An etofenamate patch composition, an etofenamate patch, and a method of preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to an ifenprodil patch composition, an ifenprodil patch and a preparation method thereof. The patch composition comprises the following components according to weight parts: 1-5 parts of a drug, 0.5-5 parts of menthol oil, 0.1-10 parts of isopropyl palmitate, 10-60 parts of a matrix material, 5-25 parts of polyisobutylene, 3-30 parts of a tackifier, 0.1-55 parts of a softening agent, and 0.1-1 part of an antioxidant, wherein the drug is ifenprodil or a pharmaceutically acceptable salt thereof. By introducing isopropyl palmitate and SIS with a specific styrene content, the stability of the patch is significantly improved by using the interaction with the drug, so that the degradation and concentration decrease of the drug can be effectively avoided or reduced, thereby making the prepared patch composition and preparation have higher effectiveness and stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an efluprofen patch composition, an efluprofen patch, and its preparation method. Background Technology

[0002] Efluprofen, a nonsteroidal anti-inflammatory drug, primarily exerts its significant anti-inflammatory and analgesic effects by strongly inhibiting the activity of cyclooxygenase to block the synthesis of prostaglandins.

[0003] In recent years, with the continuous increase in the number of patients with pain-related diseases and the intensification of the aging population trend, the clinical need for pain management has become increasingly urgent. This has driven drug research and development in the field of pain treatment, especially in transdermal drug delivery systems, with research on non-invasive dosage forms such as topical patches becoming increasingly in-depth.

[0004] Poor drug stability was a common technical bottleneck in the development of afluprofen topical patches.

[0005] Patent CN107148269A discloses a topical composition containing levorphin and peppermint oil. It is believed that by adding propylene glycol dicaprylate or tricaprylate, the levorphin content can be inhibited from decreasing over storage time, thereby improving long-term stability.

[0006] Patent CN116898831A discloses a topical composition containing levorphine or its salts. It is believed that adding one or more stabilizers selected from polyethylene glycol glycerol ester, diisopropyl adipate, PEG400, isosorbide dimethyl ether, and diethylene glycol monoethyl ether can inhibit the decrease in levorphine content, but its stability still has room for improvement.

[0007] Patent CN119770469A discloses a topical composition containing levorprofen, peppermint oil, isopropyl myristate (stabilizer), and metal stearate. This composition is believed to have high stability, effectively preventing or reducing drug precipitation, degradation, and concentration decrease, thereby improving the efficacy and stability of the formulation. However, the addition of metal stearate may reduce the in vitro release rate and skin permeability of the active ingredient, potentially affecting its absorption in the human body and its clinical efficacy.

[0008] Therefore, there is an urgent need in the field to provide an alfluprofen patch composition and alfluprofen patch with better stability. Summary of the Invention

[0009] To address the shortcomings of existing technologies, this invention provides an efluprofen patch composition, the patch itself, and a preparation method thereof. By introducing isopropyl palmitate and SIS with a specific styrene content, this invention significantly improves the stability of the patch through their interaction with the drug, effectively preventing or reducing drug degradation and concentration decrease. This results in a patch composition and patch with higher efficacy and stability.

[0010] To achieve this objective, the present invention adopts the following technical solution: In a first aspect, the present invention provides an efluprofen patch composition, the patch composition comprising, by weight, the following components: 1-5 doses of medicine Peppermint oil 0.5-5 parts Isopropyl palmitate 0.1-10 parts 10-60 parts of matrix material 5-25 parts of polyisobutylene 3-30 parts of thickener 0.1-55 parts of softener Antioxidant 0.1-1 part, The drug is levorprofen or a pharmaceutically acceptable salt thereof.

[0011] In this invention, isopropyl palmitate not only acts as a softener or solubilizer, but more importantly, as a stabilizer. Through intermolecular interactions with drug molecules, it can effectively inhibit the decrease in content, degradation, and crystallization of levonorgestrel during long-term storage, thereby significantly improving the chemical and physical stability of the patch.

[0012] In some embodiments, after the patch composition is stored at 30°C ± 2°C and 60% ± 5% relative humidity for 6 months, the drug content decreases by no more than 5%, preferably no more than 3%, and more preferably no more than 1%. This indicates that the composition of the present invention has good long-term storage stability.

