Mononitrate isosorbide orally dissolving film formulation and method of preparation thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a mononitrate isosorbide oral dissolving film and a preparation method thereof. The mononitrate isosorbide oral dissolving film preparation is composed of a drug-containing layer and isolation layers which are compounded on the upper and lower surfaces of the drug-containing layer. The drug-containing layer comprises the following raw materials in percentage by mass: cyclodextrin-encapsulated mononitrate isosorbide 10-60%, film-forming material 20-80%, plasticizer 0-20% and auxiliary material 0-10%. The isolation layer comprises the following raw materials in percentage by mass: film-forming material 70-100%, plasticizer 0-30% and auxiliary material 0-10%. The mononitrate isosorbide oral dissolving film prepared by the application has the advantages of smooth appearance, good taste, uniform drug content, rapid dissolution under the action of saliva after entering the mouth, and further release and absorption, which greatly improves the drug administration compliance and solves the problem of surface crystallization of mononitrate isosorbide after long-term storage.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an isosorbide mononitrate oral dissolving film and its preparation method. Background Technology

[0002] Isosorbide mononitrate, chemically named 1,4:3,6-didehydro-D-sorbitol-5-mononitrate, has the molecular formula C6H9NO6 and a molecular weight of 191.14. Its structural formula is as follows:

[0003]

[0004] Isosorbide mononitrate is a nitrate antianginal drug. It is the main bioactive metabolite of isosorbide dinitrate, and like other organic nitrates, its primary pharmacological action is relaxation of vascular smooth muscle. Isosorbide mononitrate releases nitric oxide (NO), which, like endothelial relaxing factor, activates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) in smooth muscle cells. This relaxes vascular smooth muscle, causing dilation of peripheral arteries and veins, with a stronger effect on veins. Venous dilation leads to peripheral blood pooling, reducing venous return and decreasing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arterial dilation reduces peripheral vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Coronary artery dilation increases coronary perfusion. The overall effect is reduced myocardial oxygen consumption and increased oxygen supply, thus relieving angina.

[0005] Currently, isosorbide mononitrate is available in oral dosage forms such as tablets, extended-release tablets, and extended-release capsules. All of these dosage forms require water to be taken, which is inconvenient, especially for elderly patients with swallowing difficulties. Furthermore, all of these dosage forms are manufactured using traditional tablet and capsule production processes. Because isosorbide mononitrate contains nitro groups, it is prone to explosion when heated or subjected to impact. Therefore, the traditional tablet and capsule production process must strictly control temperature and avoid rough handling such as impacts and knocks to prevent accidents, placing high demands on safe production practices.

[0006] Orally dissolving films are oral formulations made by uniformly dispersing the active pharmaceutical ingredient in a film-forming material. Their size, shape, and thickness are similar to a postage stamp. They dissolve and release the active pharmaceutical ingredient in the oral cavity within a short time, and are absorbed through the oral mucosa or swallowed, and then absorbed through the gastrointestinal tract. They have a rapid onset of action and high bioavailability. They can be administered rapidly and accurately anytime, anywhere without requiring water, without delaying medication administration. Isosorbide mononitrate formulations primarily benefit middle-aged and elderly patients, who often have difficulty swallowing regular tablets. Therefore, this formulation provides a safe and reliable route of administration for the elderly and those with swallowing difficulties, improving patient compliance.

[0007] For example, patent CN103784426B discloses an aripiprazole oral dissolving film containing aripiprazole encapsulated in cyclodextrin. The cyclodextrin is one or more of hydroxypropyl-β-cyclodextrin or glucosyl-β-cyclodextrin, and the weight ratio of cyclodextrin to aripiprazole is 1:1 to 3:1. This film-like preparation is uniform and smooth, easy to take (no water required), and dissolves rapidly and completely. It also has fast absorption, high bioavailability, and good therapeutic effect.

[0008] However, isosorbide mononitrate is only slightly soluble in water, and has strong lipid solubility and penetrability. When preparing oral dissolving films directly using the method described in patent CN103784426B, crystallization occurs as the product is stored for an extended period, leading to changes in properties and uneven product content. Patents CN103610650B and CN110420192B also mention that crystallization is a common phenomenon in isosorbide mononitrate formulations. Summary of the Invention

[0009] The technical problem to be solved by this invention is to provide an isosorbide mononitrate oral dissolving film with a smooth and flat appearance, good taste, and uniform drug content. After entering the mouth, it dissolves rapidly under the action of saliva, thereby releasing and absorbing the drug, which greatly improves drug administration compliance. At the same time, it solves the problem of surface crystallization of isosorbide mononitrate after long-term storage. This invention also provides a preparation method for it, which is simple and easy to industrialize.

