Efficient and stable calcitriol soft capsule and preparation method thereof

Abstract

The invention provides an efficient and stable calcitriol soft capsule and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, the efficient and stable calcitriol soft capsule comprises a content and a capsule wall, the content is prepared from olive oil, algal oil, calcitriol, vitamin E, an antioxidant and carboxymethyl guar gum-chitosan liquid, the capsule wall is prepared from glycerol and xanthan gum; the preparation method comprises the following steps: dropping the content and the capsule wall by using a pill dropping machine, cooling in liquid paraffin, collecting condensed capsules, blowing out air, shaping and drying, washing, drying and screening to obtain the efficient and stable calcitriol soft capsule.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a highly efficient and stable calcitriol soft capsule and a preparation method thereof. Background Art

[0002] Calcitriol is one of the most important active metabolites of vitamin D3, which has the functions of promoting the absorption of calcium in the small intestine and regulating the transport of inorganic salts in bones. It can effectively correct hypocalcemia, relieve bone and muscle pain, reduce or normalize the elevated plasma alkaline phosphatase, reduce the elevated plasma parathyroid concentration and make it normal, thereby promoting bone mineralization. Calcitriol plays an important role in the treatment of osteoporosis, chronic renal failure, hypoparathyroidism, rickets and other diseases. In order to improve its stability and bioavailability, researchers are committed to developing efficient and stable calcitriol preparations. Among them, soft capsules, as a common oral preparation form, have the advantages of fast drug absorption and high bioavailability. However, calcitriol is sensitive to light and air, and has poor stability when stored for a long time. Calcitriol soft capsules are easily degraded under light, high temperature and high humidity, resulting in reduced drug activity and increased impurities. This not only affects the efficacy of the drug, but may also increase the risk of adverse drug reactions. The stability of the currently commercially available calcitriol soft capsules is generally poor after long-term storage, and it is difficult to meet clinical drug needs. In the preparation process of calcitriol soft capsules in the prior art, it is often difficult to effectively control the generation of impurities. Excessive impurities not only affect the quality of the drug, but may also have adverse effects on the patient's body, such as causing allergic reactions. The existing calcitriol soft capsule preparation process often involves multiple steps and complex parameter controls, such as temperature, time, stirring speed, etc., which places high demands on production equipment and operators, and increases production costs and difficulties. Due to the limitations of the content formula and preparation process, some soft capsules have a low solubility of the drug in the body, which affects the absorption and efficacy of the drug. Therefore, the market is in urgent need of a new, efficient and stable calcitriol soft capsule and a preparation method thereof. Summary of the invention

[0003] The present invention provides a highly efficient and stable calcitriol soft capsule and a preparation method thereof, which are used to solve the problems raised in the above background technology.

[0004] In order to solve the above technical problems, the present invention discloses a highly efficient and stable calcitriol soft capsule and a preparation method thereof. The highly efficient and stable calcitriol soft capsule comprises raw materials containing carboxymethyl guar gum-chitosan solution and a capsule wall containing xanthan gum.

[0005] Furthermore, the raw materials for preparing the content containing carboxymethyl guar gum-chitosan liquid include, by weight, 140-150 parts of olive oil, 250-260 parts of algae oil, 0.5-0.7 parts of calcitriol, 5-6 parts of vitamin E, 0.5-0.6 parts of antioxidants, and 0.1-0.2 parts of carboxymethyl guar gum-chitosan liquid.

[0006] Furthermore, the antioxidants are vitamin C, natural astaxanthin and proanthocyanidins; Preferably, the weight ratio of vitamin C, natural astaxanthin and proanthocyanidins is 1:2:(2-3); preferably, the weight ratio of vitamin C, natural astaxanthin and proanthocyanidins is 1:2:2.

[0007] Furthermore, the raw materials for preparing the carboxymethyl guar gum-chitosan solution include, by weight, 20-30 parts of chitosan solution, 80-100 parts of glacial acetic acid aqueous solution, 20-40 parts of metformin hydrochloride, 40-50 parts of carboxymethyl guar gum and 50-70 parts of sodium tripolyphosphate solution.

[0008] Furthermore, the raw materials for preparing the capsule wall containing xanthan gum include 5-10 parts of glycerin, 10-20 parts of deionized water and 15-25 parts of xanthan gum by weight.

[0009] Furthermore, the preparation method of the contents containing carboxymethyl guar gum-chitosan liquid includes dissolving calcitriol with olive oil and algae oil by weight, adding vitamin E, antioxidant and carboxymethyl guar gum-chitosan liquid at a temperature of 30° C., stirring and cooling, and using a homogenizer to obtain the contents containing carboxymethyl guar gum-chitosan liquid.

[0010] Furthermore, the stirring speed is 200-300 rpm, the time is 3-6 hours, cooled to 25° C., and processed twice by a homogenizer at a pressure of 8 MPa to obtain a content containing carboxymethyl guar gum-chitosan liquid.

