Rapidly-dissolved vardenafil hydrochloride oral soluble film and preparation method thereof

Abstract

The invention discloses a rapidly-dissolved vardenafil hydrochloride oral soluble film and a preparation method thereof. The vardenafil hydrochloride tablet comprises the following components in percentage by weight: 26.5%-34.7% of vardenafil hydrochloride, 25.3%-28% of microcrystalline cellulose, 1.5%-2.1% of an isolating agent, 4.7%-11.3% of a disintegrating agent, 1.2%-1.8% of a flow aid, 0.8%-1.1% of a lubricating agent, 32.6%-36.5% of a film forming material, 0.08%-0.12% of a pH (Potential of Hydrogen) regulator, 2.7%-3.5% of a flavoring agent and purified water. Malic acid, citric acid, taurine or lauric acid is used as a pH regulator, so that the astringent taste of the vardenafil can be covered while the dissolution effect of the vardenafil oral soluble film is accelerated, the taste of the oral soluble film is improved, and meanwhile, by grinding the raw medicine and performing oscillation filtration on the medicine liquid, the oral soluble film can be prepared into the oral soluble film. According to the present invention, the dissolution residue during the use of the oral soluble film can be furthest removed, and the influence of the high temperature on the drug component can be avoided by using the low-temperature drying at the temperature of 45-50 DEG C so as to improve the taking effect of the oral soluble film.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, in particular to a rapidly dissolving orodispersible vardenafil hydrochloride film and a preparation method thereof. Background Art

[0002] Vardenafil hydrochloride is a highly selective and potent phosphodiesterase-5 inhibitor developed and marketed by Bayer Pharmaceuticals of Germany, used to treat male erectile dysfunction. Erectile dysfunction (ED) is a common disease that prevents patients from having a normal sexual life, which can seriously affect their physical and mental health and quality of life. Vardenafil hydrochloride was approved for marketing by the US FDA on August 19, 2003, and is currently available in more than 70 countries around the world. Vardenafil hydrochloride is one of the world's three best-selling anti-ED drugs, with the characteristics of rapid onset, sustained efficacy, good tolerance, few side effects, safety and reliability, etc. It is also easy to take and is not affected by food and alcohol.

[0003] After searching, the patent with announcement number CN1984661A discloses a controlled release preparation of vardenafil, which contains micronized vardenafil hydrochloride trihydrate, matrix polymers such as hydroxypropyl methylcellulose, tableting aids such as microcrystalline cellulose, lactose, magnesium stearate, silicon dioxide, etc., and / or pH-dependent release excipients such as citric acid, gluconic acid, succinic acid, tartaric acid, etc., suitable thermoplastic carriers such as polyvinyl pyrrolidone, vinyl acetate copolymers, cellulose phthalate, etc. The application of this technology can achieve slow release of the drug, but vardenafil needs to be released quickly to take effect, so it does not have an advantage in clinical application. For this reason, the present application proposes a fast-dissolving vardenafil hydrochloride oral dissolving film and a preparation method thereof. Summary of the invention

[0004] The object of the present invention is to provide a fast-dissolving vardenafil hydrochloride orodispersible film and a preparation method thereof, so as to solve the problems raised in the above-mentioned background technology.

[0005] To achieve the above object, the present invention provides the following technical solution: a rapidly dissolving vardenafil hydrochloride orodispersible film, wherein the components include the following substances by weight: 26.5%-34.7% of vardenafil hydrochloride, 25.3%-28% of microcrystalline cellulose, 1.5%-2.1% of a separator, 4.7%-11.3% of a disintegrant, 1.2%-1.8% of a glidant, 0.8%-1.1% of a lubricant, 32.6%-36.5% of a film-forming material, 0.08%-0.12% of a pH regulator, 2.7%-3.5% of a flavoring agent, and purified water.

[0006] Preferably, the pH adjuster is a mixture of one or more of malic acid, citric acid, taurine and lauric acid.

[0007] Preferably, the lubricant is one or more of magnesium stearate, hydrogenated castor oil, carnauba wax or glyceryl behenate, wherein magnesium stearate is preferred.

[0008] Preferably, the glidant is one of white micro powder silica gel or talcum powder, preferably white micro powder silica gel.