[0013] In some embodiments, the weight ratio of the drug to isopropyl palmitate is 1:0.5 to 1:5. This ratio range is a preferred range obtained by the inventors through extensive experimental screening. Within this range, isopropyl palmitate can fully exert its stabilizing effect without adversely affecting the adhesion and coating properties of the patch.

[0014] The weight ratio of the drug to the stabilizer is 1:0.5-1:5, for example, it can be 1:0.5, 1:0.6, 1:1.1, 1:3 or 1:5, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, this invention will not exhaustively list the specific values ​​included in the range.

[0015] In some embodiments, the patch composition does not contain zinc stearate. The inventors have found that the presence of zinc stearate may interact with isopropyl palmitate or the drug, thereby affecting the long-term stability of the patch. Furthermore, the addition of metal stearate salts (such as zinc stearate) can reduce the in vitro release rate and skin permeability of the active ingredient, potentially affecting its absorption and therapeutic efficacy in the human body. Therefore, the present invention preferably excludes zinc stearate to further ensure the chemical stability of the composition and avoid adverse effects on drug release and absorption.

[0016] In some embodiments, the matrix material includes one or more of styrene-isoprene-styrene block copolymers and styrene-butadiene-styrene block copolymers; the tackifier includes one or more of hydrogenated rosin glycerol esters, rosin resins, terpene resins, polyterpene resins, and petroleum resins; the softener includes one or more of liquid paraffin, silicone oil, higher fatty acids, vegetable oils, and polybutene; and the antioxidant includes one or more of butylated hydroxytoluene, methylparaben, and ethylparaben.

[0017] Preferably, the matrix material is a styrene-isoprene-styrene block copolymer with a styrene content of 15%-25%. SIS within this range is compatible with other excipients in the formulation and can be uniformly mixed with all components.

[0018] In some embodiments, the patch composition comprises the following components by weight: 1-5 doses of medicine Peppermint oil 0.5-5 parts Isopropyl palmitate 0.1-10 parts 10-60 parts of styrene-isoprene-styrene block copolymer 5-25 parts of polyisobutylene 3-30 parts of hydrogenated rosin glycerol ester Liquid paraffin 0.1-55 parts 0.1-1 part of butylated hydroxytoluene.

[0019] The weight of the drug is 1-5 parts, for example, 1 part, 3 parts, 4 parts or 5 parts, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0020] The peppermint oil is 0.5-5 parts by weight, for example, 0.5 parts, 1 part, 3 parts, 4 parts or 5 parts, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0021] The isopropyl palmitate is present in parts by weight of 0.1-10, for example, 0.5, 1, 2, 3, 4, 5, 6, 7, 8 or 10 parts, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0022] The styrene-isoprene-styrene block copolymer has a weight of 10-60 parts, for example, 10 parts, 20 parts, 30 parts, 40 parts, 50 parts or 60 parts, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0023] The polyisobutylene is in the range of 5-25 parts by weight, for example, 5 parts, 8 parts, 10 parts, 13 parts, 15 parts, 17 parts, 19 parts, 20 parts or 25 parts, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0024] The hydrogenated rosin glycerol ester is in the range of 3-30 parts by weight, for example, 3 parts, 10 parts, 13 parts, 15 parts, 17 parts, 19 parts, 25 parts or 30 parts, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0025] The liquid paraffin is in the range of 0.1-55 parts by weight, for example, 0.1 parts, 10 parts, 15 parts, 20 parts, 30 parts, 40 parts or 55 parts, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0026] The butylated hydroxytoluene is 0.1-5 parts by weight, for example, 0.1 parts, 0.3 parts, 0.5 parts, 0.8 parts, 1 part, 1.5 parts, 2 parts, 3 parts, 4 parts or 5 parts, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0027] On the other hand, the present invention provides a method for preparing an elfluprofen patch composition, the method comprising: mixing a matrix material, polyisobutylene, a softener, a thickener, and an antioxidant, stirring until melted, then adding a drug, isopropyl palmitate, and peppermint oil and continuing to stir until the mixture is uniform and no lumps or particles are visible.

