Etofenamate gel plaster and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal plasters, and discloses an etofenamate gel plaster and a preparation method thereof, the etofenamate gel plaster comprises a drug carrying layer; the medicine carrying layer is prepared from the following raw materials in percentage by weight: 0.1%-10% of etofenamate, 0.5%-5% of isopropyl myristate, 0.5%-5% of diethylene glycol monoethyl ether and the balance of auxiliary materials. According to the invention, the gel plaster is prepared by taking etofenamate as an active ingredient, and the specific isopropyl myristate and diethylene glycol monoethyl ether are selected as penetration enhancers for combined use, so that the isopropyl myristate and the diethylene glycol monoethyl ether have a synergistic interaction effect; the transdermal permeation rate and the cumulative permeation amount of the etofenamate gel plaster are effectively improved, the inhibition percentage of writhing caused by acetic acid inflammation of mice can be effectively improved, and the anti-inflammatory and analgesic effects of the etofenamate gel plaster are effectively improved.

Description

Technical Field

[0001] The invention belongs to the technical field of medicinal plasters, and particularly relates to an etofenamate gel plaster and a preparation method thereof. Background Art

[0002] The global market size of osteoarthritis diseases will reach USD 7.38 billion in 2023. Due to the high incidence of knee osteoarthritis, knee osteoarthritis treatment will occupy the largest market share in 2023.

[0003] As the population ages, the number of patients suffering from pain diseases increases, so the demand for anti-inflammatory and analgesic drugs is also increasing. It is estimated that the market for pain treatment drugs will reach a capacity of more than US$50 billion in the next few years.

[0004] Etofenamate is a nonsteroidal anti-inflammatory drug that can inhibit cyclooxygenase and esteroxidase, reduce the effects of prostaglandins and other inflammatory mediators, and thus exert anti-inflammatory and analgesic effects. It can be transdermally absorbed when applied to the skin, and its active pharmaceutical ingredients can be effectively transferred to the site of inflammation, reducing local swelling and having good tolerance. The chemical structure of Etofenamate is shown below:

[0005]

[0006] In May 1905, the etofenamate gel (trade name Traumon) developed by Bayer was first launched in Germany for the treatment of joint and soft tissue diseases of the musculoskeletal system, trauma (such as sports injuries): contusions, sprains, strains, etc. Currently, the etofenamate dosage forms available globally include gel (trade name Traumon), cream (trade name Rheumon), spray (trade name Traumon), and patch (trade name Lixim 70mg wirkstoffhaltiges Pflaster).

[0007] The dosage of etofenamate gel, cream, and spray all require administration 3 to 5 times a day, and the treatment lasts for 3-4 weeks. Frequent and multiple administrations bring many inconveniences to patients, and patients have poor medication compliance. In addition, when the drug is applied to the affected area, it is easy to be scratched by daily activities, clothing, etc., causing the drug to come off the skin, and the actual absorption of the drug is reduced. The dosage of etofenamate patch is twice a day, which significantly reduces the number of administrations and improves patient medication compliance. However, the patch has poor air permeability, and some patients are prone to skin allergies when applied for a long time, which is highly irritating to the skin.

[0008] The drug loading capacity of gel patches is relatively large, and they can play a local therapeutic role through skin penetration; gel patches generally use water-soluble high molecular polymers as drug matrices, and adhere to the skin surface after stretching, which helps to achieve medicinal value, and the air permeability and moisturizing properties are relatively high, and the comfort after application is good. Due to its good air permeability, gel patches generally do not cause irritation to the skin, so most people will not experience allergies during use, but the transdermal penetration efficiency and penetration amount of gel patches are relatively low, which affects its therapeutic effect, and there is no relevant information reported on etofenamate gel patches. Summary of the invention

[0009] The object of the present invention is to provide an etofenamate gel patch capable of improving the transdermal permeability and the cumulative permeation amount.

[0010] The above-mentioned purpose is achieved by the following technical solutions.

[0011] The first aspect of the present invention provides an etofenamate gel patch, the etofenamate gel patch comprising a drug-carrying layer; the drug-carrying layer is made of raw materials including the following components by weight percentage:

[0012] Etofenamate 0.1%-10%, isopropyl myristate 0.5-5%, diethylene glycol monoethyl ether 0.5~5%, the rest are auxiliary materials.

