Estazolam oral instant film agent and preparation method thereof

Abstract

The invention discloses an estazolam oral instant film agent and a preparation method thereof. The estazolam oral instant film agent is prepared from the following components in parts by weight: 100 parts of a film-forming solvent, 0.3-2.0 parts of an estazolam raw material medicine, 12-25 parts of a film-forming material, 0.5-9 parts of a plasticizer, 0-0.5 part of a flavoring agent and 0-0.015 part of a coloring agent. The oral cavity instant film agent prepared by the invention is convenient to take, water or a secondary container is not needed, and the medication compliance of a patient is greatly improved; in addition, the dosage can be flexibly adjusted according to the administration area.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and in particular relates to an oral fast-dissolving film preparation of estazolam and a preparation method thereof. Background Art

[0002] Estazolam is a benzodiazepine sedative hypnotic and antianxiety drug. This drug binds to the γ-aminobutyric acid (GABA) A receptor to enhance the inhibitory effect of synaptic transmission of γ-aminobutyric acid, thereby achieving antianxiety and hypnotic effects. As the dose increases, it has antianxiety, sedative hypnotic, amnesia, anticonvulsant and skeletal muscle relaxation effects. Therefore, it is widely used in clinical practice for anti-anxiety, insomnia, tension, fear, relief of pre-operative tension, anxiety, anti-epileptic, anticonvulsant, etc. It can also be used for tension headaches. It is well absorbed orally, and food has no effect on its absorption rate. The peak plasma concentration can be reached 2 hours after oral administration. It is mainly metabolized in the liver and excreted through the kidneys.

[0003] Estazolam is a white or off-white crystalline powder, odorless, bitter, with a melting point of 228°C~229°C, easily soluble in chloroform, slightly soluble in methanol, poorly soluble in acetone, ethanol, ethyl acetate and benzene, almost insoluble in ether and water, odorless, bitter. Its chemical name is: 6-phenyl-8-chloro-4H-[1,2,4]triazole-[4,3α][1,4]benzodiazepine, and its structural formula is as follows:

[0004] Estazolam was first developed by Takeda Pharmaceutical Co., Ltd. and its tablets were launched in Japan in 1975 (trade name: EURODIN), with two specifications: 1 mg / tablet and 2 mg / tablet. In 1990, it was approved by the FDA for marketing in the United States (trade name: ProSom), and has been widely used around the world for its effective therapeutic effects. In the early 1980s, Hubei Pharmaceutical Factory developed the raw material of estazolam and its tablets, which were marketed in China under the trade name "Suletan". With the continuous expansion of the Chinese market and the increase in demand, many domestic pharmaceutical companies have also begun to produce and sell estazolam.

[0005] At present, estazolam is usually used in the form of tablets and injections in clinical practice. However, both preparations have certain limitations. As a commonly used anti-anxiety and insomnia treatment drug, estazolam often requires patients to take it at home, while the injection form must be administered by professional medical staff, which brings great inconvenience to the patient's treatment. In addition, since estazolam itself is almost insoluble in water, a large amount of cosolvent is added to its injection, which may bring certain intravenous injection safety risks.

[0006] Long-term use of estazolam will produce drug resistance and dependence. Sudden discontinuation of the drug after long-term use will produce severe withdrawal symptoms. Therefore, when patients first use estazolam tablets, they should gradually increase the dose from a small dose (0.5 mg, starting) to an effective dose. When the drug needs to be discontinued, it should be gradually reduced. The discontinuation plan is: the daily dose per week is reduced by 0.25 mg (a quarter tablet) compared to the daily dose of the previous week, and the dose is reduced once a week. When the daily dose is reduced to 0.25 mg (a quarter tablet) per day, the patient can continue to take the drug at this dose for 1 week and then stop the drug.