[0010] The isosorbide mononitrate orally dissolving film of the present invention comprises a drug-containing layer and a separating layer composited on the upper and lower surfaces of the drug-containing layer; the drug-containing layer comprises the following raw materials in the indicated mass percentages:

[0011]

[0012] The insulating layer comprises the following raw materials by weight percentage:

[0013] Film-forming material 70~100%,

[0014] Plasticizer 0-30%,

[0015] Auxiliary materials: 0-10%.

[0016] In this invention, the thickness of the drug-containing layer is 10-100 μm, preferably 50-100 μm; the thickness of the isolation layer is 10-100 μm.

[0017] In this invention, the mass ratio of cyclodextrin to isosorbide mononitrate in the cyclodextrin-encapsulated isosorbide mononitrate is 0.5:1 to 3:1.

[0018] Among them, cyclodextrin is one or more of hydroxypropyl betacyclodextrin, hydroxypropyl gammacyclodextrin, and sodium sulfobutyl betacyclodextrin.

[0019] In one embodiment, the preparation method of the cyclodextrin-encapsulated isosorbide mononitrate is as follows: after adding cyclodextrin to water and stirring to dissolve it, add isosorbide mononitrate, and stir at 45-55°C for 0.5-2 hours to encapsulate it, thereby obtaining the cyclodextrin-encapsulated isosorbide mononitrate.

[0020] In this invention, the film-forming material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, and sodium alginate.

[0021] In this invention, the plasticizer is one or more of glycerol, polyethylene glycol, propylene glycol, and triethyl citrate.

[0022] In this invention, the excipients include one or both of flavoring agents and coloring agents.

[0023] The flavoring agent is one or more of sucralose, aspartame, and sodium saccharin.

[0024] The isosorbide mononitrate oral dissolving film of the present invention can be completely dissolved in water at 37°C within 60 seconds.

[0025] The method for preparing the isosorbide mononitrate oral coating of the present invention includes the following steps:

[0026] (1) Drug-containing gel: Add cyclodextrin to water and stir to dissolve, add isosorbide mononitrate, stir and encapsulate at 45-55℃ for 0.5-2h, cool to room temperature, then add plasticizer, excipients and film-forming materials, mix evenly, degas, and the drug-containing gel is obtained.

[0027] (2) Isolation layer adhesive: Add plasticizer and auxiliary materials to water and stir to dissolve, then add film-forming material, mix evenly, and degas to obtain isolation layer adhesive;

[0028] (3) Apply the release film sequentially with the release layer adhesive, the drug-containing layer adhesive, and the release layer adhesive, and dry them. Then peel them off from the release film to obtain the isosorbide mononitrate oral solution film.

[0029] In this invention, the degassing process can be performed using vacuum degassing or static degassing.

[0030] This invention utilizes cyclodextrin to encapsulate isosorbide mononitrate. An inclusion complex is a molecule whose spatial structure completely or partially encapsulates another molecule; it is also known as a molecular capsule. Due to its unique structure of being "hydrophilic on the outside and hydrophobic on the inside" and its excellent non-toxic properties, cyclodextrin can encapsulate various guest molecules. Inclusion complexes prepared using appropriate methods can improve certain properties of the guest molecules. Since the water solubility of isosorbide mononitrate (1.09 mg / ml, 25°C) is insufficient to meet the concentration requirements for preparing oral dissolving film solutions, and adding a more soluble organic solvent poses safety risks, cyclodextrin was chosen as an excipient to encapsulate isosorbide mononitrate to improve its water solubility.

[0031] However, isosorbide mononitrate still exhibits crystallization even after being encapsulated with cyclodextrin, leading to changes in drug properties and uneven product content over long-term storage. When isosorbide mononitrate is encapsulated with cyclodextrin to form an orally dissolving film, this drawback is amplified due to the film's larger surface area. This invention, through experimentation, reveals that adding a polymer coating to the drug-containing layer effectively prevents isosorbide mononitrate crystallization.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0033] (1) This invention uses cyclodextrin to encapsulate isosorbide mononitrate, thereby improving the solubility of isosorbide mononitrate in water and making the solubility of isosorbide mononitrate in water meet the concentration requirements for preparing oral soluble film solution; and by adding a polymer coating to the surface of the drug-containing layer, the crystallization phenomenon of isosorbide mononitrate is effectively avoided.

