Flurbiprofen emulsion gel external pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a flurbiprofen emulsion gel external pharmaceutical composition and a preparation method and application thereof, and the flurbiprofen emulsion gel external pharmaceutical composition comprises flurbiprofen or flurbiprofen sodium, an emulsifier, a solubilizer, isopropanol, carbomer, a pH regulator and purified water according to a specific weight ratio. The preparation method comprises the following steps: dissolving step by step, adjusting the pH value, heating and emulsifying, and cooling and filling. According to the invention, by optimizing the proportion of each component, especially the synergistic effect of the emulsifier, the solubilizer and the carbomer, the stability, dispersity and slow release property of the medicine on the skin surface are effectively improved, and the effect of continuously easing pain is achieved. Meanwhile, the unique formula design ensures good viscosity characteristics, is convenient to smear and absorb, ensures safety, and shows a remarkable curative effect in treating various inflammations or pain diseases such as osteoarthritis, muscular pain and the like.

Description

Technical Field

[0001] This application relates to the field of medicine. More specifically, it relates to an external pharmaceutical composition of flurbiprofen milk gel, its preparation method and application. Background Art

[0002] With the rapid development of medical standards and the continuous improvement of people's requirements for the quality of life, postoperative analgesia has become an important research direction in the field of anesthesiology. Although opioid drugs and local anesthetics are widely used in postoperative analgesia, their side effects such as respiratory depression, hypotension, and limited movement restrict their scope of use. The non-steroidal anti-inflammatory drug flurbiprofen has attracted much attention due to its relatively low side effects, especially its application in the local administration route, which can effectively reduce the occurrence of drug adverse reactions and improve the safety and comfort of patients' medication.

[0003] Currently, the main forms of local administration are dosage forms such as gel patches. Gel patches achieve drug release by adhering to the skin surface, but they have problems such as fixed dosage, difficulty in adapting to complex parts, and possible skin irritation. To solve these problems, the industry usually adopts the following means: optimizing the adhesive material of the patch to improve the adhesion; improving the drug release system to enhance the drug penetration efficiency; developing new matrix materials to reduce skin irritation. Although these means have improved the effect of local administration to a certain extent, they still cannot fully meet the clinical needs.

[0004] Conventional means in the prior art have not effectively solved the problems of insufficient flexibility of local administration, limited applicable parts, and high risk of skin irritation. Especially in scenarios that require individualized treatment, existing gel patches are difficult to meet the need for flexible dose adjustment and have poor adaptability to complex parts such as joints and hairy areas. Summary of the Invention

[0005] To solve the above technical problems, this application provides an external pharmaceutical composition of flurbiprofen milk gel, its preparation method and application.

[0006] This application adopts the following technical solutions: In the first aspect, this application provides an external pharmaceutical composition of flurbiprofen milk gel, which is composed of the following raw materials in parts by weight: 0.5 - 3.5 parts of flurbiprofen or sodium flurbiprofen, 1 - 5 parts of emulsifier, 2 - 10 parts of solubilizer, 15 - 30 parts of isopropanol, 0.5 - 2 parts of carbomer, 0.5 - 2 parts of pH regulator, and 50 - 70 parts of purified water.

[0007] Further, the above composition is composed of the following raw materials in parts by weight: 1 - 3 parts of flurbiprofen or sodium flurbiprofen, 1 - 3 parts of emulsifier, 5 - 10 parts of solubilizer, 15 - 25 parts of isopropanol, 0.5 - 1.5 parts of carbomer, 0.6 - 1.5 parts of pH regulator, 60 - 70 parts of purified water.

[0008] Further, the above emulsifier includes one or more of polyoxyethylene (20) cetostearyl ether, cetearyl alcohol polyoxyethylene (25) ether, polyoxyethylene (2) octadecyl ether, polyoxyethylene (40) stearate.

[0009] By adopting the above technical solution, the specific selection of the emulsifier can improve the skin permeability of the drug, enhance the dispersibility and stability of the drug on the skin surface, avoid drug crystallization, and thus achieve the rapid absorption and sustained release of the drug. At the same time, these emulsifiers endow the composition with good spreadability and skin - friendliness, are easy to clean, reduce the irritation to the skin, and improve the patient experience.

[0010] Further, the above solubilizer includes one or more of caprylic / capric triglyceride, propylene glycol, liquid paraffin, peppermint oil.