[0007] In view of the characteristics of clinical use of estazolam tablets, there are still some unmet needs in the current commercially available tablets: (1) The minimum specification of the current commercially available tablets is 1 mg, which cannot meet the clinical needs of increasing the dose from a small dose or decreasing the effective dose. In addition, since this product is a small tablet with a diameter of 7.0 mm, it is difficult to split the tablets, which is easy to produce dosage differences, resulting in inaccurate dosage and affecting the efficacy; (2) For some patients with dysphagia or special conditions, it is difficult to take the tablets, and clinical administration is difficult; (3) The tablets can only reach the peak blood concentration 2 to 3 hours after taking. For symptoms such as insomnia and anxiety, the onset time is relatively long, which is not conducive to clinical treatment. So far, some patents have proposed solutions to the problems of low compliance and difficulty in dosing of estazolam tablets. Patent CN1274298C discloses an effective taste-masking orally disintegrating tablet and preparation method, which includes estazolam orally disintegrating tablets, which can disintegrate and dissolve in the mouth in 45s. Compared with ordinary tablets, it can improve patient compliance and shorten the onset time. However, it is still a tablet and cannot solve the problem of flexible administration and medication for special patients. At the same time, the tablet preparation process is complicated, and dust flying causes a bad production environment. Patent CN114848650B proposes an estazolam nanosuspension, which reduces the particle size of the raw material drug by micronization and improves its oral bioavailability. The oral solution can be flexibly adjusted for different usage and dosage, and different administration volumes can be given according to clinical needs, thereby meeting the requirements of administration of a variety of small doses and large dose changes. However, the preparation process of the preparation is complicated, and the volume of solution administration is often difficult to control, which is easy to cause inaccurate dosage. At the same time, more surfactants are used, which is easy to cause other side effects.

[0008] Oral dispersible film (ODF) can quickly disintegrate and dissolve when it comes into contact with saliva, and enter the digestive tract with the swallowing action. Patients do not need to use water to take it. It has the advantages of short disintegration time, rapid dissolution, easy to take, and high bioavailability. It is a dosage form that can well improve patient compliance. It is especially suitable for the elderly, children and special patients with dysphagia.

[0009] The oral fast-dissolving film is similar to the size of a stamp. It can quickly dissolve and disintegrate in the mouth. There is no risk of blockage of the mouth or suffocation like conventional oral solid preparations, which improves the safety of patients' medication. At the same time, it does not need to be taken with the help of water or additional containers. For patients with insomnia and anxiety, this can simplify the medication process and quickly reduce the inner irritability; and the oral film is quickly absorbed into the blood circulation through the rich vascular network of the oral mucosa and sublingual, which can avoid the first-pass effect of the drug in the liver to a certain extent, improve bioavailability, quickly exert the drug effect, and relieve symptoms. Summary of the invention In view of the deficiencies of the prior art, the purpose of the present application is to provide an oral fast-dissolving film of estazolam and a preparation method thereof, aiming to solve the problems of low medication compliance and difficulty in dosing of existing estazolam tablets. The present invention provides an oral fast-dissolving film of estazolam with a simple preparation process, flexible dosage adjustment and rapid onset. The preparation disintegrates and dissolves in the oral cavity within 30 seconds without the need for swallowing, thereby improving the patient's medication compliance and safety, and the preparation has excellent mechanical properties, which is conducive to storage, transportation and use.

[0010] This application is specifically implemented through the following technical solutions: An estazolam oral fast-dissolving film is prepared from the following components in parts by weight: 100 parts of a film-forming solvent, 0.3-2.0 parts of an estazolam raw material, 12-25 parts of a film-forming material, 0.5 g-9 parts of a plasticizer, 0-0.5 parts of a flavoring agent, and 0-0.015 parts of a colorant.

[0011] Preferably, the oral fast-dissolving film of estazolam is prepared from the following components in parts by weight: 100 parts of a film-forming solvent, 1.2-1.75 parts of an estazolam bulk drug, 15-20 parts of a film-forming material, 3.0 g-8.76 parts of a plasticizer, 0.2-0.5 parts of a flavoring agent, and 0.002-0.01 parts of a colorant.

[0012] Preferably, the film-forming solvent is water, ethanol or ethanol-water solution.

[0013] Preferably, the film-forming material is at least one of methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone (PVP), polyvinyl alcohol-polyethylene glycol copolymer, xanthan gum, tragacanth gum, sodium alginate and pullulan, and more preferably, at least one of hydroxypropyl methylcellulose and polyvinyl alcohol.

[0014] In some embodiments, the model of hydroxypropyl methylcellulose is HPMC-E5; the model of polyvinyl alcohol is PVA 588. When at least one of HPMC-E5 and PVA 588 is used as a film-forming material, the mass ratio of the HPMC-E5 and PVA 588 to the film-forming solvent is preferably 17.5%.