[0011] Further, a homogenizer is used to obtain a carboxymethyl guar gum-chitosan solution, including: Dissolve calcitriol with olive oil and algae oil in a stirring container included in a homogenizer, add vitamin E, antioxidants and carboxymethyl guar gum-chitosan solution in the stirring container at a temperature of 30° C., and start stirring based on the stirrer included in the homogenizer; After the stirrer has been operating for a preset period of time, a stirring and mixing index of the mixed liquid is calculated based on a preset algorithm; comparing the stirring and mixing index with a preset stirring and mixing threshold; When it is determined that the stirring and mixing index is greater than or equal to a preset stirring and mixing threshold, the stirrer stops stirring to obtain contents containing carboxymethyl guar gum-chitosan liquid; The preset algorithm includes:

[0012] in, Indicates the stirring mixing index of the mixed liquid; Indicates the density value of the mixed liquid; Indicates the volume of the mixed liquid in the stirring container; represents the gravity coefficient; Indicates the preset time period for the agitator to work; represents the precision factor; Indicates the bottom area of ​​the mixing container; Indicates the unit time of detection; represents a natural constant; Indicates the viscosity index of the mixed liquid.

[0013] Further, after using a homogenizer to obtain the contents containing the carboxymethyl guar gum-chitosan liquid, the method further comprises: estimating the quality parameters of the obtained contents containing the carboxymethyl guar gum-chitosan solution to obtain a quality parameter estimation value; Comparing the quality parameter estimate with a preset quality parameter threshold; If the estimated value of the quality parameter is less than the preset quality parameter threshold, the homogenizer is used for reprocessing until the estimated value of the quality parameter is greater than or equal to the preset quality parameter threshold; The method of estimating the quality parameters of the obtained contents containing carboxymethyl guar gum-chitosan solution comprises:

[0014] in, It represents the estimated values ​​of quality parameters of contents containing carboxymethyl guar gum-chitosan solution; represents the influence coefficient of the quality of the content of the prepared raw materials; n represents the number of stirring blades; () represents the logarithm with base e; is the value of pi, take 3.14; Indicates the distance between the stirring blades included in the stirrer and the central axis of the stirring container; It indicates the average speed of the stirring blade during the total period of operation of the stirrer; Indicates the total time period during which the agitator operates; Indicates the height of the mixing container; It indicates the volume of the contents containing carboxymethyl guar gum-chitosan solution.

[0015] Furthermore, the method for preparing the capsule wall containing xanthan gum includes heating glycerin and deionized water to 65°C-80°C, adding xanthan gum, stirring and melting, keeping warm for 30min-90min, removing foam, filtering, and maintaining the temperature to obtain the capsule wall containing xanthan gum.

[0016] Furthermore, the preparation method of the carboxymethyl guar gum-chitosan solution comprises: connecting a round-bottom flask to a reflux condenser equipped with a nitrogen purge device, adding 50-80 parts of distilled water, 5-10 parts of guar gum, and 50-60 parts of a NaOH aqueous solution, stirring at 25° C. for 3-5 hours to obtain a mixture, adding 5-8 parts of a monochloroacetic acid aqueous solution to the mixture, stirring at 60° C. for 3-5 hours, cooling, neutralizing with acetic acid, washing and removing impurities with acetone, filtering, and freeze-drying to obtain carboxymethyl guar gum; dissolving 20-30 parts of the chitosan solution in 80-100 parts of an aqueous glacial acetic acid solution at 25° C., the pH value being 6.0, adding 20-40 parts of metformin hydrochloride, adding 40-50 parts of carboxymethyl guar gum dissolved in 200 parts of pure water, and stirring at high speed at 25° C. for 30-60 minutes to obtain a polymer. 10 parts of the polymer were added to 50-70 parts of a 3% w / v sodium tripolyphosphate solution and stirred until a stable colloidal dispersion was formed, the obtained nanofluid was centrifuged at 9500 rpm for 30-60 minutes using a centrifuge, the obtained supernatant was discarded, the precipitate was resuspended, ultrasonicated, and the obtained carboxymethyl guar gum-chitosan solution was freeze-dried using a freeze dryer; Preferably, the concentration of the NaOH aqueous solution is 1N; Preferably, the volume fraction of the solute in the glacial acetic acid aqueous solution is 2% v / v.

[0017] Furthermore, the preparation method of the efficient and stable calcitriol soft capsules includes dripping the contents containing carboxymethyl guar gum-chitosan liquid and the capsule wall containing xanthan gum using a pill dripping machine, cooling in liquid paraffin, collecting cold gel pills, wiping the liquid paraffin on the outer surface of the pills, blowing air at room temperature for 2-5 hours, shaping and drying at 25°C, washing the outer surface of the pills, drying at 30°C, and screening to obtain calcitriol soft capsules.

