Mepivacaine hydrochloride aqueous gel and preparation method thereof

Abstract

The invention relates to a mepivacaine hydrochloride aqueous gel and a preparation method thereof, and belongs to the field of pharmaceutical preparation production, the mepivacaine hydrochloride aqueous gel comprises the following substances by mass: 2.0% of mepivacaine hydrochloride, 0.1-12.5% of a thickener, 10.0% of a humectant, 5.0% of a penetration enhancer, 0.1% of a preservative, 0.02% of a synergistic preservative, and the balance purified water. According to the invention, mepivacaine hydrochloride is prepared into a hydrogel dosage form, so that mepivacaine hydrochloride can be directly smeared on corresponding local skin without puncturing blood vessels during local skin anesthesia until the mepivacaine hydrochloride permeates into capillary vessels of the skin, thereby reducing the influence of local anesthesia operation on a patient and improving the adaptability of the patient to local anesthesia; meanwhile, the water-based gel can be better absorbed by the skin.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparation production, and specifically relates to a mepivacaine hydrochloride aqueous gel and a preparation method thereof. Background Art

[0002] Mepivacaine hydrochloride is a relatively common local anesthetic at present. It has been widely promoted and applied because of its low cost and relatively low toxicity. However, the current mepivacaine hydrochloride is all in the form of injection. When used, it is mainly injected into the human body through a syringe puncturing a blood vessel. For some patients with needle phobia and patients with low pain tolerance such as children, the injection form of mepivacaine hydrochloride may have a certain impact on them. Therefore, there is a need for a mepivacaine hydrochloride dosage form for local anesthesia without puncturing blood vessels. Summary of the Invention

[0003] The present invention provides a mepivacaine hydrochloride aqueous gel and a preparation method thereof to solve the defects in the prior art.

[0004] The present invention is achieved through the following technical solutions:

[0005] A mepivacaine hydrochloride aqueous gel, comprising the following substances in mass percentages: mepivacaine hydrochloride 2.0%, thickening agent 0.1% - 12.5%, humectant 10.0%, penetration enhancer 5.0%, preservative 0.1%, co-preservative 0.02%, and the balance being purified water.

[0006] For the mepivacaine hydrochloride aqueous gel as described above, the thickening agent is one of hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and hydroxypropyl cellulose.

[0007] For the mepivacaine hydrochloride aqueous gel as described above, the humectant is glycerol.

[0008] For the mepivacaine hydrochloride aqueous gel as described above, the penetration enhancer is propylene glycol.

[0009] For the mepivacaine hydrochloride aqueous gel as described above, the preservative is methyl p-hydroxybenzoate.

[0010] For the mepivacaine hydrochloride aqueous gel as described above, the co-preservative is propyl p-hydroxybenzoate.

[0011] A mepivacaine hydrochloride aqueous gel as described above, wherein the thickener is any one of hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium carboxymethylcellulose. Different thickeners have different properties and their preparation methods are slightly different. Among them, hydroxypropyl methylcellulose dissolves in cold water and is stable at pH 3-11. When heated, the viscosity of its aqueous solution decreases, and heating-cooling can cause the reversible transformation of hydroxypropyl methylcellulose from solution state to gel state. In addition, the aqueous solution of hydroxypropyl methylcellulose has an anti-enzyme effect and can maintain good viscosity stability during long-term storage, but it is vulnerable to microbial invasion, so an antiseptic and antibacterial agent is added; hydroxypropyl cellulose can form a colloidal solution with water below 38°C and is insoluble in hot water; the colloidal solution of sodium carboxymethylcellulose is destroyed at high temperature and is stable within pH 4-10.

[0012] A preparation method of a mepivacaine hydrochloride aqueous gel comprises the following steps:

[0013] Step 1: Weigh mepivacaine hydrochloride, thickener, humectant, penetration enhancer, preservative, co-preservative and purified water according to the ratio.

[0014] Step 2: Mix the humectant and the penetration enhancer evenly, then add the thickener and stir until fully dispersed, and set aside.

[0015] Step 3: Add mepivacaine hydrochloride to an appropriate amount of purified water and stir until completely dissolved.

[0016] Step 4: Add the mepivacaine hydrochloride solution obtained in Step 3 to the dispersion obtained in Step 2 and stir until the thickener is completely dissolved.

[0017] Step 5: Add a pH regulator to adjust the pH to 5.5±0.2 and continuously stir for 2 min.

