High-permeability diclofenac sodium liniment and preparation method thereof

Abstract

The invention belongs to the technical field of non-steroidal anti-inflammatory drug preparations, and particularly relates to a high-permeability diclofenac sodium liniment and a preparation method thereof. The high-permeability diclofenac sodium liniment disclosed by the invention is prepared from diclofenac sodium, alanine, nonadienol, ethanol, glycerol, a pH (Potential of Hydrogen) regulator and water. In order to solve the problems of insufficient skin permeability and low safety of diclofenac sodium liniment in the prior art, the formula and the preparation method are optimized. Research finds that nonadienol-beta-alanine-glycerol is used as a novel permeation enhancing carrier, and can effectively promote the absorption of diclofenac sodium. The carrier improves the permeability of the medicine by improving the distribution of the medicine in the skin layer, so that the local curative effect of the medicine is enhanced.

Description

Technical Field

[0001] The invention belongs to the technical field of non-steroidal anti-inflammatory drug preparations, and particularly relates to a highly permeable diclofenac sodium liniment and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Diclofenac sodium is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation. Its mechanism of action includes: (1) Inhibition of inflammatory mediator synthesis: Diclofenac sodium selectively inhibits the activity of COX-1 and COX-2 enzymes, thereby reducing the synthesis of prostaglandins, which are closely related to inflammation, pain and fever. (2) Anti-inflammatory effect: By reducing the level of prostaglandins, diclofenac sodium can reduce the inflammatory response and relieve related symptoms such as swelling and pain. (3) Analgesic effect: Diclofenac sodium's inhibitory effect on pain signals makes it effective in treating various pain conditions (such as arthritis and postoperative pain).

[0004] With the development of modern medicine, diclofenac sodium, as a classic NSAID, is widely used to treat various pain symptoms such as arthritis, muscle pain, sprains, etc. due to its significant analgesic and anti-inflammatory effects, and its application in clinical pain management is becoming more and more extensive. Although traditional oral diclofenac sodium preparations can effectively relieve systemic pain, due to liver metabolism and gastrointestinal absorption, the concentration of the drug in the body may fluctuate, thereby causing adverse reactions such as gastrointestinal bleeding, liver and kidney damage, etc. In addition, the administration method of injection dosage forms often has the problems of pain and inconvenience, which limits patients' willingness and compliance to use.

[0005] Topically administered diclofenac sodium transdermal preparations have the advantage of reaching the painful area directly, which can significantly reduce the occurrence of systemic side effects. Compared with traditional preparations, topical application can achieve high concentrations of drugs at the painful area, enhance local effects, while reducing systemic absorption and reducing potential side effects. Therefore, the development of more efficient and safer topical drug delivery forms has become one of the hot topics in current medical research.

[0006] In recent years, with the development of drug delivery systems, the use of new technologies such as nanotechnology and transdermal absorption enhancers to improve drug permeability has become a research hotspot. By improving the formulation and preparation process, the permeability of diclofenac sodium in the skin can be effectively improved, allowing it to reach the target site faster and enhance the therapeutic effect. For example, the use of carrier systems such as liposomes and nanoparticles can effectively improve the permeability of drugs in the skin barrier, thereby achieving a rapid and lasting analgesic effect.

[0007] A Chinese patent with publication number CN107669661A discloses a diclofenac sodium transdermal patch, comprising a drug-carrying layer, a backing layer and an anti-adhesive layer, wherein the drug-carrying layer comprises diclofenac sodium, a penetration enhancer consisting of 1-dodecyl-aza-oxazol-2-one and limonene, and a hot-melt pressure-sensitive adhesive matrix, wherein the weight percentage of diclofenac sodium is 0.1-10%, the weight percentage of the penetration enhancer is 0.5-20%, and the balance is the hot-melt pressure-sensitive adhesive matrix.

[0008] Chinese patent publication number CN111904926A discloses a topical diclofenac sodium composition, comprising: 2% diclofenac sodium salt, 10-15% isopropyl alcohol, 10-15% propylene glycol, 2-3% carbomer, 0-10% liquid lipid forming an oil phase, 0-5% nonionic surfactant, alkaline agent, and water.

[0009] Commercially available diclofenac sodium ointment usually contains penetration enhancers such as laurocaprolactone to ensure better absorption of the drug. However, laurocaprolactone is quite irritating and may cause redness and sensitivity of the skin.

