A calcitriol self-microemulsifying orally dissolving film and a preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and specifically discloses a calcitriol self-microemulsifying oral dissolving film and a preparation method thereof, wherein the oral dissolving film comprises: calcitriol, a self-microemulsifying system, a film former, a plasticizer, an antioxidant, a flavoring agent, and a colorant, wherein the self-microemulsifying system comprises an oil phase, a surfactant, and a co-surfactant, and the calcitriol and the antioxidant are dispersed in the self-microemulsifying system. The oral dissolving film using this system can be rapidly dissolved and absorbed in the oral cavity, avoiding the first-pass effect of the liver, and is safe to take; the drug film does not require additional warm water for delivery, and does not have the risk of blocking the oral cavity or suffocation of conventional oral preparations, thereby improving the safety of patient medication.

Description

Technical Field

[0001] The invention relates to the field of novel pharmaceutical preparations, and specifically discloses a calcitriol self-microemulsification orally dissolving film and a preparation method thereof. Background Art

[0002] Calcitriol, chemically known as 9,10-opencholesterol-5Z,7E,10(19)-triene-1α,3β,25-triol. Calcitriol is one of the most important metabolic active products of vitamin D3 in the human body. It can promote calcium absorption in the intestine without hydroxylation in the liver and kidneys, and increase serum calcium levels by promoting calcium reabsorption in the kidneys. It also activates osteoclasts and osteoblasts, increases bone turnover, and promotes bone formation. Calcitriol was first produced by Roche in Switzerland and was launched in 1978 under the trade name "Rocaltrol". It is used to treat postmenopausal osteoporosis, chronic renal hypofunction, postoperative hypothyroidism, idiopathic hypoparathyroidism, pseudohypothyroidism, vitamin D-dependent rickets, hypophosphatemic vitamin D-resistant rickets, etc. Calcitriol has been used clinically for osteoporosis in Japan, New Zealand, Australia, Italy, and the United Kingdom for decades. Since calcitriol is an endogenous substance with definite efficacy, safety and stability, it is the drug of choice for osteoporosis.

[0003] At present, the calcitriol dosage forms that have been launched in China mainly include soft capsules and oral solutions. The dosage forms are relatively monotonous, and the stability of soft capsules and oral solutions is poor. During the storage process, the rubber of soft capsules is easily oxidized and cross-linked and aged, resulting in slow or no release of calcitriol in the body, which in turn affects the bioavailability. In addition, the compliance of soft capsule preparations for the elderly or patients with inconvenient swallowing is poor; although oral solutions have the advantages of rapid and efficient in vivo absorption, good patient compliance, and flexible dosage, they are especially suitable for patients with difficulty swallowing, such as the elderly and children; but they also have problems such as easy degradation, high risk of microbial contamination, and inconvenient storage and carrying. Since calcitriol is unstable to heat and light, easily oxidized, and has low solubility in water, product quality must be strictly controlled during the production process to prevent uneven content from causing medication to fail to reach the therapeutic level or produce toxic side effects. Chinese patents CN103202821 and CN109260209 disclose a calcitriol soft capsule and a method for preparing the same. Although the contents in the technology are a homogeneously dispersed system, the problem of uneven drug distribution can be reduced, and the production process does not need to go through a high temperature process, this dosage form also has its inherent limitations, such as a long production cycle, a complex production process, poor physical stability of the preparation, and easy cross-linking of the rubber. These problems may cause the capsule contents to leak and the drug content to decrease, and the treatment requirements cannot be met. Chinese patent CN103142496A discloses calcitriol controlled-release particles and a method for preparing the same, but the technology has not been promoted for industrialization and has not even been reported in the prior art, mainly because of poor stability and low bioavailability. Patent CN115297851A discloses an orodispersible film and its production and use methods. The invention defines the dosage of active ingredients as not less than 10.0%. However, the highly active substance calcitriol is directly absorbed by the small intestine in the body. This dosage far exceeds the daily dose and is likely to cause adverse reactions such as hypercalcemia. Therefore, the orodispersible film system cannot be applied to calcitriol.