[0013] In some embodiments, the drug-carrying layer includes 1-5% isopropyl myristate and 2-5% diethylene glycol monoethyl ether by weight.

[0014] In some embodiments, the drug-carrying layer includes 1-3% isopropyl myristate and 2-5% diethylene glycol monoethyl ether by weight.

[0015] In some embodiments, the drug-carrying layer includes 1-2% isopropyl myristate and 3-5% diethylene glycol monoethyl ether by weight.

[0016] In some of the embodiments, the weight ratio of isopropyl myristate to diethylene glycol monoethyl ether is 1:1-5.

[0017] In some of the embodiments, the weight ratio of isopropyl myristate to diethylene glycol monoethyl ether is 1:2.5-5.

[0018] In some of the embodiments, the weight ratio of isopropyl myristate to diethylene glycol monoethyl ether is 1:3-5.

[0019] In some of the embodiments, the weight ratio of isopropyl myristate to diethylene glycol monoethyl ether is 1:4.8-5.

[0020] In some embodiments, the drug-carrying layer comprises 0.1-6% etofenamate by weight, preferably 1-6%, more preferably 1-3%, and more preferably 2.5-3%.

[0021] In some embodiments, the auxiliary materials include solvents, high molecular weight polymers, surfactants, cross-linking agents, cross-linking regulators, fillers and water.

[0022] In some embodiments, the weight percentage of the auxiliary materials in the drug-carrying layer is: 2-40% solvent, 5-10% high molecular polymer, 0.2-3% surfactant, 0.1-0.5% cross-linking agent, 0.1-1% cross-linking regulator and 0.5-5% filler, and the rest is water; preferably, the weight percentage of the auxiliary materials in the drug-carrying layer is: 30-40% solvent, 7-10% high molecular polymer, 1-3% surfactant, 0.1-0.3% cross-linking agent, 0.1-1% cross-linking regulator and 2-5% filler, and the rest is water. Specifically, the water is purified water.

[0023] In some embodiments, the solvent is at least one of crotamiton, N-methylpyrrolidone, glycerol, purified water, and propylene glycol; and / or,

[0024] The high molecular polymer is at least one of partially neutralized sodium polyacrylate, sodium polyacrylate, sodium carboxymethyl cellulose, polyvinyl alcohol, gelatin, and polyacrylic acid.

[0025] In some embodiments, the surfactant is at least one of Tween and Span; and / or,

[0026] The cross-linking agent is at least one of aluminum glycolate and aluminum hydroxide; and / or,

[0027] The cross-linking regulator is disodium edetate; and / or,

[0028] The filler is at least one of talc, talcum powder and titanium dioxide; and / or,

[0029] The auxiliary material also includes a pH regulator, which adjusts the pH value of the drug-carrying layer to 4-7; preferably, the pH regulator is at least one of tartaric acid and sodium tartrate.

[0030] In some of the embodiments, the etofenamate gel patch further comprises a backing layer and a cover layer respectively disposed on both sides of the drug-carrying layer; preferably, the backing layer is a non-woven fabric, and the cover layer is a polypropylene film.

[0031] A second aspect of the present invention provides a method for preparing the etofenamate gel patch as described above, comprising the following steps:

[0032] preparing a gel paste containing etofenamate and excipients;

[0033] The gel paste is coated on the backing layer and covered with a cover layer to obtain the etofenamate gel patch.

[0034] In the present invention, etofenamate is used as an active ingredient to prepare a gel patch, and specific isopropyl myristate and diethylene glycol monoethyl ether are selected as penetration enhancers for combined use. The isopropyl myristate and diethylene glycol monoethyl ether have a synergistic effect, effectively improve the percutaneous penetration rate and cumulative penetration amount of the etofenamate gel patch, effectively improve the percentage of writhing inhibition caused by acetic acid inflammation in mice, and effectively improve the anti-inflammatory and analgesic effect of the etofenamate gel patch. DETAILED DESCRIPTION

[0035] In order to facilitate the understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0036] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0037] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0038] The following are specific embodiments.