[0011] By adopting the above technical solution, the specific selection of the emulsifier can effectively improve the solubility of flurbiprofen or sodium flurbiprofen in the composition, ensure the uniform distribution of the drug in the hydrogel matrix, and thus enhance the stability and release performance of the drug.

[0012] Further, the above pH regulator includes one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, and the pH regulator does not contain triethanolamine.

[0013] By adopting the above technical solution, using sodium hydroxide, potassium hydroxide, calcium hydroxide as the pH regulator can effectively avoid the use of triethanolamine, thus preventing the formation of nitrosamines and improving the safety of the drug. At the same time, these inorganic base regulators help to precisely control the pH value of the hydrogel, ensure it is within an appropriate range, and enhance the stability and skin compatibility of the drug.

[0014] Further, the above emulsifier is polyoxyethylene (20) cetostearyl ether, and the above solubilizer is liquid paraffin or caprylic / capric triglyceride.

[0015] In the second aspect, the present application provides a preparation method of the above - mentioned flurbiprofen hydrogel topical pharmaceutical composition, which includes: Dissolve the flurbiprofen or sodium flurbiprofen in the solubilizer and isopropanol to obtain Solution I; Add carbomer to water and fully swell it, then adjust the pH value to 6.0 - 8.0 using the pH regulator to obtain Solution II; After heating and dissolving the emulsifier, add it to Solution I. Subsequently, mix Solution I with Solution II, emulsify for 10 - 30 min, then cool down under stirring and fill.

[0016] By adopting the above technical solution, the preparation method can ensure the stability and effectiveness of the flurbiprofen emulgel topical pharmaceutical composition. The specific effects are as follows: Flurbiprofen or sodium flurbiprofen is mixed with a solubilizer and isopropanol to form Solution I, which improves the solubility of the main drug, ensures the uniform distribution of the drug in the preparation, and thus enhances the drug release performance and bioavailability; Carbomer is added to water and fully swollen, and then the pH value is adjusted to 6.0 - 8.0 to form Solution II, which not only forms a stable hydrogel matrix, but also optimizes the acid-base environment of the preparation, reduces the irritation to the skin, and at the same time prolongs the drug release time; The emulsifier is heated and dissolved and then added to Solution I, and then mixed and emulsified with Solution II to achieve the unique structure of the emulgel, combining the skin-friendly property of the gel and the easy-cleaning property of the microemulsion, enabling the drug to quickly penetrate the skin and continuously release, improving the therapeutic effect; The process of cooling and filling under stirring ensures the uniformity and stability of the preparation, avoids the influence of high temperature on the drug activity, and at the same time does not require additional addition of preservatives, reducing the irritation and allergy risks of the product.

[0017] Further, in the step of heating the solvent of the emulsifier, the heating temperature is 60 - 80 °C.

[0018] Further, in the process of cooling and filling under stirring, the temperature is reduced to 30 - 35 °C, and no preservative needs to be added.

[0019] In the third aspect, the present application provides an application of the above flurbiprofen emulgel topical pharmaceutical composition in the treatment of inflammatory or painful diseases, and the inflammatory or painful diseases include osteoarthritis, degenerative arthritis, scapulohumeral periarthritis, tendinitis, peritendinitis, lateral epicondylitis of the humerus, muscle pain, swelling and pain caused by trauma.

[0020] To sum up, the present application has the following beneficial effects: The flurbiprofen emulgel topical pharmaceutical composition provided by the present application can significantly improve the local utilization rate of the drug and reduce the side effects caused by systemic absorption. Specifically, by optimizing the proportion of each component, especially the synergistic effect of the emulsifier, solubilizer and carbomer, the stability, dispersibility and sustained release of the drug on the skin surface are effectively improved, avoiding drug crystallization and achieving the effect of continuous analgesia. At the same time, its unique formulation design ensures good viscosity characteristics, is convenient for application and absorption, is applicable to a variety of complex parts, reduces the risk of skin irritation, and provides a new safe and effective local analgesia option for patients. In addition, the use of preservatives and organic bases in this product effectively reduces the irritation and allergy risks of the product to the skin, and is especially suitable for people with sensitive skin. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is the viscosity measurement result of the gel provided by Examples 1-6 and Comparative Examples 1-3 in the performance test of this application; Figure 2 These are the release test results of the gels provided in Examples 1-6 and Comparative Examples 1-3 in the performance test of this application. DETAILED DESCRIPTION

[0022] The embodiments of the present invention will be described in detail below in conjunction with examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. The specific conditions not specified in the examples are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used without indicating the manufacturer are all conventional products that can be purchased commercially.