[0015] Preferably, the plasticizer is at least one of polyethylene glycol 400, glycerol, 1,2-propylene glycol, silicone oil, mannitol and sorbitol, and more preferably polyethylene glycol 400 or glycerol.

[0016] The role of plasticizers is to lower the glass transition temperature of the film, increase its plasticity and toughness, and improve elongation.

[0017] In some embodiments, when polyethylene glycol 400 is used as a plasticizer, the mass ratio of the film-forming material to the plasticizer is preferably 2:1 to 3:1; when glycerol is used as a plasticizer, the mass ratio of the film-forming material to the plasticizer is preferably 3:1.

[0018] Preferably, the flavoring agent is at least one of sucralose, fructose, sucrose, xylitol, aspartame, stevioside, glycyrrhizin, citric acid, flavor, saccharin and saccharin sodium, and more preferably sucralose and citric acid.

[0019] Flavoring agents are substances added to film dosage forms to correct bitter or other unpleasant tastes in order to improve mouthfeel and enhance patient acceptance.

[0020] In some embodiments, when sucralose and citric acid are mixed in a mass ratio of 3:2 as a flavoring agent, the bitter taste can be effectively masked.

[0021] The preparation method of the above-mentioned fast-dissolving oral estazolam film comprises the following steps: (1) Dispersing the film-forming material into a portion of the film-forming solvent according to the component ratio, heating until dissolved; then cooling to room temperature, adding a plasticizer and stirring evenly to obtain a solution A; (2) Evenly mixing the estazolam API, flavoring agent, coloring agent and remaining film-forming solvent to obtain solution B; (3) Solution A and solution B are mixed evenly, and film-formed after defoaming to prepare an oral fast-dissolving film preparation of estazolam.

[0022] Preferably, in step (1), the film-forming material is dispersed in a portion of the film-forming solvent, wherein the volume of the portion of the film-forming solvent accounts for 2 / 5 to 3 / 5 of the total solvent volume; and the film-forming material is stirred in a 60° C. water bath until dissolved.

[0023] Preferably, in step (1), when the film-forming material is PVA 588, PVA 588 is first weighed according to the component ratio and fully swelled in water, and then stirred in a water bath at 80-90° C. until dissolved.

[0024] Preferably, in step (2), the estazolam raw material is pulverized before use, and D90 after pulverization is ≤15 μm.

[0025] Preferably, in step (3), solution B is poured into solution A and stirred for 2 to 3 hours to mix them evenly.

[0026] Preferably, in step (3), defoaming is performed by ultrasonic or static method.

[0027] Preferably, in step (3), the specific operation of film making includes: coating with a coating machine, then heating and drying at 40-60° C. for 1-2 hours, cooling, removing the film, and cutting to obtain the desired preparation.

[0028] Compared with the prior art, the beneficial effects of this application include: (1) The preparation method and formulation process provided by the present invention are simple in process and highly repeatable, and can effectively control dust during the production process, which is conducive to industrial production. In addition, the preparation is easy to take without the need for water or secondary containers, which greatly improves the patient's medication compliance.

[0029] (2) The oral fast-dissolving film provided by the present invention can determine the dosage according to the administration area, so that patients can flexibly adjust the dosage according to their own symptoms, thereby solving the problem that traditional tablets are difficult to accurately divide. In addition, the preparation can be quickly hydrated and dissolved in the oral cavity, and directly enter the systemic circulation through the blood vessels under the oral mucosa, avoiding the first-pass effect of the liver, achieving rapid onset of action, and improving bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is a comparative diagram of the in vitro dissolution rates of the estazolam oral fast-dissolving film described in Example 28 and the commercially available EURODIN, wherein Estazolam ODF corresponds to the estazolam oral fast-dissolving film described in Example 28. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the present application more clear, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described here are only used to explain the present application and are not used to limit the present application.

[0032] In the following examples, the method for measuring the thickness of the oral fast-dissolving film is as follows: The film obtained by coating was cut into three small films of 2 cm × 3 cm at different positions. The thickness of the two preparations was measured by a five-point sampling method using an electronic spiral micrometer (resolution: 0.001 mm), i.e., the four corners and the center of the film. Five values ​​were recorded and the average value was calculated to obtain the thickness of the oral adhesive film preparation.