[0004] Therefore, developing a calcitriol preparation that is more suitable for oral administration has become one of the problems that need to be solved urgently by those skilled in the art. Summary of the invention

[0005] The present invention aims at many deficiencies in the prior art and provides a calcitriol self-microemulsification oral dissolving film and a preparation method thereof. The oral dissolving film comprises: calcitriol, a self-microemulsification system, a film former, a plasticizer, an antioxidant, a flavoring agent, and a colorant, wherein the self-microemulsification system comprises an oil phase, a surfactant and a co-surfactant, and calcitriol and an antioxidant are dispersed in the self-microemulsification system. The oral dissolving film using this system can be rapidly dissolved and absorbed in the oral cavity, avoiding the first-pass effect of the liver, and is safe to take; the drug film does not require additional warm water for delivery, and there is no risk of clogging the oral cavity or suffocation of conventional oral preparations. The application uses 0.0001%-0.5% of the active ingredient calcitriol, which is equivalent to 0.25 μg per soft capsule of a solid preparation, and the dosage of 2 capsules per day, and the medication safety is higher.

[0006] The main idea of ​​the present invention is: based on the physical and chemical properties of calcitriol itself, combined with the advantages of the self-microemulsification system in improving the solubility of the drug and the advantages of improving the compliance of the orodissolving film, a calcitriol self-microemulsification orodissolving film and a preparation method thereof are developed, the solubility of the drug is improved, and it has the advantages of rapid onset, rapid absorption, high bioavailability, good patient compliance and good stability. In addition, the orodissolving film dosage form can greatly improve the medication compliance problem of osteoporosis patients.

[0007] The technical solution of the calcitriol self-microemulsification orally dissolving film finally determined by the inventor is as follows:

[0008] A calcitriol self-microemulsifying orally dissolving film comprises, by weight percentage, 0.0001%-0.5% of calcitriol, 5%-40% of oil phase, 5%-35% of surfactant, 1%-20% of cosurfactant, 5%-40% of plasticizer, 0.05%-5.0% of antioxidant, 0.1%-5% of flavoring agent, 1%-5% of colorant, and the remainder is film-forming agent; wherein the oil phase, surfactant and cosurfactant constitute a self-microemulsifying system.

[0009] Preferably, the calcitriol accounts for 0.005%-0.02% of the total weight of the orodispersible film, and the calcitriol and the antioxidant are dispersed in the self-microemulsification system, and the particle size of the self-microemulsification does not exceed 200 nm.

[0010] The oil phase is selected from at least one of monoolein, monolinolein, propylene glycol dicaprylate caprate, caprylic capric mono- and diglycerides, caprylic capric triglyceride, and caprylic / capric / succinic triglyceride; the oil phase is preferably at least one of monoolein, monolinolein, and propylene glycol dicaprylate caprate, accounting for 5%-20% of the total weight of the orodispersible film;

[0011] The surfactant is selected from at least one of oleoyl polyoxyethylene glyceride, polyethylene glycol-7 stearate, soybean oil mixed fatty acid glyceride, linoleoyl polyoxyethylene-6 glyceride, polyglycerol oleate or fatty acid polyethylene glycol glyceride; the surfactant is preferably at least one of oleoyl polyoxyethylene glyceride and polyethylene glycol-7 stearate, accounting for 10%-25% of the total weight of the orodispersible film;

[0012] The co-surfactant is selected from at least one of diethylene glycol monoethyl ether, ethanol, polyethylene glycol, tetrahydrofuran polyethylene glycol ether, dimethylacetamide, N-methylpyrrolidone or glycerol; the co-surfactant is preferably at least one of diethylene glycol monoethyl ether ethanol and polyethylene glycol, preferably accounting for 2%-10% of the total weight of the orodispersible film.

[0013] It is further preferred that propylene glycol dicaprylate caprate is the oil phase, oleoyl polyoxyethylene glyceride is the surfactant, diethylene glycol monoethyl ether is the co-surfactant, and the weight ratio of propylene glycol dicaprylate caprate: oleoyl polyoxyethylene glyceride: diethylene glycol monoethyl ether is 3:6:1.

[0014] The film-forming agent is selected from at least one of hydroxyethyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, povidone K30, povidone K90, copovidone, polyoxyethylene, and ethylene-vinyl acetate copolymer; the film-forming agent is preferably one of hydroxyethyl cellulose, polyvinyl alcohol, and povidone K30; the film-forming agent preferably accounts for 40%-60% of the total weight of the orodispersible film-forming agent.

