Ketorolac tromethamine gel and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to ketorolac tromethamine gel and a preparation method thereof, and the ketorolac tromethamine gel comprises the following components: 0.1-20% of ketorolac tromethamine, 0.5-20% of a film forming matrix, 0.001-5% of vitamin E, 0.1-5% of povidone, 5-80% of an organic solvent and the balance of water; through combined use of povidone and vitamin E, the ketorolac tromethamine gel has better chemical stability, better crystal inhibition effect, better permeation amount and permeation rate, better adhesiveness and longest skin retention time.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and particularly to a tromethamine ketorolac gel and a preparation method thereof. Background Art

[0002] Tromethamine ketorolac is a non-steroidal antipyretic and analgesic drug, which inhibits the synthesis of prostaglandins by being converted into ketorolac in vivo to achieve the effect of anti-inflammatory and analgesic. Currently, there are already marketed dosage forms such as injections, eye drops, tablets, gels, nasal sprays, etc. However, in actual clinical applications, tromethamine ketorolac tablets have strong gastrointestinal side effects, which may cause bleeding and perforation; the injection has a short drug half-life (4 - 6h) and requires repeated injections; the nasal spray is highly irritating and the nasal mucosa is relatively fragile; while topical application of tromethamine ketorolac can not only effectively increase the drug concentration in the target tissue, but also avoid the gastrointestinal side effects of oral administration and reduce the systemic exposure.

[0003] Currently, there have been clinical trial reports (NCT02638831) on the use of tromethamine ketorolac gel for the treatment of knee diseases and low back pain. However, the simple gel has defects such as being easily wiped off by clothes during application, short residence time, and high dosing frequency, and cannot meet the clinical needs of long-term medication for patients with chronic pain.

[0004] In addition, tromethamine ketorolac has poor chemical stability, and it is easy to form esters with hydroxyl-containing excipients during the production and storage of the preparation to generate esterification impurities, or degrade through oxidation to generate new impurities, ultimately resulting in a decrease in the content of the active ingredient in the drug.

[0005] Therefore, providing a film-forming gel of tromethamine ketorolac with good stability and transdermal effect is an urgent technical problem to be solved in the field. Summary of the Invention

[0006] The present invention aims to provide a tromethamine ketorolac gel with good stability, adhesion performance and transdermal effect. The tromethamine ketorolac gel comprises the following components: tromethamine ketorolac 0.1 - 20%, film-forming matrix 0.5 - 20%, vitamin E 0.001 - 5%, polyvinylpyrrolidone 0.1 - 5%, organic solvent 5 - 80%, and the balance is water.

[0007] In some embodiments, the film-forming matrix is selected from one or more of polyvinyl alcohol, hydroxypropyl cellulose, amylopectin, polyvinylpyrrolidone, gelatin, pectin, hydroxyethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer and polyethylene.

[0008] In some embodiments, the film-forming matrix is selected from one or more of polyvinyl alcohol, sodium carboxymethyl cellulose, and ethyl cellulose.

[0009] Preferably, the polyvinyl alcohol is selected from one or more of polyvinyl alcohol PVA 03-88, polyvinyl alcohol PVA 03-99, polyvinyl alcohol PVA 05-88, polyvinyl alcohol PVA 05-99, polyvinyl alcohol PVA 17-88, polyvinyl alcohol PVA 17-99, polyvinyl alcohol PVA 20-88, polyvinyl alcohol PVA 20-99, polyvinyl alcohol PVA 24-88, and polyvinyl alcohol PVA 24-99; more preferably, the polyvinyl alcohol is selected from one or more of polyvinyl alcohol PVA 17-88 and polyvinyl alcohol PVA 17-99.

[0010] Preferably, the ethyl cellulose is selected from ethyl cellulose N7, ethyl cellulose N10, ethyl cellulose N14, ethyl cellulose N22, ethyl cellulose N50, ethyl cellulose N100, and ethyl cellulose T10. More preferably, the ethyl cellulose is selected from one or more of ethyl cellulose N10 and ethyl cellulose T10.

[0011] In some embodiments, the povidone is selected from povidone K90.