[0033] In the following examples, the method for determining the mechanical properties of the oral fast-dissolving film is as follows: (1) Determination of tensile strength and elongation at break Cut the film into strips of 20 mm × 150 mm, fix the two ends in the left and right clamps of the electronic stripping machine, control the tightness of the sample, and keep it in a state of being just straightened but not taut. Set the stretching speed to 30 mm / min. After the test starts, the right clamp of the electronic stripping machine moves automatically, and the sensor sensing force value and elongation are recorded. Three groups are measured in parallel, and the average value is recorded. The calculation formulas for the tensile strength and elongation at break of the film are as follows: Tensile strength = tensile force at break / initial cross-sectional area of ​​film Elongation at break = (film elongation / initial length) × 100% (2) Folding endurance test A 2 cm × 3 cm membrane sheet was folded repeatedly in the same direction at the same position until the membrane sheet broke. The number of folds was recorded and the average value was taken (n = 3).

[0034] In the following examples, the disintegration time of the oral fast-dissolving film was determined as follows: The disintegration time determination method refers to the disintegration time inspection method for orally disintegrating tablets in Part IV of the Chinese Pharmacopoeia, Item 0921. An intelligent disintegrator is used, and the up and down movement distance of the disintegrator basket is adjusted to 55mm±2mm, and the reciprocating frequency is 30-32 times / minute. The position of the basket is adjusted so that the bottom screen is 25mm away from the bottom of the beaker when the basket descends. Water is used as the medium, and the water level is adjusted so that the screen is 15mm below the water surface when the basket rises. Heat to 37℃±1℃. Place the cut estazolam oral fast-dissolving film in the basket, and record the time required for the film to completely disintegrate and pass through the screen. If a small amount of light weight floats up or adheres to the inner wall or screen, it is considered to be completely disintegrated, and the complete disintegration time of the preparation is recorded.

[0035] Embodiment 1~6 Research on the types of film-forming materials This example provides a series of estazolam oral fast-dissolving films, and the composition ratio of the estazolam oral fast-dissolving films in each example is shown in Table 1. Among them, the ratio of the weight of the film-forming material to the volume of the film-forming solvent (purified water) (w / v%) is 17.5%, the mass ratio of the film-forming material to the plasticizer is 2:1, the plasticizer is PEG400, the type and amount of the plasticizer are fixed, and the single factor variable method is used to study the appearance, thickness, disintegration time and mechanical properties of MC (methylcellulose), PVA588, PVA1788, HPMC-E3, HPMC-E5 and HPMC-E15. The research results are shown in Table 2.

[0036] The preparation method of the estazolam oral fast-dissolving film comprises the following steps: (1) According to the composition ratio in Table 1, disperse the film-forming material in 15 mL of purified water and heat until dissolved; then cool to room temperature, add the plasticizer and stir evenly to obtain solution A; (2) Evenly mix the estazolam API, flavoring agent, coloring agent, and the remaining 10 mL of purified water to obtain solution B; (3) Mix solution A and solution B evenly, let it stand overnight to remove bubbles, apply film at 40℃ using a coating machine, dry for 1 hour, let it cool and then cut.

[0037] Table 1 Preparation formula of Example 1 to Example 6

[0038] Table 2 Performance of products described in Examples 1 to 6

[0039] As can be seen from Table 2, MC and HPMC-E3 cannot form uniform instant films; PVA1788 and HPMC-E15 can form films, but the films formed by both are damaged during the film removal process; the films formed by PVA588 and HPMC-E5 are transparent and smooth, with uniform texture and good mechanical properties, and can disintegrate within 30 seconds. Therefore, PVA588 and HPMC-E5 are better film-forming materials.

[0040] Embodiment 6-10 Study on the dosage of film-forming materials The amount of film-forming material used has a crucial effect on the properties of the film. In this example, the amount of film-forming material was calculated according to the ratio of the weight of the film-forming material to the volume of the solvent (w / v%), and the film-forming properties and disintegration time of the film were investigated when the amount of the film-forming material was 12.5%, 15%, 17.5% and 20%, respectively. The results are shown in Table 4. The composition ratio of the estazolam oral fast-dissolving film described in each example is shown in Table 3, and the preparation method of the estazolam oral fast-dissolving film is the same as that in Example 1.

