Preparation method of vardenafil hydrochloride oral soluble film

Abstract

The invention discloses a preparation method of a vardenafil hydrochloride oral soluble film. The preparation method comprises the following steps: weighing materials for later use according to a prescription list; weighing a prescription amount of pigment, and adding the pigment into purified water to prepare a 5mg / ml pigment solution for later use; adding purified water accounting for 89% of the prescription dosage into the emulsification tank, heating, sequentially adding the glycerol, the flavoring agent and the polyvinyl alcohol according to the prescription dosage, and stirring until the materials are completely dissolved; stopping heating after the materials are completely dissolved, slowly adding hydroxypropyl methylcellulose while the materials are hot, stirring until the materials are completely dispersed, starting cooling, and continuously stirring to prepare liquid until the hydroxypropyl methylcellulose is completely swelled; and adding the powdered orange essence according to the prescription dosage under the condition of 30 + / -5 DEG C, and stirring for 5 minutes. The vardenafil hydrochloride oral soluble film has the beneficial effects that the compliance of the vardenafil hydrochloride oral soluble film can be effectively improved by adding the sweetening agent and the essence into the prescription; the types and the dosages of the film forming material and the disintegrating agent can effectively guarantee the properties and the disintegration performance of the film.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, in particular to a method for preparing a vardenafil hydrochloride orodispersible film. Background Art

[0002] Vardenafil hydrochloride is a highly selective phosphodiesterase 5 (PDE5) inhibitor. It increases the release of local endogenous nitric oxide in the corpus cavernosum under sexual stimulation by inhibiting phosphodiesterase type 5 (PDE5) that degrades cGMP in the human corpus cavernosum, relaxes smooth muscles, and increases blood flow in the human corpus cavernosum. Thus, vardenafil enhances the natural response to sexual stimulation. It is clinically suitable for the treatment of erectile dysfunction in adult men.

[0003] The dosage forms of vardenafil hydrochloride currently available in China and abroad include tablets and orodisintegrating tablets. Its tablets were launched in the EU on March 6, 2003, and in the United States on August 19, 2003 (withdrawn from the market due to non-safety and non-effectiveness). The imported original drug vardenafil hydrochloride tablets (trade name: Levitra, licensee: Bayer Pharma AG / Bayer AG) were approved for marketing in China in August 2004; vardenafil hydrochloride orodisintegrating tablets were launched on the market by the FDA in 2010. Currently, its orodisintegrating tablets have not been imported into China.

[0004] Oral dissolving film releases drugs quickly, is easy to administer, has good compliance, and can well protect the privacy of patients. It is widely used in the pharmaceutical industry and health care products industry to improve the compliance of special populations (children, elderly patients, and patients who have difficulty taking medicine) and to enhance the privacy of concealed medication.

[0005] After searching, the patent with the announcement number CN111655229A provides an adhesive film containing vardenafil prepared by using C3-C12 polyol, pH regulator, monovalent cation alginate or a mixture of monovalent cation alginate and dimethyl sulfoxide, etc. The preparation method introduces the organic solvent dimethyl sulfoxide, and the safe dissolution time of the active ingredient is relatively long (about 30 minutes); the patent with the announcement number CN102824333A provides an adhesive film containing polyvinyl alcohol 1788 as the film-forming material A kind of oral fast-dissolving film containing vardenafil is prepared by using polyethylene glycol 400 or a mixture of polyethylene glycol 4000 and glycerol as a plasticizer and sodium alginate as a disintegrant. The oral fast-dissolving film prepared by the preparation method can disintegrate quickly, but no research is involved in its taste correction. The oral fast-dissolving film will disintegrate quickly in the mouth after taking it, and its taste directly affects its compliance in clinical use. In order to provide a dosage form that is easy to take, safe, easy to be accepted by patients and can effectively protect patients' privacy, the present application proposes a preparation method of vardenafil hydrochloride oral fast-dissolving film. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing a vardenafil hydrochloride orodispersible film to solve the problems raised in the above background technology.