[0010] The present invention aims to develop a novel high-permeability diclofenac sodium ointment, which significantly improves the permeability of diclofenac sodium in the skin and enhances its local therapeutic effect by optimizing the formula and preparation process, while reducing side effects, thereby providing patients with a safer and more convenient pain management option. Summary of the invention

[0011] The shortcomings of the prior art are overcome, and the present invention provides a diclofenac sodium liniment with high permeability and high safety by optimizing the formula and preparation process.

[0012] The highly osmotic diclofenac sodium liniment is composed of 1% diclofenac sodium, 1.5% to 4.5% alanine, 0.5% to 2.0% nonadienol, 30% to 40% ethanol, 2.0% to 5.0% glycerol, a pH regulator, and water by mass fraction. It is recognized by those skilled in the art that nonadienol generally refers to 2,6-nonadienol, CAS: 7786-44-9, with a content of >95%. The nonadienol of the present invention is purchased from Taian Jiayue Biochemical Co., Ltd.

[0013] Wherein, the alanine is β-alanine; and the pH regulator is selected from one of a citrate buffer solution, a phosphate buffer solution, and a carbonate buffer solution.

[0014] The present invention also provides a method for preparing the highly osmotic diclofenac sodium liniment, the preparation method comprising: (1) Dissolve glycerol and alanine in an appropriate amount of water, heat in a water bath to 40°C ± 5°C, and keep warm for 4 to 6 hours to obtain a glycerol-alanine mixture; (2) Dissolve nonadienol in ethanol, mix with the glycerol-alanine mixture and diclofenac sodium, adjust the pH to 5.5-6.5 with a pH adjuster, and add water to the full amount.

[0015] Compared with the prior art, the technical effects of the present invention are: In order to solve the problems of insufficient skin permeability and low safety of diclofenac sodium liniment in the prior art, the present invention optimizes the formula and preparation method. Studies have found that nonadienol-β-alanine-glycerol, as a new type of penetration-enhancing carrier, can effectively promote the absorption of diclofenac sodium. The carrier improves the distribution of the drug in the skin layer, improves the permeability of the drug, and thus enhances its local therapeutic effect.

[0016] Specifically, nonadienol, β-alanine, and glycerol can play a synergistic role in promoting penetration. The unique structure of nonadienol enables it to interact with the lipids in the stratum corneum of the skin to form a more permeable interface, while β-alanine helps to improve the hydrophilicity of the drug, making it easier to penetrate the skin barrier. In addition, glycerol, as a moisturizer, can not only enhance the lubricity of the ointment, but also maintain the moisture of the skin and improve the penetration efficiency of the drug.

[0017] Through these optimizations, the prepared diclofenac sodium ointment showed a more superior effect in clinical applications, which can effectively relieve pain and reduce the occurrence of side effects, providing patients with a safer and more effective treatment option. This innovative formula and carrier system has opened up a new direction for the development of topical dosage forms of diclofenac sodium and has important application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 : The cumulative penetration amounts of the diclofenac sodium liniment of Examples 1 to 3 and the diclofenac sodium liniment of Comparative Examples 1 to 5. DETAILED DESCRIPTION

[0019] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0020] Example 1 Diclofenac sodium liniment Preparation method: (1) Dissolve glycerol and alanine in an appropriate amount of water, heat to 40°C in a water bath, and keep warm for 5 hours to obtain a glycerol-alanine mixture; (2) Dissolve nonadienol in ethanol, mix with the glycerol-alanine mixture and diclofenac sodium, adjust the pH to 6.2 with a pH adjuster, and add water to the full amount.

[0021] Example 2 Diclofenac sodium liniment Preparation method: (1) Dissolve glycerol and alanine in an appropriate amount of water, heat to 35°C in a water bath, and keep warm for 6 hours to obtain a glycerol-alanine mixture; (2) Dissolve nonadienol in ethanol, mix with the glycerol-alanine mixture and diclofenac sodium, adjust the pH to 5.5 with a pH adjuster, and add water to the full amount.

[0022] Example 3 Diclofenac sodium liniment Preparation method: (1) Dissolve glycerol and alanine in an appropriate amount of water, heat to 45°C in a water bath, and keep warm for 4 hours to obtain a glycerol-alanine mixture; (2) Dissolve nonadienol in ethanol, mix with the glycerol-alanine mixture and diclofenac sodium, adjust the pH to 6.5 with a pH adjuster, and add water to the full amount.

[0023] Comparative Example 1 Commercially available diclofenac sodium liniment National Medicine Approval No. H19990100 Comparative Example 2 Diclofenac sodium liniment Preparation method: (1) Dissolve glycerol and alanine in an appropriate amount of water, heat to 40°C in a water bath, and keep warm for 5 hours to obtain a glycerol-alanine mixture; (2) Mix the glycerol-alanine mixture, diclofenac sodium and ethanol, adjust the pH to 6.2 with a pH adjuster, and add water to the full amount.