[0039] The present invention provides an etofenamate gel patch, and a preparation method thereof comprises the following steps:

[0040] (1) Preparation of the bulk drug solution: first mix the components of the bulk drug solution except etofenamate, then add etofenamate after the mixing is completed, and stir to dissolve.

[0041] (2) Preparation of aqueous solution: adding each component of the aqueous solution into purified water, stirring and dissolving at a certain temperature to obtain an aqueous solution;

[0042] (3) Preparation of glycerol suspension: Add the components of the glycerol suspension into glycerol, stir and mix to obtain a glycerol suspension.

[0043] (4) The prepared raw material drug solution, aqueous solution and glycerol suspension are further mixed and stirred to obtain a gel paste (pH value is 4-7).

[0044] (5) The obtained gel paste is placed in a coating machine for coating, with a polypropylene film as a cover liner and a non-woven fabric as a backing liner to obtain an etofenamate gel patch.

[0045] According to the above method, etofenamate gel patches having the ingredients shown in Examples 1-9 were prepared according to Table 1, and etofenamate gel patches having the ingredients shown in Comparative Examples 1-9 were prepared according to Table 2.

[0046] Table 1 Prescription composition of etofenamate gel patch of embodiment 1-9 (by weight percentage)

[0047]

[0048]

[0049] Table 2 Prescription composition of etofenamate gel patch of comparative examples 1 to 9 (by weight percentage)

[0050]

[0051]

[0052]

[0053] Test Example 1: In vitro percutaneous permeation test of etofenamate gel patch of the present invention

[0054] The modified Franz diffusion cell method (diffusion cell volume 9 ml, effective diffusion area 1.776 cm 2 ), the skin used was hairless miniature pig skin (back), the skin thickness was about 600 μm. The etofenamate gel patch prepared above was applied to one side of the stratum corneum of the pig skin, and placed between the diffusion cell and the receiving cell, with the stratum corneum facing the diffusion cell and the dermis facing the receiving cell.

[0055] The receiving pool volume is 9mL, filled with pH7.4 phosphate buffer, the magnetic speed is set to 600r / min, and the temperature is 32°C ± 1°C. Sampling is performed at 2h, 4h, 6h, 8h, 12h, and 24h after the start of transdermal administration, and automatic sampling is performed, and all sampling and full supplementation are performed. About 4mL of sample is taken to determine the concentration of etofenamate by high performance liquid chromatography, and the etofenamate gel patches of Examples 1-9 and Comparative Examples 1-9 are tested respectively, and the percutaneous penetration rate and cumulative penetration amount are calculated, and the results are shown in Table 3.

[0056] Table 3 Transdermal penetration effect of etofenamate gel patch of the present invention (mean ± SD, n = 3)

[0057]

[0058]

[0059] The results show that the percutaneous permeation rate and cumulative permeation amount of the etofenamate gel patch of Examples 1 to 9 are significantly higher than the percutaneous permeation rate and cumulative permeation amount of the etofenamate gel patch of Comparative Examples 1 to 9, proving that the specific isopropyl myristate and diethylene glycol monoethyl ether are used in combination, and isopropyl myristate and diethylene glycol monoethyl ether have a synergistic effect, which can effectively improve the percutaneous permeation rate and cumulative permeation amount of the etofenamate gel patch, and the amount of etofenamate has little effect on the permeation amount, so the cumulative permeation amount in Examples 1-9 does not change much. In addition, it can be seen from the results of Examples 3 and 6-9 that the proportion of isopropyl myristate and diethylene glycol monoethyl ether will also affect the speed of the percutaneous permeation rate, wherein the weight ratio of isopropyl myristate to diethylene glycol monoethyl ether is 1:5, and the comprehensive permeation effect is the best.

