High-stability flurbiprofen anti-inflammatory patch and preparation method thereof

Abstract

The application belongs to the technical field of medicine, and particularly relates to a high-stability flurbiprofen anti-inflammatory patch and a preparation method thereof. The raw materials and mass percentage contents in the storage adhesive layer of the high-stability flurbiprofen anti-inflammatory patch are as follows: 2-3% of flurbiprofen, 25-35% of a first adhesive, 6-20% of a second adhesive, 2-3% of menthol, 5-15% of a tackifier, 40-55% of a plasticizer, 0.1-1% of an antioxidant, and 0.1-2.0% of an esterification inhibitor. The first adhesive is a maleic anhydride grafted styrene-isoprene-styrene block copolymer. The second adhesive is a mixture of high-molecular polyisobutylene and low-molecular polyisobutylene. The patch can effectively inhibit the reaction between the main drug and the penetration enhancer, improve the stability and curative effect of the product, and has good drug release and transdermal properties.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a high-stability flurbiprofen anti-inflammatory patch and a preparation method thereof. BACKGROUND

[0002] Flurbiprofen is a non-steroidal anti-inflammatory drug, and is mainly used for rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. For the above diseases, the commonly used dosage form is a patch. The patch is mainly mixed with flurbiprofen through an adhesive matrix, a tackifier, a penetration enhancer and the like, wherein the commonly used penetration enhancer is menthol. The patch has good transdermal absorption, and reduces adverse reactions such as skin rash caused by repeated application, and improves the convenience of clinical use.

[0003] With subsequent research, it is found that in the process of long-term storage, the carboxyl in the main drug flurbiprofen and the hydroxyl in the penetration enhancer L-menthol in the above-mentioned patch react to generate L-menthol ester compounds, which greatly affects the main stability and reduces the drug efficacy. Therefore, it is urgent to develop a high-stability flurbiprofen patch. SUMMARY

[0004] In view of the above problems, the application obtains an auxiliary material containing an active group by chemically modifying an auxiliary material in the flurbiprofen patch. In the storage process, the auxiliary material can effectively inhibit the reaction of the main drug and the penetration enhancer, and improve the stability and efficacy of the product.

[0005] In order to achieve the above-mentioned purpose, a high-stability flurbiprofen anti-inflammatory patch is provided. The raw materials and their mass percentage contents in the drug storage adhesive layer of the high-stability flurbiprofen anti-inflammatory patch are as follows:

[0006] Flurbiprofen 2-3%, first adhesive 25-35%, second adhesive 6-20%, menthol 2-3%, tackifier 5-15%, plasticizer 40-55%, antioxidant 0.1-1%, and esterification inhibitor 0.1-2.0%;

[0007] The first adhesive is a maleic anhydride grafted styrene-isoprene-styrene block copolymer.

[0008] The second adhesive is a mixture of high-molecular polyisobutylene and low-molecular polyisobutylene.

[0009] In specific embodiments, the raw materials and their mass percentage contents in the drug storage adhesive layer of the high-stability flurbiprofen anti-inflammatory patch are as follows:

[0010] Flurbiprofen 2~3%, first adhesive 27.5~32.5%, second adhesive 7~15%, menthol 2~3%, tackifier 5~15%, plasticizer 40~55%, antioxidant 0.1~1%, esterification inhibitor 0.5~1.0%.

[0011] In specific embodiments, the grafting rate of maleic anhydride groups in the maleic anhydride grafted styrene-isoprene-styrene block copolymer is 3~5%, and the molecular weight of the maleic anhydride grafted styrene-isoprene-styrene block copolymer is 100000~150000.

[0012] In specific embodiments, the preparation method of the maleic anhydride grafted styrene-isoprene-styrene block copolymer is: melt extruding styrene-isoprene-styrene block copolymer, peroxide and maleic anhydride, and the extrusion temperature is 150~200℃.

[0013] In specific embodiments, the peroxide is one or more of di-tert-butyl peroxide, tert-butyl 2-ethylhexyl peroxycarbonate or ethyl 3,3-di(tert-butylperoxy)butyrate.

[0014] In specific embodiments, the molecular weight of the high molecular polyisobutylene in the second adhesive is 400000~800000, and the addition amount of the high molecular polyisobutylene accounts for 1~10% of the raw materials of the drug storage adhesive layer; the molecular weight of the low molecular polyisobutylene in the second adhesive is 40000~100000, and the addition amount of the low molecular polyisobutylene accounts for 5~10% of the raw materials of the drug storage adhesive layer.