[0034] (2) The isosorbide mononitrate oral dissolving film of the present invention has a smooth and flat appearance, good taste, and uniform drug content. It does not need to be taken with water after ingestion. It dissolves rapidly under the action of saliva and is then released and absorbed, which greatly improves the medication compliance. At the same time, it solves the problem of surface crystallization of isosorbide mononitrate after long-term storage. Attached Figure Description

[0035] Figure 1 Comparison of crystallization phenomena of the oral dissolution membrane in Comparative Example 1 before and after 3 days of storage;

[0036] In the image: the left side shows crystallization after 3 days; the right side shows crystallization immediately after being peeled off from the release film. Detailed Implementation

[0037] The present invention will be further described below with reference to embodiments, but the scope of protection of the present invention is not limited thereto. Any changes made to the technical solutions of the present invention by those skilled in the art should fall within the scope of protection of the present invention.

[0038] Unless otherwise specified, the raw materials used in the embodiments are all commercially available conventional raw materials; unless otherwise specified, the process methods used in the embodiments are all conventional methods in the art.

[0039] Example 1

[0040] An isosorbide mononitrate orally disintegrating film comprises a drug-containing layer and an isolation layer composited on the upper and lower surfaces of the drug-containing layer, wherein the thickness of the drug-containing layer is 70 μm and the thickness of the isolation layer is 17 μm.

[0041] The prescription for the drug-containing layer is as follows:

[0042] Isosorbide mononitrate 20g, hydroxypropyl beta-cyclodextrin 16g, hydroxypropyl methylcellulose E5 20g, hydroxypropyl cellulose 5g, glycerin 4.8g, sucralose 0.4g, peach powder flavoring 0.8g, purified water 80g.

[0043] The isolation layer prescription is as follows:

[0044] Hydroxypropyl methylcellulose E520g, hydroxypropyl cellulose 5g, glycerin 4.8g, sucralose 0.4g, peach powder flavoring 0.8g, purified water 60g.

[0045] Purified water is used as the solvent for the adhesive and is removed during the process.

[0046] Preparation is as follows:

[0047] (1) Drug-containing gel: Hydroxypropyl β-cyclodextrin is added to water and stirred to dissolve. Isosorbide mononitrate is added and stirred at 50°C for 2 hours. After cooling to room temperature, glycerol, sucralose, peach powder flavoring, hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 are added and mixed evenly. The mixture is allowed to stand to remove bubbles, and the drug-containing gel is obtained.

[0048] (2) Isolation layer adhesive: Add glycerin, purified water, sucralose and peach powder flavoring to water and stir to dissolve. Then add hydroxypropyl cellulose and hydroxypropyl methylcellulose E5, mix evenly, and let stand to remove bubbles to obtain the isolation layer adhesive.

[0049] (3) Apply the release layer adhesive to the release film and dry it at 50°C. After drying, apply and dry the drug-containing layer adhesive and the release layer adhesive in sequence according to the same method. Then peel it off from the release film, cut and divide it, and seal it for packaging to obtain isosorbide mononitrate oral dissolving film.

[0050] Example 2

[0051] An isosorbide mononitrate orally disintegrating film comprises a drug-containing layer and an isolation layer composited on the upper and lower surfaces of the drug-containing layer, wherein the thickness of the drug-containing layer is 95 μm and the thickness of the isolation layer is 15 μm.

[0052] The prescription for the drug-containing layer is as follows:

[0053] Isosorbide mononitrate 20g, hydroxypropyl gamma cyclodextrin 34g, polyvinyl alcohol 178832g, glycerin 4.8g, polyethylene glycol 4002g, aspartame 0.2g, peach powder flavoring 0.4g, purified water 50g.

[0054] The isolation layer prescription is as follows:

[0055] Polyvinyl alcohol 178824g, glycerin 3.6g, polyethylene glycol 4001.5g, aspartame 0.15g, peach powder flavoring 0.3g, purified water 48g.

[0056] Purified water is used as the solvent for the adhesive and is removed during the process.

[0057] Preparation is as follows:

[0058] (1) Drug-containing gel:

[0059] Polyvinyl alcohol 1788 was dissolved in 30g of purified water at 80℃ to obtain a polymer solution, which was then cooled to room temperature. Hydroxypropyl γ-cyclodextrin was added to the remaining 20g of water and stirred to dissolve. Isosorbide mononitrate was added and stirred at 50℃ for 1 hour to encapsulate the mixture. The mixture was then cooled to room temperature. Glycerin, polyethylene glycol 400, aspartame, and peach powder flavoring were then added and mixed evenly. The mixture was then added to the polymer solution and mixed evenly. The mixture was allowed to stand to remove bubbles, thus obtaining the drug-containing layer solution.