[0015] The plasticizer is selected from at least one of sorbitol, sorbitol solution, sorbitol sorbitan solution, ethanol, ethylene glycol, butylene glycol, polysorbate, and maltitol; preferably, the plasticizer is selected from sorbitol solution, sorbitol sorbitan solution, ethanol, and polysorbate, accounting for 10%-25% of the total weight of the orodispersible film.

[0016] The antioxidant is selected from butylated hydroxyanisole and dibutylated hydroxytoluene, and the weight ratio of the two is 1:1; the antioxidant preferably accounts for 0.5%-1% of the total weight of the orodispersible film.

[0017] The flavoring agent is selected from one or any combination of mint flavor, citric acid, sucralose, fructose, lactose, aspartame, acesulfame potassium or stevioside; the flavoring agent is preferably at least one of mint flavor, citric acid and sucralose, preferably accounting for 0.1%-1% of the total weight of the orodispersible film.

[0018] The colorant is selected from one or any combination of titanium dioxide, red iron oxide, yellow iron oxide, sunset yellow, brown iron oxide, and erythrosine; the colorant is preferably at least one of titanium dioxide, red iron oxide, and yellow iron oxide, preferably accounting for 0.5%-1% of the total weight of the orodispersible film.

[0019] After further research, the inventors found that the best formula combination of the calcitriol self-microemulsification orally dissolving film described in the present application is as follows: calcitriol, propylene glycol dicaprylate caprate, oleoyl polyoxyethylene glyceride, diethylene glycol monoethyl ether, hydroxyethyl cellulose, sorbitol solution, sucralose, and titanium dioxide; among which the best formula combination of the self-microemulsification system is: calcitriol, propylene glycol dicaprylate caprate, oleoyl polyoxyethylene glyceride, and diethylene glycol monoethyl ether.

[0020] In addition, the inventors also provide a method for preparing the calcitriol self-microemulsification orally dissolving film, the specific steps of which are as follows:

[0021] 1) preparing a self-microemulsifying system, stirring and mixing an oil phase, a surfactant and a co-surfactant in a water bath at 35-40° C. to obtain a blank self-microemulsifying system with a particle size not exceeding 200 nm, then adding calcitriol and an antioxidant to the self-microemulsifying system, and continuing to stir for 30 minutes to obtain a self-microemulsifying system solution 1;

[0022] 2) dissolving the film-forming agent, plasticizer, colorant and flavoring agent in purified water accounting for 40 wt% of the prescription amount, stirring and dispersing them uniformly to obtain a film-forming solvent solution 2;

[0023] 3) Add solution 1 to solution 2, continue to stir and disperse evenly, let the mixture stand for 3 hours to degas, then spread the material evenly on the base film with a thickness of 0.3 mm, place it in a dark place at 30° C. to dry for 1-2 hours, and cut it into calcitriol orodispersible film preparations of uniform size after drying.

[0024] The calcitriol self-microemulsion oral dissolving film preparation provided by the present invention combines the dual advantages of the self-microemulsion system and the film preparation, stabilizes and uniformly disperses the self-microemulsion system in the film-forming polymer, and can achieve the purpose of rapid onset, improved bioavailability and improved compliance. Compared with the soft capsules that have been on the market, the self-microemulsion oral dissolving film of the present invention can spontaneously form a microemulsion with a particle size not exceeding 200nm under the action of oral saliva, and the calcitriol in the microemulsion is in a dissolved state; the calcitriol embedded in the emulsion droplets also avoids the degradation reaction caused by the influence of light and oxygen; the oral dissolving film does not require a large amount of solvent to dissolve the calcitriol, so a large amount of cost can also be saved. The calcitriol self-microemulsion oral dissolving film is rapidly released in the oral cavity and directly absorbed by the oral mucosa, eliminating the process of disintegration in the stomach and absorption in the intestine after taking the medicine, so that the calcitriol is rapidly metabolized in the body, and it is easier to exert the efficacy and improve the bioavailability. As a dosage form that can improve patient compliance, it can be taken without drinking water, which can avoid the phenomenon of hiding and vomiting medicine, and can greatly improve the problem of patient medication compliance. At the same time, the self-microemulsifying orally dissolving film can also be used to prepare products with different drug loadings according to the needs of clinical treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1is the standard curve for determining the content of calcitriol of the present invention;