[0018] Compared with the prior art, the present invention provides a highly efficient and stable calcitriol soft capsule and a preparation method thereof, which has the following beneficial effects: (1) Carboxymethyl guar gum and chitosan are natural polymer materials with good biocompatibility and degradability. They can form stable hydrogels or films to protect calcitriol from the influence of the external environment, such as light, oxidation, etc., improve the stability of the drug, help improve the dissolution behavior of the drug, promote the absorption and utilization of the drug in the body, and improve the bioavailability. Since carboxymethyl guar gum and chitosan have excellent biocompatibility, they can be used as drug carriers to reduce the stimulation and damage of drugs to organs such as the gastrointestinal tract and reduce the adverse reactions of drugs. Adding carboxymethyl guar gum-chitosan solution to the content can improve the stability, solubility and bioavailability of calcitriol. (2) The antioxidants are vitamin C, natural astaxanthin and proanthocyanidins. Vitamin C is a water-soluble antioxidant that has the function of scavenging free radicals. It can promote collagen synthesis in the body, enhance the elasticity and toughness of blood vessels, reduce the incidence of cardiovascular and cerebrovascular diseases, and promote iron absorption to prevent iron deficiency anemia. Natural astaxanthin is a fat-soluble antioxidant and a keto-oxygen derivative of carotenoids. It has significant effects in enhancing the body's immunity, anti-inflammation, preventing ultraviolet radiation, anti-cancer, protecting the eyes and central nervous system, etc. Proanthocyanidins are a mixture of bioflavonoids with a special molecular structure and have strong in vivo activity. In addition to the antioxidant effect, they also participate in the metabolism of phosphoric acid and arachidonic acid and protein phosphorylation, protecting lipids from peroxidation damage. The three, at an appropriate weight ratio, have multi-angle antioxidant effects from water-soluble antioxidants and fat-soluble antioxidants. Combined with the water-soluble carboxymethyl guar gum and xanthan gum in the formula of the efficient and stable calcitriol soft capsules and the fat-soluble olive oil and algae oil, they exert a more comprehensive antioxidant effect. (3) Olive oil is rich in monounsaturated fatty acids (mainly oleic acid) and ω-3 fatty acids, which have many health benefits for the human body, such as reducing the risk of cardiovascular disease and promoting bone health. The antioxidants in olive oil also help protect calcitriol from oxidative damage and maintain its activity. Algae oil is rich in ω-3 fatty acids (such as DHA and EPA), which have significant effects on promoting brain and retinal development and reducing inflammatory responses. Olive oil is rich in monounsaturated fatty acids (such as oleic acid), and algae oil is rich in ω-3 polyunsaturated fatty acids (such as DHA and EPA). These two fatty acids have different physiological functions in the human body. Their combined use can achieve fatty acid complementarity and provide more comprehensive nutritional support. Both olive oil and algae oil have good fat solubility, which helps calcitriol dissolve and absorb in the body. Compared with other oils, these two oils can improve the biological benefits of calcitriol. The use of olive oil and algae oil can make it enter the blood circulation faster and play a role. It is not only easy to absorb, but also provides additional nutritional support, which helps to improve the overall health of patients. The fatty acid components in olive oil and algae oil can help lower blood lipid and cholesterol levels, reduce the formation of atherosclerosis, and thus reduce the risk of cardiovascular disease. DHA and EPA in algae oil are essential for the development of the brain and nervous system. Especially during pregnancy, moderate intake can help the fetus's neural development and memory enhancement. Olive oil and algae oil are also rich in antioxidants and vitamins, such as vitamin E, vitamin A, etc. These ingredients help to resist the damage of free radicals, delay the aging process, and may have anti-inflammatory, anti-cancer and other health benefits; (4) As one of the main components of the capsule wall, xanthan gum has excellent film-forming properties and viscoelasticity, providing a stable structural basis for the entire capsule. The double helix structure of xanthan gum can form a network in the solution, enhance the strength and toughness of the capsule wall, and prevent leakage of the contents. When xanthan gum is combined with hydrophilic colloids such as carboxymethyl guar gum in B, a strong synergistic effect can be produced. This effect not only increases the overall viscosity of the system, but also enhances the stability of the capsule contents, preventing stratification or precipitation during storage and transportation. Carboxymethyl guar gum, as a thickener, can significantly increase the viscosity of the solution. After combining with chitosan, the stability and emulsification of the system are further enhanced. This stable emulsified system helps to uniformly disperse and stably exist calcitriol in D. Chitosan has good biocompatibility and degradability, which can reduce the toxic side effects of the capsule in the body and improve the safety of the drug. At the same time, chitosan also has certain antibacterial properties, which helps to extend the shelf life of the capsules. Antioxidants can effectively remove free radicals and prevent active ingredients such as calcitriol from oxidative degradation during storage and transportation, thereby maintaining their biological activity and stability. By inhibiting the occurrence of oxidation reactions, antioxidants can significantly extend the shelf life of the capsules and ensure that the product maintains good quality within its validity period. Therefore, the xanthan gum in the capsule wall containing xanthan gum can synergistically enhance the effect with the carboxymethyl guar gum-chitosan liquid, antioxidants and calcitriol dissolved in olive oil and seaweed oil in the contents. From the aspect of structural stability and protection: xanthan gum provides a stable structural basis for the capsule to prevent leakage of the contents; antioxidants protect calcitriol from oxidative damage; olive oil and seaweed oil as solvents improve the bioavailability of calcitriol; from the aspect of thickening and emulsification, the carboxymethyl guar gum-chitosan liquid (B) enhances the viscosity and stability of the system to form a stable emulsified system; xanthan gum and hydrophilic colloids such as carboxymethyl guar gum produce a synergistic thickening effect to further improve the overall stability of the system; from the aspect of biocompatibility and safety, the biocompatibility and degradability of chitosan reduce the toxic side effects of the capsule in the body; olive oil and seaweed oil are natural oil sources, highly safe and easily absorbed by the human body, and the various formulas work together to improve the stability, solubility and bioavailability of calcitriol under light and accelerated conditions. DETAILED DESCRIPTION