[0028] In some embodiments, the preparation method includes the following steps: (1) Mix the matrix material, polyisobutylene, softener, tackifier and antioxidant according to the ratio, and stir at 160℃-180℃ until completely melted to form a uniform molten mixture; (2) Add the drug, isopropyl palmitate, and peppermint oil, and continue stirring until the mixture is smooth and free of lumps or particles. (3) Optionally, the resulting mixture is subjected to vacuum degassing treatment to remove air bubbles and ensure coating quality.

[0029] The patch composition prepared by the above method has a uniform dispersion and good coating performance.

[0030] Thirdly, the present invention provides an efluprofen patch, the efluprofen patch comprising a backing layer, a drug storage layer and a protective layer arranged sequentially, wherein the raw materials for preparing the drug storage layer include the efluprofen patch composition.

[0031] In some implementations: the backing layer is selected from nonwoven fabric, polyester film (such as PET), polyurethane film, polyethylene film, polypropylene film, or composites thereof. The backing layer should have good flexibility and breathability to provide a comfortable user experience. The protective layer is a release film, selected from fluorinated release film, silicone release film, or polyethylene terephthalate (PET) release film. The protective layer can be peeled off before use to expose the drug reservoir layer for application to the skin.

[0032] Fourthly, the present invention provides a method for preparing the elfluprofen patch. The preparation method includes the following steps: coating an elfluprofen patch composition onto a protective layer to form a drug storage layer with a protective layer; and laminating a backing layer onto the drug storage layer to obtain the elfluprofen patch.

[0033] In some embodiments, the preparation method includes the following steps: (1) The levorprofen patch composition described in the first aspect (or the composition prepared according to the method described in the second aspect) is uniformly coated onto the protective layer by hot melt coating method to form a drug storage layer with a protective layer; (2) A backing layer is laminated onto the drug storage layer to obtain a patch composite structure; (3) Optionally, the composite patch structure is punched to obtain a single patch unit; the shape of the punched patch unit can be square, round, elliptical, etc. (4) Optionally, the die-cut patch unit is inner packaged, wherein the inner packaging is made of aluminum-plastic composite film or paper-aluminum-plastic composite film to provide additional moisture-proof and light-proof protection.

[0034] The levonorfen patch prepared by the above method has strong bonding between each layer and uniform drug distribution, making it suitable for industrial production.

[0035] Fifthly, the present invention provides the use of the said efluprofen patch composition or efluprofen patch in the preparation of a medicament for treating pain and / or inflammation.

[0036] In some embodiments, the pain is selected from one or more of the following: arthritis pain (including osteoarthritis, rheumatoid arthritis), muscle pain, lower back pain, neck and shoulder pain, and soft tissue injury pain (such as sprains, strains, contusions).

[0037] In some embodiments, the inflammation is selected from one or more of rheumatic inflammation, osteoarthritis, and soft tissue inflammation.

[0038] The patch of this invention allows efluprofen to act directly on the local lesion via transdermal administration, exerting analgesic and anti-inflammatory effects, while avoiding the gastrointestinal adverse reactions that may be caused by oral administration, thus improving the safety of medication and patient compliance.

[0039] The levonorfen patch composition provided by this invention has outstanding stability advantages, and can significantly inhibit drug precipitation, degradation and content decline, ensuring that the prepared levonorfen patch has both higher efficacy reliability and storage stability. Attached Figure Description

[0040] Figure 1 This is a comparison graph showing the in vitro release behavior of the formulations in Comparative Example 4 and Example 2. Detailed Implementation

[0041] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0042] The terms “comprising,” “including,” “having,” “containing,” or any other variations thereof, as used herein, are intended to cover non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not limited to those elements and may also include other elements not expressly listed or elements inherent to such composition, step, method, article, or apparatus.

[0043] "Optional" or "any one" means that the matter or event described thereafter may or may not occur, and the description includes both the possibility that the event may occur and the possibility that the event may not occur.

[0044] The indefinite articles “a” and “an” preceding an element or component of this invention do not impose any limitation on the quantity (i.e., number of occurrences) of the element or component. Therefore, “an” or “a” should be interpreted as including one or at least one, and the singular form of an element or component also includes the plural form, unless the quantity clearly refers only to the singular form.