[0018] Step 6: Dissolve the preservative and the co-preservative in 1-2% by weight of purified water at 80-90°C, cool and then add it to the gel matrix obtained in Step 5 and stir evenly.

[0019] Step 7: Add the remaining purified water and the gel matrix obtained in Step 6 to a homogenizer, stir at a rotation speed of 6000-7500 r / min for 8-12 min, remove the gas in the gel matrix while stirring evenly, and after stirring is completed, divide and package to obtain the mepivacaine hydrochloride aqueous gel.

[0020] A preparation method of a mepivacaine hydrochloride aqueous gel as described above, wherein the pH regulator is hydrochloric acid.

[0021] The advantages of the present invention are as follows: By preparing mepivacaine hydrochloride into a water-based gel dosage form, it can be directly applied to the corresponding local skin without puncturing blood vessels during local skin anesthesia, and then wait for it to penetrate into the skin capillaries, thereby reducing the impact of local anesthesia operation on patients and improving the adaptability of patients to local anesthesia; at the same time, the water-based gel can be better absorbed by the skin. Brief Description of the Drawings

[0022] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required to be used in the description of the embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0023] Figure 1 It is a schematic diagram of the mepivacaine hydrochloride water-based gel prepared in Example 1 of the present invention;

[0024] Figure 2 It is a schematic diagram of the mepivacaine hydrochloride water-based gel prepared in Example 2 of the present invention;

[0025] Figure 3 It is a schematic diagram of the mepivacaine hydrochloride water-based gel prepared in Example 3 of the present invention;

[0026] Figure 4 It is an HPLC chromatogram of the purity detection of mepivacaine hydrochloride in Example 1 of the present invention;

[0027] Figure 5 It is an HPLC chromatogram of the reference substance for the content detection of mepivacaine hydrochloride in Example 1 of the present invention;

[0028] Figure 6 It is an HPLC chromatogram of the content detection of mepivacaine hydrochloride in Example 1 of the present invention;

[0029] Figure 7 It is an HPLC chromatogram of the purity detection of mepivacaine hydrochloride in Example 2 of the present invention;

[0030] Figure 8 It is an HPLC chromatogram of the reference substance for the content detection of mepivacaine hydrochloride in Example 2 of the present invention;

[0031] Figure 9 It is an HPLC chromatogram of the content detection of mepivacaine hydrochloride in Example 2 of the present invention;

[0032] Figure 10 It is an HPLC chromatogram of the purity detection of mepivacaine hydrochloride in Example 3 of the present invention;

[0033] Figure 11It is the HPLC chromatogram of the reference substance for the determination of the mepivacaine hydrochloride content in Example 3 of the present invention;

[0034] Figure 12 It is the HPLC chromatogram for the determination of the mepivacaine hydrochloride content in Example 3 of the present invention. Detailed implementation manners

[0035] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.

[0036] Example 1

[0037] Step 1: Weigh substances according to the following weight percentages: mepivacaine hydrochloride 2.0%, hypromellose E50 6.0%, glycerol 10.0%, propylene glycol 5.0%, methyl paraben 0.1%, propyl paraben 0.02%, purified water 76.88%;

[0038] Step 2: Mix glycerol and propylene glycol evenly and then add hypromellose E50, stir until fully dispersed, and set aside;

[0039] Step 3: Add mepivacaine hydrochloride to 65% by weight of purified water, and stir until completely dissolved;

[0040] Step 4: Add the mepivacaine hydrochloride solution obtained in Step 3 to the dispersion obtained in Step 2, and stir until hypromellose E50 is completely dissolved;

[0041] Step 5: Slowly add hydrochloric acid to adjust the pH to 5.5, and continuously stir for 2 min;

[0042] Step 6: Dissolve methyl paraben and propyl paraben in 1% by weight of purified water at 90 °C, cool and then add to the gel matrix obtained in Step 5, and stir evenly;

[0043] Step 7: Add the remaining purified water and the gel matrix obtained in Step 6 to a homogenizer, stir at a speed of 7500 r / min for 12 min, remove the gas in the gel matrix while stirring evenly, and after stirring is completed, divide and package to obtain the mepivacaine hydrochloride aqueous gel (as Figure 1 shown).