[0015] In specific embodiments, the tackifier is hydrogenated rosin glyceride; the plasticizer is liquid paraffin; the antioxidant is dibutylhydroxytoluene; and the esterification inhibitor is zinc stearate.

[0016] In specific embodiments, the high-stability flurbiprofen anti-inflammatory patch further comprises a protective layer and a backing layer.

[0017] Based on the same inventive embodiments, the application further provides a preparation method of the high-stability flurbiprofen anti-inflammatory patch, which comprises:

[0018] Mixing and heating the first adhesive, the second adhesive, the plasticizer, the antioxidant, the esterification inhibitor and the tackifier to completely dissolve, then adding flurbiprofen and menthol in sequence, stirring uniformly to obtain a drug storage adhesive layer paste;

[0019] Uniformly coating the drug storage adhesive layer paste on the protective layer, and then adhering with the backing layer to obtain the high-stability flurbiprofen anti-inflammatory patch.

[0020] In specific embodiments, the temperature for complete dissolution by heating is 120~150℃.

[0021] Compared with the prior art, the technical scheme of the present application has the following beneficial effects:

[0022] The present application adopts maleic anhydride grafted styrene-isoprene-styrene block copolymer obtained by chemical modification and high and low molecular weight polyisobutylene as an adhesive, adopts menthol as a penetration enhancer, and optimizes the prescription ratio of the fluorobiprofen to form a patch, wherein the maleic anhydride grafted styrene-isoprene-styrene block copolymer has high chemical activity, and when the temperature is high during storage, the maleic anhydride grafted styrene-isoprene-styrene block copolymer can preferentially react with menthol, thereby inhibiting the reaction between fluorobiprofen and menthol, further improving the stability and curative effect of the product, and meanwhile, the patch has good drug release characteristics and excellent transdermal performance. BRIEF DESCRIPTION OF DRAWINGS

[0023] In order to more clearly illustrate the technical scheme in the embodiments of the present application or the prior art, the drawings needed to be used in the following embodiment or prior art description will be briefly introduced. Obviously, the drawings in the following description are some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without any creative effort on the basis of these drawings.

[0024] Figure 1 The present application provides the in vitro release curve of the fluorobiprofen anti-inflammatory patch. DETAILED DESCRIPTION

[0025] In order to facilitate the understanding of the present application, the present application will be described more fully below with reference to the accompanying drawings and preferred embodiments, but the protection scope of the present application is not limited to the following specific embodiments.

[0026] Unless otherwise defined, all the professional terms used in the following description have the same meaning as understood by those skilled in the art. The professional terms used in the present application are only for the purpose of describing the specific embodiments and are not intended to limit the protection scope of the present application.

[0027] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present application can be purchased from the market or can be prepared by existing methods.

[0028] The existing fluorobiprofen anti-inflammatory patch has poor stability, and the present application provides a high-stability fluorobiprofen anti-inflammatory patch to further improve the stability on the basis of ensuring the drug release characteristics and transdermal performance. The raw materials and their mass percentage in the drug storage adhesive layer of the high-stability fluorobiprofen anti-inflammatory patch are as follows:

[0029] The pharmaceutical active ingredient is a non-steroidal anti-inflammatory drug: fluorobiprofen 2-3%.

[0030] The first adhesive 25-35% (preferably 27.5-32.5%) is specifically a maleic anhydride grafted styrene-isoprene-styrene block copolymer with a molecular weight of 100000-150000. The specific chemical formula is as follows:

[0031] [CH2-CH(C6H5)] n [CH2-C(CH3)=CH-CH2] y -MAH [CH2-CH(C6H5)] n

[0032] MAH is a maleic anhydride group. The preparation method is: mixing styrene-isoprene-styrene (SIS) block copolymer, peroxide, grafted maleic anhydride, and then melt extruding in a single screw extruder, with an extrusion temperature of 150-200°C. The peroxide includes DTBP, t-butyl peroxy-2-ethylhexyl carbonate, or 3,3-di(t-butyl peroxy) butyl acetate, etc.

