Vanodenafil hydrochloride solid dispersion, tablet containing same and preparation method of vardenafil hydrochloride solid dispersion
By preparing vardenafil hydrochloride solid dispersion tablets, the problems of low dissolution and poor stability of vardenafil hydrochloride tablets were solved by using specific polymers and optimizing component ratios, achieving rapid release and high bioavailability.
Patent Information
- Application Number
- CN202511213783.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-28
- Publication Date
- 2025-11-25
AI Technical Summary
Existing vardenafil hydrochloride tablets have problems with stability and dissolution rate, resulting in low dissolution and difficulty in achieving rapid onset of action.
Vardenafil hydrochloride raw material is used to form a solid dispersion with pharmaceutically acceptable polymers such as hydroxypropyl methylcellulose acetate succinate or vinylpyrrolidone ethyl acetate copolymer. Tablets are prepared by spray drying. By combining fillers, disintegrants and lubricants, optimizing the raw material ratio and solvent selection, the dissolution and stability are improved.
The prepared vardenafil hydrochloride solid dispersion tablets significantly improved dissolution and stability, achieving rapid drug release and bioavailability, and meeting bioequivalence requirements.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a vardenafil hydrochloride solid dispersion and tablets comprising the same, and a method for preparing the same. Background Technology
[0004] CN1681481A discloses a method for preparing a drug comprising vardenafil hydrochloride trihydrate in solid form. The claims protect the method for preparing vardenafil hydrochloride trihydrate and the coated tablets containing vardenafil hydrochloride trihydrate. This patent is for vardenafil hydrochloride tablets, disclosing the composition and content of the coated tablets: vardenafil hydrochloride trihydrate accounts for 0.1-70% by weight, disintegrant accounts for 0.1-10% by weight, lubricant accounts for 0.1-2% by weight, and optionally, also includes a gliding agent and some fillers. The preparation method in this patent is quite unique, requiring specific temperature and humidity control. Moist air is introduced during the coating process to wet the tablets, obtaining a uniform and reproducible form of vardenafil hydrochloride trihydrate. Tablets prepared according to this formulation are unstable during stable storage, and the drug dissolves slowly in hydrochloric acid solution at pH 1.2, with less than 80% dissolution within 5 minutes, failing to achieve rapid onset of action.
[0005] Solid dispersion technology is an effective method to improve the bioavailability of poorly soluble drugs. In solid dispersions, the drug exists in an amorphous form, exhibiting high dissolution and bioavailability. By converting crystalline drugs into an amorphous form, it can significantly improve the dissolution rate of poorly soluble drugs, facilitating rapid drug release and absorption. Summary of the Invention
[0006] Purpose of the invention: The purpose of this invention is to solve the above-mentioned technical problems and provide a vardenafil hydrochloride solid dispersion, tablets containing the same, and a preparation method thereof. The preparation process is simple, improves the dissolution rate of oral preparations, and ensures good stability.
[0007] Technical solution: The present invention provides a vardenafil hydrochloride solid dispersion comprising vardenafil hydrochloride raw material and a pharmaceutically acceptable polymer, wherein the vardenafil hydrochloride raw material is dispersed in a polymer matrix formed by the polymer to form the vardenafil hydrochloride solid dispersion.
[0008] Furthermore, the pharmaceutically acceptable polymer is selected from hydroxypropyl methylcellulose acetate succinate or vinylpyrrolidone ethyl acetate copolymer. Hydroxypropyl methylcellulose acetate succinate is preferred, wherein the dissolution rate of vardenafil hydrochloride tablets prepared from H-type hydroxypropyl methylcellulose acetate succinate is closer to that of the reference.
[0009] Furthermore, the pharmaceutically acceptable mass ratio of vardenafil hydrochloride raw material to polymer is 2:5-6. Tablets prepared with a mass ratio of vardenafil hydrochloride raw material to polymer of 2:5 exhibit better mixing uniformity.
[0010] The present invention also provides a vardenafil hydrochloride tablet comprising the above-mentioned vardenafil hydrochloride solid dispersion, and further comprising a filler, a disintegrant, and a lubricant.
[0011] Furthermore, the filler is microcrystalline cellulose.
[0012] Furthermore, the disintegrant is cross-linked polyvinylpyrrolidone.
[0013] Furthermore, the flow aid is selected from colloidal silica or talc; the lubricant is magnesium stearate.
[0014] This invention also provides a method for preparing vardenafil hydrochloride tablets, comprising the following steps:
[0015] 1) Preparation of solid dispersion: Vardenafil hydrochloride and a pharmaceutically acceptable polymer were added to an organic solvent to prepare a solid dispersion solution; then, the solid dispersion was prepared by spray drying.
[0016] 2) The solid dispersion prepared in step 1) is mixed with filler, disintegrant, glidant and lubricant and then compressed into tablets.