[0009] Preferably, the disintegrant is one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch or cross-linked polyvinyl pyrrolidone, preferably low-substituted hydroxypropyl cellulose.

[0010] Preferably, the flavoring agent is one or more of orange flavor, mint flavor, banana flavor, strawberry flavor, and milk flavor.

[0011] A method for preparing a rapidly dissolving vardenafil hydrochloride oral dissolving film, characterized in that it comprises the following steps:

[0012] S1. Weigh the corresponding weight of the original medicine according to the formula, and grind and sieve them one by one;

[0013] S2, placing purified water in a mixing tank and adding flavoring agent and film-forming material, stirring until completely dispersed, to prepare a film-forming material solution containing flavoring agent for standby use;

[0014] S3, adding a glidant and a lubricant to the above solution, stirring thoroughly to obtain a mixed solution, and heating the mixed solution;

[0015] S4, after the temperature is raised, vardenafil hydrochloride, microcrystalline cellulose and disintegrant are added to the mixed solution, and the mixture is fully mixed under vacuum conditions, and degassed after dispersion to obtain a drug solution;

[0016] S5, adding a separator and a pH adjuster to the drug solution to prepare the drug, and after mixing evenly, oscillating and filtering until all particles in the drug solution are removed, and then storing in a sealed can;

[0017] S6. Use a coating machine to evenly coat the above-mentioned drug on the flat backing material, and dry and roll it at a temperature of 45-50°C;

[0018] S7. Cut the rolled drug into pieces according to the drug content of the orodispersible film, and pack and seal the pieces.

[0019] Preferably, the mesh size of the sieve used to grind and sieve the original drug in step S1 is 300-800 mesh.

[0020] Preferably, the temperature of the mixed solution after heating in step S3 is 30°C-65°C.

[0021] Preferably, in step S4, the vacuum condition is -0.05±0.01 MPa, the mixing time is 70-110 minutes, and the mixing speed is 120-180 r / min.

[0022] Compared with the prior art, the present invention has the following beneficial effects: the disintegrant of the present invention selects low-substituted hydroxypropyl cellulose, and malic acid, citric acid, taurine or lauric acid is used as a pH regulator, which can accelerate the dissolution effect of vardenafil oral dissolving film while masking the astringency of vardenafil, which is beneficial to improving the mouthfeel of the oral dissolving film. At the same time, by grinding the original drug and oscillating and filtering the drug solution, the dissolution residue during the use of the oral dissolving film can be removed to the greatest extent, and the low-temperature drying at 45-50°C can also avoid the influence of high temperature on the drug components, thereby improving the taking effect of the oral dissolving film. DETAILED DESCRIPTION

[0023] The present invention is described in detail below, and the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0024] The present invention is described in detail below, and the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] The present invention provides a technical solution:

[0026] The invention discloses a rapidly dissolving vardenafil hydrochloride oral dissolving film, wherein the components include the following substances by weight: 26.5%-34.7% of vardenafil hydrochloride, 25.3%-28% of microcrystalline cellulose, 1.5%-2.1% of a separator, 4.7%-11.3% of a disintegrant, 1.2%-1.8% of a glidant, 0.8%-1.1% of a lubricant, 32.6%-36.5% of a film-forming material, 0.08%-0.12% of a pH regulator, 2.7%-3.5% of a flavoring agent and purified water.

[0027] Wherein, the pH regulator is a mixture of one or more of malic acid, citric acid, taurine and lauric acid.

[0028] Wherein, the lubricant is one or more of magnesium stearate, hydrogenated castor oil, carnauba wax or glyceryl behenate, wherein magnesium stearate is preferred.

[0029] Wherein, the glidant is one of white micro powder silica gel or talcum powder, preferably white micro powder silica gel.

[0030] The disintegrant is one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch or cross-linked polyvinyl pyrrolidone, preferably low-substituted hydroxypropyl cellulose.

[0031] Wherein, the flavoring agent is one or more of orange flavor, mint flavor, banana flavor, strawberry flavor, and milk flavor.