[0012] In some embodiments, the organic solvent is ethanol and / or isopropanol.

[0013] In some embodiments, the ketorolac tromethamine gel further comprises 0-5% of a plasticizer.

[0014] Preferably, the plasticizer is selected from one or several of propylene glycol, glycerol, tributyl citrate, triethyl citrate, triethanolamine, tributyl acetyl citrate, triethyl acetyl citrate, chlorobutanol, dibutyl phthalate, diethyl butyrate, dimethyl phthalate, glycerol monostearate, lanolin alcohol, and polyethylene glycol.

[0015] In some embodiments, the ketorolac tromethamine gel comprises the following components: 0.5-10% of ketorolac tromethamine, 2-10% of a film-forming matrix, 0.1-2% of vitamin E, 0.5-2% of povidone, 0-3% of a plasticizer, 10-30% of an organic solvent, and the balance being water.

[0016] Preferably, the ketorolac tromethamine gel comprises the following components: 0.8-5% of ketorolac tromethamine, 3-5% of a film-forming matrix, 0.15-1% of vitamin E, 0.8-1.5% of povidone, 0-2% of a plasticizer, 15-25% of an organic solvent, and the balance being water.

[0017] On the other hand, this method provides a preparation method of a ketorolac tromethamine gel, comprising the following steps:

[0018] Step 1: Dissolve ketorolac tromethamine and the film-forming matrix in water to obtain the first mixture;

[0019] Step 2: Dissolve povidone, plasticizer, and vitamin in an organic solvent to obtain the second mixture;

[0020] Step 3: Mix the second mixture with the first mixture.

[0021] The present invention has the following advantages:

[0022] 1. The ketorolac tromethamine gel prepared by combining povidone and vitamin E can achieve better chemical stability;

[0023] 2. The ketorolac tromethamine gel prepared by combining povidone and vitamin E can achieve better crystal inhibition effect;

[0024] 3. The ketorolac tromethamine gel prepared by combining povidone and vitamin E has the largest penetration amount and the fastest penetration rate compared with other samples;

[0025] 4. The ketorolac tromethamine gel prepared by combining povidone and vitamin E has better adhesiveness and the longest skin retention time compared with other samples;

[0026] 5. By adding polyvinyl alcohol film-forming gel matrix, the ketorolac tromethamine gel can quickly form a film-like gel during use, and can adhere to the application site for a longer time compared with ordinary gel preparations, so as to achieve the purpose of long-acting drug release. Description of the Drawings

[0027] Appendix Figure 1 It is a comparison chart of the cumulative penetration amount per unit area of the ketorolac tromethamine gel prepared in Examples 1-4. Detailed Embodiments

[0028] In the following description, many specific details are set forth in order to fully understand the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the description of the present invention are only for the purpose of describing specific embodiments, and are not intended to limit the present invention.

[0030] Preparation of the ketorolac tromethamine gel of Examples 1-4

[0031] Table 1 Prescription table of Examples 1-4

[0032]

[0033] Preparation method:

[0034] 1. Phase A: Add 50 parts of purified water into a beaker, and then sequentially add 1 part of tromethamine ketorolac, 3 parts of polyvinyl alcohol 17-88, and 0.5 part of sodium carboxymethylcellulose, and stir at 65 °C until the solution is clear.

[0035] 2. Phase B: Add 20 parts of absolute ethanol into a beaker, and then sequentially add 1 part of povidone K90, 0.5 part of ethylcellulose, 1 part of propylene glycol, and 0.2 part of tocopherol, and stir at room temperature until the solution is clear.

[0036] 3. Mixing: Slowly add Phase B into the beaker of Phase A while stirring, and make up the remaining purified water to a total of 100 parts, and continue stirring until the temperature is the same as room temperature.

[0037] Example 5 Stability experiment

[0038] Use high performance liquid chromatography to determine the change of oxidation impurities in each sample after investigation under the condition of high temperature of 50 °C.

