Sildenafil citrate oral soluble film preparation and preparation method thereof

Abstract

The invention relates to a sildenafil citrate oral soluble film preparation and a preparation method thereof. The oral soluble film preparation comprises 20-70% of sildenafil citrate, 15-50% of a film forming material, 3-20% of a plasticizer, 1-10% of a filler and 0-1% of an opacifier, and the film forming material is a composition of hydroxypropyl methyl cellulose, hydroxypropyl cellulose and a polyvinyl alcohol-polyethylene glycol copolymer. The sildenafil citrate oral soluble film preparation provided by the invention has good stability, peroxide impurities are not easy to exist, and the preparation method is simple and suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a sildenafil citrate orally disintegrating film preparation and a preparation method thereof. Background Art

[0002] Sildenafil citrate, the active ingredient in sildenafil, is a selective inhibitor of phosphodiesterase type 5 (PDE5). This inhibits the production of nitric oxide (NO) by nerves and endothelial cells, which stimulates the breakdown of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. This leads to relaxation of the corpus cavernosum smooth muscle and increases blood flow, thus treating erectile dysfunction. Currently, sildenafil citrate has been reported or marketed in tablets, injections, suspensions, and films. Among these, orally disintegrating film formulations avoid the first-pass effect of conventional oral preparations, improve bioavailability, and do not require chewing or water for administration, making them a promising formulation for improving patient compliance.

[0003] Currently, there are numerous reports on sildenafil citrate orally disintegrating films, but none address the fact that sildenafil citrate is susceptible to the generation of degradation impurities under oxidative conditions. Sildenafil citrate can easily react with excipients containing peroxides to produce degradation impurities, leading to product quality issues and potential drug safety risks. Therefore, based on existing clinical needs in China, it is necessary to develop an orally disintegrating sildenafil citrate film with a stable impurity content and higher product quality. Summary of the Invention

[0004] To address the aforementioned issues in the prior art, the present invention aims to provide an orally disintegrating film formulation of sildenafil citrate that improves its stability, and a method for preparing the same. The present invention investigates different film-forming materials, screens for those with excellent impurity stability, and prepares an orally disintegrating film formulation of sildenafil citrate supplemented with a sunscreen. This formulation improves patient compliance with the drug dosage form while addressing formulation stability issues. Furthermore, the preparation process is simple and stable, making it suitable for large-scale industrial production.

[0005] The present invention provides an orally disintegrating sildenafil citrate film preparation, comprising a drug-containing layer, wherein the drug-containing layer comprises the following components by weight: 20-70% of sildenafil citrate, 15-50% of a film-forming material, 3-20% of a plasticizer, 1-10% of a filler, and 0-1% of a sunscreen; the film-forming material is a composition of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and a polyvinyl alcohol-polyethylene glycol copolymer.

[0006] In some embodiments, the ratio of hydroxypropyl methylcellulose to hydroxypropyl cellulose to polyvinyl alcohol-polyethylene glycol copolymer in the film-forming material is 10-30:1-15:1-15.

[0007] In some embodiments, the plasticizer comprises one or more of glycerol, ethylene glycol, sorbitol, and propylene glycol.

[0008] In some embodiments, the filler comprises polydextrose.

[0009] In some embodiments, the sunscreen comprises titanium dioxide.

[0010] In addition, in some embodiments, the sildenafil citrate orally disintegrating film formulation of the present invention may further include certain pharmaceutically common additives. For example, to improve the mouthfeel of the orally disintegrating film, 0-2% of a flavoring agent and / or 0-3% of a sweetener may be added to the drug-containing layer of the formulation; to increase the recognizability of the orally disintegrating film, 0-0.5% of a colorant may be added to the drug-containing layer of the formulation.

[0011] Specifically, in some embodiments, the flavoring agent comprises one or more of mint essence, L-menthol, peppermint oil, licorice extract, and neohesperidin; in some embodiments, the sweetener comprises one or more of sucralose, sucrose, and stevioside; in some embodiments, the colorant comprises red iron oxide and / or carmine.

[0012] Furthermore, the drug-containing layer of the sildenafil citrate orally disintegrating film preparation comprises the following components in percentage by weight:

[0013] Sildenafil citrate 20-70%,

[0014] Film-forming materials (hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvinyl alcohol·polyethylene glycol copolymer) 15-50%,

[0015] Glycerol 3-20%,

[0016] Polydextrose 1-10%,

[0017] Titanium dioxide 0~1%,

[0018] Mint essence 0-2%,

[0019] Sucralose 0-3%,

[0020] Red iron oxide 0-0.5%.

[0021] As a specific embodiment, the drug-containing layer of the sildenafil citrate orally disintegrating film preparation comprises the following components in percentage by weight:

[0022] Sildenafil citrate 43%,

[0023] Hydroxypropyl methylcellulose 25%,

[0024] Hydroxypropyl cellulose 6%,

[0025] Polyvinyl alcohol·polyethylene glycol copolymer 6%,

[0026] Glycerin 12%,

[0027] Polydextrose 6.28%,

[0028] Titanium dioxide 0.1%,

[0029] Mint flavor 0.1%,

[0030] Sucralose 1.5%,

[0031] Red iron oxide 0.02%.