[0020] In the present invention, the descriptions of "first", "second", etc. are only used for descriptive purposes, and do not specifically refer to the order or sequence, nor are they used to limit the present invention. They are only used to distinguish components or operations described with the same technical terms, and cannot be understood as indicating or implying their relative importance or implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions and technical features between the various embodiments can be combined with each other, but they must be based on the ability of ordinary technicians in the field to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0021] Unless otherwise specified, the examples and comparative examples are parallel tests with the same components, component contents, preparation steps and preparation parameters. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are analytical reagents (AR) unless otherwise specified. Parts are parts by weight unless otherwise specified, and the materials are purchased from commercial channels.

[0022] Metformin hydrochloride was purchased from SigmaAldrich, CAS No.: 1115-70-4; chitosan was purchased from SigmaAldrich, CAS No.: 9012-76-4; guar gum was purchased from Shanghai Weiqing Biotechnology Co., Ltd., net content 99%, 100 mesh; xanthan gum was purchased from Anhui Zhonghong Bioengineering Co., Ltd., CAS No.: 1168-42-9, net content 99%, 100 mesh; xanthan gum and guar gum were both food grade.

[0023] Example 1 Preparation of Carboxymethyl Guar Gum: The round-bottom flask was connected to a reflux condenser equipped with a nitrogen purge device, 50 parts of distilled water, 5 parts of guar gum, and 50 parts of 1N NaOH aqueous solution were added, and the mixture was stirred at 25°C for 1 hour to obtain a mixture. 15 g of monochloroacetic acid aqueous solution was prepared with 25 ml of distilled water, and 5 parts of monochloroacetic acid aqueous solution were added to the mixture, and the mixture was stirred at 60°C for 3 hours. The mixture was cooled and neutralized with acetic acid, washed with acetone to remove impurities, filtered, and freeze-dried to obtain carboxymethyl guar gum.

[0024] Preparation of carboxymethyl guar gum-chitosan solution: 20 parts of chitosan solution were dissolved in 80 parts of glacial acetic acid aqueous solution (2% v / v) at 25°C, pH value was 6.0, 20 parts of metformin hydrochloride were added, 40 parts of carboxymethyl guar gum dissolved in 200 parts of pure water were added, and the polymer was obtained by high-speed stirring at 25°C for 30 minutes. 10 parts of the polymer were added to 50 parts of 3% w / v sodium tripolyphosphate solution and stirred until a stable colloidal dispersion was formed, and the obtained nanofluid was centrifuged at 9500 rpm for 15 minutes using a centrifuge, the obtained supernatant was discarded, the precipitate was resuspended, ultrasonicated, and the obtained carboxymethyl guar gum-chitosan solution was freeze-dried using a freeze dryer.

[0025] Calcitriol Soft Capsules (1) preparing a content containing carboxymethyl guar gum-chitosan liquid: dissolving 0.5 parts of calcitriol in 150 parts of olive oil and 250 parts of algae oil by weight, adding 5 parts of vitamin E, 0.5 parts of antioxidant (0.1 parts of vitamin C, 0.2 parts of natural astaxanthin, 0.2 parts of proanthocyanidins), and 0.2 parts of carboxymethyl guar gum-chitosan liquid at a temperature of 30° C., stirring at 200 rpm for 3 hours, naturally cooling to 25° C., and treating twice with a homogenizer at a pressure of 8 MPa to obtain a content containing carboxymethyl guar gum-chitosan liquid; The contents of the carboxymethyl guar gum-chitosan liquid are obtained by using a homogenizer, including: Dissolve calcitriol with olive oil and algae oil in a stirring container included in a homogenizer, add vitamin E, antioxidants and carboxymethyl guar gum-chitosan solution in the stirring container at a temperature of 30° C., and start stirring based on the stirrer included in the homogenizer; After the stirrer has been operating for a preset period of time, a stirring and mixing index of the mixed liquid is calculated based on a preset algorithm; comparing the stirring and mixing index with a preset stirring and mixing threshold; When it is determined that the stirring and mixing index is greater than or equal to a preset stirring and mixing threshold, the stirrer stops stirring to obtain contents containing carboxymethyl guar gum-chitosan liquid; The preset algorithm includes:

[0026] in, Indicates the stirring mixing index of the mixed liquid; Indicates the density value of the mixed liquid; Indicates the volume of the mixed liquid in the stirring container; represents the gravity coefficient; Indicates the preset time period for the agitator to work; represents the precision factor; Indicates the bottom area of ​​the mixing container; Indicates the unit time of detection; represents a natural constant; Indicates the viscosity index of the mixed liquid.