[0023] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0024] Example 1 This embodiment provides a flurbiprofen emulsion gel external pharmaceutical composition, the preparation method of which comprises: 1. Prepare materials: Prepare materials according to Table 1; 2. Add 23.2 g of flurbiprofen to a solubilizer (20 g of coconut oil caprylate and 20 g of liquid paraffin) and 160 g of isopropanol, and stir at 500 rpm with an OS20-Pro LCD digitally controlled overhead electronic stirrer until completely dissolved.

[0025] 3. Add 9.6 g of Carbomer 974P to 504 g of water and fully disperse, and use about 7.2 g of pH adjuster sodium hydroxide to adjust the pH value to 6.0-7.0.

[0026] 4. Place 16 g of the emulsifier polyoxyethylene (20) cetearyl ether in a DF-101S heat-collecting constant temperature heating magnetic stirrer at 60-70°C to dissolve, add it to an IKALR100 controlled reactor (which contains an aqueous solution of Carbomer 974P), then add the flurbiprofen solution, and emulsify it in an IKAT25 disperser for 25-30 minutes.

[0027] 5. Cool down while stirring and fill into aluminum-plastic composite tube or aluminum tube at about 32°C to obtain latex gel.

[0028] Example 2-3 The difference between this group of examples and Example 1 is that different specific raw materials are selected, as shown in Table 1: Table 1. Name 1 2 3 Flurbiprofen 2.9 2.9 2.9 Carbomer (Carbomer 974P) 1.2 1.2 1.2 Polyoxyethylene (20) Cetostearyl Ether 2 / 1 Ceteareth-25 / 2 1 Caprylic / Capric / Capric Triglyceride 2.5 2.5 2.5 Liquid Paraffin 2.5 2.5 2.5 Propylene Glycol 5 5 5 Sodium Hydroxide ≈0.9 ≈0.9 / Calcium Hydroxide / / ≈0.9 Isopropyl Alcohol 20 20 20 Water 63 63 63 Total 100 100 100 Example 4 This embodiment provides a flurbiprofen emulsion gel external pharmaceutical composition, the preparation method of which comprises: (1) Material preparation: Prepare materials according to Table 2; (2) Add 23.2 g of flurbiprofen sodium to 80 g of a solubilizer and 160 g of isopropanol (the solubilizer is 20 g of coconut oil caprylate, 20 g of liquid paraffin, and 40 g of propylene glycol), and stir at 500 rpm using an OS20-Pro LCD digitally controlled overhead electronic stirrer until the mixture is completely dissolved.

[0029] (3) 9.6 g of Carbomer 974P was added to 504 g of water and fully dispersed, and the pH value was adjusted to 6.0-7.0 using about 7.2 g of sodium hydroxide as a pH adjuster.

[0030] (4) 16 g of the emulsifier polyoxyethylene (20) cetearyl ether was heated to 70-80° C. in a DF-101S heat-collecting constant temperature heating magnetic stirrer to dissolve, and added to an IKALR100 controlled reactor (which contained an aqueous solution of carbomer 974P), and then the flurbiprofen sodium solution was added, and emulsified in an IKAT25 disperser for 20-25 minutes.

[0031] (5) Cooling down under stirring and filling into an aluminum-plastic composite tube or an aluminum tube at about 34° C. to obtain a latex gel.

[0032] Embodiment 5-8 The difference between this group of examples and Example 4 is that different specific raw materials are selected, as shown in Table 2: Table 2. Name 4 5 6 7 8 Sodium Flurbiprofen 3.2 3.2 3.2 3.5 1.5 Carbomer (Carbomer 974P) 1.2 1.2 1.2 2.0 0.8 Polyoxyethylene (20) Cetostearyl Ether 2 / 2 / / Ceteareth-25 / 2 / / / Polyoxyethylene (2) Stearyl Ether / / / 2 / Polyoxyethylene (40) Stearate / / / / 2 Caprylic / Capric / Capric Triglyceride 2.5 2.5 2.5 2.5 2.5 Liquid Paraffin 2.5 2.5 2.5 / / Propylene Glycol 5 5 5 2.5 / Peppermint Oil / / / / 2.5 Sodium Hydroxide ≈0.8 ≈0.8 / / ≈0.9 Calcium Hydroxide / / ≈0.8 ≈0.9 / Isopropyl Alcohol 20 20 20 20 20 Water 62.8 62.8 62.8 66.6 69.8 Total 100 100 100 100 100 Comparative Example Comparative Example 1 / 3 This group of comparative examples provides a flurbiprofen emulsion gel external pharmaceutical composition, and its preparation method comprises: (1) Material preparation: Prepare materials according to Table 3; (2) Flurbiprofen or flurbiprofen sodium was added to 160 g of isopropyl alcohol, 20 g of coconut oil caprylate, 20 g of liquid paraffin, and 40 g of propylene glycol, and stirred and heated at 500 rpm by an OS20-Pro LCD digitally controlled overhead electronic stirrer to dissolve.