[0060] (2) Isolation layer adhesive: Polyvinyl alcohol 1788 is dissolved in purified water under 80°C water bath conditions to obtain polymer adhesive, and cooled to room temperature; glycerin, polyethylene glycol 400, aspartame and peach powder fragrance are added and stirred evenly, and allowed to stand to remove bubbles to obtain isolation layer adhesive.

[0061] (3) Apply the release layer adhesive to the release film and dry it at 50°C. After drying, apply and dry the drug-containing layer adhesive and the release layer adhesive in sequence according to the same method. Then peel it off from the release film, cut and divide it, and seal it for packaging to obtain isosorbide mononitrate oral dissolving film.

[0062] Example 3

[0063] An isosorbide mononitrate orally disintegrating film comprises a drug-containing layer and an isolation layer composited on the upper and lower surfaces of the drug-containing layer, wherein the thickness of the drug-containing layer is 68 μm and the thickness of the isolation layer is 15 μm.

[0064] The prescription for the drug-containing layer is as follows:

[0065] Isosorbide mononitrate 20g, hydroxypropyl beta-cyclodextrin 16g, pullulan 20g, hydroxypropyl methylcellulose E 154g, glycerol 3.6g, sucralose 0.4g, peach powder flavoring 0.8g, purified water 70g.

[0066] The isolation layer prescription is as follows:

[0067] Pullulan 20g, hydroxypropyl methylcellulose E 154g, glycerin 3.6g, sucralose 0.4g, peach powder flavoring 0.8g, purified water 52g.

[0068] Purified water is used as the solvent for the adhesive and is removed during the process.

[0069] Preparation is as follows:

[0070] (1) Drug-containing gel: Hydroxypropyl β-cyclodextrin was added to water and stirred to dissolve. Isosorbide mononitrate was added and stirred at 50°C for 2 hours. After cooling to room temperature, glycerol, sucralose, peach powder flavoring, pullulan and hydroxypropyl methylcellulose E15 were added and mixed evenly. The mixture was allowed to stand to remove bubbles, and the drug-containing gel was obtained.

[0071] (2) Isolation layer adhesive: Add glycerin, purified water, sucralose and peach powder flavoring to water and stir to dissolve. Then add pullulan polysaccharide and hydroxypropyl methylcellulose E15, mix well, and let stand to remove bubbles to obtain the isolation layer adhesive.

[0072] (3) Apply the release layer adhesive to the release film and dry it at 50°C. After drying, apply and dry the drug-containing layer adhesive and the release layer adhesive in sequence according to the same method. Then peel it off from the release film, cut and divide it, and seal it for packaging to obtain isosorbide mononitrate oral dissolving film.

[0073] Example 4

[0074] An isosorbide mononitrate orally disintegrating film comprises a drug-containing layer and an isolation layer composited on the upper and lower surfaces of the drug-containing layer, wherein the thickness of the drug-containing layer is 64 μm and the thickness of the isolation layer is 16 μm.

[0075] The prescription for the drug-containing layer is as follows:

[0076] Isosorbide mononitrate 20g, hydroxypropyl β-cyclodextrin 16g, polyvinylpyrrolidone 20g, propylene glycol 4g, sodium saccharin 0.4g, peach powder flavoring 0.8g, purified water 76g.

[0077] The isolation layer prescription is as follows:

[0078] Polyvinylpyrrolidone 24g, propylene glycol 4.8g, sodium saccharin 0.48g, peach powder flavoring 0.96g, purified water 50g.

[0079] Purified water is used as the solvent for the adhesive and is removed during the process.

[0080] Preparation is as follows:

[0081] (1) Drug-containing adhesive solution: Hydroxypropyl β-cyclodextrin is added to water and stirred to dissolve. Isosorbide mononitrate is added and stirred at 50°C for 2 hours to encapsulate. After cooling to room temperature, propylene glycol, sodium saccharin, peach powder flavoring and polyvinylpyrrolidone are added, mixed evenly, and allowed to stand to remove bubbles to obtain the drug-containing adhesive solution.

[0082] (2) Isolation layer adhesive: Add propylene glycol, purified water, sodium saccharin and peach powder flavoring to water and stir to dissolve. Then add polyvinylpyrrolidone, mix evenly, and let stand to remove bubbles to obtain the isolation layer adhesive.

[0083] (3) Apply the release layer adhesive to the release film and dry it at 50°C. After drying, apply and dry the drug-containing layer adhesive and the release layer adhesive in sequence according to the same method. Then peel it off from the release film, cut and divide it, and seal it for packaging to obtain isosorbide mononitrate oral dissolving film.