[0017] Furthermore, the organic solvent in step 1) is ethanol or dimethyl sulfoxide. Ethanol is preferred, especially 75% ethanol, which has lower levels of related substance impurities.
[0018] Beneficial Effects: This invention employs a spray drying method to completely convert vardenafil hydrochloride raw material into an amorphous form, preparing a vardenafil hydrochloride solid dispersion. Tablets prepared using this solid dispersion improve the dissolution rate of poorly soluble drugs, facilitating rapid drug release and absorption, while also ensuring good stability. By using different polymers, adjusting the ratio of vardenafil hydrochloride raw material to polymers, and selecting appropriate solvents during preparation, this invention can prepare a stable vardenafil hydrochloride solid dispersion and its tablets, while maintaining low levels of related substance impurities and ensuring dissolution rates consistent with in vivo bioequivalence and the reference formulation. Detailed Implementation
[0019] To enhance understanding of the present invention, the present invention will be further described in detail below with reference to embodiments. These embodiments are only used to explain the present invention and do not constitute a limitation on the scope of protection of the present invention.
[0020] In the following examples, vardenafil hydrochloride was purchased from (manufacturer: Shandong Jikun Biopharmaceutical Co., Ltd.); hydroxypropyl methylcellulose acetate succinate was purchased from (manufacturer: Anhui Shanhe Pharmaceutical Excipients Co., Ltd., models: L, M, H); microcrystalline cellulose (manufacturer: International N&H USA, Inc., model: PH102); cross-linked polyvinylpyrrolidone (manufacturer: ISP Chemicals LLC; model: XL-10); colloidal silica (manufacturer: Evonik Operations GmbH; model: AEROSIL 200Pharma); magnesium stearate (manufacturer: Anhui Shanhe Pharmaceutical Excipients Co., Ltd., model: SH-YM-M); vinylpyrrolidone ethyl acetate copolymer (manufacturer: BASF SE; model: VA64); ethanol (manufacturer: Jiangxi Hanjiang Pharmaceutical Co., Ltd.); and dimethyl sulfoxide (manufacturer: Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.).
[0021] Example 1: Preparation of vardenafil hydrochloride tablets
[0022] A solid dispersion solution was prepared by adding the prescribed amounts of vardenafil hydrochloride and hydroxypropyl methylcellulose acetate succinate to 200g of 75% ethanol. The solid dispersion solution was then spray-dried to prepare solid dispersion particles. The solid dispersion, along with the prescribed amounts of microcrystalline cellulose, cross-linked polyvinylpyrrolidone (XL-10), and colloidal silica, was placed in a hopper mixer and mixed at 20 rpm for 5 minutes. The resulting mixture was then passed through a granulator with a 1.0mm screen and a speed of 200 rpm. The sieved material was then placed back into the hopper mixer and mixed at 20 rpm for 10 minutes. Finally, magnesium stearate was added and mixed at 20 rpm for 5 minutes. The mixture was then pressed into tablets with a target weight of 8mm using a shallow concave die, achieving a hardness of 10–16 kg.
[0023] Example 2: Formulation of Vardenafil Hydrochloride Tablets
[0024] Tables 1, 2, and 3 list the formulations of different examples. The three examples differ in the type of polymer hydroxypropyl methylcellulose acetate succinate, while the amounts of each component are the same. Vardenafil hydrochloride tablets were prepared according to the formulations of Examples 1-1, 1-2, and 1-3, respectively, using the preparation method of Example 1.
[0025] Table 1 2-1 Formula composition of vardenafil hydrochloride tablets
[0026] Prescription composition Unit dose mg vardenafil hydrochloride 20 (in vardenafil) Hydroxypropyl methylcellulose acetate succinate (L) 50 Microcrystalline cellulose PH102 112 Cross-linked polyvinylpyrrolidone (XL-10) 15 colloidal silica 1 magnesium stearate 2
[0027] Table 2.2 Composition of Vardenafil Hydrochloride Tablets
[0028]
[0029]
[0030] Table 3 2-3 Composition of Vardenafil Hydrochloride Tablets:
[0031] Prescription composition Unit dose mg vardenafil hydrochloride 20 (in vardenafil) Hydroxypropyl methylcellulose acetate succinate (H) 50 Microcrystalline cellulose PH102 112 Cross-linked polyvinylpyrrolidone (XL-10) 15 colloidal silica 1 magnesium stearate 2
[0032] Dissolution tests were conducted on the vardenafil hydrochloride tablets 2-1, 2-2, and 2-3 prepared above.