[0033] (3) 9.6 g of Carbomer 974P was added to water and fully dispersed. About 7.2 g of sodium hydroxide, a pH adjuster, was used to adjust the pH value to 6.0-7.0. In an IKALR100 controlled reactor, Carbomer 974P aqueous solution and flurbiprofen solution were added. The mixture was emulsified with an IKA AT25 disperser for 10-30 min.

[0034] (4) Cooling down under stirring and filling into an aluminum-plastic composite tube or an aluminum tube at about 32° C. to obtain a latex gel.

[0035] Comparative Example 2 This group of comparative examples provides a flurbiprofen emulsion gel external pharmaceutical composition, and its preparation method comprises: (1) Material preparation: Prepare materials according to Table 3; (2) Add flurbiprofen or flurbiprofen sodium to 160 g of isopropyl alcohol, 20 g of liquid paraffin, and 40 g of propylene glycol, and stir and heat to dissolve using an OS20-Pro LCD digitally controlled overhead electronic stirrer at 500 rpm.

[0036] (3) 9.6 g of Carbomer 974P was added to water and fully dispersed, and the pH value was adjusted to 6.0-7.0 using about 7.2 g of sodium hydroxide as a pH adjuster.

[0037] (4) 16 g of the emulsifier polyoxyethylene (20) cetearyl ether or cetostearyl alcohol polyoxyethylene (25) ether was heated to 70-80° C. in a DF-101S heat-collecting constant temperature heating magnetic stirrer to dissolve, and added to an IKALR100 controlled reactor (which contained an aqueous solution of Carbomer 974P), and then flurbiprofen or flurbiprofen sodium solution was added, and emulsified in an IKAT25 disperser for 20-25 minutes.

[0038] Table 3. Performance testing Detection Methods The following tests were performed on the latex gels obtained in Examples 1-6 and the gels obtained in Comparative Examples 1-3: 1. Viscosity: Brookfield Model D220 viscometer, rotor 95#, speed 100 rpm; specific method: take a sample, use a rotational viscometer to measure the viscosity, the measuring temperature is 32°C, and record the results; The results are shown in Figure 1 , it can be seen that the viscosity of the latex gel prepared in the present application is much greater than that of the comparative example, especially Example 1 is the best. This shows that in the raw material formula of the gel, the selection of the emulsifier and the solubilizer has a great influence on the viscosity of the gel.

[0039] 2. Diffusion study was measured using the RT800 automatic sampling transdermal diffusion system Determination method: Franz diffusion cell method.

[0040] Apparatus: The Franz diffusion cell consists of a supply cell and a receptor cell, separated by a semipermeable membrane in the middle.

[0041] Sample preparation: The hydrogel or gel was evenly applied on the semipermeable membrane and fixed in the diffusion cell.

[0042] Release medium: The pH 7.2 phosphate buffer solution was selected as the receptor solution, and the diffusion cell was placed in an environment with a constant temperature of 32°C ± 1°C. Stirring speed: 300 rpm. Samples were taken at the set time points: 2, 3, 4, 6, 8, and 10 hours. The content of the drug in the receptor solution was analyzed by HPLC, and the release rate and cumulative release amount of the drug were calculated. The measurement temperature was 32°C. The results are shown in Table 4 and Figure 2 .