[0026] Figure 2 is the particle size distribution of the calcitriol self-microemulsification system of the present invention;

[0027] Figure 3 The dissolution curves of calcitriol self-microemulsion oral dissolving films of the three formulations of the present invention are shown;

[0028] Figure 4 This is a schematic diagram of the appearance of the calcitriol self-microemulsion orally dissolving film of the present invention;

[0029] Figure 5 It is a schematic diagram of the thickness position test of the orally dissolving film of calcitriol self-microemulsion of the present invention. DETAILED DESCRIPTION

[0030] In order to better understand the present invention, the content of the present invention is further explained below in conjunction with examples, but the content of the present invention is not limited to the following embodiments.

[0031] The materials used in the following embodiments may be selected but are not limited to:

[0032] Propylene glycol dicaprylate (batch number 187377), monolinoleyl glyceryl (batch number 183103), oleoyl polyoxyethylene glyceride (batch number 189637), and diethylene glycol monoethyl ether (batch number 176615) were purchased from Jiafashi China Co., Ltd.; sesame oil (batch number 0001964282) was purchased from Croda.Inc; isopropyl alcohol (batch number DW355B21F06) was purchased from Hubei Futon Biochemical Technology Co., Ltd.; caprylic capric acid polyethylene glycol glyceride (batch number C12880792) was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; glycerol (batch number 20221222) was purchased from Nanchang Baiyun Pharmaceutical Co., Ltd.; anhydrous ethanol (batch number 230404142B) was purchased from Nanjing Chemical Reagent Co., Ltd.; calcitriol (batch number 040166) was purchased from CARBOCEN AMCIS Company; n-hexane (HPLC, batch number FT369121B05) was purchased from Hubei Futon Biochemical Technology Co., Ltd.; ethyl acetate (HPLC, batch number WXBD8204V) was purchased from Sigma; n-propanol (HPLC, batch number 20231031) was purchased from Sinopharm Chemical Reagent Co., Ltd.

[0033] The equipment used in the experiment is:

[0034] Agilent 1260 high performance liquid chromatograph (Agilent Technologies, Inc., USA); MS16001LE electronic balance (METTLER TOLEDO); EU50 electric stirrer (Shanghai Fluke Technology Development Co., Ltd.); TG16 high-speed centrifuge (Shanghai Lu Xiangyi Centrifuge Instrument Co., Ltd.), laser particle size tester (Symptech, Germany), DZF-6126 vacuum drying oven (Shanghai Yiheng Scientific Instrument Co., Ltd.), ZB-1D intelligent disintegration instrument (Tianjin University Precision Instrument Factory); FADT-1202 automatic dissolution instrument (Shanghai Fucox Analytical Instrument Co., Ltd.).

[0035] Content determination method:

[0036] High performance liquid chromatography was used, and the chromatographic conditions were silica gel column Inertsil SIL-100A (250mm×4.6mm, 3.0μm); mobile phase: ethyl acetate-n-hexane-n-propanol (25:75:5); flow rate: 1.5mL / min; column temperature 40℃; detection wavelength: 265nm; injection volume: 100μL. The method was validated by methodology, and the theoretical plate number of the method was greater than 10000, and the calcitriol concentration (c) had a good linear relationship with the peak area (y) in the range of 0.4776-1.4328μg / ml, and the standard curve equation was y=150.49x+4.437(R 2 =0.9998), such as Figure 1 shown.

[0037] Example 1 Preparation of Calcitriol Self-Microemulsification System

[0038] 1. Solubility test

[0039] Excess calcitriol was added to different types of oil phase, surfactant and co-surfactant, placed in a 37℃ water bath and stirred at 75rpm for 30 minutes to dissolve, and oscillated in a 37℃ water bath for 1 hour, centrifuged (10000rpm) for 8 minutes, the supernatant was removed, filtered through a 0.45μm filter membrane, and diluted to an appropriate concentration with a mobile phase of ethyl acetate-n-hexane-n-propanol (25:75:5), and the solubility of calcitriol in different excipients was determined by high performance liquid chromatography. The results (Table 1) show that the solubility of calcitriol in the oil phase propylene glycol dicaprylate and monolinoleylglycerol is better than sesame oil; the solubility in surfactants oleoyl polyoxyethylene glyceride and caprylic capric polyethylene glycol glyceride is better than Span 85; the solubility of calcitriol in diethylene glycol monoethyl ether among co-surfactants is significantly better than glycerol and isopropanol. Therefore, this experiment selected propylene glycol dicaprylate as the oil phase, oleoyl polyoxyethylene glyceride as the surfactant, and diethylene glycol monoethyl ether as the co-surfactant, and further screened the dosage of each component in the calcitriol self-microemulsion formulation.