[0041] Table 3 Preparation prescriptions of Examples 7 to 10

[0042] Table 4 Film-forming properties of the products of Examples 7 to 10

[0043] From the results in Table 4, it can be seen that when the film-forming material is HPMC-E5, when the w / v% is 12.5% ​​or 15%, due to the low viscosity of the film-forming glue, the glue flows out due to the low surface tension, the thickness of the obtained film is uneven, and the edge is incomplete; when the w / v% is 20%, the concentration of the film material increases, the difficulty of dissolution increases, and at the same time, the excessive concentration of the glue increases the loss during transfer, resulting in unqualified preparation content; when the w / v% is 17.5%, the viscosity of the glue is moderate, suitable for coating, and the obtained film is smooth and uniform, and disintegrates quickly. When the film-forming material is PVA0588, when the w / v% is 12.5% ​​or 15%, the solution is too dilute and flows around; when the w / v% is 17.5%, the film has uniform texture, disintegrates quickly, and is suitable for coating; when the w / v% is 20%, the viscosity of the glue increases slightly, but the coating is smooth, and the film has uniform texture and disintegrates quickly. Considering that PVA588 needs to swell for a long time and then be stirred at high temperature before it can be dissolved, there are great safety hazards in industrial production with long-term high-temperature stirring. Therefore, it is necessary to choose low-concentration PVA588 or other film-forming materials as much as possible.

[0044] Embodiments 11 to 14 Research on plasticizer types Oral film should have certain mechanical strength to ensure that it is not damaged during transportation, storage and use. Plasticizers are generally used to adjust the flexibility of the film, and the mechanical strength of the film is improved by reducing the glass transition temperature of the film material. Different plasticizers often have different effects on the improvement of film toughness, and it is necessary to select a suitable plasticizer to match the film-forming material. The present invention investigates the film-forming ability, mechanical properties and disintegration time of the film when polyethylene glycol 400, glycerol, propylene glycol and triethyl citrate are plasticizers through Examples 11-14, and then determines the type of plasticizer, and the test results are shown in Table 6. The composition ratio of the oral instant dissolving film of estazolam described in each embodiment is shown in Table 5, and the preparation method of the oral instant dissolving film of estazolam is the same as Example 1.

[0045] Table 5 Preparation prescriptions of Examples 11 to 14

[0046] Table 6 Film-forming properties of different plasticizers

[0047] From the results in Table 6, it can be seen that when propylene glycol and triethyl citrate are used as plasticizers, the mechanical properties of the film are not good. In comparison, propylene glycol performs better. When PEG400 or glycerol is used as a plasticizer, the mechanical properties of the film are significantly improved. Therefore, one of the two is selected as the plasticizer for research.

[0048] Embodiments 15 to 22 Study on the amount of plasticizer The amount of plasticizer used will also affect the mechanical properties of the film. Too high a concentration may damage the moisture resistance of the film, causing the film to become sticky or the stability to deteriorate; too low a concentration will not improve the toughness of the film, resulting in poor mechanical properties of the film. Therefore, it is necessary to optimize the ratio of plasticizer to film material. In Examples 15-22, the present invention uses HPMC-E5 as a film-forming material, PEG400 or glycerol as a plasticizer, and adjusts the mass ratio of HPMC-E5 to the plasticizer to 2:1, 3:1, 4:1 or 5:1 to screen the amount of plasticizer. The composition ratio of the oral fast-dissolving film of estazolam described in each embodiment is shown in Table 7, and the preparation method of the oral fast-dissolving film of estazolam is the same as that in Example 1. The test results are shown in Table 8.

[0049] Table 7 Preparation formula of Example 15 to Example 22

[0050] Table 8 Effect of different amounts of plasticizer on film properties

[0051] From the results in Table 8, it can be seen that when the plasticizer is PEG400, the film obtained is harder when the dosage is low, the mechanical properties are poor and it is easy to curl. As the amount of plasticizer increases, the mechanical properties of the film are significantly improved, and it is smooth and flat. When the mass ratio of HPMC-E5 to PEG400 is 2:1~3:1, the film has excellent mechanical properties, is smooth and flat, and is suitable for use, storage and transportation. When the plasticizer is glycerol, a high concentration will make the film soft to the touch, and it is easy to absorb moisture, thicken and soften during storage. When the mass ratio of HPMC-E5 to glycerol is 3:1, the film has excellent mechanical properties and is not prone to moisture absorption and softening. Therefore, PEG400 or glycerol was selected as the plasticizer for research.

