Oral dissolving film formulation, preparation method therefor, and use thereof

Abstract

The present invention provides an oral dissolving film formulation, a preparation method therefor, and use thereof. The oral dissolving film formulation comprises a main drug, a polymer film-forming material, an optional plasticizer, and an optional flavoring agent, wherein the main drug has a structure represented by the following formula (I), and the weight percentage of the main drug in the oral dissolving film formulation is 10-60%, preferably 30-50%.

Description

An orally dissolving film formulation, its preparation method and application Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to an orally disintegrating film preparation and a method for preparing the preparation. Background Technology

[0002] Studies show that about half of men over 40 years of age suffer from erectile dysfunction, which seriously affects their quality of life. Erectile dysfunction (ED), commonly known as "impotence," refers to a man's inability to achieve or maintain a sufficient erection for satisfactory sexual intercourse under sexual stimulation. A clinical diagnosis of ED is typically made after a course of more than 3 months.

[0003] In the drug treatment of erectile dysfunction (ED), phosphodiesterase 5 (PDE5) inhibitors are convenient, safe, effective, and easily accepted by most patients, making them the first-line drugs in clinical practice. Currently, the approved oral PDE5 inhibitors for treating erectile dysfunction are: sildenafil (Viagra), vardenafil (Levitra), tadalafil (Cialis), and avanafil (Stendra). Sildenafil, developed by Pfizer, was approved by the FDA in 1998, becoming the first FDA-approved oral drug for treating ED. Subsequently, in 2003, Bayer and GlaxoSmithKline jointly launched vardenafil, and Eli Lilly launched tadalafil. In 2012, the FDA approved avanafil.

[0004] Since phosphodiesterases (PDE5s) have at least 11 enzyme systems and more subtypes, highly selective PDE5 inhibitors are crucial for developing treatments for erectile dysfunction. Of the four currently marketed PDE5 inhibitors, sildenafil and vardenafil have poor selectivity for PDE1 and PDE6, leading to side effects such as facial flushing and visual disturbances, and posing potential cardiovascular risks. Furthermore, both compounds have short half-lives, making them unsuitable for long-term use. Tadalafil has a longer half-life, allowing for once-daily dosing, but its poor selectivity for PDE11 and side effects such as back pain and muscle soreness affect patient compliance. Avanafil, while having lower clinical adverse reactions due to its high selectivity, also has a short half-life, making it unsuitable for long-term use. Unmet clinical needs remain for PDE5 inhibitors, and highly selective, long-half-life PDE5 inhibitors represent the future direction of PDE5 inhibitor development.

[0005] Epimedium (Epimedium brevicornum Maxim.) has a long history of medicinal use in China. Due to its effects of tonifying kidney yang, strengthening tendons and bones, and dispelling wind and dampness, it is mainly used to treat impotence and premature ejaculation. With the development of basic sciences and scientific research instruments, research on traditional natural medicines like Epimedium has become increasingly in-depth and comprehensive. Studies have shown that Epimedium contains a complex and numerous effective components, among which the main component is icariin (molecular formula: C...). 33 H 40 O 15 (Molecular weight 676.67) belongs to the flavonoid class of compounds. The structures of some flavonoid compounds in Epimedium are shown below:

[0006] Icariin has a specific physiological effect of producing sexual arousal. The CO-cGMP-PDE5 pathway plays a key role in the treatment of erectile dysfunction. It reduces apoptosis of the smooth muscle of the corpus cavernosum by inhibiting fibrosis, oxidation and protection, and regulates the secretion of sex hormones and gonadotropins, thus protecting the sex organs and gonads.

[0007] Based on long-term research and accumulation of knowledge on the natural drug Epimedium, the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, discovered a compound with high phosphodiesterase (PDE5) inhibitory activity in the extract of Epimedium. Using the natural product Epimedium flavonoids as the lead structure and referencing computational chemistry data, the team conducted meticulous "structural fine-tuning" design and synthesis work through structural modification and splicing synthesis techniques. Ultimately, they obtained a candidate compound with better overall drug-likeness than sildenafil, and its hydrochloride structure is shown in formula (I).

