A granisetron transdermal patch composition and a method for preparing the same

Abstract

The application relates to the technical field of medicines, in particular to a granisetron transdermal patch composition and a preparation method thereof. The granisetron transdermal patch composition comprises the following components in proportion by weight: 30-38 parts of granisetron and 480-595 parts of pressure-sensitive adhesive, wherein the pressure-sensitive adhesive comprises at least one of 4802B, 4801 and P-7305. The application has the advantages of high stability under high humidity conditions and difficulty in crystallization.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a granisetron transdermal patch composition and its preparation method. Background Technology

[0002] Granisetron is a highly selective 5-HT3 receptor antagonist with good preventive and therapeutic effects on nausea and vomiting induced by radiotherapy, chemotherapy, and surgery. Radiotherapy, chemotherapy, and surgery can cause enterochromaffin cells to release 5-HT, which can activate 5-HT3 receptors in the central nervous system or vagus nerve, triggering the vomiting reflex. The mechanism by which Granisetron controls nausea and vomiting is by antagonizing 5-HT3 receptors in the central chemoreceptor area and peripheral vagal nerve endings, thereby inhibiting the occurrence of nausea and vomiting.

[0003] Currently, granisetron is mainly administered via oral and intravenous injection in clinical practice. However, patients with nausea and vomiting cannot take the medication orally and require long-term use. Furthermore, oral administration suffers from a severe first-pass effect, reducing the drug's bioavailability. Intravenous administration requires the presence of a qualified medical professional and carries certain risks.

[0004] A patch is a thin, sheet-like formulation that can be adhered to the skin to produce systemic or localized effects of medication. Transdermal absorption formulations are patches or transdermal patches that are absorbed through the skin and, through a controlled-release mechanism, deliver medication rapidly and persistently throughout the body at the required dosage. Patches can address the aforementioned issues associated with oral and intravenous administration; however, the common problem with patches is the tendency for active pharmaceutical ingredient (API) to leach out.

[0005] Chinese patent CN102416009B discloses an adhesive patch for transdermal granisetron administration, comprising an acrylic adhesive containing a non-acidic nucleophilic portion, said nucleophilic portion primarily increasing the flux of granisetron through the skin. This patch does not contain any plasticizers or penetration enhancers, such as isopropyl myristate (IPM), reducing the number of ingredients and eliminating potential irritants and substances that reduce adhesive cohesion; however, the patch exhibits crystallization during storage.

[0006] Chinese patent application CN1747724A discloses a granisetron adhesive patch containing a non-acidic hydroxyl moiety of acrylic adhesive. No crystallization was observed after storage at room temperature and normal pressure for one month, but crystallization occurred after the patch was stored at 40°C and 75% relative humidity for one month.

[0007] Therefore, it is essential to develop a granisetron transdermal patch composition and its preparation method that can solve the above-mentioned technical problems. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of the prior art and provide a granisetron transdermal patch composition with high stability and low crystallization under high humidity conditions, as well as its preparation method.

[0009] This invention is achieved through the following technical solutions:

[0010] A granisetron transdermal patch composition, by weight, comprises the following components: 30-38 parts granisetron and 480-595 parts pressure-sensitive adhesive, wherein the pressure-sensitive adhesive includes... 4802B 4801 and At least one of P-7305.

[0011] 4801 Composition: 2-Ethylhexyl acrylate, 2-Ethylhexyl methacrylate, and dodecyl methacrylate copolymer solution.

[0012] Composition of 4802B: 2-ethylhexyl acrylate-vinylpyrrolidone copolymer solution.

[0013] P-7305 composition: acrylate-vinyl acetate copolymer.

[0014] Preferably, the composition comprises, by weight, the following components: 30.87-37.73 parts granisetron and 483.94-591.48 parts pressure-sensitive adhesive.

[0015] Preferably, the pressure-sensitive adhesive is... 4801 and A mixture of 4802B.

[0016] More preferably, the 4801 and The mass ratio of 4802B is 0.5-2:1.

[0017] The present invention also relates to a method for preparing the above-described composition, characterized by comprising the following steps:

[0018] (1) Mix pressure-sensitive adhesive with ethyl acetate to obtain an adhesive solution;

[0019] (2) Granisetron was dissolved in N,N-dimethylacetamide to obtain a granisetron solution;

[0020] (3) Mix the adhesive solution with the granisetron solution to obtain the adhesive solution.