[0027] In this embodiment, the preset stirring and mixing threshold is set in advance based on industry experience.

[0028] In this embodiment, the precision factor is the product of the precision of the density sensor in the mixed liquid and the precision of the agitator working time timer, and the density sensor is installed inside the stirring container.

[0029] The beneficial effects of the above technical solution are: by calculating the stirring and mixing index and comparing it with the threshold value, the stirring effect can be accurately controlled to ensure product quality; the influence of various factors such as density, volume, gravity, time, etc. on the stirring and mixing effect is comprehensively considered to make the process more scientific and reasonable; the whole process reflects the strict control and optimization of product quality, which is conducive to improving the stability and reliability of the product.

[0030] After using a homogenizer to obtain the contents containing carboxymethyl guar gum-chitosan liquid, it also includes: estimating the quality parameters of the obtained contents containing the carboxymethyl guar gum-chitosan solution to obtain a quality parameter estimation value; Comparing the quality parameter estimate with a preset quality parameter threshold; If the estimated value of the quality parameter is less than the preset quality parameter threshold, the homogenizer is used for reprocessing until the estimated value of the quality parameter is greater than or equal to the preset quality parameter threshold; The method of estimating the quality parameters of the obtained contents containing carboxymethyl guar gum-chitosan solution comprises:

[0031] in, It represents the estimated values ​​of quality parameters of contents containing carboxymethyl guar gum-chitosan solution; represents the influence coefficient of the quality of the content of the prepared raw materials; n represents the number of stirring blades; () represents the logarithm with base e; is the value of pi, take 3.14; Indicates the distance between the stirring blades included in the stirrer and the central axis of the stirring container; It indicates the average speed of the stirring blade during the total period of operation of the stirrer; Indicates the total time period during which the agitator operates; Indicates the height of the mixing container; It indicates the volume of the contents containing carboxymethyl guar gum-chitosan solution.

[0032] In this embodiment, the preset quality parameter threshold is set in advance based on industry experience.

[0033] In this embodiment, the total time period of the agitator operation includes the preset time period of the agitator operation and the time period when the stirring and mixing index changes from being less than the stirring and mixing threshold to being greater than or equal to the stirring and mixing threshold.

[0034] In this embodiment, the influence coefficient of the quality of the content of the raw material is related to the raw material origin, raw material date and storage environment of the raw material in the raw material preparation. The raw material origin coefficient, raw material date coefficient and raw material storage environment coefficient in the raw material preparation can be formulated based on industry experience;

[0035] in, The influence coefficient indicating the quality of the content of the prepared raw materials; , , are weight coefficients, and the sum is 1. A represents the raw material origin coefficient, B represents the raw material date coefficient, and C represents the raw material storage environment coefficient.

[0036] The beneficial effects of the above technical solution are: by estimating the quality parameters of the processed contents and comparing them with the threshold values, it can be ensured that the product meets certain quality standards, which is beneficial to ensuring the stability and consistency of product quality; the quality parameter estimates are calculated by comprehensively considering various factors (such as raw material quality, stirring-related parameters, etc.), making the evaluation more scientific and comprehensive; when the quality parameter estimates do not meet the requirements, reprocessing is carried out, which helps to continuously optimize product quality and reduce the production of unqualified products.

[0037] (2) preparing a capsule wall containing xanthan gum: heating 8 parts of glycerol and 15 parts of deionized water to 70° C., adding 20 parts of xanthan gum, stirring and melting, keeping the temperature for 60 minutes, removing the floating foam, filtering, and maintaining the temperature to obtain a capsule wall containing xanthan gum; (3) Preparation of calcitriol soft capsules: the contents and capsule wall are dripped by a pill dripping machine, cooled in liquid paraffin, and the cold gel pellets are collected. The liquid paraffin on the outer surface of the capsules is wiped off, and air is blown at room temperature for 3 hours. The capsules are shaped and dried at 25°C, and the outer surface of the capsules is washed. The capsules are dried at 30°C and screened to obtain calcitriol soft capsules.

[0038] Example 2 Preparation of Carboxymethyl Guar Gum: The round-bottom flask was connected to a reflux condenser equipped with a nitrogen purge device, 50 parts of distilled water, 5 parts of guar gum, and 50 parts of 1N NaOH aqueous solution were added, and the mixture was stirred at 25°C for 1 hour to obtain a mixture. 15 g of monochloroacetic acid aqueous solution was prepared with 25 ml of distilled water, and 5 parts of monochloroacetic acid aqueous solution were added to the mixture, and the mixture was stirred at 60°C for 3 hours. The mixture was cooled and neutralized with acetic acid, washed with acetone to remove impurities, filtered, and freeze-dried to obtain carboxymethyl guar gum.