[0032] Furthermore, the present invention provides a method for preparing the above-mentioned sildenafil citrate orally disintegrating film preparation, comprising the following steps: uniformly mixing a first mixed liquid and a second mixed liquid, then adding sildenafil citrate, a film-forming material, and an optional flavoring agent, stirring and swelling, and degassing to obtain a drug-containing matrix liquid, and then coating, drying, and cutting the obtained drug-containing matrix liquid to obtain a sildenafil citrate orally disintegrating film preparation; the first mixed liquid is a dispersion of a colorant and a sunscreen in water, and the second mixed liquid is a dispersion of a plasticizer, a filler, and an optional sweetener in water.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] 1. The present invention reduces peroxide impurities by adding a certain proportion of hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvinyl alcohol-polyethylene glycol copolymer as film-forming materials, thereby obtaining a sildenafil citrate orally disintegrating film preparation with controllable quality;

[0035] 2. Furthermore, the present invention adds 3-20% plasticizer, 1-10% filler, 0-1% sunscreen and other additives to prepare an orally dissolving sildenafil citrate film preparation with better stability and better taste. This provides a new sildenafil citrate preparation that is light in weight and small in volume, does not require chewing or water to be taken, and the active ingredients of the drug dissolve rapidly in the oral cavity to exert therapeutic effects. It is easy for patients to swallow and is portable. DETAILED DESCRIPTION

[0036] The present invention will be further described in detail with reference to the following specific examples, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, variations and advantages that can be imagined by those skilled in the art are included in the present invention, and are protected by the appended claims. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are common knowledge and common common sense in the art, and the present invention has no special restrictions. Unless otherwise stated, percentages and ratios are weight percentages and weight ratios.

[0037] Example 1 Compatibility screening of raw and auxiliary materials

[0038] The compatibility of the active pharmaceutical ingredient (API) sildenafil citrate with some excipients was investigated, and the results of related substance detection by HPLC are shown in Table 1. Based on the acceptance criteria for related substances in sildenafil citrate preparations (impurity A ≤ 0.15%, impurity B ≤ 0.15%, other single impurities ≤ 0.20%, total impurities ≤ 0.50%), sildenafil citrate has compatibility risks with povidone, polyethylene glycol, and crospovidone, and the higher the ratio of polyethylene glycol to crospovidone, the greater the impurity content.

[0039] Table 1 Screening results of relevant excipients

[0040]

[0041] Note: Only impurities of 0.02% and above are counted. ND stands for not detected.

[0042] Example 2 Preparation of Sildenafil Citrate Orally Dissolving Film Formulation

[0043] According to the prescription in Table 2, a certain amount of components were weighed to prepare sildenafil citrate orally disintegrating film preparations of Examples 1-8 and Comparative Examples 1-3, respectively. The specific preparation method comprises the following steps:

[0044] Step 1: Disperse red iron oxide and titanium dioxide in an appropriate amount of purified water at 20-50°C to prepare a first mixed solution;

[0045] Step 2: Add polydextrose, sucralose, and glycerol to the remaining 20-50°C purified water and stir to dissolve into a second mixed solution;

[0046] Step 3: Mix the first mixed solution and the second mixed solution, disperse them evenly, then add sildenafil citrate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, L-menthol, and mint essence, stir and swell, and degas to obtain a drug-containing matrix solution;

[0047] Step 4: Apply the above-mentioned drug-containing matrix liquid, dry it at 30-90° C., and cut it into appropriate sizes to obtain the sildenafil citrate orally disintegrating film preparation.

[0048] Table 2 Prescription of Sildenafil Citrate Orally Disintegrating Film Preparation

[0049]

[0050] Example 3 Stability Investigation Test

[0051] The samples obtained in Examples 1-2, Examples 7-8 and Comparative Examples 1-3 were placed at a high temperature of 50° C. to test the stability of each sildenafil orally dissolving film preparation. The relevant substances were determined by HPLC. The results are shown in Table 3.

[0052] Table 3 Relevant substance detection data

[0053]

[0054] Note: ND means not detected.

[0055] As shown in the above experimental results, the samples of Example 7-8 and Comparative Example 1 were placed at high temperature for 10 days, and the sample of Example 1 was placed at high temperature for 30 days, and the related substances of Example 1 were increased compared with those of 0 day, but the trend was controllable. The sample of Example 2 was placed at high temperature for 30 days, and the related substances of Example 2 were not increased compared with those of 0 day, indicating that the stability of the orally dissolving sildenafil citrate film preparation can be improved by limiting the film-forming material composition ratio (hydroxypropyl methylcellulose: hydroxypropyl cellulose: polyvinyl alcohol polyethylene glycol copolymer = 10 ~ 30: 1 ~ 15: 1 ~ 15) in the embodiment of the present invention, and the impurity content all meets the acceptable standard of the related substances, ensuring that the patient's medication safety is safe. And when the film-forming material of the preparation adopts hydroxypropyl methylcellulose and hydroxypropyl cellulose (Comparative Example 2), hydroxypropyl methylcellulose and polyvinyl alcohol polyethylene glycol copolymer (Comparative Example 3), the impurity content growth trend is uncontrollable, and the single miscellaneous or total impurity content has the risk of exceeding the limit regulation.