[0045] In this invention, features specified as "first" and "second" may explicitly or implicitly include one or more of these features, used to distinguish and describe features, without any order or emphasis. In the description of this invention, unless otherwise stated, "multiple" means two or more.

[0046] Examples 1-5: Investigation of Stabilizers Table 1 Prescription Table for Examples 1-5

[0047] Preparation method: Weigh styrene / isoprene / styrene block copolymer (SIS), polyisobutylene, hydrogenated rosin glycerol ester, liquid paraffin, and dibutylhydroxytoluene into a temperature-controlled electric furnace. Control the temperature at 160-180℃ and stir until melted. Then add levorprofen, peppermint oil, and stabilizer and continue stirring. After observing that the system is uniformly mixed and free of lumps, transfer the adhesive to a coating machine for coating, laminating with a backing, and cutting to the target size to obtain the final product.

[0048] Examples 6-8: Investigation of SIS Table 2 Prescription Table for Examples 6-8

[0049] The preparation method is the same as in Examples 1-5.

[0050] Comparative Examples 1-4 Table 3 Prescription Tables for Comparative Examples 1-4

[0051] Preparation method: According to the formula in Table 2, weigh styrene / isoprene / styrene block copolymer (SIS), polyisobutylene, hydrogenated rosin glycerol ester, liquid paraffin, butylated hydroxytoluene, and crystal inhibitor into a temperature-controlled electric furnace, control the temperature at 160-180℃, stir until melted, then add levonorfen, peppermint oil, and stabilizer and continue stirring. After observing that the system is uniformly mixed and free of lumps, transfer the adhesive to a coating machine for coating, laminating with a backing, and cutting to the target size to obtain the final product.

[0052] Comparative Examples 5-6 Table 3. Prescriptions for Comparative Examples 5-6

[0053] The preparation method is the same as in Examples 1-5.

[0054] Example 9: Stability Test The efluprofen patch samples prepared in each example and comparative example were placed under accelerated conditions (40℃, 65%RH) and long-term conditions (30℃, 60%RH) using paper-aluminum or aluminum-plastic sealed packaging, and left for 6 months. The efluprofen content in the efluprofen patch was then detected, and the results are as follows: Table 4. Stability data for Examples 1-5 and Comparative Examples 1-3

[0055] As shown in the table above, after 6 months of accelerated (40℃, 65%RH) and long-term (30℃, 60%RH) conditions, the degradation trend of efluprofen in Examples 1-5 was significantly weaker than that in Comparative Examples 1-3. Furthermore, the inhibitory effect increased with the increase in the proportion of isopropyl palmitate. The inhibitory effect on the stability process of efluprofen gradually increased from 1.0 parts to 2.0 parts to 4.0 parts to 6.0 parts, but there was no significant change in the inhibitory effect on the stability process of efluprofen at 6.0 parts and 8.0 parts. This indicates that there is a threshold for the effect of isopropyl palmitate on the stability of efluprofen in the patch. When the proportion of isopropyl palmitate is low, its inhibitory effect on the stability process of efluprofen is not significant; when the ratio of drug to isopropyl palmitate is greater than 1:0.4, isopropyl palmitate will damage the matrix and affect the adhesion of the patch.

[0056] Table 5. Stability data for Examples 6-8 and Comparative Examples 5-6

[0057] In this invention, styrene-isoprene-styrene triblock copolymer and polyisobutylene are used as the matrix of the patch. Styrene-isoprene-styrene triblock copolymer (SIS) refers to a block copolymer of styrene and isoprene, with polystyrene at both ends. This invention unexpectedly discovered that the patch exhibits better stability when the styrene content in the styrene-isoprene-styrene triblock copolymer is 15-25%.

[0058] Example 10 Adhesion Force Measurement Experiment According to the Chinese Pharmacopoeia 2025 edition, 0952, method for determination of adhesion, the adhesion force was determined, and the results are as follows: Table 6. Adhesion force measurement results of Examples 6-8 and Comparative Examples 5-6

[0059] The data in the table above shows that when the styrene content in the SIS is within the range of 12%-29%, all adhesion indicators are relatively similar except for holding power. Further analysis revealed that when the styrene content is between 15%-22%, the holding power is higher and the test results are more stable. Holding power measures the ability of an adhesive to resist deformation or breakage caused by persistent external forces; the higher the value, the stronger the resistance to deformation. Therefore, based on comprehensive judgment, when the styrene content in the SIS is within the range of 15%-22%, the overall adhesive performance of the patch is superior.