[0033] Dissolution test method: Using pH 1.2 hydrochloric acid solution and 900 nm of dissolution medium, the dissolution and release rate were determined according to the method for determining dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Samples were taken at 5 min, 10 min, 20 min, and 30 min, and the absorbance was measured at a wavelength of 245 nm using ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0401). The amount dissolved per tablet was calculated. The results are as follows:
[0034]
[0035] Examples 2-1, 2-2, and 2-3 used different types of hydroxypropyl methylcellulose acetate succinate to prepare solid dispersions, all of which exhibited rapid release. Among them, type L had the fastest dissolution rate at 5 min, while type H had the slowest rate, which was close to that of the reference formulation.
[0036] Example 3: Vardenafil Hydrochloride Tablet Formulation
[0037] The difference between this embodiment and Examples 2-3 is that the amount of polymer used, the mass ratio of hydroxypropyl methylcellulose acetate succinate to vardenafil hydrochloride is 3:1, and the preparation method and other components are the same as in Examples 2-3.
[0038] Table 4. Composition of Vardenafil Hydrochloride Tablets in Example 3
[0039]
[0040]
[0041] The effect of different proportions of hydroxypropyl methylcellulose acetate succinate on the overall uniformity of the mixture was investigated. The mixture was prepared according to the formulations of Examples 2-3 and Example 3, and the following steps were performed to obtain the mixed particles. The content of vardenafil hydrochloride in the particles was detected and the RSD value was calculated. The results are shown in Table 5 below.
[0042] A solid dispersion solution was prepared by adding the prescribed amounts of vardenafil hydrochloride and hydroxypropyl methylcellulose acetate succinate to 200g of 75% ethanol. Solid dispersion particles were then prepared from the solid dispersion solution by spray drying. The solid dispersion, along with the prescribed amounts of microcrystalline cellulose, cross-linked polyvinylpyrrolidone (XL-10), and colloidal silica, was placed in a hopper mixer and mixed at 20 rpm for 5 minutes. The resulting mixture was then passed through a granulator with a 1.0mm screen and a speed of 200 rpm. The sieved material was then placed in a hopper mixer and mixed at 20 rpm for 10 minutes. Finally, magnesium stearate was added, and the mixture was mixed at 20 rpm for 5 minutes.
[0043] Table 5 Mixing uniformity
[0044]
[0045] Examples 2-3 and 3 used different proportions of hydroxypropyl methylcellulose acetate succinate. The test results showed that the RSD% of Examples 2-3 was <2.0, indicating better mixing uniformity.
[0046] Example 4: Vardenafil Hydrochloride Tablet Formulation
[0047] Table 6. Composition of Vardenafil Hydrochloride Tablets in Example 4
[0048] Prescription composition Unit dose mg vardenafil hydrochloride 20 (in vardenafil) Vinylpyrrolidone ethyl acetate copolymer 50 Microcrystalline cellulose PH102 112 Cross-linked carboxymethyl cellulose sodium 15 colloidal silica 1 magnesium stearate 2
[0049] Example 5: Preparation of vardenafil hydrochloride tablets
[0050] A solid dispersion solution was prepared by adding the prescribed amounts of vardenafil hydrochloride and hydroxypropyl methylcellulose acetate succinate (H) to 200g of dimethyl sulfoxide. The solid dispersion solution was then spray-dried to prepare solid dispersion particles. The solid dispersion, along with the prescribed amounts of microcrystalline cellulose (PH302), crosslinked polyvinyl chloride (XL-10), and colloidal silica, was placed in a hopper mixer and mixed at 20 rpm for 5 minutes. The mixed material was then passed through a granulator with a 1.0mm screen and a speed of 200 rpm. The sieved material was then placed in a hopper mixer and mixed at 20 rpm for 10 minutes. Finally, magnesium stearate was added and mixed at 20 rpm for 5 minutes. The mixture was then pressed into tablets with a target tablet weight of 8mm using a shallow concave die, achieving a hardness of 10–16 kg. The formulation composition of this embodiment is consistent with Examples 2-3 of Example 2, the only difference being the solvent used for the dispersing polymer in the preparation process.
[0051] Example 6 Related Substance Tests
[0052] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).
[0053] Solvent: Acetonitrile - 0.1 mol / L hydrochloric acid (2:8).
[0054] Take 5 tablets of this product, place them in a 100ml volumetric flask, add an appropriate amount of solvent, sonicate for 15 minutes, dilute to the mark with solvent, shake well, filter, and collect the filtrate.
[0055] Accurately measure an appropriate amount of the test solution and quantitatively dilute it with a solvent to prepare a solution containing approximately 10 μg per ml.
[0056] For the sensitivity solution, accurately measure an appropriate amount of the control solution and dilute it with a solvent to prepare a solution containing approximately 1 μg per 1 ml.