[0021] Preferably, the pressure-sensitive adhesive solids content in the adhesive solution is 41-51%, more preferably 41.4-50.6%.

[0022] Preferably, the granisetron concentration in the granisetron solution is 12-16%, more preferably 12.6-15.4%.

[0023] In another embodiment of the invention, the composition further comprises 5-6.5 parts by weight of a transdermal penetration enhancer.

[0024] Preferably, the composition further includes 5.148 to 6.292 parts of a transdermal penetration enhancer.

[0025] More preferably, the transdermal penetration enhancer includes at least one of phosphoric acid and fatty acid triglycerides.

[0026] More preferably, the fatty acid triglycerides include tri-medium-chain fatty acid triglycerides.

[0027] The present invention also relates to a method for preparing the above-described composition, comprising the following steps:

[0028] (1) Mix pressure-sensitive adhesive with ethyl acetate to obtain an adhesive solution;

[0029] (2) Granisetron was dissolved in N,N-dimethylacetamide to obtain a granisetron solution;

[0030] (3) Mix the adhesive solution with the granisetron solution, add the transdermal penetration enhancer, stir and mix evenly to obtain the adhesive solution.

[0031] Preferably, the pressure-sensitive adhesive solids content in the adhesive solution is 41-51%, more preferably 41.4-50.6%.

[0032] Preferably, the granisetron concentration in the granisetron solution is 12-16%, more preferably 12.6-15.4%.

[0033] The present invention also relates to a granisetron transdermal patch, comprising a backing layer, a release film, and a granisetron transdermal patch composition, wherein the composition is the composition described above or a composition prepared by the preparation method described above.

[0034] Preferably, the backing layer is a matte PET film.

[0035] Preferably, the release film is made of PET material. The PET material surface of the release film has a release coating.

[0036] This invention also relates to a method for preparing the above-mentioned granisetron transdermal patch, comprising the following steps:

[0037] The granisetron transdermal patch composition is coated onto a release film, dried, and then laminated with a backing layer to obtain the final product.

[0038] Preferably, the coating temperature is 40-70℃ and the coating speed is 10-30cm / min.

[0039] The beneficial effects of this invention are:

[0040] This invention optimizes the composition of the pressure-sensitive adhesive to... 4802B 4801 and At least one of P-7305 significantly improves the stability of the composition under high humidity conditions, while also improving the adhesion of the composition.

[0041] This invention further optimizes the composition of the pressure-sensitive adhesive to... 4801 and The mixture of 4802B does not crystallize under high humidity (92.5%) conditions for one month, and its stability under high humidity conditions is further improved.

[0042] The present invention also adds a transdermal penetration enhancer, and by optimizing its composition to at least one of phosphoric acid and fatty acid triglycerides, the transdermal effect of the composition is significantly improved. Detailed Implementation

[0043] The present invention will be further described below with reference to specific embodiments, and the advantages and features of the present invention will become clearer as a result. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the present invention, but all such modifications and substitutions fall within the protection scope of the present invention.

[0044] Example 1

[0045]

[0046] Raw material dosage unit: mg / patch.

[0047] Preparation process:

[0048] ① The solid content of the pressure-sensitive adhesive was determined and diluted to 46% with ethyl acetate. Then, the solution was stirred evenly with a stirrer to obtain the adhesive solution.

[0049] ② Dissolve granisetron in N,N-dimethylacetamide to prepare a 14wt% concentration, stir to dissolve and set aside for later use, to obtain a granisetron solution.

[0050] ③ Mix the adhesive solution with the granisetron solution to obtain the adhesive solution.

[0051] ④ Apply the adhesive to a PET release film (100μm thick), and dry it at 60℃ at a speed of 20cm / min to a thickness of approximately 400μm. After drying, laminate it with a PET backing layer (15μm thick) under a pressure of 2bar. After drying, 52cm... 2 The drug content in the treatment area reached 34.3 mg.

[0052] Example 2

[0053]

[0054] The raw material dosage units and preparation process are the same as in Example 1. The tri-chain fatty acid glycerides were purchased from Liaoning Xinxing Pharmaceutical Co., Ltd.

[0055] Example 3: Investigation of the range of raw material usage

[0056]

[0057] The raw material usage units and preparation process are the same as in Example 1.