[0084] Example 5

[0085] An isosorbide mononitrate orally disintegrating film comprises a drug-containing layer and an isolation layer composited on the upper and lower surfaces of the drug-containing layer, wherein the thickness of the drug-containing layer is 70 μm and the thickness of the isolation layer is 52 μm.

[0086] The prescription for the drug-containing layer is as follows:

[0087] Isosorbide mononitrate 20g, hydroxypropyl beta-cyclodextrin 16g, hydroxypropyl methylcellulose E5 20g, hydroxypropyl cellulose 5g, glycerin 4.8g, sucralose 0.4g, peach powder flavoring 0.8g, purified water 80g.

[0088] The isolation layer prescription is as follows:

[0089] Hydroxypropyl methylcellulose E 564g, hydroxypropyl cellulose 16g, glycerin 15.4g, sucralose 1.28g, peach powder flavoring 2.56g, purified water 192g.

[0090] Purified water is used as the solvent for the adhesive and is removed during the process.

[0091] Preparation is as follows:

[0092] (1) Drug-containing gel: Hydroxypropyl β-cyclodextrin is added to water and stirred to dissolve. Isosorbide mononitrate is added and stirred at 50°C for 2 hours. After cooling to room temperature, glycerol, sucralose, peach powder flavoring, hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 are added and mixed evenly. The mixture is allowed to stand to remove bubbles, and the drug-containing gel is obtained.

[0093] (2) Isolation layer adhesive: Add glycerin, purified water, sucralose and peach powder flavoring to water and stir to dissolve. Then add hydroxypropyl cellulose and hydroxypropyl methylcellulose E5, mix evenly, and let stand to remove bubbles to obtain the isolation layer adhesive.

[0094] (3) Apply the release layer adhesive to the release film and dry it at 50°C. After drying, apply and dry the drug-containing layer adhesive and the release layer adhesive in sequence according to the same method. Then peel it off from the release film, cut and divide it, and seal it for packaging to obtain isosorbide mononitrate oral dissolving film.

[0095] The performance of the oral dissolving film products prepared in Examples 1-5 was tested. The test methods and results are as follows.

[0096] 1. Physical property testing:

[0097] (1) Peelability:

[0098] After the film coating dries, assess the ease with which the film can be peeled off from the release liner of the coated carrier material. Take a 5cm x 5cm piece of film and gently peel off the film coating by hand to evaluate the ease of peeling.

[0099] (2) Tensile strength and elongation at break:

[0100] The prepared isosorbide mononitrate oral dissolving films were cut into 20mm × 5mm shapes and tested using an electronic universal testing machine. The breaking load and elongation at break of the oral dissolving films were recorded, and the test was repeated three times. The tensile strength and elongation were calculated according to the formula: Tensile strength (N·mm) -2 = Breaking load / cross-sectional area; Elongation at break % = tensile length / initial length × 100%.

[0101] The test results are shown in Table 1.

[0102] Table 1. Results of physical property testing of oral dissolving film products prepared in Examples 1-5

[0103] Sample group Peeling force <![CDATA[Tensile strength (N﹒mm -2 )]]> Elongation at break (%) Example 1 Easy to peel 16.6±0.5 20.9±0.8 Example 2 Easy to peel 15.7±0.4 19.8±1.1 Example 3 Easy to peel 20.7±0.5 23.3±0.7 Example 4 Easy to peel 16.3±0.7 18.3±0.4 Example 5 Easy to peel 36.1±0.7 15.0±1.7

[0104] As can be seen from the test results in Table 1, the oral dissolving films prepared by the present invention can all meet the mechanical performance requirements.

[0105] 2. Quality determination:

[0106] The isosorbide mononitrate oral dissolving films from Examples 1-5 were formulated into a 20mg specification and compared with the isosorbide mononitrate tablet reference preparation (20mg specification, manufactured by KREMERS URBAN PHARMACEUTICALS INC) listed in the 14th batch of the reference preparation catalog published by the National Medical Products Administration.

[0107] (1) Properties:

[0108] Visual inspection is used to directly observe the appearance of the product.

[0109] (2) Content:

[0110] The chromatographic conditions were as follows: octadecylsilane-bonded silica gel was used as the stationary phase; methanol-water (25:75) was used as the mobile phase; the detection wavelength was 210 nm; and the injection volume was 20 μL.

[0111] System suitability requirements: In the system suitability solution chromatogram, the theoretical plate number, calculated based on the isosorbide mononitrate peak, should be no less than 3000, and the resolution between the isosorbide mononitrate peak and the 2-isosorbide mononitrate peak should be greater than 2.0. Calculations should be based on peak area using the external standard method.