[0060] Test Example 2: Anti-inflammatory and analgesic effect test of etofenamate gel patch of the present invention

[0061] 70 female mice weighing 18-25 g were randomly divided into a blank group, a positive control group of etofenamate commercially available gel (trade name Traumon, Meda Pharma GmbH & Co. KG), and an etofenamate gel patch group of Examples 1-5, with 10 mice in each group. The blank group was not treated with any treatment, and the gel patch group was given 2.5 cm 2 The above gel patch. 30 minutes after administration, acetic acid solution (1.5%, 0.1 ml / 10 g) was intraperitoneally injected. When the abdomen of the mouse was sunken, the trunk and hind limbs were stretched, and the body was twisted, it was considered that the writhing reaction occurred. The timing was started from the injection of acetic acid, and the time when the mouse started to twist and the number of twists within 30 minutes were recorded, and the percentage of writhing inhibition (PIP) was calculated, PIP = (mean number of twists in the blank group - mean number of twists in the drug group) / mean number of twists in the blank group × 100%.

[0062] Table 2 Anti-inflammatory and analgesic effects of etofenamate gel patch of the present invention

[0063]

[0064]

[0065] The results show that the etofenamate gel patch of the present invention has a better inhibition rate on writhing caused by acetic acid inflammation in mice than the commercially available etofenamate gel, indicating that it has better anti-inflammatory and analgesic effects.

[0066] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0067] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. An etofenamate gel patch, characterized in that: The etofenamate gel patch comprises a drug-carrying layer; the drug-carrying layer is made of raw materials including the following components by weight percentage: Etofenamate 0.1%-10%, isopropyl myristate 0.5-5%, diethylene glycol monoethyl ether 0.5-5%, and the rest are auxiliary materials.

2. The etofenamate gel patch as claimed in claim 1, characterized in that, By weight percentage, the drug-carrying layer comprises 1-5% isopropyl myristate and 2-5% diethylene glycol monoethyl ether; preferably, by weight percentage, the drug-carrying layer comprises 1-3% isopropyl myristate and 2-5% diethylene glycol monoethyl ether.

3. The etofenamate gel patch as claimed in claim 1, characterized in that, The weight ratio of isopropyl myristate to diethylene glycol monoethyl ether is 1:1-5; preferably, the weight ratio of isopropyl myristate to diethylene glycol monoethyl ether is 1:2.5-5.

4. The etofenamate gel patch as claimed in claim 1, characterized in that, In terms of weight percentage, the drug-carrying layer comprises 0.1-6% etofenamate, preferably 1-6%.

5. The etofenamate gel patch according to any one of claims 1 to 4, characterized in that The auxiliary materials include solvent, high molecular polymer, surfactant, cross-linking agent, cross-linking regulator, filler and water.

6. The etofenamate gel patch as claimed in claim 5, characterized in that, The weight percentages of the auxiliary materials in the drug-carrying layer are: 2-40% solvent, 5-10% high molecular polymer, 0.2-3% surfactant, 0.1%-0.5% crosslinking agent, 0.1%-1% crosslinking regulator and 0.5-5% filler, and the rest is water.

7. The etofenamate gel patch as claimed in claim 5, characterized in that, The solvent is at least one of crotamiton, N-methylpyrrolidone, glycerol, purified water and propylene glycol; and / or, The high molecular polymer is at least one of partially neutralized sodium polyacrylate, sodium polyacrylate, sodium carboxymethyl cellulose, polyvinyl alcohol, gelatin, and polyacrylic acid.

8. The etofenamate gel patch as claimed in claim 5, characterized in that, The surfactant is at least one of Tween and Span; and / or, The cross-linking agent is at least one of aluminum glycolate and aluminum hydroxide; and / or, The cross-linking regulator is edetate disodium; and / or, The filler is at least one of kaolin, talc and titanium dioxide; and / or, The auxiliary material also includes a pH regulator, which adjusts the pH value of the drug-carrying layer to 4-7; preferably, the pH regulator is at least one of tartaric acid and sodium tartrate.

9. The etofenamate gel patch according to any one of claims 1 to 4, characterized in that The etofenamate gel patch further comprises a backing layer and a cover layer respectively arranged on both sides of the drug-carrying layer; preferably, the backing layer is a non-woven fabric, and the cover layer is a polypropylene film.

10. A method for preparing the etofenamate gel patch according to any one of claims 1 to 9, characterized in that: The steps include: preparing a gel paste containing etofenamate and excipients; The gel paste is coated on the backing layer and covered with a cover layer to obtain the etofenamate gel patch.

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