Indometacin emulsifiable paste and preparation method thereof

Abstract

The invention discloses indometacin emulsifiable paste and a preparation method thereof, and aims to solve the problems that the existing oral indometacin is large in gastrointestinal irritation, and an external preparation is low in solubility, poor in transdermal permeability and insufficient in stability. The emulsifiable paste comprises the following components in parts by weight: an oil-phase matrix consisting of indometacin, dimethyl sulfoxide, liquid paraffin, white vaseline, octadecanol and hexadecanol, and a water-phase matrix consisting of lauryl sodium sulfate, urea and the like. The emulsifiable paste is high in indometacin solubility, excellent in transdermal efficiency, good in stability and free of gastrointestinal tract irritation, is suitable for the elderly, special crowds with hepatic and renal insufficiency and the like, and is suitable for industrialization and clinical application.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to external preparations for treating arthritis, and more particularly to an indometacin cream and a preparation method thereof. BACKGROUND

[0002] Non-steroidal anti-inflammatory drugs are widely used in clinical anti-inflammatory, analgesic, antipyretic drugs, and indometacin as a typical representative of this class of drugs can reduce prostaglandin synthesis by inhibiting cyclooxygenase activity, thereby exerting strong anti-inflammatory and analgesic effects. However, traditional oral indometacin preparations have many limitations in clinical application: after oral administration, the drug will be distributed throughout the body, not only directly stimulating the gastrointestinal mucosa, but also inhibiting the synthesis of prostaglandins with gastric mucosa protective effect, which can easily cause nausea, vomiting, indigestion, and even serious gastrointestinal adverse reactions such as gastric ulcer, bleeding, and perforation. According to the reports of China Pharmacy and related clinical studies, the incidence of gastrointestinal ulcers in patients taking indometacin long-term can reach 25%-30%; at the same time, it may also be accompanied by headache, dizziness, liver and kidney function damage, skin rash and other systemic side effects, which limits the medication of special groups such as elderly patients and patients with liver and kidney dysfunction, and also makes it difficult for patients to adhere to long-term treatment due to these adverse reactions, thereby affecting the control effect of the disease.

[0003] In order to overcome the disadvantages of oral administration, external preparations have become the research direction. By making indometacin into an external cream, local administration through the skin can achieve a high concentration of the drug in the lesion area to directly exert the drug effect, while reducing the amount of drug entering the systemic circulation, thereby reducing the risk of systemic adverse reactions. However, existing external indometacin preparations still face many challenges: indometacin is a poorly soluble drug, with low solubility in both aqueous and ordinary oil phases, making it difficult to form a uniform and stable dispersion system in the cream base, which directly affects the transdermal absorption and efficacy of the drug; moreover, the skin itself is a natural barrier, and the transdermal rate of indometacin is slow through passive diffusion alone, making it difficult to achieve an effective therapeutic concentration in a short time; in addition, some formulations may also have stability problems such as delamination, crystallization, and color change due to compatibility or process problems, which adversely affect the product quality and shelf life.

[0004] Therefore, it is of great clinical significance and market value to develop a new type of external compound preparation that can effectively solve the problems of low solubility, poor transdermal absorption, and insufficient stability of indometacin, while maintaining its strong anti-inflammatory and analgesic effects. The present application is based on this. SUMMARY

[0005] The present application aims to provide an indometacin cream with high solubility, good transdermal absorption, and high stability; and another object of the present application is to provide a preparation method of the indometacin cream.

[0006] In order to solve the problems in the background art and achieve the above-mentioned object, the present application adopts the following technical scheme: The present application discloses an indomethacin cream, which is prepared from active ingredient indomethacin, solvent, oil phase matrix and water phase matrix.

[0007] Further, the solvent is dimethyl sulfoxide.

[0008] Further, the oil phase matrix comprises one or more of liquid paraffin, white vaseline, octadecanol and cetyl alcohol.