[0033] The second adhesive 6-20% specifically includes a mixture of high molecular weight polyisobutylene and low molecular weight polyisobutylene, wherein the molecular weight of the high molecular weight polyisobutylene is 400000-800000, and the high molecular weight polyisobutylene accounts for 1-10% (preferably 2-6%) of the raw materials of the drug storage adhesive layer; the molecular weight of the low molecular weight polyisobutylene is 40000-100000, and the low molecular weight polyisobutylene accounts for 5-10% (preferably 5%) of the raw materials of the drug storage adhesive layer.

[0034] Menthol 2-3%; tackifier 5-15% (preferably 8-12%), specifically hydrogenated rosin glycerin ester; plasticizer 40-55%, specifically liquid paraffin; antioxidant 0.1-1%, specifically dibutylhydroxytoluene; esterification inhibitor 0.1-2.0%, specifically aliphatic metal salt, including zinc stearate, etc.

[0035] The high-stability flurbiprofen anti-inflammatory patch further includes a protective layer and a backing layer in addition to the drug storage adhesive layer.

[0036] The preparation method of the above anti-inflammatory patch specifically includes the following steps:

[0037] The first adhesive, the second adhesive, the plasticizer, the antioxidant, the esterification inhibitor, and the tackifier are mixed in a specific ratio and heated to 120°C-150°C to completely dissolve, and then flurbiprofen and menthol are added in sequence, stirred uniformly to obtain a drug storage adhesive layer paste. Finally, the drug storage adhesive layer paste is uniformly coated on the protective layer, and then combined with the backing layer to obtain the high-stability flurbiprofen anti-inflammatory patch.

[0038] The specific embodiments of the application are introduced above. In order to objectively illustrate the technical effects of the application, the high-stability flurbiprofen anti-inflammatory patch and the preparation method thereof provided by the application will be further illustrated below in combination with examples, and relevant drug performance and impurity content tests will be performed.

[0039] The maleic anhydride grafted styrene-isoprene-styrene block copolymer used in the examples was purchased from China Xinseng Times New Material (Dongying) Co., Ltd.

[0040] Examples 1 and 2

[0041] The proportions of the raw materials in Examples 1 and 2 are shown in Table 1.

[0042] Table 1 Proportions of raw materials in Examples 1 and 2

[0043]

[0044] The raw materials were weighed according to the above mass percentages, and the maleic anhydride grafted styrene-isoprene-styrene block copolymer, low molecular weight polyisobutylene, high molecular weight polyisobutylene, hydrogenated rosin glycerin ester, liquid paraffin, dibutylhydroxytoluene and zinc stearate were mixed and heated to 125°C to completely melt, stirred uniformly, flurbiprofen was added and stirred uniformly, and finally menthol was added and stirred uniformly to obtain a drug storage adhesive layer paste. The drug storage adhesive layer paste was uniformly coated on the protective layer, and then the backing layer was attached to obtain a high-stability flurbiprofen anti-inflammatory patch.

[0045] The flurbiprofen patch developed by Japan Taisho Pharmaceutical Co., Ltd. was used as a comparative example.

[0046] The quality attributes of the anti-inflammatory patches of Examples 1 and 2 and the comparative example were compared. The results are shown in Table 2.

[0047] Table 2 Comparison of quality attributes of anti-inflammatory patches of Examples 1 and 2 and the comparative example

[0048]

[0049] ※ The flurbiprofen menthyl ester increases with the storage time, and the anti-inflammatory patch of the comparative example has been on the market for 6 months.

[0050] The test data show that the test results of the samples of Examples 1, 2 and the comparative example in the main quality items (including appearance, identification, related substances, content uniformity, release rate, adhesion, microbial limit and content) all meet the specified standards, indicating that the key quality attributes of the three are consistent.

[0051] Stability investigation of flurbiprofen anti-inflammatory patch

[0052] The percentage content of flurbiprofen menthyl ester and total impurities at the initial time was determined, and the accelerated test was carried out under the condition of temperature 40℃ and humidity 65%, and the percentage content of flurbiprofen menthyl ester and total impurities after three months was determined. At the same time, the accelerated test was carried out under the condition of temperature 50℃ and humidity 65%, and the percentage content of flurbiprofen menthyl ester and total impurities after 30 days was determined. The specific percentage content results are as follows:

[0053] Table 3 Stability results under accelerated condition 40℃

[0054]

[0055] ※ The total impurities are other impurities not containing flurbiprofen menthyl ester.