[0024] Comparative Example 3 Diclofenac sodium liniment Preparation method: (1) Dissolve glycerol in an appropriate amount of water, heat in a water bath to 40°C, and keep warm for 5 hours to obtain a glycerol-alanine mixture; (2) Dissolve nonadienol in ethanol, mix with the glycerol-alanine mixture and diclofenac sodium, adjust the pH to 6.2 with a pH adjuster, and add water to the full amount.

[0025] Comparative Example 4 Diclofenac Sodium Liniment Preparation method: (1) Dissolve glycerol and alanine in an appropriate amount of water, heat to 40°C in a water bath, and keep warm for 5 hours to obtain a glycerol-alanine mixture; (2) Dissolve nonadienol in ethanol, mix with the glycerol-alanine mixture and diclofenac sodium, adjust the pH to 6.2 with a pH adjuster, and add water to the full amount.

[0026] Comparative Example 5 Diclofenac Sodium Liniment Preparation method: (1) dissolving glycerol and alanine in an appropriate amount of water to obtain a glycerol-alanine mixture; (2) Dissolve nonadienol in ethanol, mix with the glycerol-alanine mixture and diclofenac sodium, adjust the pH to 6.2 with a pH adjuster, and add water to the full amount.

[0027] Quality evaluation of diclofenac sodium liniment Transdermal permeation test of diclofenac sodium liniment Preparation of ex vivo mouse skin: SD rats (SYXK(Lu) 2018 0008), SPF grade, 180-220 g, were depilated with 8% sodium sulfide solution, washed and raised for 24 hours, and then killed by cervical dislocation. The abdominal skin was taken, subcutaneous fat was removed, and the skin was repeatedly washed with saline, and the water was absorbed with filter paper for later use.

[0028] Transdermal experiment: The treated rat abdominal skin was fixed in the transdermal instrument, with the stratum corneum facing the supply pool, and the effective transdermal area was equal. The same dose of diclofenac sodium liniment of Examples 1, 2, and 3 and the diclofenac sodium liniment of Comparative Examples 1 to 5 were placed in the supply pool. The receiving solution was 20% ethanol-pH 7.4 phosphate buffer. Samples were taken at 5min, 10min, 20min, 30min, and 60min, and the corresponding volume of receiving solution was added. The sample was filtered through a 0.22μm microporous membrane, the content of diclofenac sodium in the receiving solution was determined, and the cumulative penetration amount was calculated.

[0029] ) / A Where V is the total volume of the receiving solution, Cn is the drug concentration measured at the nth sampling point (μg / mL), C is the drug concentration measured at the ith sampling point (μg / mL), V is the sampling volume, and A is the diffusion permeation area (cm 2 ).

[0030] Figure 1It is the cumulative penetration amount of the diclofenac sodium liniment of Examples 1 to 3 and the diclofenac sodium liniment of Comparative Examples 1 to 5. It can be seen that the diclofenac sodium liniment of the present invention has a strong penetration ability, diclofenac sodium can effectively penetrate the skin barrier, and the osmotic effect of the mixture carrier of β-alanine, nonadienol, and glycerol is significant, which promotes the penetration of diclofenac sodium, thereby increasing the cumulative penetration amount.

[0031] Skin retention experiment: After the in vitro transdermal test, the rat skin was taken out of the diffusion cell, the surface was cleaned with water, and the cotton was wiped dry and cut into pieces. Then 5 mL of pH 7.4 phosphate buffer was added for homogenization, centrifuged at 5000 r·min⁻¹ for 5 minutes, the supernatant was taken and filtered with a 0.22μm filter membrane, and finally the content of diclofenac sodium in the skin was determined by high performance liquid chromatography to calculate the skin retention.

[0032] Table 1 Skin retention of diclofenac sodium liniment Table 1 shows that the retention amounts of diclofenac sodium in Examples 1, 2, and 3 are 2.23±0.40, 1.98±0.37, and 2.31±0.43, respectively, showing relatively high skin retention capacity, indicating that the formulation and preparation method of the present invention can more effectively retain the drug on the skin. Relatively speaking, the skin retention amounts of diclofenac sodium ointments in Comparative Examples 1 to 5 are relatively low, ranging from 1.26±0.42 to 1.60±0.41, indicating that the drug retention effects of these comparative examples are not as good as those of the embodiments. This shows that the formulations of Examples 1 to 3 of the present invention have obvious advantages in increasing the skin retention amount of diclofenac sodium, which helps to improve the local efficacy of the drug.