[0009] Further, the water phase matrix comprises one or more of sodium dodecyl sulfate, urea, glycerol and hydroxyphenyl ethyl ester.

[0010] Further, the indomethacin cream comprises the following components by weight: Active ingredient: indomethacin 35-45 parts; Solvent: dimethyl sulfoxide 60-75 parts; Oil phase matrix: liquid paraffin 50-60 parts, white vaseline 40-50 parts, octadecanol 50-55 parts, and cetyl alcohol 25-30 parts; Water phase matrix: sodium dodecyl sulfate 8-12 parts, urea 30-40 parts, glycerol 45-55 parts, and hydroxyphenyl ethyl ester 1.5-2.5 parts; The balance is purified water, and the total weight of the components is 1000 parts; The pH value of the indomethacin cream is 5.5-7.0.

[0011] Further, the indomethacin cream comprises the following components by weight: Active ingredient: indomethacin 40 parts; Solvent: dimethyl sulfoxide 67 parts; Oil phase matrix: liquid paraffin 55 parts, white vaseline 45 parts, octadecanol 52 parts, and cetyl alcohol 28 parts; Water phase matrix: sodium dodecyl sulfate 10 parts, urea 35 parts, glycerol 50 parts, and hydroxyphenyl ethyl ester 2 parts; The balance is purified water, and the total weight of the components is 1000 parts.

[0012] Further, the water phase matrix further comprises 1-3 parts of azone.

[0013] The present application also discloses a preparation method of the indomethacin cream, which comprises the following steps: (1) Oil phase preparation: octadecanol, cetyl alcohol, white vaseline and liquid paraffin are added into an oil phase dissolving pot, heated and stirred to obtain an oil phase; (2) Water phase preparation: purified water was added to the water phase kettle, and sodium dodecyl sulfate, urea, glycerol, and hydroxyphenyl ethyl ester were sequentially added and stirred until completely dissolved to obtain the water phase; (3) Indometacin dissolution: indometacin was dissolved in dimethyl sulfoxide to obtain an indometacin solution; (4) Emulsification: the emulsification kettle was vacuumed, and the oil phase of step (1) and the water phase of step (2) were sequentially drawn into the emulsification kettle, stirring was started, and the indometacin solution of step (3) was added and stirred; (5) Homogenization: the material of step (4) was homogenized under vacuum, and the homogenization speed was 1800-2200 rpm; (6) Cooling and discharging: the material after step (5) was cooled and discharged for inspection; (7) Filling: filling was performed according to the set filling parameters to obtain the finished indometacin cream.

[0014] Further, the oil phase dissolution kettle of step (1) was heated to 80±2℃, stirred at a speed of 800-1000 rpm and kept for 25-35 minutes to obtain the oil phase.

[0015] Further, step (2) water phase preparation: purified water was added to the water phase kettle, heated to 80±2℃, and sodium dodecyl sulfate, urea, glycerol, and hydroxyphenyl ethyl ester were sequentially added and stirred until completely dissolved and kept to obtain the water phase.

[0016] Further, step (4) emulsification: the emulsification kettle was vacuumed to -0.04MPa to -0.06MPa, the oil phase of step (1) and the water phase of step (2) were sequentially drawn into the emulsification kettle through a screen, stirring was started at a speed of 60-70 rpm, the indometacin solution of step (3) was added, and stirring was kept at 80±2℃ for 25-35 minutes under vacuum; Further, the homogenization of step (5) was twice, each time at a speed of 2000 rpm, and each time for 10 minutes.