[0056] Example 4 Dissolution Test

[0057] Dissolution determination method: Take the samples of Comparative Example 1, Example 1 and Example 5-6, and adopt the paddle disc method. Each preparation sample is respectively 900mL 0.01M hydrochloric acid solution (release medium), pH4.5 acetate solution, and pH6.8 phosphate solution (differentiation medium) as the dissolution medium. The speed is 50 rpm. The cumulative dissolution rate of the drug is measured at 5min, 10min, 15min, 20min, and 30min. The results of the HPLC method are shown in Table 4. It can be seen that Comparative Example 1 dissolves faster in the release medium and dissolves slower in the differentiation medium. In contrast, the dissolution rates of the samples of Example 1 and Example 5-6 in the dissolution media of different pH values are all greater than 85% at 15min. The dissolution rate is basically the same, and there is no phenomenon of dissolution too fast or too slow, which ensures that sildenafil citrate can be dissolved quickly and stably to exert its therapeutic effect.

[0058] Table 4 Dissolution test data

[0059]

[0060] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A sildenafil citrate orally disintegrating film preparation, characterized in that: The preparation includes a drug-containing layer, which contains the following components by weight: 20-70% of sildenafil citrate, 15-50% of a film-forming material, 3-20% of a plasticizer, 1-10% of a filler, and 0-1% of a sunscreen; the film-forming material is a composition of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and a polyvinyl alcohol-polyethylene glycol copolymer.

2. The sildenafil citrate orally disintegrating film preparation according to claim 1, wherein The ratio of hydroxypropyl methylcellulose to hydroxypropyl cellulose to polyvinyl alcohol-polyethylene glycol copolymer in the film-forming material is 10-30:1-15:1-15.

3. The sildenafil citrate orally disintegrating film preparation according to claim 1, wherein The plasticizer comprises one or more of glycerol, ethylene glycol, sorbitol, and propylene glycol.

4. The sildenafil citrate orally disintegrating film preparation according to claim 1, wherein The filler comprises polydextrose.

5. The sildenafil citrate orally disintegrating film preparation according to claim 1, wherein The sunscreen comprises titanium dioxide.

6. The sildenafil citrate orally disintegrating film preparation according to claim 1, wherein The drug-containing layer of the preparation further comprises, by weight percentage, 0-2% of flavoring agent and / or 0-3% of sweetener and / or 0-0.5% of colorant.

7. The sildenafil citrate orally disintegrating film preparation according to claim 6, wherein: The flavoring agent comprises one or more of mint essence, L-menthol, mint oil, licorice extract, and neohesperidin; the sweetener comprises one or more of sucralose, sucrose, and stevioside; and the colorant comprises red iron oxide and / or carmine.

8. The sildenafil citrate orally disintegrating film preparation according to claim 1, wherein The drug-containing layer of the preparation comprises the following components by weight percentage: Sildenafil citrate 20-70%, Film-forming materials (hydroxypropyl methylcellulose, hydroxypropyl cellulose and polyvinyl alcohol·polyethylene glycol copolymer) 15-50%, Glycerol 3-20%, Polydextrose 1-10%, Titanium dioxide 0~1%, Mint essence 0-2%, Sucralose 0-3%, Red iron oxide 0-0.5%.

9. The sildenafil citrate orally disintegrating film preparation according to any one of claims 1 to 8, characterized in that: The drug-containing layer of the preparation comprises the following components by weight percentage: Sildenafil citrate 43%, Hydroxypropyl methylcellulose 25%, Hydroxypropyl cellulose 6%, Polyvinyl alcohol·polyethylene glycol copolymer 6%, Glycerin 12%, Polydextrose 6.28%, Titanium dioxide 0.1%, Mint flavor 0.1%, Sucralose 1.5%, Red iron oxide 0.02%.

10. A method for preparing the sildenafil citrate orally disintegrating film preparation according to any one of claims 1 to 9, characterized in that: The method comprises the following steps: uniformly mixing a first mixed liquid and a second mixed liquid, adding sildenafil citrate, a film-forming material and an optional flavoring agent, stirring and swelling the mixture, and degassing the mixture to obtain a drug-containing matrix liquid, and then coating, drying and cutting the obtained drug-containing matrix liquid to obtain a sildenafil citrate orally dissolving film preparation; the first mixed liquid is a dispersion of a colorant and a sunscreen in water, and the second mixed liquid is a dispersion of a plasticizer, a filler and an optional sweetener in water.

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