[0008] This compound is a selective PDE5 inhibitor, screened from numerous active compounds based on extensive structure-activity relationship studies. Preclinical toxicology, pharmacodynamics, and pharmacokinetic studies have revealed that its activity is an order of magnitude higher than sildenafil, and its selectivity relative to other isoenzymes (including PDE1 and PDE6) is significantly improved compared to sildenafil. Compared to sildenafil, it possesses numerous advantages, including high activity, high selectivity, low toxicity, well-defined efficacy, and a simple structure that is easy to synthesize. Furthermore, it has independent intellectual property rights (see WO2010066111A1).

[0009] Oral soluble films are oral formulations in which the active pharmaceutical ingredient is uniformly dispersed in a film-forming material. This type of immediate-release dosage form is crucial in the pharmaceutical industry. It disintegrates in saliva within a short time, releasing the active pharmaceutical ingredient, which is then absorbed through the oral mucosa or swallowed and subsequently absorbed through the gastrointestinal tract. It offers rapid onset of action and high bioavailability. It allows for rapid and precise administration anytime, anywhere, without the need for water, ensuring timely medication administration. This provides a safe and reliable route of administration, improving patient compliance. Summary of the Invention

[0010] The purpose of this invention is to provide an orally disintegrating film preparation of formula (I) compound, its preparation method and application. The orally disintegrating film preparation is absorbed in the oral cavity, has good efficacy, does not require drinking water, and is convenient to take. While improving the symptoms of ED patients, it allows for free selection of sexual intercourse time, without the need to deliberately plan medication and sexual intercourse time, thereby improving the quality of sexual life.

[0011] On one hand, the present invention provides an orally disintegrating film formulation comprising an active pharmaceutical ingredient, a polymeric film-forming material, an optional plasticizer, and an optional flavoring agent, wherein the active pharmaceutical ingredient has the structure shown in formula (I) and comprises 10-60% by weight, preferably 30-50%, in the orally disintegrating film formulation:

[0012] In some embodiments, in the orally disintegrating film formulation of the present invention, the polymeric film-forming material may be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, amylopectin, or any combination thereof; preferably, the polymeric film-forming material may be hydroxypropyl methylcellulose, such as hydroxypropyl methylcellulose E15 or hydroxypropyl methylcellulose K100LV. In some embodiments, the weight percentage of the polymeric film-forming material in the orally disintegrating film formulation may be 25-70%, preferably 35-60%.

[0013] In some embodiments, in the orally disintegrating film formulation of the present invention, the plasticizer may be selected from polyethylene glycol, glycerin, polysorbate, propylene glycol, or any combination thereof, preferably selected from polyethylene glycol, glycerin, or combinations thereof. In some embodiments, the plasticizer may constitute 0-20% by weight in the orally disintegrating film formulation, preferably 8-20%.

[0014] In the oral dissolving film formulation of the present invention, the flavoring agent may be selected from one or any combination of aspartame, sucralose, glucose, and xylitol. In some embodiments, the flavoring agent is 0-5% by weight in the oral dissolving film formulation, preferably 1-3%.

[0015] The size of the oral dissolving film formulation of the present invention can be 2cm × 3cm, and the thickness of the oral dissolving film formulation can be ≤100μm, preferably ≤80μm. The oral dissolving film formulation can be completely dispersed and dissolved in water at 37°C within 60 seconds.

[0016] In the oral disintegrating film formulation of the present invention, part of the active ingredient can be rapidly absorbed by the oral mucosa, and part of it enters the gastrointestinal tract with saliva for absorption, which can achieve the effective concentration more quickly and improve the therapeutic effect. Moreover, due to the novel dosage form, the patient's medication privacy is better, and the patient can take the medication at any time and in any place without attracting the attention of the surrounding people or creating the psychological suggestion that the patient is taking medication, which greatly improves the treatment effect of ED patients and improves the patient's quality of life.

[0017] On the other hand, the present invention provides a method for preparing the above-mentioned orally disintegrating film formulation, comprising the following steps:

[0018] S1, The polymer film-forming material is added to purified water under stirring to obtain a dispersion system;

[0019] Optionally in step S2, a plasticizer is added to the dispersion system obtained in step S1 and stirred until homogeneous to obtain the dispersion system.