[0060] Example 11 In vitro release experiment Comparison of in vitro release of formulations prepared in Comparative Example 4 and Example 2.

[0061] Measurement method: (1) Release medium: pH 7.2 phosphate medium; (2) Release conditions: paddle disc method, 50 rpm, 900 ml medium, 32±1℃, n=6; (3) Sampling time: 0.17h, 0.33h, 0.5h, 0.75h, 1h, 2h, 3h, 4h, 6h.

[0062] Place the large mesh disc in the dissolution vessel. Cut the formulation into 30mm diameter circular patches, peel off the protective layer, and attach them to the center of the lower mesh disc with the paste side facing up. Cover with the upper mesh disc and place it in the dissolution vessel, positioning it at the bottom. Use a glass rod to adjust the large mesh disc to a horizontal position. Collect the dissolution solution and inject it directly.

[0063] Table 7. In vitro release data of the formulations prepared in Comparative Example 4 and Example 2

[0064] As shown in the table above, the drug release of the combination of zinc stearate and isopropyl palmitate was significantly reduced during the stability study; while the formulation using isopropyl palmitate alone maintained stable in vitro release under the same conditions.

Claims

1. An efluprofen patch composition, characterized in that, The patch composition comprises the following components in parts by weight: 1-5 doses of medicine Peppermint oil 0.5-5 parts Isopropyl palmitate 0.1-10 parts 10-60 parts of matrix material 5-25 parts of polyisobutylene 3-30 parts of thickener 0.1-55 parts of softener Antioxidant 0.1-1 part, The drug is levorprofen or a pharmaceutically acceptable salt thereof.

2. The patch composition according to claim 1, characterized in that, After the patch composition is placed at 30℃±2℃ and relative humidity of 60%±5% for 6 months, the drug content decreases by no more than 5%.

3. The patch composition according to claim 1, characterized in that, The weight ratio of the drug to isopropyl palmitate is 1:0.5-1:

5.

4. The patch composition according to claim 1, characterized in that, The patch composition does not contain zinc stearate.

5. The patch composition according to claim 1, characterized in that, The matrix material includes one or more of styrene-isoprene-styrene block copolymer and styrene-butadiene-styrene block copolymer; the tackifier includes one or more of hydrogenated rosin glycerol ester, rosin resin, terpene resin, polyterpene resin, and petroleum resin; the softener includes one or more of liquid paraffin, silicone oil, higher fatty acids, vegetable oil, and polybutene; and the antioxidant includes one or more of butylated hydroxytoluene, methylparaben, and ethylparaben.

6. The patch composition according to claim 5, characterized in that, The matrix material is a styrene-isoprene-styrene block copolymer with a styrene content of 15%-25%.

7. The patch composition according to claim 1, characterized in that, The patch composition comprises the following components in parts by weight: 1-5 doses of medicine Peppermint oil 0.5-5 parts Isopropyl palmitate 0.1-10 parts 10-60 parts of styrene-isoprene-styrene block copolymer 5-25 parts of polyisobutylene 3-30 parts of hydrogenated rosin glycerol ester Liquid paraffin 0.1-55 parts 0.1-1 part of butylated hydroxytoluene.

8. A method for preparing an efluprofen patch composition as described in any one of claims 1-7, characterized in that, The preparation method includes: mixing matrix material, polyisobutylene, softener, thickener, and antioxidant, stirring until melted, then adding drug, isopropyl palmitate, and peppermint oil and continuing to stir until uniform and free of lumps.

9. An efluprofen patch, characterized in that, The elfluprofen patch comprises a backing layer, a drug storage layer, and a protective layer arranged sequentially, wherein the raw materials for preparing the drug storage layer include the elfluprofen patch composition as described in any one of claims 1-7.

10. A method for preparing the levonorfen patch as described in claim 9, characterized in that, The preparation method includes: coating the efluprofen patch composition onto a protective layer to form a drug storage layer with a protective layer; and laminating a backing layer onto the drug storage layer to obtain the efluprofen patch.

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