[0017] The indometacin cream and the preparation method thereof of the present application realize multi-dimensional optimization while retaining the potent anti-inflammatory and analgesic core efficacy of indometacin: relying on the high solubility of dimethyl sulfoxide to indometacin and the penetration-promoting effect of urea, the drug can quickly reach an effective therapeutic concentration in the local skin, directly acting on the lesion, and the anti-inflammatory and analgesic effect is equivalent to that of oral preparations and takes effect faster, which can timely relieve local discomfort caused by rheumatoid arthritis, osteoarthritis and the like; the use of external preparations completely avoids the stimulation of oral administration to the gastrointestinal tract and the potential damage to liver and kidney function, greatly improves the medication safety of special populations such as the elderly and patients with insufficient liver and kidney function, and improves the long-term medication compliance; the optimized oil phase, water phase composition and twice homogenization process enable the cream to form a stable emulsion system, in the stability test, the appearance is uniform, there is no delamination or crystallization, the drug content and pH value are stable, meeting the industrialization and clinical use requirements; at the same time, the cream has a delicate texture, is easy to spread, has no greasy feeling after application and is quickly absorbed, the base has a moisturizing effect, improving the use comfort, and the overall advantages in efficacy, safety, stability and experience, the clinical and market value are outstanding. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 : Stability accelerated test of indometacin content change curve. DETAILED DESCRIPTION

[0019] The present application will be further described below by examples, but the protection scope of the present application is not limited by the examples.

[0020] Example 1: Indometacin cream 1. Prescription composition (by weight) Active ingredient: indometacin 40 parts Solvent: dimethyl sulfoxide 67 parts Oil phase base: liquid paraffin 55 parts, white vaseline 45 parts, octadecanol 52 parts, cetyl alcohol 28 parts Water phase base: sodium dodecyl sulfate 10 parts, urea 35 parts, glycerol 50 parts, hydroxyphenyl ethyl ester 2 parts Purified water: 655 parts 2. Preparation method (1) Oil phase preparation: add the oil phase base (liquid paraffin 55 parts, white vaseline 45 parts, octadecanol 52 parts, cetyl alcohol 28 parts) into the oil phase dissolving pot, start heating to 80℃, stir at a speed of 900 rpm, and keep the temperature for 30 minutes to ensure that all the solid bases are completely dissolved, to obtain a clear and transparent oil phase; (2) Water phase preparation: add purified water 655 parts into the water phase pot, heat to 80℃, and then add the water phase base (sodium dodecyl sulfate 10 parts, urea 35 parts, glycerol 50 parts, hydroxyphenyl ethyl ester 2 parts) in sequence, stir at a speed of 900 rpm until all the components are completely dissolved, to obtain a clear water phase; (3) Indometacin dissolving: Indometacin 40 parts was added into dimethyl sulfoxide 67 parts, stirred at room temperature for 15 minutes until indometacin was completely dissolved to obtain a uniform indometacin solution; (4) Emulsification: The emulsification kettle was vacuumed to -0.05 MPa, the oil phase of step (1) and the water phase of step (2) were successively sucked into the emulsification kettle through a 120 mesh sieve, stirring was started (rotation speed 65 revolutions / minute), then the indometacin solution of step (3) was slowly added, and the temperature was kept at 80°C for 30 minutes, and the vacuum state was maintained throughout the process; (5) Homogenization: under vacuum, the homogenizer was started at a rotation speed of 2000 revolutions / minute for the first homogenization, which lasted for 10 minutes; after emulsification, the same rotation speed of 2000 revolutions / minute was used for the second homogenization, which lasted for 10 minutes, to ensure that the material formed a uniform emulsion; (6) Cooling and discharging: the heating was turned off, the material was naturally cooled to 35°C, and then discharged into a sterile stainless steel container for on-site sampling and inspection; (7) Filling: according to the "NF-80A full-automatic soft tube filling and tail sealing machine standard operating procedures", the filling temperature was set to 500°C, the filling amount control scale was set to 340, the filling speed was set to 60 per minute, the control of single filling amount was ≥ 93% of the marked amount, and the finished product was obtained.

[0021] 3. Product characterization Appearance and pH value: white and uniform cream, pH = 6.2, which meets the requirements.