[0039] The main conditions of liquid chromatography are as follows:

[0040] Mobile phase: 0.05 mol / L ammonium dihydrogen phosphate solution (adjust the pH value to 3.0 with phosphoric acid) - tetrahydrofuran (70:30)

[0041] Chromatographic column: ZORBOX SB-C18, 4.6 * 250 mm, 5 μm

[0042] Flow rate: 1.0 ml / min

[0043] Column temperature: 40 °C

[0044] Wavelength: 313 nm.

[0045] Table 2 Stability data of Examples 1-4

[0046]

[0047] Table 2 results show that the film-forming gels added with antioxidant tocopherol (Example 2, Example 4) generated fewer oxidation impurities under high-temperature conditions. We surprisingly found that the film-forming gel added with crystal inhibitor povidone K90 (Example 3) generated fewer oxidation impurities under high-temperature conditions compared to the film-forming gel without the crystal inhibitor povidone K90 (Example 1), while the film-forming gel added with both povidone K90 and tocopherol (Example 4) generated the fewest oxidation impurities under high-temperature conditions, indicating that the combined use of povidone K90 and tocopherol can achieve a better effect of improving the chemical stability of tromethamine ketorolac.

[0048] Drug crystallization experiment of Example 6

[0049] Take about 0.1 g of each sample of the examples and place them on a glass slide, and use a cotton swab to evenly apply them within a range of 1 cm 2 . Let it stand for about 5 min. After the gel is completely dried and formed into a film, observe under a microscope whether there is drug crystallization.

[0050] Crystallization situation of Examples 1-4 in Table 3

[0051] Example Drug crystallization Example 1 Mass crystallization Example 2 Mass crystallization Example 3 Minor crystallization Example 4 No crystallization

[0052] The results show that the film-forming gels added with the crystal inhibitor povidone K90 (Example 3, Example 4) crystallized less after drying; at the same time, we surprisingly found that the film-forming gel added with the crystal inhibitor povidone K90 and antioxidant tocopherol (Example 4) did not precipitate the drug at all after drying compared to other samples, indicating that the combined use of povidone K90 and tocopherol can achieve a better crystal inhibition effect.

[0053] Transdermal experiment of Example 7

[0054] Turn the horny layer of the abdominal skin of the Bama mini-pig upward, place a mold ring with an inner diameter of 15 mm and a thickness of 0.6 mm on the pig skin, coat the above samples of the examples into the mold ring respectively, level it with a flat plate, and after naturally drying and forming a film at room temperature, take out the mold ring and cut off the excess edges. Fix the pig skin on a Franz vertical diffusion cell with an effective area of 1.77 cm 2 . The receiving solution is a phosphate buffer solution with a pH of 7.4, the temperature is (32 ± 0.5) °C, and it is stirred at a constant speed. Samples are taken from the receiving pool at 0, 2, 4, 6, 8, 12, and 24 h to detect the concentration of tromethamine ketorolac in the receiving solution, and calculate the cumulative permeation rate and the cumulative permeation amount per unit area.

[0055] The results are as shown in the appendix Figure 1 The cumulative permeation rate of Example 1 is 4.83 ± 0.6 μg / (cm 2 ·h); the cumulative permeation rate of Example 2 is 5.06 ± 0.9 μg / (cm 2· h); The cumulative permeation rate of Example 3 was 10.75 ± 2.3 μg / (cm 2 · h); The cumulative permeation rate of Example 4 was 12.71 ± 3.1 μg / (cm 2 · h). The results showed that the cumulative permeation amount per unit area and the permeation rate of the drug were closely related to whether crystallization occurred during use. After the drug crystallized, its diffusion thermodynamic activity decreased significantly. The film-forming gels (Example 3 and Example 4) added with the crystallization inhibitor povidone K90 had a faster cumulative permeation rate per unit area and a larger cumulative permeation amount; the film-forming gel (Example 4) added with both the crystallization inhibitor povidone K90 and the antioxidant tocopherol showed the largest permeation amount and the fastest permeation rate compared with other samples (P < 0.05).