[0039] Preparation of carboxymethyl guar gum-chitosan solution: 20 parts of chitosan solution were dissolved in 80 parts of glacial acetic acid aqueous solution (2% v / v) at 25°C, pH value was 6.0, 20 parts of metformin hydrochloride were added, 40 parts of carboxymethyl guar gum dissolved in 200 parts of pure water were added, and the polymer was obtained by high-speed stirring at 25°C for 30 minutes. 10 parts of the polymer were added to 50 parts of 3% w / v sodium tripolyphosphate solution and stirred until a stable colloidal dispersion was formed, and the obtained nanofluid was centrifuged at 9500 rpm for 15 minutes using a centrifuge, the obtained supernatant was discarded, the precipitate was resuspended, ultrasonicated, and the obtained carboxymethyl guar gum-chitosan solution was freeze-dried using a freeze dryer.

[0040] Calcitriol Soft Capsules (1) Preparing a content containing carboxymethyl guar gum-chitosan liquid: dissolving 0.5 parts of calcitriol in 140 parts of olive oil and 250 parts of algae oil by weight, adding 5 parts of vitamin E, 0.5 parts of antioxidant (0.1 parts of vitamin C, 0.2 parts of natural astaxanthin, 0.2 parts of proanthocyanidins), and 0.1 parts of carboxymethyl guar gum-chitosan liquid at a temperature of 30° C., stirring at 200 rpm for 3 hours, naturally cooling to 25° C., and using a homogenizer to process twice at a pressure of 8 MPa to obtain a content containing carboxymethyl guar gum-chitosan liquid; (2) preparing a capsule wall containing xanthan gum: heating 5 parts of glycerol and 10 parts of deionized water to 65° C., adding 15 parts of xanthan gum, stirring and melting, keeping the temperature for 30 minutes, removing the floating foam, filtering, and maintaining the temperature to obtain a capsule wall containing xanthan gum; (3) Preparation of calcitriol soft capsules: the contents and capsule wall are dripped by a pill dripping machine, cooled in liquid paraffin, and the cold gel pellets are collected. The liquid paraffin on the outer surface of the capsules is wiped off, and air is blown at room temperature for 3 hours. The capsules are shaped and dried at 25°C, and the outer surface of the capsules is washed. The capsules are dried at 30°C and screened to obtain calcitriol soft capsules.

[0041] Example 3 Preparation of Carboxymethyl Guar Gum: The round-bottom flask was connected to a reflux condenser equipped with a nitrogen purge device, 50 parts of distilled water, 5 parts of guar gum, and 50 parts of 1N NaOH aqueous solution were added, and the mixture was stirred at 25°C for 1 hour to obtain a mixture. 15 g of monochloroacetic acid aqueous solution was prepared with 25 ml of distilled water, and 5 parts of monochloroacetic acid aqueous solution were added to the mixture, and the mixture was stirred at 60°C for 3 hours. The mixture was cooled and neutralized with acetic acid, washed with acetone to remove impurities, filtered, and freeze-dried to obtain carboxymethyl guar gum.

[0042] Preparation of carboxymethyl guar gum-chitosan solution: 30 parts of chitosan solution were dissolved in 100 parts of glacial acetic acid aqueous solution (2% v / v) at 25°C, pH value was 6.0, 40 parts of metformin hydrochloride were added, 50 parts of carboxymethyl guar gum dissolved in 200 parts of pure water were added, and the polymer was obtained by high-speed stirring at 25°C for 30 minutes. 10 parts of the polymer were added to 70 parts of 3% w / v sodium tripolyphosphate solution and stirred until a stable colloidal dispersion was formed, and the obtained nanofluid was centrifuged at 9500 rpm for 15 minutes using a centrifuge, the obtained supernatant was discarded, the precipitate was resuspended, ultrasonic treatment was performed, and the obtained carboxymethyl guar gum-chitosan solution was freeze-dried using a freeze dryer.

[0043] Calcitriol Soft Capsules (1) Preparing a content containing carboxymethyl guar gum-chitosan liquid: dissolving 0.7 parts of calcitriol in 150 parts of olive oil and 260 parts of algae oil by weight, adding 5 parts of vitamin E, 0.6 parts of antioxidant (0.1 parts of vitamin C, 0.2 parts of natural astaxanthin, 0.3 parts of proanthocyanidins), and 0.2 parts of carboxymethyl guar gum-chitosan liquid at a temperature of 30° C., stirring at 300 rpm for 6 hours, naturally cooling to 25° C., and using a homogenizer to process twice at a pressure of 8 MPa to obtain a content containing carboxymethyl guar gum-chitosan liquid; (2) preparing a capsule wall containing xanthan gum: heating 10 parts of glycerol and 20 parts of deionized water to 80° C., adding 25 parts of xanthan gum, stirring and melting, keeping the temperature for 90 minutes, removing the floating foam, filtering, and maintaining the temperature to obtain a capsule wall containing xanthan gum; (3) Preparation of calcitriol soft capsules: the contents and capsule wall are dripped by a pill dripping machine, cooled in liquid paraffin, and the cold gel pellets are collected. The liquid paraffin on the outer surface of the capsules is wiped off, and air is blown at room temperature for 3 hours. The capsules are shaped and dried at 25°C, and the outer surface of the capsules is washed. The capsules are dried at 30°C and screened to obtain calcitriol soft capsules.

[0044] Example 4 The difference from Example 1 is that the contents of the carboxymethyl guar gum-chitosan solution are prepared as follows: by weight, 0.6 parts of antioxidants (0.1 parts of vitamin C, 0.2 parts of natural astaxanthin, 0.3 parts of proanthocyanidins), and the rest are the same.