[0007] To achieve the above object, the present invention provides the following technical solution: a method for preparing a vardenafil hydrochloride orodispersible film, wherein the components of the orodispersible film are recorded as follows by weight: vardenafil hydrochloride 20.5%-21%, hydroxypropyl methylcellulose (E50) 32.3%-33.6%, polyvinyl alcohol 13.5%-15%, glycerol 20.2%-21.4%, disintegrant 8.1%-8.4%, colorant 2.7%-3.1%, flavoring agent 0.5%-0.7%, powdered orange flavor 2.1%-2.3%, pigment 0.06%-0.08% and appropriate amount of purified water;

[0008] The preparation method of the vardenafil hydrochloride orosoluble film comprises the following steps:

[0009] S1. Weighing:

[0010] Weigh all materials according to the prescription list;

[0011] S2. Liquid preparation:

[0012] S21, weigh the pigment in the prescribed amount, add it into purified water, prepare a 5 mg / ml pigment solution, and set aside;

[0013] S22, add 89% of the prescribed amount of purified water into the emulsification tank and heat it, and add the prescribed amount of glycerin, flavoring agent and polyvinyl alcohol in sequence, and stir until completely dissolved;

[0014] S23, stop heating after the above materials are completely dissolved, slowly add hypromellose while hot, stir until completely dispersed, start cooling and continue stirring, and prepare the liquid until the hypromellose is completely swollen;

[0015] S24, add the prescribed amount of powdered orange flavor and stir for 5 minutes at 30℃±5℃;

[0016] S25. After the powdered orange flavor is completely dissolved, add the colorant, API, disintegrant and 5 mg / ml pigment solution, homogenize and disperse the above glue solution evenly under vacuum conditions and defoam, and then transfer it to the buffer tank;

[0017] S3, coating:

[0018] The glue solution is coated on the polyester film coated with dimethyl silicone oil by using a coating machine and then dried;

[0019] S4, cutting:

[0020] Ensure that the tablet weight difference limit is ±8% and cut the film into the specified size;

[0021] S5. Packaging:

[0022] It is packaged with polyester / aluminum / polyethylene pharmaceutical composite film and bag and stored in a light-proof and sealed place below 30°C.

[0023] Preferably, the disintegrant is low-substituted hydroxypropyl cellulose, and the concentration of the disintegrant is 15 mg / ml.

[0024] Preferably, the colorant is titanium dioxide, and the concentration of the colorant is 5 mg / ml.

[0025] Preferably, the flavoring agent is aspartame, and the concentration of the flavoring agent is 1 mg / ml.

[0026] Preferably, the pigment is carmine, and the concentration of the pigment is 0.11 mg / ml.

[0027] Preferably, the coating width in step S3 is 450 mm, and the drying temperature is 60° C.-95° C.

[0028] Preferably, the tablet weight of the film in S4 is determined based on the determination result of the vardenafil content, and the calculation formula is: tablet weight = theoretical specification / vardenafil content.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. The present invention adds sweeteners and flavors to the prescription to effectively improve the compliance of vardenafil hydrochloride orodispersible film;

[0031] 2. The types and dosages of the film-forming materials and disintegrants of the present invention can effectively guarantee the properties and disintegration performance of the film;

[0032] 3. The present invention provides a preparation process for orally dissolving vardenafil hydrochloride film, and preferentially adds easily soluble components. After the components are dissolved, they are evenly dispersed while hot according to the properties of hydroxypropyl cellulose, and then the liquid is cooled to ensure sufficient swelling of hydroxypropyl cellulose. Preferentially adding easily soluble components is also beneficial to the judgment of the swelling condition of hydroxypropyl cellulose. DETAILED DESCRIPTION

[0033] The present invention provides a technical solution: a method for preparing a vardenafil hydrochloride orodispersible film, wherein the components of the orodispersible film are recorded as follows by weight: 20.5%-21% of vardenafil hydrochloride, 32.3%-33.6% of hydroxypropyl methylcellulose (E50), 13.5%-15% of polyvinyl alcohol, 20.2%-21.4% of glycerol, 8.1%-8.4% of disintegrant, 2.7%-3.1% of colorant, 0.5%-0.7% of flavoring agent, 2.1%-2.3% of powdered orange flavor, 0.06%-0.08% of pigment and an appropriate amount of purified water;

[0034] The preparation method of the vardenafil hydrochloride orosoluble film comprises the following steps:

[0035] S1. Weighing:

[0036] Weigh all materials according to the prescription list;

[0037] S2. Liquid preparation:

[0038] S21, weigh the food additive carmine in a prescribed amount, add it into purified water, prepare a 5 mg / ml carmine solution, and set aside;

[0039] S22, add 89% of the prescribed amount of purified water into the emulsification tank and heat it, and add the prescribed amount of glycerin, flavoring agent and polyvinyl alcohol in sequence, and stir until completely dissolved;

[0040] S23. After the above materials are completely dissolved, stop heating, slowly add the prescribed amount of hypromellose while hot, and stir until completely dispersed (center stirring speed: 50±5rpm, scraping wall stirring speed: 40±5rpm, stirring for 10 minutes); at the same time, start cooling (to 30℃±5℃), continue stirring (center stirring speed: 50±5rpm, scraping wall stirring speed: 40±5rpm, homogenization speed: 2500±100rpm, stirring for 30 minutes), and prepare the liquid until the hypromellose is completely swollen;