[0040] Table 1 Calcitriol solubility determination results ( n=3)

[0041]

[0042] 2. Screening of oil phase, surfactant and co-surfactant

[0043] According to the solubility data, the oil phase that is better for calcitriol is selected, namely propylene glycol dicaprylate caprate, surfactant oleoyl polyoxyethylene glyceride, and co-surfactant diethylene glycol monoethyl ether. By adjusting the ratio and dosage of each component, the optimal formula is screened out based on appearance, stability and particle size as indicators:

[0044] A certain amount of propylene glycol dicaprylate, oleoyl polyoxyethylene glyceride and diethylene glycol monoethyl ether were weighed into a 100 ml beaker, and stirred at 75 rpm for 40 minutes until uniformly dispersed to prepare a blank self-microemulsifying system; then calcitriol and antioxidant were added to the blank self-microemulsifying system, and stirring was continued for 30 minutes to obtain a drug-containing self-microemulsifying system solution 1. Then 20 ml of the drug-containing self-microemulsifying system solution 1 was taken, and stirring was continued. During the stirring process, 20 times the amount of purified water was added, and the formation of the self-microemulsion was observed to obtain a drug-containing self-microemulsifying system.

[0045] A series of prescription screening was performed according to Table 2 below, and the A3 prescription was selected as the best prescription for calcitriol self-microemulsion based on appearance, stability and particle size, that is, propylene glycol dicaprylate caprate: oleoyl polyoxyethylene glyceride: diethylene glycol monoethyl ether in a ratio of 3:6:1. The results are shown in Table 3.

[0046] Table 2 Self-microemulsification system screening (mg)

[0047] Components A1 A2 A3 A4 A5 Calcitriol 2.5 2.5 2.5 2.5 2.5 Butylated Hydroxyanisole 160 160 160 160 160 Butylated Hydroxytoluene 160 160 160 160 160 Propylene glycol dicaprylate 1800 3600 5400 7200 9000 Oleoyl polyoxyethylene glycerides 14400 12600 10800 9000 7200 Diethylene glycol monoethyl ether 1800 1800 1800 1800 1800

[0048] Table 3 Appearance, stability and particle size measurement results

[0049] formula Appearance stability Particle size / nm A1 Milky white oily solution Layered, with precipitation 131±0.45 A2 Milky white oily solution After standing for 1 hour, separate the layers 51±0.42 A3 Milky white oily solution After standing for 24 hours, no stratification 15±0.38 A4 Milky white oily solution After standing for 12 hours, separate the layers 32±0.47 A5 Milky white oily solution After standing for 1 hour, separate the layers 68±0.35

[0050] Example 2 Preparation and evaluation of calcitriol self-microemulsion orally dissolving film

[0051] 1. Preparation of calcitriol self-microemulsion orally dissolving film

[0052] First, a film-forming agent, a plasticizer, a flavoring agent, and a colorant are dissolved in 40 wt% of a total amount of purified water, and the mixture is fully stirred and dispersed for 50 minutes to prepare a film-forming system; then, the self-microemulsion (without water) prepared in Example 1 is added to the film-forming agent, and the mixture is fully stirred and dispersed. After standing for 3 hours to degas, the mixture is evenly coated on a coating machine with a thickness of 0.3 mm, dried at 25-35° C. for 1-2 hours, and then cut into samples of 1×1 cm in size and packaged in polyester / aluminum / polyethylene packaging bags.

[0053] The specific prescriptions are listed in the table below:

[0054] Table 4 Recipe 1

[0055]

[0056]

[0057] *Prescribed but removed during processing.

