amount range should be between 0.27-0.33g. During the capsule filling process, the capsule shell is pre-treated with plasma treatment technology with a processing power of 80-120W and a processing time of 10-20 seconds to reduce the surface roughness of the capsule shell to 0.1-0.2μm.

[0074] 3. Comparative experiments and results:

[0075] (I) Stability test

[0076] Experimental methods:

[0077] The preparation of the present invention and the traditional preparation (mainly composed of saxagliptin and conventional excipients, the types and proportions of the excipients being different from those of the present invention) were respectively taken and stored at a temperature of 40° C. and a relative humidity of 75% for 3 months, and the contents of the active ingredients were measured before storage and at the first, second and third months after storage.

[0078] Experimental results:

[0079] The active ingredient content of the preparation of the present invention is 100% of the set standard before storage, 99.2% after 1 month of storage, 98.6% after 2 months of storage, and 97.3% after 3 months of storage, and the change in the active ingredient content is less than 3%.

[0080] The active ingredient content of the traditional preparation before storage was 100% of the set standard. After 1 month of storage, the active ingredient content was 94.5%. After 2 months of storage, the active ingredient content was 92.8%. After 3 months of storage, the active ingredient content was 90.2%. The change in active ingredient content was greater than 8%.

[0081] (II) Bioavailability experiment:

[0082] Experimental methods:

[0083] A number of healthy adult rats were selected and randomly divided into two groups, each with the same number of rats. One group was given the preparation of the present invention, and the other group was given the traditional preparation. The dosage was the same and met the drug administration specifications for rats. After administration, blood samples were collected at different time points (such as 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, etc.), and the blood drug concentration was determined by high performance liquid chromatography, and the bioavailability was calculated according to the blood drug concentration-time curve.

[0084] Experimental results:

[0085] After administration of the preparation of the present invention, the blood drug concentration of rats reaches a peak value in about 1 hour, and the calculated bioavailability is about 75%.

[0086] After administration of the traditional preparation, the blood drug concentration of rats reached a peak in about 2 hours, and the calculated bioavailability was about 50%. The bioavailability was increased by about 25%.

[0087] (III) Flexibility test:

[0088] Experimental methods:

[0089] Tablets (same shape and size) made from the preparation of the present invention and the traditional preparation were tested using a bending tester. The tablets were fixed on the tester, and external force was gradually applied until the tablet broke, and the bending angle at the time of breaking was recorded.

[0090] Experimental results:

[0091] The tablets prepared by the preparation of the invention have good flexibility, and the bending angle can reach 130°-150°, and the average bending angle is 140°.

[0092] Tablets made from traditional preparations have poor flexibility, with a bending angle of less than 90° and an average bending angle of 75°.

[0093] The comparative experiments and results are shown in the following table:

[0094]

[0095]

[0096] It can be seen from the above comparative experiments that the saxagliptin preparation of the present invention has obvious advantages in terms of stability, bioavailability and flexibility.

[0097] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. Such modifications or replacements will not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A saxagliptin preparation, characterized in that: The preparation consists of the following components in parts by weight: 5-15 parts of saxagliptin or its salt, 15-30 parts of sodium alginate, 10-20 parts of chitosan, 10-25 parts of polylactic acid-glycolic acid copolymer (PLGA), 5-15 parts of polyvinyl alcohol, 3-8 parts of N-acetylcysteine, 2-6 parts of vitamin E and 1-5 parts of sodium lauryl sulfate.

2. The saxagliptin preparation according to claim 1, characterized in that Chitosan is a low molecular weight chitosan with a deacetylation degree between 80% and 95%; PLGA is a biodegradable polymer with a lactic acid to glycolic acid ratio of 75:25-50:

50.

3. The saxagliptin preparation according to claim 1, characterized in that Polyvinyl alcohol as a hydrophilic polymer; N-acetylcysteine ​​acts as an antioxidant.

4. The saxagliptin preparation according to claim 1, characterized in that Vitamin E also has antioxidant effects; sodium lauryl sulfate acts as a surfactant.

5. The method for preparing the saxagliptin preparation according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: S100: dissolving sodium alginate in an appropriate amount of water to prepare a sodium alginate solution with a concentration of 5%-10% (w / v), and dissolving chitosan in a dilute acetic acid solution to prepare a chitosan solution with a concentration of 3%-6% (w / v); S200: slowly adding saxagliptin or its salt to the sodium alginate solution under stirring, and continuing stirring until completely dissolved to obtain a drug-sodium alginate mixed solution; S300: adding the chitosan solution dropwise into the drug-sodium alginate mixed solution, and adjusting the pH value to between 5.0 and 6.5, so that the sodium alginate and the chitosan undergo a polyelectrolyte complex reaction to form a gel-like substance; S400: dissolving PLGA in an organic solvent to prepare a PLGA solution with a concentration of 10%-20% (w / v), adding the solution to the gel-like substance, and stirring and mixing thoroughly; S500: Add polyvinyl alcohol to the above mixture, heat to 60-80°C, and continue stirring until the polyvinyl alcohol is completely dissolved to form a uniform dispersion system; S600: Dissolve N-acetylcysteine, vitamin E and sodium lauryl sulfate in a small amount of water respectively, add them into the dispersion system in sequence, and continue to stir evenly; S700: freeze-drying the obtained mixture at a freezing temperature of -40--20°C, a vacuum degree of 0.1-0.5 mbar, and a drying time of 24-48 hours to obtain a dry saxagliptin preparation powder.

6. The method for preparing the saxagliptin preparation according to claim 5, characterized in that: If the saxagliptin preparation powder prepared in step S700 is to be prepared into a specific dosage form, if it is a tablet, the powder can be added with an appropriate amount of auxiliary materials, mixed evenly and then tableted; If it is a capsule, the powder is directly filled into the capsule shell. During the tableting process, the pressure is controlled to be 80-120MPa, and the tablet weight difference is within ±5%. When filling the capsule, the filling amount difference is controlled to be within ±10%.

7. The method for preparing the saxagliptin preparation according to claim 5, characterized in that: Before the freeze-drying treatment in step S700, the mixture is filtered using a filter membrane with a pore size of 0.22-0.45 μm, and the filtering process is performed at a constant temperature of 25-30°C.

8. The method for preparing the saxagliptin preparation according to claim 5, characterized in that: When adding polyvinyl alcohol in step S500, glycerol accounting for 5% to 10% of the weight of polyvinyl alcohol is added as a plasticizer, and the mixture is stirred at high speed for 30 to 60 minutes, wherein the rotation speed is 800 to 1200 rpm to improve the flexibility of the preparation.

9. The method for preparing the saxagliptin preparation according to claim 6, characterized in that: For the prepared tablets, a mixed solution of hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG) is used for coating treatment, wherein the mass ratio of HPMC to PEG is 3:1-2:1, and the coating weight gain is 3%-5% of the tablet weight. The coating operation is carried out in an environment of temperature of 40-50°C and relative humidity of 40%-60%.

10. The method for preparing the saxagliptin preparation according to claim 6, characterized in that: During the capsule filling process, the capsule shell is pre-treated with plasma treatment technology, with a treatment power of 80-120 W and a treatment time of 10-20 seconds, so that the surface roughness of the capsule shell is reduced to 0.1-0.2 μm.

Images