[0056] Table 4 Stability results under accelerated condition 50℃

[0057]

[0058] ※ Wherein the flurbiprofen menthyl ester increases with the storage time, and the anti-inflammatory patch has been on the market for 24 months when the experiment is carried out.

[0059] The results show that the impurity growth rate of flurbiprofen menthyl ester in Example 1 is 2.67%, Example 2 is 2.82%, and Comparative Example 1 is 5.12% after 3 months under accelerated test conditions; the impurity growth rate of Example 1 is 1.81%, Example 2 is 2.18%, and Comparative Example 1 is 3.18% after 30 days under high temperature condition of 50℃. It can be known from the above that the flurbiprofen patch prepared in the examples shows better stability compared with the comparative example. The improvement in stability is attributed to the use of chemically modified styrene-isoprene-styrene (SIS) block copolymer, which can effectively inhibit the reaction between the main drug (non-steroidal anti-inflammatory analgesic component flurbiprofen) and the penetration enhancer menthol, thereby avoiding the generation of L-menthol ester compounds, and significantly enhancing the storage stability of the product.

[0060] Comparison of in vitro release performance:

[0061] The anti-inflammatory patches of Example 1 and Comparative Example were taken, and circular slices with a diameter of 3.0 cm were cut. The protective layer was peeled off, and the weight was accurately determined. According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 edition four general rules 0931 fourth method (paddle method) method 2), 700 ml of 0.9% sodium chloride solution was used as the release medium, and the rotation speed was 50 revolutions per minute. The samples were taken and detected at 10 min, 20 min, 30 min, 60 min, 120 min, 180 min, 240 min, 360 min, 540 min, 720 min, and the results are shown in Table 5 and Figure 1 .

[0062] Table 5 In vitro release results of examples and comparative examples

[0063]

[0064] The similarity of in vitro release curves of Example 1, Example 2 and comparative examples was compared. Referring to the release data of the comparative examples, the cumulative release degrees at time points of 10, 20, 30, 60, 120, 180 and 360 minutes were selected, and the similarity factors (f2 values) of Example 1 and Example 2 were calculated to be 90 and 73 respectively. Both f2 values are greater than 50, indicating that Example 1 and Example 2 have similarity in in vitro release behavior with the comparative examples.

[0065] In vitro permeation test

[0066] The samples of examples and comparative examples were taken, and circular slices with a diameter of 14 mm were cut. The protective layer was peeled off, accurately weighed, attached to the animal skin, and in vitro transdermal test was carried out by using Franz diffusion cell method. The results are shown in Table 6 and Table 7.

[0067] Table 6 In vitro permeation test results of Example 1 and comparative examples- cumulative permeation amount

[0068]

[0069] Table 7 In vitro permeation test results of Example 1 and comparative examples- maximum flux

[0070]

[0071] Note: T represents Example 1, and R represents comparative example.

[0072] According to the equivalence determination criteria in FDA “In Vitro Permeation Test Studies for Topical Drug Products Submitted in ANDAs” and CDE “Technical Guidelines for In Vitro Release (IVRT) and In Vitro Permeation (IVPT) Studies of Topical Chemical Generic Drugs (Trial)”, the in vitro transdermal test of Example 1 (T) and comparative example (R) was carried out with the design of 6 skin donors (j = 6) and 6 repeats (i = 6) for each donor. As shown in the above table, the standard deviation SWR calculated according to the final maximum flux (Jmax) and total cumulative permeation amount (AMT) results is less than 0.294. The equivalence was determined by using the conventional average bioequivalence (ABE) method, and the results showed that the 90% confidence interval fell within the range of 0.8000-1.2500, meeting the equivalence requirement, indicating that the examples and comparative examples have equivalence in in vitro transdermal behavior.

[0073] From the above results, it can be seen that the application adopts the chemically modified maleic anhydride grafted styrene-isoprene-styrene block copolymer (MAH-SIS), which effectively inhibits the reaction between the main drug (non-steroidal anti-inflammatory analgesic component flurbiprofen) and the penetration enhancer menthol, thereby avoiding the generation of L-menthol ester compounds, and significantly improving the stability of the product. By optimizing the prescription ratio, a flurbiprofen anti-inflammatory patch with good drug release characteristics and excellent transdermal performance is successfully prepared. The experimental results show that the product is equivalent to the original research preparation in terms of key quality attributes (such as drug release characteristics, transdermal performance and adhesion), and is better than the original research preparation in terms of stability and impurity control, and the level of menthol ester impurities is significantly lower than that of the original research preparation. In summary, the flurbiprofen anti-inflammatory patch prepared by the application is superior to the original research preparation in overall quality.