[0044] Example 2

[0045] Step 1: Weigh the substances according to the following weight percentages: mepivacaine hydrochloride 2.0%, sodium carboxymethylcellulose 0.10%, glycerol 10.0%, propylene glycol 5.0%, methylparaben 0.1%, propylparaben 0.02%, purified water 82.78%;

[0046] Step 2: Mix glycerol and propylene glycol evenly and then add sodium carboxymethylcellulose, stir until fully dispersed, and set aside;

[0047] Step 3: Add mepivacaine hydrochloride to 50% by weight of purified water, stir until completely dissolved; Step 4: Add the mepivacaine hydrochloride solution obtained in Step 3 to the dispersion obtained in Step 2, and stir until sodium carboxymethylcellulose is completely dissolved;

[0048] Step 5: Slowly add hydrochloric acid to adjust the pH to 5.5, and continuously stir for 2 min;

[0049] Step 6: Dissolve methylparaben and propylparaben in 2% by weight of purified water at 80 °C, cool and then add to the gel matrix obtained in Step 5, and stir evenly;

[0050] Step 7: Add the remaining purified water and the gel matrix obtained in Step 6 to a homogenizer, stir at a speed of 7500 r / min for 8 min, remove the gas in the gel matrix while stirring evenly, and after stirring is completed, divide and package to obtain the mepivacaine hydrochloride aqueous gel (as Figure 2 shown).

[0051] Example 3

[0052] Step 1: Weigh the substances according to the following weight percentages: mepivacaine hydrochloride 2.0%, hydroxypropyl cellulose EF 12.5%, glycerol 10.0%, propylene glycol 5.0%, methylparaben 0.1%, propylparaben 0.02%, purified water 70.38%;

[0053] Step 2: Add mepivacaine hydrochloride to 65% by weight of purified water, stir until completely dissolved and set aside;

[0054] Step 3: Mix glycerol and propylene glycol evenly and then add them to the mepivacaine hydrochloride solution obtained in Step 2, stir and mix evenly, then add hydroxypropyl cellulose EF, and stir until completely dissolved;

[0055] Step 5: Slowly add hydrochloric acid to adjust the pH to 5.6, and continuously stir for 2 min;

[0056] Step 6: Dissolve methylparaben and propylparaben in 1.5% by weight of purified water at 85 °C, cool and then add to the gel matrix obtained in Step 5, and stir evenly;

[0057] Step 7: Add the remaining purified water and the gel matrix obtained in Step 6 into a homogenizer, stir at a speed of 6500 r / min for 10 min, remove the gas in the gel matrix while stirring evenly, and after stirring, divide and package to obtain mepivacaine hydrochloride aqueous gel (as Figure 3 shown).

[0058] Detect the purity and content of mepivacaine hydrochloride in Examples 1-3 (the corresponding chromatograms are as Figures 4 - 12 ), and the results are shown in Table 1.

[0059]

[0060] Table 1

[0061] It can be seen from the data in Table 1 that the gel matrices formed by different thickeners have no influence on the quality of this product, and the content and related substances are all within the control range. Therefore, the product prepared by the present invention can be effectively promoted and applied.

[0062] Among them, the related substances in mepivacaine hydrochloride are determined by high performance liquid chromatography (General Chapter 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0063] For the test solution, accurately measure mepivacaine hydrochloride and quantitatively dilute it with the mobile phase to prepare a solution containing 2 mg of mepivacaine hydrochloride per 1 ml.

[0064] For the reference solution, accurately weigh appropriate amounts of impurity A reference substance and mepivacaine hydrochloride reference substance, dissolve them with the mobile phase and quantitatively dilute to prepare a solution containing about 0.2 μg of impurity A and 4 μg of mepivacaine hydrochloride per 1 ml.

[0065] For the sensitivity solution, accurately measure 1 ml of the reference solution, place it in a 100-ml volumetric flask, dilute it to the mark with the mobile phase, and shake well.

[0066] For the system suitability solution, take appropriate amounts of mepivacaine hydrochloride, impurity A and impurity F reference substances, dissolve them with the mobile phase and dilute to prepare a mixed solution containing about 0.2 mg of mepivacaine hydrochloride, 2 μg of each of impurity A and impurity F per 1 ml.

[0067] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (KINGFUN Eldath Xtimate 250 mm×4.6 mm, 5 μm or a chromatographic column with equivalent efficiency); use 0.02 mol / L phosphoric acid solution (adjust the pH value to 7.10 with sodium hydroxide test solution)-acetonitrile (65:35) as the mobile phase; the detection wavelength is 220 nm; the injection volume is 20 μl.