[0045] Example 5 The difference from Example 1 is that the capsule wall containing xanthan gum is prepared: 5 parts of glycerol and 10 parts of deionized water are heated to 70°C, 15 parts of xanthan gum are added, stirred to melt, kept warm for 60 minutes, the foam is removed, filtered, and the temperature is maintained to obtain the capsule wall containing xanthan gum. The rest are the same.

[0046] Comparative Example 1 The difference from Example 1 is that an equal weight portion of carboxymethyl guar gum-chitosan solution is missing when preparing the contents, and the rest is the same.

[0047] Comparative Example 2 The difference from Example 1 is that when preparing the contents containing carboxymethyl guar gum-chitosan solution, 0.5 parts of antioxidants are 0.1 parts of vitamin C, 0.3 parts of natural astaxanthin and 0.1 parts of proanthocyanidins, and the rest are the same.

[0048] Comparative Example 3 The difference from Example 1 is that when preparing the contents containing carboxymethyl guar gum-chitosan solution, 0.5 parts of antioxidants are 0.2 parts of vitamin C, 0.1 parts of natural astaxanthin and 0.2 parts of proanthocyanidins, and the rest are the same.

[0049] Comparative Example 4 The difference from Example 1 is that when preparing the capsule wall containing xanthan gum, the xanthan gum is replaced with gelatin in an equal weight portion, and the other parts are the same.

[0050] Comparative Example 5 The difference from Example 1 is that the step of preparing carboxymethyl guar gum is omitted, and guar gum of equal weight parts is directly used to prepare carboxymethyl guar gum-chitosan solution, and the other steps are the same.

[0051] Performance Testing 1. Effect of light exposure test on the stability of highly efficient and stable calcitriol soft capsules The highly efficient and stable calcitriol soft capsules prepared in the example, the calcitriol soft capsules prepared in the comparative example, and the reference preparation (National Medicine Standard No. H20143141) were respectively used as test samples, and the opening was placed in a light box equipped with a fluorescent lamp, and placed under an illumination of 4500lx±500lx for 30 days. Samples were taken on the 0th day, the 10th day, and the 30th day, respectively, to detect the calcitriol content.

[0052] Table 1 Effect of light test on the content of calcitriol in calcitriol soft capsules

[0053] Table 1 shows the effect of light exposure test on the calcitriol content in calcitriol soft capsules. The results show that the highly efficient and stable calcitriol soft capsules prepared by the present invention have high tolerance to light exposure.

[0054] 2. Effect of accelerated test on the stability of calcitriol soft capsules The highly efficient and stable calcitriol soft capsules prepared in the example, the calcitriol soft capsules prepared in the comparative example, and the reference preparation (National Medicine Standard No. H20143141) were respectively used as test samples for an accelerated test. They were packaged as reference preparations and placed at a temperature of 40±2°C and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the first month, the second month, and the sixth month during the test to detect the calcitriol content.

[0055] Table 2 Effect of accelerated test on calcitriol content in calcitriol soft capsules

[0056] Table 2 shows that in the accelerated test, the change in the calcitriol content in the high-efficiency and stable calcitriol soft capsules prepared by the present invention is relatively small, indicating that the high-efficiency and stable calcitriol soft capsules prepared by the present invention have high stability under high temperature and high humidity conditions.

[0057] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. If these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A highly efficient and stable calcitriol soft capsule, the preparation raw materials of which include contents containing carboxymethyl guar gum-chitosan solution and capsule wall containing xanthan gum.

2. The highly effective and stable calcitriol soft capsule according to claim 1, characterized in that: The raw materials for preparing the content containing carboxymethyl guar gum-chitosan liquid include, by weight, 140-150 parts of olive oil, 250-260 parts of algae oil, 0.5-0.7 parts of calcitriol, 5-6 parts of vitamin E, 0.5-0.6 parts of antioxidants, and 0.1-0.2 parts of carboxymethyl guar gum-chitosan liquid.

3. The highly effective and stable calcitriol soft capsule according to claim 1, characterized in that: The raw materials for preparing the capsule wall containing xanthan gum include 5-10 parts of glycerin, 10-20 parts of deionized water and 15-25 parts of xanthan gum by weight.

4. The highly effective and stable calcitriol soft capsule according to claim 1 or 2, characterized in that: The preparation method of the contents containing carboxymethyl guar gum-chitosan liquid comprises the following steps: dissolving calcitriol with olive oil and algae oil by weight, adding vitamin E, antioxidant and carboxymethyl guar gum-chitosan liquid at a temperature of 30° C., stirring and cooling, and using a homogenizer to obtain the contents containing carboxymethyl guar gum-chitosan liquid.

5. The highly effective and stable calcitriol soft capsule according to claim 4, characterized in that: The stirring speed is 200-300 rpm, the time is 3-6 hours, cooled to 25° C., and processed twice by a homogenizer at a pressure of 8 MPa to obtain a content containing carboxymethyl guar gum-chitosan liquid.