[0112] (3) Content uniformity:

[0113] According to the content uniformity test method in General Chapter 0941 of the 2020 edition of the Chinese Pharmacopoeia, take 10 tablets of this product and place them in separate volumetric flasks (100ml for 10mg and 200ml for 20mg). Add an appropriate amount of mobile phase, shake for about 20 minutes to dissolve isosorbide mononitrate, dilute to the mark with mobile phase, shake well, filter, and use the filtrate as the test solution. Determine the content according to the method under the content determination section, calculate the content of each tablet, and calculate the mean and standard deviation S of the relative content X of each tablet with the labeled amount as 100%, as well as the absolute value A of the difference between the labeled content and the mean. If A + 2.2S ≤ 15.0, the content uniformity of the test sample meets the requirements.

[0114] (4) Related substances:

[0115] The chromatographic conditions and system usability requirements are the same as those for the content detection items.

[0116] For the assay, accurately measure the test solution and the control solution and inject them separately into the liquid chromatograph. Record the chromatograms up to 1.1 times the retention time of the isosorbide dinitrate peak.

[0117] In the chromatogram of the limit test solution, if there are chromatographic peaks with retention times consistent with the peaks of isosorbide nitrate and 2-monosorbide nitrate, the peak area calculated by the external standard method shall not exceed 0.25%; the area of ​​other individual impurity peaks shall not be greater than 0.5 times (0.25%) the peak area of ​​isosorbide nitrate in the control solution, and the total amount of impurities shall not exceed 0.5%.

[0118] (5) Disintegration time limit:

[0119] Fix the oral disintegration film with a paperclip and place it in a beaker containing 50ml of water at a temperature of 37±0.5℃ (the beaker is placed under constant temperature water bath conditions). Observe and record the disintegration time.

[0120] (6) Dissolution curve:

[0121] Reference preparation:

[0122] According to the dissolution test method (Chinese Pharmacopoeia 2020 Edition, Part IV, Appendix II), using 500 ml of water as the dissolution medium and a rotation speed of 50 rpm, perform the operation as described above. After 5 min, 10 min, 15 min, and 30 min, take an appropriate amount of solution, filter, and use the filtrate as the test solution. Separately, accurately weigh an appropriate amount of isosorbide mononitrate reference standard and prepare a solution containing 40 μg per ml as the reference solution. Determine the content according to the assay method and calculate the dissolution amount per tablet.

[0123] Oral dissolving films of isosorbide mononitrate in Examples 1-5:

[0124] According to the assay method (paddle method, <1004> MUCOSAL DRUGPRODUCTS-PERFORMANCE TESTS) described in USP 43-38, using 500 ml of water as the dissolution medium and a rotation speed of 50 rpm, perform the procedure as described above. After 5 min, 10 min, 15 min, and 30 min, take an appropriate amount of solution, filter, and use the filtrate as the test solution. Separately, accurately weigh an appropriate amount of isosorbide mononitrate reference standard and prepare a solution containing 40 μg (20 mg specification) per ml as the reference solution. Determine the content according to the assay method and calculate the dissolution amount per tablet.

[0125] The test results are shown in Table 2-3.

[0126] Table 2. Quality determination results of reference formulation and oral dissolution film products of Examples 1-5

[0127] Group Properties content(%) Total impurities (%) Content uniformity Disintegration time limit Reference formulation White film 99.7 0.10 7 / Example 1 translucent sheet-like film 99.5 0.12 3 23s Example 2 translucent sheet-like film 99.7 0.11 4 30s Example 3 translucent sheet-like film 101.2 0.11 3 24s Example 4 translucent sheet-like film 100.8 0.10 3 27s Example 5 translucent sheet-like film 100.6 0.11 3 37s

[0128] Table 3. Results of oral film dissolution assay for reference formulation and Examples 1-5

[0129]

[0130] 3. Stability test:

[0131] The isosorbide mononitrate oral dissolving films from Examples 1-5 were formulated into a 20mg specification and compared with the isosorbide mononitrate tablet reference preparation (20mg specification, manufactured by KREMERS URBAN PHARMACEUTICALS INC) listed in the 14th batch of the reference preparation catalog published by the National Medical Products Administration.

[0132] Test conditions: The sample was placed at 40℃ and RH 75% for 6 months, and the quality change was investigated.

[0133] The results are shown in Table 4-5.

[0134] Table 4. Accelerated six-month quality determination results of the reference formulation and oral dissolution film products of Examples 1-5

[0135] Group Properties content(%) Total impurities (%) Disintegration time limit Reference formulation White film 99.8 0.12 / Example 1 translucent sheet-like film 99.6 0.12 24s Example 2 translucent sheet-like film 99.8 0.13 30s Example 3 translucent sheet-like film 100.4 0.11 22s Example 4 translucent sheet-like film 101.6 0.11 29s Example 5 translucent sheet-like film 100.9 0.12 44s

[0136] Table 5. Results of accelerated dissolution assays of reference formulations and Examples 1-5 over six months.