[0020] S3, add the active ingredient to the dispersion system obtained in step S1 or S2, and stir thoroughly to obtain a drug-containing colloid solution;

[0021] S4, optionally add a flavoring agent to the medicated adhesive solution obtained in step S3 and stir evenly, and degas the medicated adhesive solution;

[0022] S5, the medicated adhesive solution obtained in step S3 or S4 is coated, dried and cut to obtain the oral dissolving film preparation.

[0023] In some embodiments, the drying temperature in step S5 of the above preparation method can be 20-90°C, preferably 40-50°C.

[0024] In another aspect, the present invention provides a pharmaceutical use of the above-mentioned orally disintegrating film preparation, such as its use in a medicament for the prevention and / or treatment of erectile dysfunction.

[0025] The oral disintegrating film preparations prepared according to the present invention are environmentally friendly, convenient to use, rapidly absorbed, fast-acting, and have good privacy. They take effect faster than ordinary tablets after administration, and no organic solvents are used in the preparation process, making them safe and environmentally friendly. Attached Figure Description

[0026] Figure 1 shows the dissolution curve of the orally dissolving film formulation of the present invention. Detailed Implementation

[0027] To make the technical solution and beneficial effects of the present invention more apparent and understandable, specific embodiments are listed below to further illustrate the present invention. It should be understood that the embodiments of the present invention are merely illustrative and not intended to limit the invention. Any product identical or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0028] Unless otherwise specified, the techniques or conditions described in the following embodiments are generally performed in accordance with conventional techniques or conditions described in the literature in this field, or in accordance with the product manual and the manufacturer's recommendations.

[0029] The detection methods for evaluation indicators such as dissolution time, taste, and in vitro dissolution rate in the embodiments or specific examples of the present invention are as follows:

[0030] Dissolution time: This is an important quality indicator for film-forming products. The speed at which a drug dissolves in the mouth affects clinical compliance and absorption. In accordance with the general requirements for oral preparations and films in the 2020 edition of the Chinese Pharmacopoeia, Part II, the dissolution time of the film-forming product of this invention is set to less than 60 seconds.

[0031] Hold the upper edge of the oral dissolving film preparation with tweezers and partially immerse it vertically into purified water in a 250ml beaker (temperature 37℃, water volume in the beaker approximately 170ml), ensuring that about half of the oral dissolving film preparation is below the liquid surface. The dissolution time is defined as the time it takes for the portion of the oral dissolving film preparation to fall to the bottom of the beaker after contact with the water surface.

[0032] Taste: The bitterness, astringency, and numbing sensation were evaluated by administering the medication orally to six healthy volunteers. Bitterness was categorized as follows: "+++" strong bitterness; "++" noticeable bitterness, tolerable; "+" slight bitterness; "-" no noticeable bitterness. Astringency was categorized as follows: "+++" strong astringency; "++" noticeable astringency, tolerable; "+" slight astringency; "-" no noticeable astringency. Numbness was categorized as follows: "+++" strong numbness; "++" noticeable numbness, tolerable; "+" slight numbness; "-" no noticeable numbness. Overall taste evaluation: (×) unacceptable, (√) acceptable, (√√) good.

[0033] In vitro dissolution: The dissolution was determined according to Method 2 of Section IV of the 2020 Chinese Pharmacopoeia. The dissolution medium was pH 6.8 phosphate buffer, with a volume of 900 mL and a rotation speed of 50 rpm. Samples were taken at 5, 10, 15, 30 and 45 minutes to test the dissolution.

[0034] Unless otherwise specified in the following examples, all raw materials were commercially available or prepared using conventional methods in the art. The raw materials were purchased from, but are not limited to, the following companies: Shandong Tefaman Pharmaceutical Co., Ltd., Anhui Shanhe Pharmaceutical Excipients Co., Ltd., Nanjing Well Pharmaceutical Group Co., Ltd., Yancheng Jiekang Sucralose Manufacturing Co., Ltd., Shandong Kangnaxin Biotechnology Co., Ltd., and Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.