[0022] Example 2: Optimized formula of indometacin cream containing azone 1. Prescription composition (by weight) Active ingredient: indometacin 40 parts; Solvent: dimethyl sulfoxide 67 parts; Oil phase matrix: liquid paraffin 55 parts, white vaseline 45 parts, octadecanol 52 parts, hexadecanol 28 parts; Water phase matrix: sodium dodecyl sulfate 10 parts, urea 35 parts, glycerol 50 parts, hydroxyphenyl ethyl ester 2 parts, azone 2 parts; Purified water: 653 parts.

[0023] 2. Preparation method Steps (1)-(7) are basically the same as in Example 1, except that in step (2) of water phase preparation, azone 2 parts and urea 35 parts are added together into the water phase kettle, and the remaining operation conditions are unchanged.

[0024] 3. Product characterization Appearance and pH value: white and uniform cream, pH = 6.1, which meets the requirements.

[0025] Example 3: Indometacin cream 1. Formulation composition (by weight) Active ingredient: indomethacin 35 parts; Solvent: dimethyl sulfoxide 60 parts; Oil phase base: liquid paraffin 50 parts, white vaseline 40 parts, octadecanol 50 parts, cetyl alcohol 25 parts; Water phase base: sodium lauryl sulfate 8 parts, urea 30 parts, glycerin 45 parts, hydroxyphenyl ethyl ester 1.5 parts; Purified water: 675.5 parts.

[0026] 2. Preparation method (1) Oil phase preparation: heated to 78°C, stirring speed 800 rpm, 25 minutes; (2) Water phase preparation: heated to 78°C, stirring speed 800 rpm, 25 minutes; (3)-(7) Same as Example 1, wherein the emulsification vacuum is -0.04 MPa, the homogenization speed is 2000 rpm, and each time is 10 minutes.

[0027] 3. Product characterization Appearance: white uniform cream, no stratification; pH value: 5.8, meets the requirements; Example 4: indomethacin cream 1. Formulation composition (by weight) Active ingredient: indomethacin 45 parts; Solvent: dimethyl sulfoxide 75 parts; Oil phase base: liquid paraffin 60 parts, white vaseline 50 parts, octadecanol 55 parts, cetyl alcohol 30 parts; Water phase base: sodium lauryl sulfate 12 parts, urea 40 parts, glycerin 55 parts, hydroxyphenyl ethyl ester 2.5 parts; Purified water: 575.5 parts.

[0028] 2. Preparation method (1) Oil phase preparation: heated to 82°C (upper limit of 80±2°C), stirring speed 1000 rpm, 35 minutes; (2) Water phase preparation: heated to 82°C, stirring speed 1000 rpm, 35 minutes; (3)-(7) Same as Example 1, wherein the emulsification vacuum is -0.06 MPa (upper limit), the homogenization speed is 2000 rpm, and each time is 10 minutes.

[0029] 3. Product characterization Appearance: white uniform cream, slightly thick but easy to spread; pH value: 6.8, meets the requirements; Comparative Example 1: Dimethyl sulfoxide is replaced with water, and the rest of the formulation and preparation method are the same as in Example 1.

[0030] Comparative Example 2: Nitrogen ketone in Example 2 is cancelled, and the rest of the formulation and preparation method are the same as in Example 2.

[0031] Comparative Example 3: Replace "octadecanol 52 parts + hexadecanol 28 parts" in the oil phase with an equal amount of glyceryl monostearate (80 parts), and the rest of the components and weight parts remain unchanged; the preparation method is the same as in Example 1.

[0032] Comparative Example 4: The formulation and Example 1 are the same; in the preparation process, replace "two homogenizations (2000 rpm each time, 10 minutes)" with "one homogenization (2000 rpm, 20 minutes)", and the rest of the process remains unchanged and is the same as in Example 1.

[0033] Test: (I) Solubility test (for Comparative Example 1, to verify the necessity of DMSO for solubility) 1. Test purpose To verify the effect of dimethyl sulfoxide on the solubility of indometacin in the cream base.