[0033] Intact skin irritation test of diclofenac sodium liniment Experimental animals: ordinary New Zealand rabbits, experimental animal license number: SYXK (Lu) 2018 0008, adaptive feeding for one week.

[0034] Experimental groups: The rats were randomly divided into a negative control group, a normal saline group, the diclofenac sodium ointment of Examples 1, 2, and 3, and the diclofenac sodium ointment of Comparative Example 1, with 6 rats in each group, half of which were male and half were female.

[0035] method: Skin treatment: 24 hours before the test, remove hair from the back, about 5cm×5cm. Make sure the skin is not damaged.

[0036] Administration: Physiological saline, the diclofenac sodium liniment of Examples 1, 2, 3, and the diclofenac sodium liniment of Comparative Example 1 were applied to the depilated skin of the grouped New Zealand rabbits, respectively, for a single administration.

[0037] Observation: Observe the skin reaction under natural light. The main investigation index is redness and swelling. Record the local skin reaction 5min, 10min, 20min, 30min, and 60min after administration.

[0038] Table 2 Diclofenac sodium liniment intact skin irritation test The intact skin irritation test is an important indicator for evaluating the safety of the drug, which means that it may be more suitable for patients when applied topically and can reduce the risk of adverse reactions. The diclofenac sodium liniment of Examples 1, 2, and 3 of the present invention has low irritation and does not cause obvious local reactions, indicating that its ingredients and formula are relatively mild, indicating that the preparation process of the liniment, the purity of the ingredients, and the rationality of the formula all meet the standards, ensuring the safety of the product.

[0039] Stability of diclofenac sodium liniment According to commercial packaging, accelerated testing was carried out at a temperature of 40℃±2℃ and a relative humidity of 75%±5%. Sampling was carried out on the 1st day and the 180th day to check the properties, content, pH, etc.

[0040] Table 3 Properties, homogeneity and pH of diclofenac sodium ointment In order to ensure and judge the quality, safety and effectiveness of diclofenac sodium ointment, the quality of diclofenac sodium ointment of Examples 1 to 3 and Comparative Examples 1 to 5 was evaluated. According to Table 3, the diclofenac sodium ointment remained stable in the accelerated test and met the standards of the Chinese Pharmacopoeia.

Claims

1. A highly osmotic diclofenac sodium liniment, characterized in that: The highly osmotic diclofenac sodium ointment consists of 1% diclofenac sodium, 1.5%-4.5% alanine, 0.5%-2.0% nonadienol, 30%-40% ethanol, 2.0%-5.0% glycerol, a pH regulator and water.

2. The highly osmotic diclofenac sodium liniment according to claim 1, characterized in that: The alanine is β-alanine.

3. The highly osmotic diclofenac sodium liniment according to claim 1, characterized in that: The highly osmotic diclofenac sodium ointment consists of 1% diclofenac sodium, 2.5% alanine, 1.2% nonadienol, 35% ethanol, 3.5% glycerol, a pH regulator and water.

4. The highly osmotic diclofenac sodium liniment according to claim 1, characterized in that: The highly osmotic diclofenac sodium ointment consists of 1% diclofenac sodium, 1.5% alanine, 0.5% nonadienol, 30% ethanol, 2.0% glycerol, a pH regulator and water.

5. The highly osmotic diclofenac sodium liniment according to claim 1, characterized in that: The highly osmotic diclofenac sodium ointment consists of 1% diclofenac sodium, 4.5% alanine, 2.0% nonadienol, 40% ethanol, 5.0% glycerol, a pH regulator and water.

6. The highly osmotic diclofenac sodium liniment according to claim 1, characterized in that: The pH regulator is selected from one of a citrate buffer solution, a phosphate buffer solution and a carbonate buffer solution.

7. The highly osmotic diclofenac sodium liniment according to claim 6, characterized in that: The pH adjuster is a phosphate buffer solution.

8. A method for preparing the highly osmotic diclofenac sodium liniment according to claim 1, characterized in that: The preparation method is: (1) Dissolve glycerol and alanine in an appropriate amount of water, heat in a water bath to 40°C ± 5°C, and keep warm for 4 to 6 hours to obtain a glycerol-alanine mixture; (2) Dissolve nonadienol in ethanol, mix with the glycerol-alanine mixture and diclofenac sodium, adjust the pH to 5.5-6.5 with a pH adjuster, and add water to the full amount.

9. The preparation method according to claim 8, characterized in that: The pH=6.

2.

10. The preparation method according to claim 8, characterized in that: The water bath was heated to 40°C and kept warm for 5 hours.

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