[0035] The compound of formula (I) used as the main drug is prepared into a basic compound according to WO2010066111A1 and then reacted with hydrochloric acid to form a salt.

[0036] The preferred preparation method of the orally disintegrating film formulation of the present invention is as follows:

[0037] Step 1): Add the polymer film-forming material to purified water under stirring to obtain a dispersion system;

[0038] Step 2): Add plasticizer to the dispersion system obtained in Step 1) and stir until homogeneous to obtain the dispersion system;

[0039] Step 3): Add the active pharmaceutical ingredient to the dispersion system obtained in Step 2) and stir thoroughly to obtain a drug-containing colloid solution;

[0040] Step 4): Add flavoring agent to the medicated adhesive solution obtained in Step 3) and stir evenly, and degas the medicated adhesive solution;

[0041] Step 5): Coat the medicated adhesive solution obtained in Step 4), dry it at 40-50℃, and cut it into 2cm×3cm pieces with a thickness ≤80μm to obtain the oral dissolving film preparation.

[0042] Example 1: The Influence of Different Types of Polymer Film-Forming Materials on Product Quality

[0043] Note: *: Used in the prescription but can be removed in the final product.

[0044] The film prepared from the above components has the following characteristics: it is transparent to semi-transparent in appearance; the film prepared from hydroxypropyl methylcellulose E15 and hydroxypropyl methylcellulose K100LV has good smoothness and foldability; it can be completely dissolved in 30 seconds at 37°C with no significant difference.

[0045] Example 2: The effect of the dosage of active pharmaceutical ingredient and polymeric film-forming material on product quality

[0046] Note: *: Used in the prescription but can be removed in the final product.

[0047] The films prepared from the above components exhibit the following characteristics: They are transparent to semi-transparent in appearance, formulations 3 to 5, and possess good flatness and foldability, meeting the requirements for cutting, packaging, transportation, and clinical use. The melting time is consistently around 30 seconds, with no significant differences observed. These results indicate that when the proportion of active pharmaceutical ingredient (API) is in the range of 30–50% and the proportion of polymeric film-forming material is in the range of 35–60%, the products demonstrate good properties in terms of flatness, foldability, and melting time.

[0048] Example 3: The effect of plasticizer dosage on product quality

[0049] Note: *: Used in the prescription but can be removed in the final product.

[0050] The film prepared from the above components has the following characteristics: it is transparent to semi-transparent in appearance, has good flexibility, does not affect product cutting, packaging, and handling, and has a melting time of approximately 30 seconds. The results indicate that a plasticizer ratio of 8–20% meets the requirements for cutting, packaging, transportation, and clinical use.

[0051] Example 4: The effect of glycerin as a plasticizer on product quality

[0052] Note: *: Used in the prescription but can be removed in the final product.

[0053] The film prepared using glycerin as a plasticizer has the following characteristics: it is transparent to semi-transparent in appearance, has good flexibility, does not affect product cutting, packaging and handling, and has a melting time of about 30 seconds.

[0054] Example 5: The effect of sucralose dosage on product quality

[0055] Note: *: Used in the prescription but can be removed in the final product.

[0056] The film prepared from the above components has the following characteristics: it is transparent to semi-transparent in appearance, and the film is flat and has good foldability.

[0057] The results showed that prescription 13 had a distinct bitter taste that permeated the mouth and was difficult to accept. Prescriptions 14 to 16 had no obvious bitter, astringent, or numbing taste, and had a good taste effect and were more acceptable.

[0058] This invention relates to an orally disintegrating film formulation and its preparation method. The formulation comprises a main drug and excipients; the main drug is a compound represented by formula (I), and the excipients include a polymeric film-forming material, a plasticizer, and a flavoring agent. The orally disintegrating film formulation is easy to take, disintegrating within seconds of being placed on the tongue. While improving symptoms in patients with erectile dysfunction (ED), it allows for flexible selection of sexual activity time, eliminating the need for deliberate planning of medication and timing, thus improving the quality of sexual life.