[0043] Table 4. Cumulative Release Amount (mg) 2h 3h 4h 6h 8h 10h Example 1 0.017 0.026 0.036 0.055 0.078 0.097 Example 2 0.017 0.025 0.034 0.053 0.074 0.091 Example 3 0.017 0.025 0.035 0.053 0.076 0.093 Example 4 0.014 0.022 0.031 0.049 0.071 0.090 Example 5 0.012 0.020 0.029 0.047 0.068 0.087 Example 6 0.012 0.020 0.029 0.046 0.068 0.088 Comparative Example 1 0.021 0.026 0.029 0.032 0.034 0.037 Comparative Example 2 0.021 0.025 0.028 0.031 0.034 0.036 Comparative Example 3 0.020 0.023 0.027 0.029 0.033 0.036 As can be seen from Table 4 and Figure 2 it can be known that the total release amount of the gel agents in Examples 1 - 6 of this application was about 0.091 mg on average in 10 h, and the average release rate was 0.0095 mg / h; while the total release amount of the gel agents in Comparative Examples 1 - 3 was about 0.036 mg on average in 10 h, and the average release rate was 0.0020 mg / h. In terms of the total release amount, the examples were 2.5 times that of the comparative examples, and in terms of the average release rate, the examples were 4.9 times that of the comparative examples. Thus, it can be seen that the gel agent provided in the examples of this application can achieve the purpose of sustained release and achieve the effect of continuous analgesia through the synergistic effect of the emulsifier, solubilizer, and carbomer.

[0044] This specific embodiment is only an interpretation of this application and does not limit this application. After reading this specification, those skilled in the art can make modifications to this embodiment without creative contributions as needed, but as long as it is within the scope of the claims of this application, it is protected by the patent law.

Claims

1. A flurbiprofen emulsion gel external medicinal composition, characterized in that: It is composed of the following raw materials in parts by weight: 0.5-3.5 parts of flurbiprofen or flurbiprofen sodium, 1-5 parts of emulsifier, 2-10 parts of solubilizer, 15-30 parts of isopropyl alcohol, 0.5-2 parts of carbomer, 0.5-2 parts of pH regulator, and 50-70 parts of purified water.

2. The flurbiprofen emulsion-gel external-use pharmaceutical composition according to claim 1, characterized in that: The composition is composed of the following raw materials in parts by weight: 1-3 parts of flurbiprofen or flurbiprofen sodium, 1-3 parts of emulsifier, 5-10 parts of solubilizer, 15-25 parts of isopropyl alcohol, 0.5-1.5 parts of carbomer, 0.6-1.5 parts of pH regulator, and 60-70 parts of purified water.

3. The flurbiprofen emulsion-gel external-use pharmaceutical composition according to claim 1 or 2, characterized in that: The emulsifier includes one or more of polyoxyethylene (20) cetearyl ether, polyoxyethylene (25) cetostearyl alcohol ether, polyoxyethylene (2) stearyl ether, and polyoxyethylene (40) stearate.

4. The flurbiprofen emulsion-gel external-use pharmaceutical composition according to claim 1 or 2, characterized in that: The solubilizer includes one or more of caprylic and capric coconut oil esters, propylene glycol, liquid paraffin, and peppermint oil.

5. The flurbiprofen emulsion-gel external pharmaceutical composition according to claim 1 or 2, characterized in that: The pH adjuster includes one or more of sodium hydroxide, potassium hydroxide, and calcium hydroxide, and the pH adjuster does not contain triethanolamine.

6. The flurbiprofen emulsion-gel external pharmaceutical composition according to claim 1 or 2, characterized in that: The emulsifier is polyoxyethylene (20) cetearyl ether, and the solubilizer is liquid paraffin or caprylic and capric coconut oil esters.

7. A method for preparing the flurbiprofen emulsion-gel external pharmaceutical composition according to any one of claims 1 to 6, characterized in that: It includes: Dissolving the flurbiprofen or flurbiprofen sodium in a solubilizing agent and isopropanol to obtain a solution I; After adding carbomer into water to fully swell, a pH adjuster is used to adjust the pH value to 6.0-8.0 to obtain solution II; After the emulsifier is heated and dissolved, it is added to the solution I, and then the solution I is mixed with the solution II. After emulsification for 10-30 minutes, the temperature is reduced while stirring and the solution is filled.

8. The method for preparing the flurbiprofen emulsion-gel external-use pharmaceutical composition according to claim 7, characterized in that: In the step of heating the solvent of the emulsifier, the heating temperature is 60-80°C.

9. The method for preparing the flurbiprofen emulsion-gel external medicinal composition according to claim 7, characterized in that: During the cooling and filling process under stirring, the temperature drops to 30-35°C and no preservatives need to be added.

10. Use of the flurbiprofen emulsion gel external pharmaceutical composition according to any one of claims 1 to 6 in treating inflammation or pain diseases, characterized in that: The inflammatory or painful diseases include osteoarthritis, degenerative arthritis, scapulohumeral periarthritis, tendinitis, peritenosylvistitis, lateral epicondylitis, muscle pain, and swelling and pain caused by trauma.

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