6. The highly effective and stable calcitriol soft capsule according to claim 5, characterized in that: The contents of the carboxymethyl guar gum-chitosan liquid are obtained by using a homogenizer, including: Dissolve calcitriol with olive oil and algae oil in a stirring container included in a homogenizer, add vitamin E, antioxidants and carboxymethyl guar gum-chitosan solution in the stirring container at a temperature of 30° C., and start stirring based on the stirrer included in the homogenizer; After the stirrer has been operating for a preset period of time, a stirring and mixing index of the mixed liquid is calculated based on a preset algorithm; comparing the stirring and mixing index with a preset stirring and mixing threshold; When it is determined that the stirring and mixing index is greater than or equal to a preset stirring and mixing threshold, the stirrer stops stirring to obtain contents containing carboxymethyl guar gum-chitosan liquid; The preset algorithm includes: in, Indicates the stirring mixing index of the mixed liquid; Indicates the density value of the mixed liquid; Indicates the volume of the mixed liquid in the stirring container; represents the gravity coefficient; Indicates the preset time period for the agitator to work; represents the precision factor; Indicates the bottom area of ​​the mixing container; Indicates the unit time of detection; represents a natural constant; Indicates the viscosity index of the mixed liquid.

7. The highly effective and stable calcitriol soft capsule according to claim 6, characterized in that: After using a homogenizer to obtain the contents containing carboxymethyl guar gum-chitosan liquid, it also includes: estimating the quality parameters of the obtained contents containing the carboxymethyl guar gum-chitosan solution to obtain a quality parameter estimation value; Comparing the quality parameter estimate with a preset quality parameter threshold; If the estimated value of the quality parameter is less than the preset quality parameter threshold, the homogenizer is used for reprocessing until the estimated value of the quality parameter is greater than or equal to the preset quality parameter threshold; The method of estimating the quality parameters of the obtained contents containing carboxymethyl guar gum-chitosan solution comprises: in, It represents the estimated values ​​of quality parameters of contents containing carboxymethyl guar gum-chitosan solution; represents the influence coefficient of the quality of the content of the prepared raw materials; n represents the number of stirring blades; () represents the logarithm with base e; is the value of pi, take 3.14; Indicates the distance between the stirring blades included in the stirrer and the central axis of the stirring container; It indicates the average speed of the stirring blade during the total period of operation of the stirrer; Indicates the total time period during which the agitator operates; Indicates the height of the mixing container; It indicates the volume of the contents containing carboxymethyl guar gum-chitosan solution.

8. The highly effective and stable calcitriol soft capsule according to claim 1 or 3, characterized in that: The method for preparing the capsule wall containing xanthan gum comprises heating glycerin and deionized water to 65-80° C., adding xanthan gum, stirring and melting, keeping warm for 30-90 minutes, removing floating foam, filtering, and maintaining the temperature to obtain the capsule wall containing xanthan gum.

9. The highly effective and stable calcitriol soft capsule according to claim 1 or 2, characterized in that: The preparation method of the carboxymethyl guar gum-chitosan solution comprises: connecting a round-bottom bottle with a reflux condenser equipped with a nitrogen purge device, adding 50-80 parts of distilled water, 5-10 parts of guar gum, and 50-60 parts of a NaOH aqueous solution, stirring at 25° C. for 3-5 hours to obtain a mixture, adding 5-8 parts of a monochloroacetic acid aqueous solution to the mixture, stirring at 60° C. for 3-5 hours, cooling, neutralizing with acetic acid, washing and removing impurities with acetone, filtering, and freeze-drying to obtain carboxymethyl guar gum; dissolving 20-30 parts of the chitosan solution in 80-100 parts of glacial vinegar at 25° C. In an acid aqueous solution, the pH value is 6.0, 20-40 parts of metformin hydrochloride are added, 40-50 parts of carboxymethyl guar gum dissolved in 200 parts of pure water are added, and the mixture is stirred at high speed for 30-60 minutes at 25° C. to obtain a polymer, 10 parts of the polymer are added to 50-70 parts of a 3% w / v sodium tripolyphosphate solution and stirred until a stable colloidal dispersion is formed, the obtained nanofluid is centrifuged at 9500 rpm for 30-60 minutes using a centrifuge, the obtained supernatant is discarded, the precipitate is resuspended, ultrasonically treated, and the obtained carboxymethyl guar gum-chitosan solution is freeze-dried using a freeze dryer; Preferably, the concentration of the NaOH aqueous solution is 1N; Preferably, the volume fraction of the solute in the glacial acetic acid aqueous solution is 2% v / v.

10. A method for preparing the highly effective and stable calcitriol soft capsules according to claims 1-9, characterized in that: The method comprises dripping the contents containing carboxymethyl guar gum-chitosan liquid and the capsule wall containing xanthan gum by using a pill dripping machine, cooling in liquid paraffin, collecting cold gel pills, wiping off the liquid paraffin on the outer surface of the pills, blowing air at room temperature for 2-5 hours, shaping and drying at 25 DEG C, washing the outer surface of the pills, drying at 30 DEG C, and screening to obtain calcitriol soft capsules.

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