[0058] Table 5 Recipe 2

[0059] Raw / auxiliary materials Dosage (mg) Calcitriol 2.5 Butylated Hydroxyanisole 160 Butylated Hydroxytoluene 160 Propylene glycol dicaprylate 5400 Oleoyl polyoxyethylene glycerides 10800 Diethylene glycol monoethyl ether 1800 Polyvinyl alcohol polyethylene glycol copolymer 23000 Sorbitol solution 8500 Sucralose 250 Titanium Dioxide 300 Purified water* 20000

[0060] *Prescribed but removed during processing.

[0061] Table 6 Recipe 3

[0062] Raw / auxiliary materials Dosage (mg) Calcitriol 2.5 Butylated Hydroxyanisole 160 Butylated Hydroxytoluene 160 Propylene glycol dicaprylate 5400 Oleoyl polyoxyethylene glycerides 10800 Diethylene glycol monoethyl ether 1800 Hydroxyethyl Cellulose 25000 Sorbitol solution 6500 Sucralose 250 Titanium Dioxide 300 Purified water* 20000

[0063] *Prescribed but removed during processing.

[0064] 2. Evaluation of calcitriol self-microemulsifying orally dissolving film

[0065] 2.1 Determination of particle size of calcitriol self-microemulsion

[0066] Using formula 1, a calcitriol self-microemulsion was prepared according to the preparation method of Example 1. Then 20 ml of the calcitriol self-microemulsion solution was taken, and stirring was continued. During the stirring process, 20 times the amount of purified water was added. The emulsification was observed and the particle size was measured by a laser particle size analyzer. The results are as follows: Figure 2 shown.

[0067] The particle size of the self-microemulsifier is an important factor affecting the stability of the self-microemulsifier system, and the particle size also affects the dissolution rate. Figure 2As shown in the figure, the particle size (D90) of calcitriol self-microemulsion is 15±0.38nm, indicating that the particle size of calcitriol self-microemulsion is small and uniform. The smaller the particle size, the larger the oil-water interface area of ​​the formed microemulsion, and the greater the surface free energy of the droplet particles. At this time, there is a tendency to reduce the interfacial free energy, driving small droplets to aggregate to form large droplets, and reducing the total oil-water interface area by reducing the specific surface area. At the same time, according to the Stokes equation, the smaller the particle size, the smaller the sedimentation rate, which is more conducive to the stability of the system after self-nanoemulsion emulsification. At the same time, a small particle size is also conducive to the penetration of calcitriol from the self-microemulsion oral dissolution film through the intestinal mucosal tissue, enhancing absorption.

[0068] 2.2 Determination of the thickness of the calcitriol self-microemulsion orally dissolving film

[0069] The prepared calcitriol self-microemulsion orally dissolving film (appearance as Figure 4 The thickness gauge is used for measurement, and the measurement position is as shown in Figure 5 As shown, the thickness of the orodispersible film at 5 locations was recorded in sequence and the average value was calculated. The result met the requirements.

[0070] Table 7 Calcitriol self-microemulsion oral dissolving film thickness (n=3, )

[0071] formula Thickness / μm P1 302.11±2.06 P2 304.68±3.85 P3 305.46±2.13

[0072] 2.3 Study on the disintegration time and in vitro dissolution of calcitriol self-dissolving microemulsion film

[0073] The prepared calcitriol self-microemulsion oral dissolving film was evaluated for quality by disintegration time and dissolution. Disintegration time: Take 6 oral dissolving films and clamp them with paper clips. Check according to the method under the 0921 tablet item of the 2020 edition of the Chinese Pharmacopoeia. Observe and record the time when the film completely disintegrates and passes through the sieve; Dissolution: Take the sample and place it in a sinker. Determine it according to the second method of 0931 of the 2020 edition of the Chinese Pharmacopoeia. The dissolution medium is water, the volume is 500ml, the temperature is 37±0.5℃, the speed is 50rpm, and the timing starts from the time the sample contacts the dissolution medium. Sampling is taken at 5 minutes, filtered through a 0.22μm microporous filter membrane, and the filtrate is taken as the test solution. The dissolution test is carried out according to the "Assay Method". The results are shown in Table 8.