[0052] Embodiments 23 to 27 Research on flavoring agents Estazolam tastes bitter, and the oral dissolving film dissolves and disintegrates directly in the oral cavity, so its taste masking problem needs to be considered. The present invention reduces bitterness by reducing the drug particle size on the one hand, and covers bitterness by introducing sweetener sucralose and salivary stimulant citric acid on the other hand. Citric acid has sour taste and can stimulate saliva secretion, which is conducive to the disintegration of oral fast-dissolving film in the mouth, and can also neutralize some bitterness. Sucralose is a relatively ideal sweetener, and its sweetness is about 300-1000 times that of sucrose. Only a small amount of addition is needed to achieve a very sweet taste, and there is no energy intake, which is suitable for diabetics. Therefore, sucralose is the most commonly used and most effective sweetener when the oral dissolving film is flavored. The present invention introduces sucralose and citric acid and screens its dosage to evaluate its flavoring effect. The composition ratio of the oral fast-dissolving film of each embodiment is shown in Table 9, and the preparation method of the oral fast-dissolving film of estazolam is the same as that of Example 1. The test results are shown in Table 10.

[0053] Table 9 Composition of estazolam orodispersible film prepared with different amounts of sucralose and citric acid

[0054] Table 10 Performance of estazolam orodispersible films prepared with different amounts of sucralose and citric acid

[0055] From the results in Table 10, it can be seen that when the mass ratio of sucralose to citric acid is 3:2, the bitter taste of estazolam can be effectively masked through the regulatory effect between sweetness and sourness, and after adding different amounts of sucralose and citric acid, the morphology, mechanical strength and disintegration time of the film did not change significantly. Therefore, according to the final results obtained by tasting, the mass ratio of sucralose to citric acid was selected as 3:2 as the most effective flavor correction option.

[0056] Embodiment 28 Introduction of colorants The final preparation of the present invention is 2×3 cm 2 The film pays attention to the privacy protection of patients and the convenience of medication, and prevents the loss and difficulty of finding the preparation after unpacking. Consider adding colorants to enhance the drug identification. The specific prescription is as follows: Estazolam API 0.35g HPMC-E54.38g PEG4002.00g Sucralose 0.03g Citric acid 0.02g Methylene blue 0.004g 25.00mL of purified water.

[0057] The preparation method is the same as that in Example 1. The prepared film is light blue with obvious coloring and strong recognition. The film has uniform texture, is flat and smooth, has a thickness of 60±2.13μm, a disintegration time of 25±2.15s, a tensile strength of 12.04±2.30Mpa, and an elongation at break of 22.18±2.33%. It can be seen that the addition of the colorant has no effect on the properties of the film.

[0058] Evaluation of in vitro dissolution of estazolam oral fast-dissolving film Referring to the in vitro dissolution method of the commercially available preparation EURODIN, the present invention uses EURODIN (Teva Takeda Pharma Ltd.) as a reference, water as a dissolution medium, a volume of 900 mL, and a dissolution experiment is performed at 37°C ± 1°C at a speed of 50 rpm. 5 mL of samples are taken at 1 min, 3 min, 5 min, 10 min, 15 min and 20 min, and then 5 mL of 37°C dissolution medium is added to keep the total volume at 900 mL. After filtering with a filter with a pore size of 0.45 μm, 10 μL of the filtrate is taken for liquid phase analysis (n=6). The analysis results are shown in Figure 1 shown.

[0059] from Figure 1 From the analysis results, we can see that compared with the reference preparation, estazolam tablets (EURODIN), estazolam orodispersible film disintegrates faster in the mouth, releases the drug more quickly, and takes effect faster. It has better clinical effectiveness for patients with anxiety and insomnia.

[0060] Study on the stability of orodispersible estazolam film The orally dissolving film obtained in Example 28 was cut into 2×3 cm 2 Half of the films of different sizes were packed in aluminum foil bags, and the other half were not packed. Several portions of each were spread flat in weighing bottles and placed in a constant temperature dryer (60°C) for 10 days; several portions of each were spread flat in weighing bottles and placed in a constant temperature dryer (25°C / 75%RH) for 10 days (the lower layer of the dessicator was placed with a saturated NaCl solution, and the dessicator was sealed with vaseline). Under the above two conditions, the films were sampled on the 5th and 10th days to examine the changes in the appearance, mechanical properties, disintegration time and content of the films.