[0041] S24. Add the prescribed amount of powdered orange flavor and stir for 5 minutes at 30°C ± 5°C (center stirring speed: 50 ± 5 rpm, wall scraping stirring speed: 40 ± 5 rpm, homogenizing speed: 2500 ± 100 rpm);

[0042] S25. After the powdered orange flavor is completely dissolved, add the prescribed amount of titanium dioxide, API, low-substituted hydroxypropyl cellulose and 5 mg / ml carmine solution, homogenize the above glue solution under vacuum conditions (-0.08±0.01MPa) (center stirring speed: 50±5rpm, scraping stirring speed: 40±5rpm, homogenization speed: 2500±100rpm, stirring for 40 minutes) until it is evenly dispersed and defoamed, and then transfer it to a buffer tank;

[0043] S3, coating:

[0044] The glue solution is coated on the polyester film coated with dimethyl silicone oil by using a coating machine and then dried. During the coating process, the coating width is controlled to be 450 mm, and the coating gap is adjusted according to the test results of the coated sheet weight;

[0045] S4, cutting:

[0046] Cut the membrane into (20±2) mm×(30±2) mm size, and the limit of the difference in the weight of the membrane is ±8%;

[0047] S5. Packaging:

[0048] It is packaged with polyester / aluminum / polyethylene pharmaceutical composite film and bag and stored in a light-proof and sealed place below 30°C.

[0049] Wherein, the disintegrant is low-substituted hydroxypropyl cellulose, and the concentration of the disintegrant is 15 mg / ml.

[0050] Wherein, the colorant is titanium dioxide, and the concentration of the colorant is 5 mg / ml.

[0051] Wherein, the flavoring agent is aspartame, and the concentration of the flavoring agent is 1 mg / ml.

[0052] Wherein, the pigment is carmine, and the concentration of the pigment is 0.11 mg / ml.

[0053] Wherein, the coating width in step S3 is 450 mm, and the drying temperature is 60° C.-95° C.

[0054] The weight of the film in S4 is determined based on the result of the vardenafil content determination, and the calculation formula is: film weight = theoretical specification / vardenafil content.

[0055] Embodiment 1:

[0056]

[0057]

[0058] Prepare the pigment into a 5mg / ml carmine solution for later use; add the plasticizer, sweetener and polyvinyl alcohol to purified water at 60℃±5℃ in sequence, stir until completely dissolved, then stop heating, add hydroxypropyl methylcellulose while hot, stir until completely dispersed, then cool to 30℃±5℃ for swelling. After the hydroxypropyl methylcellulose swells, add flavors, colorants, API disintegrants and colorants, homogenize and defoam under vacuum conditions, and then apply, dry and cut.

[0059] Embodiment 2:

[0060] Element Concentration (mg / ml) Vardenafil hydrochloride 38 Hydroxypropyl methylcellulose (E50) 50 Polyvinyl alcohol 25 Plasticizers 37.5 Disintegrants 15 Colorants 5 Sweeteners 1 essence 4 pigment 0.11 Purified water (removed during drying process) /

[0061] Prepare the pigment into a 5mg / ml carmine solution for later use; add the plasticizer, sweetener and polyvinyl alcohol to purified water at 60℃±5℃ in sequence, stir until completely dissolved, then stop heating, add hydroxypropyl methylcellulose while hot, stir until completely dispersed, then cool to 30℃±5℃ for swelling. After the hydroxypropyl methylcellulose swells, add flavors, colorants, API disintegrants and colorants, homogenize and defoam under vacuum conditions, and then apply, dry and cut.

[0062] Embodiment 3:

[0063]

[0064]

[0065] Prepare the pigment into a 5mg / ml carmine solution for later use; add the plasticizer, sweetener and polyvinyl alcohol to purified water at 60℃±5℃ in sequence, stir until completely dissolved, then stop heating, add hydroxypropyl methylcellulose while hot, stir until completely dispersed, then cool to 30℃±5℃ for swelling. After the hydroxypropyl methylcellulose swells, add flavors, colorants, API disintegrants and colorants, homogenize and defoam under vacuum conditions, and then apply, dry and cut.

[0066] The comparative test results of Example 1 and Examples 2-3 are as follows:

[0067]

[0068] Note: When using E3 and E5 types of HPMC for sample preparation, the viscosity of the solution is too low and difficult to apply; the film properties are poor.