[0034] 2. Test method Take 10g of the cream of Example 1 and the cream of Comparative Example 1, respectively, add 50mL of purified water, and ultrasonically extract for 30 minutes, then filter with a 0.22μm filter membrane; Determine the concentration of indometacin in the filtrate by high performance liquid chromatography (HPLC) method, and calculate the solubility of indometacin in the cream base (mg / mL).

[0035] 3. Test results Sample Indometacin solubility (mg / mL) Solubility qualification criteria (> 5 mg / mL) Result determination Example 1 12.3 Yes Pass Comparative Example 1 1.8 No Fail 4. Conclusion Dimethyl sulfoxide can significantly improve the solubility of indometacin in the cream base, and is the key component to solve the problem of poor solubility of indometacin; without DMSO, the solubility of indometacin is far below the required concentration for effective treatment, and cannot meet the efficacy requirements.

[0036] (II) Transdermal absorption test (for Comparative Example 2, to verify the necessity of azone for penetration) 1. Test purpose To verify the effect of azone on the transdermal rate of indometacin and solve the problem of poor transdermal absorption in the prior art.

[0037] 2. Test method Franz diffusion cell method, fresh pig skin (hair removal, subcutaneous fat peeling, thickness 0.3-0.5mm) as transdermal medium, receiving pool is normal saline (containing 5% ethanol), temperature 32℃±0.5℃, stirring speed 300r / min; 0.5g of the cream of Example 2 and the cream of Comparative Example 2, respectively, were evenly applied to the surface of the keratin layer of pig skin (effective diffusion area 2.83cm²); 5mL of samples were taken at 1h, 2h, 4h, 6h, 8h, 12h, 24h (while adding an equal amount of fresh receiving liquid), the concentration of indomethacin in the receiving liquid was determined by HPLC method, and the cumulative transdermal amount (μg / cm²) and transdermal rate (μg / (cm²·h)) were calculated.

[0038] 3. Test results Sample 24 h cumulative transdermal amount (μg / cm²) Transdermal rate (μg / (cm²-h)) Example 2 8.6 0.36 Comparative Example 2 5.3 0.22 4. Conclusion Azones can significantly improve the transdermal efficiency of indomethacin, and the transdermal rate is increased by more than 60%; without azones, the drug is difficult to effectively penetrate the skin barrier, and cannot reach an effective therapeutic concentration in the lesion site, verifying the necessity of azones as a penetration enhancer.

[0039] (III) Stability test (6-month accelerated test) 1. Test purpose To verify the 6-month accelerated stability of Example 1-Example 4 and Comparative Example 3 and Comparative Example 4.

[0040] 2. Test method Accelerated stability test: place the creams of Example 1-Example 4, Comparative Example 3, and Comparative Example 4 in a constant temperature and humidity box at 40℃±2℃ and 75%±5% relative humidity for 6 months, and take samples at 0 months, 1 month, 2 months, 3 months, and 6 months. The content of indomethacin (HPLC method) and centrifugal stability (3000r / min, 30min) are determined. 3. Test results: The content change curve of the 6-month accelerated test is shown in Figure 1 ; Sample Appearance pH change (0 month -> 6 month) Indometacin content retention rate (%) Centrifugal stability Example 1 Uniform cream, no delamination or crystallization 6.2→6.0 97.7 No delamination Example 2 Uniform cream, no delamination or crystallization 6.1-6.0 97.8 No delamination Example 3 Uniform cream, no delamination or crystallization 5.8-5.7 97.8 No delamination Example 4 Uniform cream, no delamination or crystallization 6.0-5.9 96.5 No delamination Comparative Example 3 Delamination occurred, lower layer was turbid 6.2→5.5 92.5 Obvious delamination Comparative Example 4 Slight crystallization, uneven texture 6.2→5.8 94.9 Slight delamination 4. Conclusion: The oil phase combination of "octadecanol + hexadecanol" in the example can form a stable emulsion system with the water phase. After replacing it with glyceryl monostearate in Comparative Example 3, the cream is easily layered and the content decreases significantly, verifying the necessity of the specific oil phase combination. The "two homogenization" process in the example can ensure uniform particle size of the cream (D90=5.2μm). After changing to one homogenization in Comparative Example 4, the particle size increases (D90=12.8μm) and is prone to crystallization and layering, verifying the necessity of the two homogenization process.