[0137]

[0138] As can be seen from the test results in Tables 4-5, after being placed under accelerated experimental conditions for 6 months, the properties, content, related substances, and dissolution of the samples in each embodiment of the present invention did not change significantly, indicating good stability and meeting product quality requirements. The reference formulation showed a slight decrease in dissolution during the stability period, which is detrimental to the drug's dissolution and efficacy. Compared with the reference formulation, the advantages of the product of the present invention are: safe and reliable preparation process, rapid product release, better content uniformity, better stability, pleasant taste, and no need for water to take it.

[0139] 4. Determination of disintegration time for different isolation layer thicknesses:

[0140] Investigations into the thickness of the isolation layer revealed that when the thickness of the isolation layer on one side is less than 10 μm, it is difficult for the polymer material to form a continuous film, resulting in a very high risk of drug-containing layer exposure and hindering the crystallization of isosorbide mononitrate. Therefore, the thickness of the isolation layer on one side should not be less than 10 μm.

[0141] Meanwhile, the disintegration time of the orally disintegrating film under different isolation layer thicknesses was investigated. Referring to the drug-containing layer and isolation layer formulation of Example 1, orally disintegrating films with isolation layers of different thicknesses were prepared (the drug-containing layer thickness was uniform at approximately 70 μm, with isolation layers of different thicknesses coated on both sides), and the disintegration time was investigated.

[0142] Disintegration time determination method: Fix the oral soluble membrane with a paperclip and place it in a beaker containing 50ml of water at a temperature of 37±0.5℃ (the beaker is placed under constant temperature water bath conditions), observe and record the disintegration time.

[0143] The measurement results are shown in Table 6.

[0144] Table 6. Results of disintegration time determination for different isolation layer thicknesses.

[0145] Insulation layer thickness (thickness on one side) Disintegration time limit 11μm 20s 21μm 23s 40μm 31s 66μm 39s 98μm 49s

[0146] As can be seen from Table 6, the samples with isolation layers of different thicknesses below 100 μm all have a relatively fast dissolution and release rate, and can completely disintegrate in water at 37℃ within 60 seconds. As the thickness of the isolation layer increases, the disintegration time of the drug also increases. Under the condition of thickness below 100 μm, the disintegration time of the prepared orally disintegrating film meets the requirements.

[0147] Comparative Example 1

[0148] The oral dissolving film in this comparative example did not have a composite isolation layer; it consisted only of a drug-containing layer with a thickness of 70 μm. The formulation of the drug-containing layer is as follows:

[0149] Isosorbide mononitrate 20g, hydroxypropyl beta-cyclodextrin 16g, hydroxypropyl methylcellulose E5 20g, hydroxypropyl cellulose 5g, glycerin 4.8g, sucralose 0.4g, peach powder flavoring 0.8g, purified water 80g.

[0150] Purified water is used as the solvent for the adhesive and is removed during the process.

[0151] Preparation is as follows:

[0152] (1) Drug-containing gel: Hydroxypropyl β-cyclodextrin is added to water and stirred to dissolve. Isosorbide mononitrate is added and stirred at 50°C for 2 hours. After cooling to room temperature, glycerol, sucralose, peach powder flavoring, hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 are added and mixed evenly. The mixture is allowed to stand to remove bubbles, and the drug-containing gel is obtained.

[0153] (2) Coat the release film with the drug-containing adhesive layer, dry at 50°C, then peel it off from the release film, cut and divide it, seal and package it to obtain isosorbide mononitrate oral dissolving film.

[0154] The oral dissolving film prepared in Comparative Example 1 began to crystallize after being placed at room temperature for 3 days. Figure 1 As shown, this phenomenon becomes more pronounced over time. Analysis revealed the precipitate to be isosorbide mononitrate. This is because isosorbide mononitrate partially exposed on the oral thallium surface crystallizes and migrates. This continuous migration creates micropores within the oral thallium, exposing deeper layers of isosorbide mononitrate, which in turn triggers a chain reaction that exacerbates the phenomenon.

[0155] Comparative Example 2

[0156] The oral dissolving film of this comparative example has only a single-sided composite isolation layer, which consists of a drug-containing layer and an isolation layer composited on a single surface of the drug-containing layer. The thickness of the drug-containing layer is 70 μm, and the thickness of the isolation layer is 17 μm.