[0074] The above is a further detailed description of the application in combination with specific preferred embodiments, and cannot be considered as limiting the specific implementation of the application to these descriptions. For ordinary skilled persons in the art to which the application belongs, a number of simple deductions or substitutions can be made without departing from the concept of the application, and all of them should be considered as falling within the protection scope of the application.

Claims

1. A high-stability flurbiprofen anti-inflammatory patch, characterized by, The high-stability flurbiprofen anti-inflammatory patch has the following raw materials and mass percentage contents in the storage adhesive layer: Flurbiprofen 2~3%, first adhesive 25~35%, second adhesive 6~20%, menthol 2~3%, tackifier 5~15%, plasticizer 40~55%, antioxidant 0.1~1%, esterification inhibitor 0.1~2.0%; The first adhesive is a maleic anhydride grafted styrene-isoprene-styrene block copolymer; The second adhesive is a mixture of high-molecular polyisobutylene and low-molecular polyisobutylene; The esterification inhibitor is zinc stearate.

2. The high stability flurbiprofen anti-inflammatory patch according to claim 1, characterized in that, The high-stability flurbiprofen anti-inflammatory patch has the following raw materials and mass percentage contents in the storage adhesive layer: Flurbiprofen 2~3%, first adhesive 27.5~32.5%, second adhesive 7~15%, menthol 2~3%, tackifier 5~15%, plasticizer 40~55%, antioxidant 0.1~1%, esterification inhibitor 0.5~1.0%.

3. The high stability flurbiprofen anti-inflammatory patch according to claim 1, characterized in that, The grafting rate of maleic anhydride groups in the maleic anhydride grafted styrene-isoprene-styrene block copolymer is 3~5%, and the molecular weight of the maleic anhydride grafted styrene-isoprene-styrene block copolymer is 100000~150000.

4. The high stability flurbiprofen anti-inflammatory patch according to claim 1, characterized in that, The preparation method of the maleic anhydride grafted styrene-isoprene-styrene block copolymer is: mixing styrene-isoprene-styrene block copolymer, peroxide and maleic anhydride and melt extruding, and the extrusion temperature is 150~200℃.

5. The high stability flurbiprofen anti-inflammatory patch according to claim 4, characterized in that, The peroxide is one or more of di-tert-butyl peroxide, tert-butyl 2-ethylhexyl peroxycarbonate or ethyl 3,3-di(tert-butylperoxy)butyrate.

6. The high stability flurbiprofen anti-inflammatory patch according to claim 1, wherein The molecular weight of the high-molecular polyisobutylene in the second adhesive is 400000~800000, and the addition amount of the high-molecular polyisobutylene accounts for 1~10% of the raw materials of the storage adhesive layer; the molecular weight of the low-molecular polyisobutylene in the second adhesive is 40000~100000, and the addition amount of the low-molecular polyisobutylene accounts for 5~10% of the raw materials of the storage adhesive layer.

7. The high stability flurbiprofen anti-inflammatory patch according to claim 1, characterized in that, The tackifier is hydrogenated rosin glyceride; the plasticizer is liquid paraffin; and the antioxidant is dibutylhydroxytoluene.

8. The high stability flurbiprofen anti-inflammatory patch according to claim 1, wherein The high-stability flurbiprofen anti-inflammatory patch further comprises a protective layer and a backing layer.

9. The method for preparing the highly stable flurbiprofen anti-inflammatory patch according to any one of claims 1 to 8, characterized in that, The preparation method comprises: Mixing and heating the first adhesive, the second adhesive, the plasticizer, the antioxidant, the esterification inhibitor and the tackifier to completely dissolve, then adding flurbiprofen and menthol in sequence, stirring uniformly to obtain a storage adhesive layer paste; Uniformly coating the storage adhesive layer paste on the protective layer, then adhering the backing layer to obtain the high-stability flurbiprofen anti-inflammatory patch.

10. The process for the preparation of high stability flurbiprofen anti-inflammatory patch according to claim 9, characterized in that, The temperature for complete dissolution by heating is 120~150℃.

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