[0061] Table 11 Stability of Estazolam Oral Rapidly Dissolving Film

[0062] From the results in Table 11, it can be seen that when the estazolam oral fast-dissolving film is not packaged, it is easy to evaporate water under high temperature conditions, making the film hard and brittle, and the mechanical properties are reduced; under high humidity conditions, it is easy to absorb moisture to increase the film, causing wrinkles on the surface, softening, and the mechanical properties are also reduced. When packaged in an aluminum foil bag, the estazolam oral fast-dissolving film will still lose water and dry under high temperature conditions, but maintain a high stability under high humidity conditions. Therefore, the estazolam oral fast-dissolving film should be stored in a cool and dry environment.

[0063] The specific implementation methods of the present application described above do not constitute a limitation on the protection scope of the present application. Any other corresponding changes and modifications made according to the technical concept of the present application should be included in the protection scope of the claims of the present application.

Claims

1. An estazolam oral fast-dissolving film, characterized in that: The composition is prepared from the following components in parts by weight: 100 parts of a film-forming solvent, 0.3-2.0 parts of an estazolam raw material, 12-25 parts of a film-forming material, 0.5-9 parts of a plasticizer, 0-0.5 parts of a flavoring agent, and 0-0.015 parts of a colorant.

2. The oral fast-dissolving estazolam film according to claim 1, characterized in that: The composition is prepared from the following components in parts by weight: 100 parts of a film-forming solvent, 1.2-1.75 parts of an estazolam raw material, 15-20 parts of a film-forming material, 3.0-8.76 parts of a plasticizer, 0.2-0.5 parts of a flavoring agent and 0.002-0.01 parts of a colorant.

3. The oral fast-dissolving estazolam film according to claim 1, characterized in that: The film-forming solvent is water, ethanol or ethanol-water solution; The flavoring agent is at least one of sucralose, fructose, sucrose, xylitol, aspartame, stevioside, glycyrrhizin, citric acid, flavor, saccharin and saccharin sodium.

4. The oral fast-dissolving estazolam film according to claim 2, characterized in that: The film-forming material is at least one of methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol-polyethylene glycol copolymer, xanthan gum, tragacanth gum, sodium alginate and pullulan; The plasticizer is at least one of polyethylene glycol 400, glycerol, 1,2-propylene glycol, silicone oil, mannitol and sorbitol.

5. The estazolam oral fast-dissolving film according to claim 4, characterized in that: When at least one of hydroxypropyl methylcellulose and polyvinyl alcohol is used as a film-forming material, its mass ratio to the film-forming solvent is 17.5%; When polyethylene glycol 400 is used as a plasticizer, the mass ratio of film-forming material to plasticizer is 2:1~3:1; When glycerol is used as a plasticizer, the mass ratio of film-forming material to plasticizer is 3:1; When sucralose and citric acid are used as flavoring agents, the mass ratio of sucralose to citric acid is 3:

2.

6. The method for preparing the fast-dissolving oral estazolam film according to any one of claims 1 to 5, characterized in that: The steps include: (1) Dispersing the film-forming material into a portion of the film-forming solvent according to the component ratio, heating until dissolved; then cooling to room temperature, adding a plasticizer and stirring evenly to obtain a solution A; (2) Evenly mixing the estazolam API, flavoring agent, coloring agent and remaining film-forming solvent to obtain solution B; (3) The solution A and the solution B are mixed evenly, and after defoaming, a film is formed to prepare the estazolam oral fast-dissolving film.

7. The method for preparing the fast-dissolving oral estazolam film according to claim 6, characterized in that: The film-forming material in step (1) is dispersed in a portion of the film-forming solvent, wherein the volume of the film-forming solvent accounts for 2 / 5 to 3 / 5 of the total solvent volume; and is stirred in a 60° C. water bath until dissolved.

8. The method for preparing the fast-dissolving oral estazolam film according to claim 6, characterized in that: The estazolam raw material drug in step (2) is pulverized before use, and D90 is ≤15 μm after pulverization.

9. The method for preparing the estazolam oral fast-dissolving film according to claim 6, characterized in that: In step (3), solution B is poured into solution A and stirred for 2 to 3 hours to make the mixture uniform; In step (3), defoaming is performed by ultrasonic or static method.

10. The method for preparing the fast-dissolving oral estazolam film according to claim 6, characterized in that: The specific operation of the film-making in step (3) includes: coating with a coating machine, then heating and drying at 40-60° C. for 1-2 hours, cooling, removing the film, and cutting to obtain the desired preparation.

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