[0041] The above embodiments are only used to illustrate the technical solutions of the present application, rather than limit them. Even though the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can be made to the technical solutions described in the foregoing embodiments, or some or all of the technical features therein can be replaced by equivalent features; and these modifications or replacements do not cause the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. An indomethacin cream, characterized in that, It is prepared from an active ingredient indomethacin, a solvent, an oil phase matrix, and an aqueous phase matrix.

2. The indomethacin cream according to claim 1, characterized in that, The solvent is dimethyl sulfoxide.

3. The indomethacin cream according to claim 1, characterized in that, The oil phase matrix includes one or more of liquid paraffin, white petrolatum, octadecanol, and cetyl alcohol.

4. An indomethacin cream according to claim 1, characterized in that, The aqueous matrix comprises one or more of sodium dodecyl sulfate, urea, glycerol, and ethylparaben.

5. The indomethacin cream according to any one of claims 1-4, characterized in that, By weight, it contains the following components: Active ingredient: Indomethacin 35-45 parts; Solvent: 60-75 parts of dimethyl sulfoxide; Oil phase matrix: 50-60 parts liquid paraffin, 40-50 parts white petrolatum, 50-55 parts octadecyl alcohol, 25-30 parts cetyl alcohol; Aqueous matrix: 8-12 parts sodium dodecyl sulfate, 30-40 parts urea, 45-55 parts glycerol, 1.5-2.5 parts ethylparaben; The remainder is purified water, making the total weight of all components 1000 parts; The pH value of the indomethacin cream is 5.5-7.

0.

6. An indomethacin cream according to claim 5, characterized in that, The aqueous matrix also contains 1-3 parts of nitrogen ketone.

7. An indomethacin cream according to claim 6, characterized in that, By weight, it includes the following components: Active ingredient: Indomethacin 40 parts; Solvent: 67 parts dimethyl sulfoxide; Oil phase matrix: 55 parts liquid paraffin, 45 parts white petrolatum, 52 parts octadecanol, and 28 parts hexadecyl alcohol; Aqueous matrix: 10 parts sodium dodecyl sulfate, 35 parts urea, 50 parts glycerol, 2 parts ethylparaben, 2 parts azone; The remainder is purified water, making the total weight of all components 1000 parts.

8. The method for preparing an indomethacin cream according to claim 5, characterized in that, Includes the following steps: (1) Preparation of oil phase: The oil phase matrix is ​​added to the oil phase dissolving pot, heated and stirred to obtain the oil phase; (2) Preparation of aqueous phase: Add purified water to the aqueous phase pot, add the aqueous phase matrix in sequence, and stir until completely dissolved to obtain the aqueous phase; (3) Indomethacin dissolution: Indomethacin is dissolved in dimethyl sulfoxide to obtain an indomethacin solution; (4) Emulsification: Vacuum the emulsification pot and pump the oil phase from step (1) and the aqueous phase from step (2) into the emulsification pot one after another. Start stirring and then add the indomethacin solution from step (3) and stir. (5) Homogenization: The material from step (4) is homogenized under vacuum. (6) Cooling and discharge: After cooling the material processed in step (5), discharge and inspect it; (7) Filling: Fill according to the set filling parameters to obtain the finished indomethacin cream.

9. The method for preparing an indomethacin cream according to claim 8, characterized in that, The homogenization process described in step (5) is two homogenizations, with a rotation speed of 2000 rpm for each homogenization and a homogenization time of 10 minutes.

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