[0074] Table 8 Disintegration time and dissolution test results

[0075] formula Disintegration time / s Dissolution / % P1 31±2 99.7 P2 35±1 98.5 P3 32±1 99.4

[0076] like Figure 3As shown in the figure, the disintegration speed and solubility of the calcitriol self-microemulsion oral dissolving film are fast, and it can be completely disintegrated within 35 seconds and basically completely dissolved in 5 minutes. This is because the calcitriol self-microemulsion is combined with the oral dissolving film. The oral dissolving film can be quickly emulsified to form a micro-sized oil-in-water (o / w) microemulsion during the hydration process of the medium. Since the calcitriol in the self-microemulsion system is already in a dissolved state, it directly skips the dissolution process, so it has a faster dissolution rate.

[0077] 2.4 Study on the stability of calcitriol self-microemulsification orally dissolving film preparation

[0078] The prepared calcitriol self-microemulsion orally dissolving film was placed in an environment of 40±2°C and RH75±5% for 30 days. The results are shown in Table 9.

[0079] Table 9 Accelerated 30-day disintegration time and dissolution test results

[0080]

[0081] As shown in Table 9, the disintegration time and dissolution rate of the calcitriol self-microemulsion orally dissolving film did not change significantly after being placed under accelerated conditions for 30 days, indicating that the preparation can maintain stability.

[0082] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A calcitriol self-microemulsifying orally dissolving film, characterized in that: The composition is calculated by weight percentage, calcitriol 0.005%-0.02%, oil phase 5%-20%, surfactant 10%-25%, cosurfactant 2%-10%, plasticizer 5%-40%, antioxidant 0.05%-5.0%, flavoring agent 0.1%-5%, colorant 1%-5%, and the balance is film-forming agent; wherein the oil phase, surfactant and cosurfactant constitute a self-microemulsification system; The plasticizer is selected from sorbitol solution; propylene glycol dicaprylate caprate is selected as the oil phase, oleoyl polyoxyethylene glyceride is selected as the surfactant, diethylene glycol monoethyl ether is selected as the co-surfactant, and the weight ratio of propylene glycol dicaprylate caprate: oleoyl polyoxyethylene glyceride: diethylene glycol monoethyl ether is 3:6:

1.

2. The calcitriol self-microemulsification orally dissolving film according to claim 1, characterized in that: The film-forming agent is selected from at least one of hydroxyethyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, povidone K30, povidone K90, copovidone, polyoxyethylene, and ethylene-vinyl acetate copolymer; the film-forming agent accounts for 40%-60% of the total weight of the orodispersible film.

3. The calcitriol self-microemulsification orally dissolving film according to claim 1, characterized in that: The antioxidant is selected from a mixture of butylated hydroxyanisole and dibutylated hydroxytoluene in a weight ratio of 1:1; the antioxidant accounts for 0.5%-1% of the total weight of the orodispersible film.

4. The calcitriol self-microemulsification orally dissolving film according to claim 1, characterized in that: The flavoring agent is selected from one or any combination of mint essence, citric acid, sucralose, fructose, lactose, aspartame, acesulfame potassium or steviol glycoside; the flavoring agent accounts for 0.1%-1% of the total weight of the orodispersible film.

5. The calcitriol self-microemulsification orally dissolving film according to claim 1, characterized in that: The colorant is selected from one or any combination of titanium dioxide, red iron oxide, yellow iron oxide, sunset yellow, brown iron oxide, and erythrosine; the colorant accounts for 0.5%-1% of the total weight of the orodispersible film.

6. The method for preparing the calcitriol self-microemulsification orally dissolving film according to any one of claims 1 to 5, characterized in that: The specific steps are as follows: 1) preparing a self-microemulsifying system, stirring and mixing the oil phase, the surfactant and the co-surfactant in a water bath at 35-40° C. to obtain a blank self-microemulsifying system with a particle size not exceeding 200 nm, then adding calcitriol and an antioxidant to the self-microemulsifying system, and continuing to stir for 30 minutes to obtain a self-microemulsifying system solution 1; 2) dissolving the film-forming agent, plasticizer, colorant and flavoring agent in purified water accounting for 40 wt% of the prescription amount, stirring and dispersing them evenly to obtain a film-forming solvent solution 2; 3) Add solution 1 to solution 2, continue to stir and disperse evenly, let the mixture stand for 3 hours to degas, then spread the material evenly on the base film with a thickness of 0.3 mm, place it in a dark place at 30°C to dry for 1-2 hours, and cut it into calcitriol orodispersible film preparations of uniform size after drying.

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