[0056] Investigation on the skin adhesion performance, erosion status and residence time of Example 8

[0057] Thirty-two experimental rats were randomly divided into 4 groups, with 8 rats in each group. The four limbs of the rats were fixed, the hair on one side of the ankle joint of the rats was cut off, and the fine hair on the surface was shaved off with a razor, disinfected with alcohol, and after drying, the gel samples prepared in the 4 examples were respectively applied to the treated skin in a thin layer. After waiting for the sample to dry and form a film, the hind limb on the drug administration side of the rat was loosened to enable it to move freely. The adhesion performance of the film and the residence time on the skin (counted by the disappearance of 1 / 2 of the film area) were observed, and the results are shown in Table 4 below.

[0058] The results showed that the adhesion and skin residence time of the film-forming gel were closely related to whether crystallization occurred during use. Drug crystallization would destroy the original dense polymer network structure. The film-forming gels (Example 3 and Example 4) added with the crystallization inhibitor povidone K90 had better adhesion and longer skin residence time; the film-forming gel (Example 4) added with both the crystallization inhibitor povidone K90 and the antioxidant tocopherol showed the best adhesion and the longest skin residence time compared with other samples.

[0059] Table 4 Investigation results of the skin adhesion performance, erosion status and residence time of Examples 1 - 4

[0060]

Claims

1. A ketorolac tromethamine gel, characterized in that The ketorolac tromethamine gel comprises the following components: 0.1-20% of ketorolac tromethamine, 0.5-20% of film-forming matrix, 0.001-5% of vitamin E, 0.1-5% of povidone, 5-80% of organic solvent, and the balance is water.

2. The ketorolac tromethamine gel according to claim 1, characterized in that The film-forming matrix is ​​selected from one or more of polyvinyl alcohol, hydroxypropyl cellulose, pullulan, polyvinyl pyrrolidone, gelatin, pectin, hydroxyethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer and polyethylene.

3. The ketorolac tromethamine gel according to claim 2, characterized in that The film-forming matrix is ​​selected from one or more of polyvinyl alcohol, sodium carboxymethyl cellulose and ethyl cellulose.

4. The ketorolac tromethamine gel according to claim 3, characterized in that The film-forming matrix is ​​selected from one or more of polyvinyl alcohol PVA17-88, polyvinyl alcohol PVA17-99, sodium carboxymethyl cellulose, ethyl cellulose N10, and ethyl cellulose T10.

5. The ketorolac tromethamine gel according to claim 1, characterized in that The povidone is selected from povidone K90.

6. The ketorolac tromethamine gel according to claim 1, characterized in that The organic solvent is ethanol and / or isopropanol.

7. The ketorolac tromethamine gel according to any one of claims 1 to 6, characterized in that The ketorolac tromethamine gel also includes 0-5% of a plasticizer.

8. The ketorolac tromethamine gel according to claim 7, characterized in that The plasticizer is selected from one or more of propylene glycol, glycerol, tributyl citrate, triethyl citrate, triethanolamine, acetyl tributyl citrate, acetyl triethyl citrate, chlorobutanol, dibutyl phthalate, diethyl butyrate, dimethyl phthalate, glyceryl monostearate, lanolin alcohol, and polyethylene glycol.

9. The ketorolac tromethamine gel according to any one of claims 1 to 8, characterized in that The ketorolac tromethamine gel comprises the following components: 0.5-10% of ketorolac tromethamine, 2-10% of film-forming matrix, 0.1-2% of vitamin E, 0.5-2% of povidone, 0-3% of plasticizer, 10-30% of organic solvent, and the balance is water.

10. The ketorolac tromethamine gel according to claim 9, characterized in that The ketorolac tromethamine gel comprises the following components: 0.8-5% of ketorolac tromethamine, 3-5% of film-forming matrix, 0.15-1% of vitamin E, 0.8-1.5% of povidone, 0-2% of plasticizer, 15-25% of organic solvent, and the balance is water.

11. A method for preparing the ketorolac gel according to any one of claims 1 to 10, comprising the following steps: Step 1: dissolving ketorolac tromethamine and a film-forming matrix in water to obtain a first mixture; Step 2: dissolving povidone, plasticizer and vitamin in an organic solvent to obtain a second mixture; Step 3: Mix the second mixture with the first mixture.

Images