[0058] Test Example 1

[0059] 1) The crystallization of different pressure-sensitive adhesive matrices was investigated to screen for pressure-sensitive adhesive matrices with high solubility of the active pharmaceutical ingredient. All humidity levels used in the testing process were relative humidity. The results are shown in Table 1.

[0060] Table 1

[0061]

[0062] Note: / : No crystals formed, √: Crystals formed; Commercially available products are derived from Formula 1. (4801) is replaced with (87-2287), other conditions are the same as prescription 1, and the composition of the following commercially available products is the same as in Table 1.

[0063] (87-2287) Composition: Random copolymer of 2-ethylhexyl acrylate, vinyl acetate, 2-hydroxyethyl acrylate and glycidyl methacrylate in an organic solvent (ethyl acetate).

[0064] 2) Adhesion

[0065] The adhesion test method was based on the 2020 edition of the Chinese Pharmacopoeia, section 0952, "Adhesion Determination Method." The results are shown in Table 2. Notably, the commercially available product and prescriptions 1-6 could adhere to the same maximum ball size initially (28#), but the distance between them differed significantly; a shorter distance indicated higher initial adhesion. Holding power and peel strength were tested under the following conditions: relative humidity 60±5%, temperature 18-25℃.

[0066] Table 2

[0067]

[0068] 3) In vitro transdermal effect

[0069] The in vitro transdermal efficacy testing methods are shown in Table 3. The test results are shown in Tables 4 and 5.

[0070] Table 3

[0071]

[0072] Table 4

[0073]

[0074]

[0075] Table 5

[0076] Time (h) Prescription 9 Prescription 10 1 0.2 0.86 2 1.0 2.64 4 6.3 11.08 6 19.3 26.32 8 38.7 46.31 12 86.8 94.65 24 270.3 276.77 24-hour cumulative permeate (μg) 270.3 276.77 Intradermal retention (μg) 208.76 217.23

[0077] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A method for preparing a granisetron transdermal patch composition, characterized in that, Includes the following steps: (1) Mix the pressure-sensitive adhesive with ethyl acetate to obtain an adhesive solution; (2) Granisetron is dissolved in N,N-dimethylacetamide to obtain a granisetron solution; (3) Mix the adhesive solution with the granisetron solution to obtain the adhesive solution; By weight, granisetron is 30-38 parts, and pressure-sensitive adhesive is 480-595 parts; The pressure-sensitive adhesive is Diafit. 4801 and Diafit A mixture of 4802B, with a mass ratio of 0.5-2:

1.

2. The preparation method according to claim 1, characterized in that, By weight, granisetron is 30.87-37.73 parts, and pressure-sensitive adhesive is 483.94-591.48 parts.

3. A method for preparing a granisetron transdermal patch composition, characterized in that, Includes the following steps: (1) Mix the pressure-sensitive adhesive with ethyl acetate to obtain an adhesive solution; (2) Granisetron is dissolved in N,N-dimethylacetamide to obtain a granisetron solution; (3) Mix the adhesive solution with the granisetron solution, add the transdermal penetration enhancer phosphoric acid, stir and mix evenly to obtain the adhesive solution; By weight, the composition is 30-38 parts granisetron, 480-595 parts pressure-sensitive adhesive, and 5-6.5 parts phosphoric acid; the pressure-sensitive adhesive is Diafit. 4801 and Diafit A mixture of 4802B, with a mass ratio of 0.5-2:

1.

4. The preparation method according to any one of claims 1-3, characterized in that, The pressure-sensitive adhesive solids content in the adhesive solution is 41-51%; the granisetron mass concentration in the granisetron solution is 12-16%.

5. The granisetron transdermal patch composition prepared by the preparation method according to any one of claims 1-4.

6. A granisetron transdermal patch, characterized in that, The composition comprises a backing layer, a release film, and a granisetron transdermal patch, wherein the composition is the composition of claim 5 or the composition prepared by any of the preparation methods of claims 1-4; The backing layer is a matte PET film; the release film is made of PET material; The preparation method of the granisetron transdermal patch includes the following steps: The granisetron transdermal patch composition is coated onto a release film at a temperature of 40-70°C and a speed of 10-30 cm / min. After drying, it is laminated with a backing layer to obtain the final product.

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