[0059] The beneficial effects of the present invention have been confirmed by the following comparative experiments.

[0060] Comparative Example 1:

[0061] Note: *: Used in the prescription but can be removed in the final product.

[0062] The film prepared from the above components has the following characteristics: When the orally soluble film is observed during the drying process, shrinkage can be seen, which makes it impossible to accurately control the drug uniformity and thickness of the orally soluble film.

[0063] Comparative Example 2:

[0064] Note: *: Used in the prescription but can be removed in the final product.

[0065] The film prepared from the above components has the following characteristics: it is transparent to semi-transparent in appearance, cannot be completely demolded, and has poor demolding performance.

[0066] Table 1: Results of in vitro dissolution test

[0067] Six films each of formulations 1, 4, 5, and 8 from Examples were taken and dissolved according to the dissolution test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), using 900 ml of pH 6.8 phosphate buffer as solvent and a rotation speed of 50 rpm. The dissolution was measured by high-performance liquid chromatography (HPLC) at 5, 10, 15, 30, and 45 minutes. The dissolution amount at different times was calculated, and the dissolution curves are shown in Figure 1. The results in Figure 1 show that the orally dissolving film of the present invention dissolves rapidly, with a dissolution rate of over 85% within 5 minutes.

Claims

1. An orally disintegrating film formulation comprising an active pharmaceutical ingredient, a polymeric film-forming material, an optional plasticizer, and an optional flavoring agent, wherein the active pharmaceutical ingredient has the structure shown in formula (I) and constitutes 10-60% by weight, preferably 30-50%, of the orally disintegrating film formulation:

2. The orally disintegrating film formulation according to claim 1, wherein the polymeric film-forming material is selected from one or any combination of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, and amylopectin; preferably, the polymeric film-forming material is hydroxypropyl methylcellulose, such as hydroxypropyl methylcellulose E15 or hydroxypropyl methylcellulose K100LV.

3. The orally disintegrating film formulation according to claim 1, wherein, The polymeric film-forming material comprises 25-70% by weight in the oral dissolving film formulation, preferably 35-60%.

4. The orally disintegrating film formulation according to claim 1, wherein, The plasticizer is selected from polyethylene glycol, glycerin, polysorbate, propylene glycol or any combination thereof, preferably selected from polyethylene glycol, glycerin or combinations thereof, and preferably, the plasticizer is 0-20% by weight in the oral film formulation, more preferably 8-20%.

5. The orally disintegrating film formulation according to claim 1, wherein, The flavoring agent is selected from one or any combination of aspartame, sucralose, glucose, and xylitol. Preferably, the flavoring agent accounts for 0-5% of the weight percentage of the oral dissolving film preparation, and more preferably 1-3%.

6. The orally disintegrating film formulation according to claim 1, wherein, The oral dissolving film formulation has a size of 2cm × 3cm and a thickness of ≤100μm, preferably ≤80μm.

7. The orally disintegrating film formulation according to claim 1, wherein, The oral dissolving film formulation can be completely dispersed and dissolved in water at 37°C within 60 seconds.

8. A method for preparing an orally disintegrating film formulation as described in any one of claims 1-7, comprising the following steps: S1, The polymer film-forming material is added to purified water under stirring to obtain a dispersion system; Optionally in step S2, a plasticizer is added to the dispersion system obtained in step S1 and stirred until homogeneous to obtain the dispersion system. S3, add the active ingredient to the dispersion system obtained in step S1 or S2, and stir thoroughly to obtain a drug-containing gel; S4, optionally add a flavoring agent to the medicated adhesive solution obtained in step S3 and stir evenly, and degas the medicated adhesive solution; S5, the medicated adhesive solution obtained in step S3 or S4 is coated, dried and cut to obtain the oral dissolving film preparation.

9. The preparation method according to claim 8, wherein, The drying temperature in step S5 is 20–90°C, preferably 40–50°C.

10. Use of an orally disintegrating film formulation as described in any one of claims 1-7 or an orally disintegrating film formulation prepared by the method described in claim 8 in the preparation of a medicament, particularly a medicament for the prevention and / or treatment of erectile dysfunction.

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