[0057] For system suitability solutions, weigh appropriate amounts of impurity D reference standard and impurity E reference standard, dissolve and dilute them with solvent to prepare a solution containing approximately 0.2 mg per ml, as impurity stock solution a; weigh an appropriate amount of impurity B reference standard, dissolve and dilute it with acetonitrile-0.1 mol / L hydrochloric acid (5:5) to prepare a solution containing approximately 0.2 mg per ml, as impurity stock solution b; take an appropriate amount of vardenafil hydrochloride reference standard, dissolve it with an appropriate amount of solvent, measure appropriate amounts of each impurity stock solution, and dilute with solvent to prepare a mixed solution containing approximately 1 mg of vardenafil and approximately 10 μg of each impurity per ml.
[0058] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Kromasil C18 4.6mm × 250mm, 5μm or equivalent column); mobile phase A was acetate solution (0.8g ammonium acetate dissolved in 900ml water, then 100ml acetonitrile was added and mixed well), and mobile phase B was acetate solution (0.8g ammonium acetate dissolved in 100ml water, then 900ml acetonitrile was added and mixed well). Linear gradient elution was performed according to the table below; the flow rate was 1.5ml per minute; the detection wavelength was 245nm; the column temperature was 40℃; and the injection volume was 5μl.
[0059]
[0060] Note: A mobile phase impurity trapping column (4.6 mm × 50 mm) needs to be added before the injector.
[0061] System suitability requirements: In the solution chromatogram, the elution order is impurity B, impurity D, impurity E, and vardenafil, and the resolution between each substance peak should meet the requirements; In the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak should be greater than 10.
[0062] For the assay, accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms.
[0063] If impurity peaks are present in the chromatogram of the limit test solution, after deducting the solvent peak, the peak areas of impurity B, impurity D, and impurity E shall not exceed 0.3 times (0.3%) the area of the main peak of the control solution, the area of any other single impurity peak shall not exceed 0.2 times (0.2%) the area of the main peak of the control solution, the sum of the areas of all impurity peaks shall not exceed the area of the main peak of the control solution (1.0%), and chromatographic peaks less than 0.05 times (0.05%) the area of the main peak of the control solution shall be ignored.
[0064] The results of related substances analysis for vardenafil hydrochloride tablets under accelerated conditions (40℃, 75% RH) are as follows:
[0065]
[0066] Stability data showed that the formulations in Examples 2-3 had better stability and their product quality was comparable to that of the reference formulation.
[0067] In vivo bioequivalence studies (fasting) n=8, results are as follows:
[0068]
[0069] The tablets prepared in Examples 2-3 had a 90% confidence interval of 80.00%-125.00% in the bioequivalence experiment, which met the acceptance criteria for bioequivalence, i.e., the test formulation and the reference formulation were bioequivalent under fasting administration conditions.
[0070] In summary, the vardenafil hydrochloride solid dispersion and its formulation provided by this invention have the highest similarity to the reference formulation both in vitro and in vivo, and are significantly superior to other currently available domestically produced commercial products.
[0071] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A vardenafil hydrochloride solid dispersion, characterized in that, The product comprises vardenafil hydrochloride raw material and a pharmaceutically acceptable polymer, wherein the vardenafil hydrochloride raw material is dispersed in a polymer matrix formed by the polymer to form a vardenafil hydrochloride solid dispersion.
2. The vardenafil hydrochloride solid dispersion according to claim 1, characterized in that, The pharmaceutically acceptable polymer is selected from one of hydroxypropyl methylcellulose acetate succinate or vinylpyrrolidone ethyl acetate copolymer.
3. The vardenafil hydrochloride solid dispersion according to claim 2, characterized in that, The pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate, preferably of type H.
4. The vardenafil hydrochloride solid dispersion according to claim 2, characterized in that, The pharmaceutically acceptable mass ratio of vardenafil hydrochloride raw material to polymer is 2:5-6.
5. A vardenafil hydrochloride tablet, characterized in that, The solid dispersion of vardenafil hydrochloride according to any one of claims 1-3 further includes fillers, disintegrants and lubricants.
6. The vardenafil hydrochloride tablets according to claim 5, characterized in that, The filler is microcrystalline cellulose.
7. The vardenafil hydrochloride tablets according to claim 5, characterized in that, The disintegrant is cross-linked polyvinylpyrrolidone.
8. The vardenafil hydrochloride tablets according to claim 5, characterized in that, The flow aid is selected from colloidal silica or talc; the lubricant is magnesium stearate.
9. A method for preparing vardenafil hydrochloride tablets, characterized in that, Includes the following steps: 1) Preparation of solid dispersion: Vardenafil hydrochloride and a pharmaceutically acceptable polymer were added to an organic solvent to prepare a solid dispersion solution; then, the solid dispersion was prepared by spray drying. 2) The solid dispersion prepared in step 1) is mixed with filler, disintegrant, glidant and lubricant and then compressed into tablets.
10. The method for preparing vardenafil hydrochloride tablets according to claim 11, characterized in that, The organic solvent in step 1) is ethanol or dimethyl sulfoxide.