[0069] When the dosage of HPMC is 50 mg / ml and 60 mg / ml, there is no significant difference in the disintegration time of the product. When the dosage is further increased to 70 mg / ml, the disintegration time of the product is significantly prolonged. By comparing the elastic modulus, tensile strength and elongation at break of different homemade samples, it can be seen that when the dosage of HPMC is 50 mg / ml, the elastic modulus of the product is larger and the elongation at break is lower, which may be unfavorable for production operations. Therefore, the dosage of HPMC is planned to be 60 mg / ml.

[0070] Embodiment 4:

[0071] Compared with Example 1, the dosage ratio of hydroxypropyl methylcellulose and polyvinyl alcohol is adjusted to 1:1, i.e., 42.5:42.5, and the process is consistent with Example 1.

[0072] Embodiment 5:

[0073] Compared with Example 1, the dosage ratio of hydroxypropyl methylcellulose and polyvinyl alcohol is adjusted to 25:60, and the process is consistent with Example 1.

[0074] The comparative test results of Example 1 and Examples 4-5 are as follows:

[0075]

[0076] When the ratio of HPMC to PVA is 60:25, the sample disintegrates faster, and its mechanical properties (elastic modulus, tensile strength and elongation at break) are better than or close to those of the same dosage form product; keeping the total amount of film-forming material unchanged and adjusting the ratio of HPMC to PVA to 1:1 (42.5:42.5), the disintegration time of the sample is prolonged, and its elastic modulus increases, while the elongation at break decreases; further reducing the amount of HPMC and increasing the amount of PVA (25:60) significantly reduces the mechanical properties of the sample, which is not conducive to the operation of the production process. Based on the above results, in order to ensure the disintegration performance, mechanical properties and convenience of production operation of the product, the ratio of HPMC to PVA is proposed to be 60:25.

[0077] Embodiment 6:

[0078] The same process steps as in Example 1 were used to test the effects of different types of disintegrants on the disintegration time. The test results are as follows: low-substituted hydroxypropyl cellulose was selected as the disintegrant, which could significantly shorten the disintegration time.

[0079]

[0080] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing vardenafil hydrochloride orodispersible film, characterized in that: The components of the orodispersible film are recorded as follows by weight: 20.5%-21% of vardenafil hydrochloride, 32.3%-33.6% of hydroxypropyl methylcellulose (E50), 13.5%-15% of polyvinyl alcohol, 20.2%-21.4% of glycerol, 8.1%-8.4% of disintegrant, 2.7%-3.1% of colorant, 0.5%-0.7% of flavoring agent, 2.1%-2.3% of powdered orange flavor, 0.06%-0.08% of pigment and appropriate amount of purified water; The preparation method of the vardenafil hydrochloride orosoluble film comprises the following steps: S1. Weighing: Weigh all materials according to the prescription list; S2. Liquid preparation: S21, weigh the pigment in the prescribed amount, add it into purified water, prepare a 5 mg / ml pigment solution, and set aside; S22, add 89% of the prescribed amount of purified water into the emulsification tank and heat it, and add the prescribed amount of glycerin, flavoring agent and polyvinyl alcohol in sequence, and stir until completely dissolved; S23, stop heating after the above materials are completely dissolved, slowly add hypromellose while hot, stir until completely dispersed, start cooling and continue stirring, and prepare the liquid until the hypromellose is completely swollen; S24, add the prescribed amount of powdered orange flavor and stir for 5 minutes at 30℃±5℃; S25. After the powdered orange flavor is completely dissolved, add the colorant, API, disintegrant and 5 mg / ml pigment solution, homogenize and disperse the above glue solution evenly under vacuum conditions and defoam, and then transfer it to the buffer tank; S3, coating: The glue solution is coated on the polyester film coated with dimethyl silicone oil by using a coating machine and then dried; S4, cutting: Ensure that the tablet weight difference limit is ±8% and cut the film into the specified size; S5. Packaging: It is packaged with polyester / aluminum / polyethylene pharmaceutical composite film and bag and stored in a light-proof and sealed place below 30°C.

2. The method for preparing a vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The disintegrant is low-substituted hydroxypropyl cellulose, and the concentration of the disintegrant is 15 mg / ml.

3. The method for preparing a vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The colorant is titanium dioxide, and the concentration of the colorant is 5 mg / ml.

4. The method for preparing a vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The flavoring agent is aspartame, and the concentration of the flavoring agent is 1 mg / ml.

5. The method for preparing a vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The pigment is carmine, and the concentration of the pigment is 0.11 mg / ml.

6. The method for preparing a vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The coating width in step S3 is 450 mm, and the drying temperature is 60° C.-95° C.

7. The method for preparing a vardenafil hydrochloride orodispersible film according to claim 1, characterized in that: The tablet weight of the film in S4 is determined based on the determination result of the vardenafil content, and the calculation formula is: tablet weight = theoretical specification / vardenafil content.

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