[0032] A method for preparing a rapidly dissolving vardenafil hydrochloride oral dissolving film, characterized in that it comprises the following steps:

[0033] S1. Weigh the corresponding weight of the original medicine according to the formula, and grind and sieve them one by one;

[0034] S2, placing purified water in a mixing tank and adding flavoring agent and film-forming material, stirring until completely dispersed, to prepare a film-forming material solution containing flavoring agent for standby use;

[0035] S3, adding a glidant and a lubricant to the above solution, stirring thoroughly to obtain a mixed solution, and heating the mixed solution;

[0036] S4, after the temperature is raised, vardenafil hydrochloride, microcrystalline cellulose and disintegrant are added to the mixed solution, and the mixture is fully mixed under vacuum conditions, and degassed after dispersion to obtain a drug solution;

[0037] S5, adding a separator and a pH adjuster to the drug solution to prepare the drug, and after mixing evenly, oscillating and filtering until all particles in the drug solution are removed, and then storing in a sealed can;

[0038] S6. Use a coating machine to evenly coat the above-mentioned drug on the flat backing material, and dry and roll it at a temperature of 45-50°C;

[0039] S7. Cut the rolled drug into pieces according to the drug content of the orodispersible film, and pack and seal the pieces.

[0040] Wherein, the mesh size of the sieve used for grinding and sieving the original drug in step S1 is 300-800 mesh.

[0041] Wherein, the temperature of the mixed solution after heating in step S3 is 30°C-65°C.

[0042] Wherein, in step S4, the vacuum condition is -0.05±0.01 MPa, the mixing time is 70-110 minutes, and the mixing speed is 120-180 r / min.

[0043] Embodiment 1:

[0044] The orodispersible film of vardenafil hydrochloride is prepared from the following materials: 28.5% vardenafil hydrochloride, 25.3% microcrystalline cellulose, 1.5% isolation agent, 5.7% low-substituted hydroxypropyl cellulose, 1.2% white micro powder silica gel, 0.8% magnesium stearate, 34.22% film-forming material, 0.08% malic acid, 2.7% orange flavor and purified water;

[0045] Weigh the original drug of corresponding weight according to the formula, and grind it one by one through a 650-mesh sieve until all of them are sieved; put purified water in a mixing tank and add orange flavor and film-forming material, stir until completely dispersed, and prepare a film-forming material solution containing orange flavor for standby use; add white micropowder silica gel and magnesium stearate to the above solution, stir thoroughly to obtain a mixed solution, and heat the mixed solution to 45°C; after the heating is completed, add vardenafil hydrochloride, microcrystalline cellulose and low-substituted hydroxypropyl cellulose to the mixed solution, and mix at a speed of 120rmp for 75 minutes under vacuum conditions, degas after dispersion, and prepare a drug solution; add a release agent and malic acid to the drug solution to prepare the drug, and after mixing evenly, oscillate and filter until all particles in the drug solution are removed, and then store in a sealed can; use a coating machine to evenly coat the above drug on a flat backing material, and dry and roll it at a temperature of 45°C; cut the rolled drug according to the drug content of the orodispersible film, and bag and seal it.

[0046] Embodiment 2:

[0047] The vardenafil hydrochloride orodispersible film is prepared from the following materials: vardenafil hydrochloride 29.5%, microcrystalline cellulose 26%, release agent 1.8%, sodium carboxymethyl starch 5.2%, talc 1.5%, glyceryl behenate 0.9%, film-forming material 32%, citric acid 0.1%, strawberry flavor 3% and purified water;

[0048] Weigh the original drug of corresponding weight according to the formula, and grind them one by one through a 350-mesh sieve until all of them are sieved; put purified water in a mixing tank and add strawberry flavor and film-forming material, stir until completely dispersed, and prepare a film-forming material solution containing strawberry flavor for standby use; add talcum powder and glyceryl behenate to the above solution, stir thoroughly to obtain a mixed solution, and heat the mixed solution to 60°C; after the heating is completed, add vardenafil hydrochloride, microcrystalline cellulose and sodium carboxymethyl starch to the mixed solution, and mix at a speed of 180rmp for 100 minutes under vacuum conditions, degas after dispersion, and prepare a drug solution; add a release agent and citric acid to the drug solution to prepare the drug, and after mixing evenly, oscillate and filter until all particles in the drug solution are removed, and then store in a sealed can; use a coating machine to evenly coat the above drug on a flat backing material, and dry and roll it at a temperature of 50°C; cut the rolled drug according to the drug content of the orodispersible film, and bag and seal it.