[0157] The prescription for the drug-containing layer is as follows:

[0158] Isosorbide mononitrate 20g, hydroxypropyl beta-cyclodextrin 16g, hydroxypropyl methylcellulose E5 20g, hydroxypropyl cellulose 5g, glycerin 4.8g, sucralose 0.4g, peach powder flavoring 0.8g, purified water 80g.

[0159] The isolation layer prescription is as follows:

[0160] Hydroxypropyl methylcellulose E5 10g, hydroxypropyl cellulose 2.5g, glycerin 2.4g, sucralose 0.2g, peach powder flavoring 0.4g, purified water 30g.

[0161] Purified water is used as the solvent for the adhesive and is removed during the process.

[0162] Preparation is as follows:

[0163] (1) Drug-containing gel: Hydroxypropyl β-cyclodextrin is added to water and stirred to dissolve. Isosorbide mononitrate is added and stirred at 50°C for 2 hours. After cooling to room temperature, glycerol, sucralose, peach powder flavoring, hydroxypropyl cellulose and hydroxypropyl methylcellulose E5 are added and mixed evenly. The mixture is allowed to stand to remove bubbles, and the drug-containing gel is obtained.

[0164] (2) Isolation layer adhesive: Add glycerin, purified water, sucralose and peach powder flavoring to water and stir to dissolve. Then add hydroxypropyl cellulose and hydroxypropyl methylcellulose E5, mix evenly, and let stand to remove bubbles to obtain the isolation layer adhesive.

[0165] (3) Apply the release layer adhesive to the release film and dry it at 50°C. After drying, apply and dry the drug-containing layer adhesive and the release layer adhesive in sequence according to the same method. Then peel it off from the release film, cut and divide it, and seal it for packaging to obtain isosorbide mononitrate oral dissolving film.

[0166] The orally dissolving film prepared in this comparative example was a single-sided composite isolation layer orally dissolving film. After placement, the side without the composite isolation layer also exhibited the crystallization phenomenon seen in Comparative Example 1, and the precipitate was identified as isosorbide mononitrate. However, no crystallization phenomenon was observed on the side with the composite isolation layer. This indicates that using a dense polymer material as an isolation layer on the surface of the drug-containing layer can effectively inhibit the initial crystallization and migration of isosorbide mononitrate, thus preventing a chain reaction.

Claims

1. An oral dissolving film formulation of isosorbide mononitrate, characterized in that: It consists of a drug-containing layer and a separating layer composited on the upper and lower surfaces of the drug-containing layer; the drug-containing layer comprises the following raw materials in the following mass percentages: Cyclodextrin encapsulates 10-60% isosorbide mononitrate. Film-forming material 20~80%, Plasticizer 5-20%, Auxiliary materials: 0.5-10%; The insulating layer comprises the following raw materials by weight percentage: Film-forming material 70~90%, Plasticizer 9-25%, Auxiliary materials 1-5%; In the cyclodextrin-encapsulated isosorbide mononitrate, the mass ratio of cyclodextrin to isosorbide mononitrate is 0.5:1 to 3:

1. The cyclodextrin is hydroxypropyl beta-cyclodextrin or hydroxypropyl gamma-cyclodextrin; The film-forming material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, polyvinyl alcohol, or polyvinylpyrrolidone; The plasticizer is one or more of glycerin, polyethylene glycol, or propylene glycol; The excipients include one or both of flavoring agents or coloring agents; The method for preparing the isosorbide mononitrate oral coating includes the following steps: (1) Drug-containing gel: Add cyclodextrin to water and stir to dissolve, add isosorbide mononitrate, stir and encapsulate at 45-55℃ for 0.5-2h, cool to room temperature, then add plasticizer, excipients and film-forming materials, mix evenly, degas, and the drug-containing gel is obtained. (2) Isolation layer adhesive: Add plasticizer and auxiliary materials to water and stir to dissolve, then add film-forming material, mix evenly, and degas to obtain isolation layer adhesive; (3) Apply the release film sequentially with the release layer adhesive, the drug-containing layer adhesive, and the release layer adhesive, and dry them. Then peel them off from the release film to obtain the isosorbide mononitrate oral solution film.

2. The isosorbide mononitrate oral dissolving film formulation according to claim 1, characterized in that: The thickness of the drug-containing layer is 10–100 μm, and the thickness of the isolation layer is 10–100 μm.

3. The isosorbide mononitrate oral dissolving film formulation according to claim 1, characterized in that: The flavoring agent is one or more of sucralose, aspartame, and sodium saccharin.

4. The isosorbide mononitrate oral dissolving film formulation according to claim 1, characterized in that: The degassing process employs either vacuum degassing or static degassing.

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