[0049] 30 patients with primary premature ejaculation and erectile dysfunction were selected, with an age range of 28-35 years old and an average age of 31.5 years old. The patients were divided into groups of 15 and the orosoluble films prepared in Example 1 and Example 2 were used respectively;

[0050] 30 patients with premature ejaculation and erectile dysfunction were collected, 2 patients were lost to follow-up and dropped out, and finally 28 patients completed the trial. After 2 weeks of treatment, the IELT of patients with premature ejaculation and erectile dysfunction was significantly improved compared with that before treatment. The ejaculation time of patients treated with Example 1 increased from an average of 4.5 minutes to 6.7 minutes; the ejaculation time of patients treated with Example 2 increased from an average of 3.8 minutes to 5.7 minutes;

[0051] Taste evaluation: Example 1 dissolves in an average of 15.6 seconds after administration, has no obvious astringency, tastes like orange, and has no residue in the mouth;

[0052] The average dissolution rate of Example 2 after taking is 17.2 seconds, there is no obvious astringency, the taste is strawberry, and there is no obvious residue in the mouth.

[0053] The above description enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A fast-dissolving vardenafil hydrochloride orodispersible film, characterized in that: The components include the following substances by weight: Vardenafil hydrochloride 26.5%-34.7%, microcrystalline cellulose 25.3%-28%, isolation agent 1.5%-2.1%, disintegrant 4.7%-11.3%, glidant 1.2%-1.8%, lubricant 0.8%-1.1%, film-forming material 32.6%-36.5%, pH adjuster 0.08%-0.12%, flavoring agent 2.7%-3.5% and purified water.

2. The fast-dissolving vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The pH adjuster is a mixture of one or more of malic acid, citric acid, taurine and lauric acid.

3. The fast-dissolving vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The lubricant is one or more of magnesium stearate, hydrogenated castor oil, carnauba wax or glyceryl behenate, wherein magnesium stearate is preferred.

4. The fast-dissolving vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The glidant is one of white micro powder silica gel or talcum powder, preferably white micro powder silica gel.

5. The fast-dissolving vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The disintegrant is one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch or cross-linked polyvinyl pyrrolidone, preferably low-substituted hydroxypropyl cellulose.

6. The fast-dissolving vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The flavoring agent is one or more of orange flavor, mint flavor, banana flavor, strawberry flavor, and milk flavor.

7. A method for preparing a rapidly dissolving vardenafil hydrochloride orodispersible film, characterized in that: The following steps are involved: S1. Weigh the corresponding weight of the original medicine according to the formula, and grind and sieve them one by one; S2, placing purified water in a mixing tank and adding flavoring agent and film-forming material, stirring until completely dispersed, to prepare a film-forming material solution containing flavoring agent for standby use; S3, adding a glidant and a lubricant to the above solution, stirring thoroughly to obtain a mixed solution, and heating the mixed solution; S4, after the temperature is raised, vardenafil hydrochloride, microcrystalline cellulose and disintegrant are added to the mixed solution, and the mixture is fully mixed under vacuum conditions, and degassed after dispersion to obtain a drug solution; S5, adding a separator and a pH adjuster to the drug solution to prepare the drug, and after mixing evenly, oscillating and filtering until all particles in the drug solution are removed, and then storing in a sealed can; S6. Use a coating machine to evenly coat the above-mentioned drug on the flat backing material, and dry and roll it at a temperature of 45-50°C; S7. Cut the rolled drug into pieces according to the drug content of the orodispersible film, and pack and seal the pieces.

8. The method for preparing a fast-dissolving vardenafil hydrochloride oral dissolving film according to claim 7, characterized in that: In the step S1, the mesh size of the sieve used to grind and sieve the original drug is 300-800 meshes.

9. The method for preparing a fast-dissolving vardenafil hydrochloride oral dissolving film according to claim 7, characterized in that: The temperature of the mixed solution after heating in step S3 is 30°C-65°C.

10. The method for preparing a fast-dissolving vardenafil hydrochloride oral dissolving film according to claim 7, characterized in that: In step S4, the vacuum condition is -0.05±0.01 MPa, the mixing time is 70-110 minutes, and the mixing speed is 120-180 r / min.