[0068] System suitability requires that in the chromatogram of the system suitability solution, the elution order of the peaks is impurity F, mepivacaine, and impurity A in sequence. The resolution between each peak should meet the requirements, and the number of theoretical plates calculated based on the mepivacaine peak should be not less than 2000. In the chromatogram of the sensitivity solution, the signal-to-noise ratio of the main component peak height should be greater than 10.

[0069] Assay Precisely measure the test solution and the reference solution, and inject them into the liquid chromatograph separately. Record the chromatogram until 5 times the retention time of the main component peak.

[0070] Limit If there are impurity peaks in the chromatogram of the test solution, calculate by the external standard method based on the peak area. Impurity A shall not exceed 0.05% of the labeled amount; impurity F shall not exceed 0.05% of the labeled amount calculated by the external standard method based on the peak area of mepivacaine, other individual impurities shall not exceed 0.5% of the labeled amount, and the sum of other impurity peaks shall not exceed 2.0% of the labeled amount.

[0071] Among them, the content determination of mepivacaine hydrochloride is carried out according to the high performance liquid chromatography method (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0072] Test solution Weigh 2 g of this product, place it in a 50 ml volumetric flask, dilute it to the mark with the mobile phase, shake well, precisely measure 5 ml, place it in a 50 ml volumetric flask, dilute it to the mark with the mobile phase, and shake well.

[0073] Reference solution Weigh accurately about 20 mg of mepivacaine hydrochloride reference substance, place it in a 25 ml volumetric flask, dilute it to the mark with the mobile phase, shake well, precisely measure 5 ml, place it in a 50 ml volumetric flask, dilute it to the mark with the mobile phase, and shake well.

[0074] System suitability solution, chromatographic conditions and system suitability requirements are shown under related substances.

[0075] Assay Precisely measure the test solution and the reference solution, and inject them into the liquid chromatograph separately. Record the chromatogram. Calculate by the external standard method based on the peak area.

[0076] Calculation formula:

[0077]

[0078] Where: A 样 is the peak area of the main peak in the test solution;

[0079] A 对 is the peak area of the main peak in the reference solution;

[0080] C 对 is the concentration of the reference substance, mg / ml;

[0081] W 样 is the weighed amount of the test sample;

[0082] The specification is 2%.

[0083] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A mepivacaine hydrochloride aqueous gel, characterized in that: It comprises the following substances in mass percentages: mepivacaine hydrochloride 2.0%, thickening agent 0.1 - 12.5%, humectant 10.0%, penetration enhancer 5.0%, preservative 0.1%, co-preservative 0.02%, and the balance is purified water.

2. The mepivacaine hydrochloride aqueous gel according to claim 1, wherein: The thickening agent is any one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sodium carboxymethylcellulose.

3. The mepivacaine hydrochloride aqueous gel according to claim 1, characterized in that: The humectant is glycerol.

4. The mepivacaine hydrochloride aqueous gel according to claim 1, characterized in that: The penetration enhancer is propylene glycol.

5. The mepivacaine hydrochloride aqueous gel according to claim 1, characterized in that: The preservative is methyl paraben.

6. The mepivacaine hydrochloride aqueous gel according to claim 1, wherein: The co-preservative is propyl paraben.

7. A preparation method of mepivacaine hydrochloride aqueous gel, characterized in that: It comprises the following steps: Step 1: Weigh mepivacaine hydrochloride, thickening agent, humectant, penetration enhancer, preservative, co-preservative, and purified water according to the ratio. Step 2: Add the thickening agent to the mixed solution of the humectant and the penetration enhancer, stir until fully dispersed, and set aside. Step 3: Add mepivacaine hydrochloride to an appropriate amount of purified water and stir until completely dissolved. Step 4: Add the mepivacaine hydrochloride solution obtained in Step 3 to the dispersion obtained in Step 2 and stir until the thickening agent is completely dissolved. Step 5: Add a pH regulator to adjust the pH to 5.5 ± 0.2 and stir for 2 min. Step 6: Dissolve the preservative and the co-preservative in purified water at 80 - 90 °C with a weight of 1 - 2%, cool it, and then add it to the gel matrix obtained in Step 5 and stir evenly. Step 7: Add the remaining purified water and the gel matrix obtained in Step 6 to a homogenizer, stir at a speed of 6000 - 7500 r / min for 8 - 12 min, remove the gas in the gel matrix while stirring evenly, and after the stirring is completed, subpackage to obtain the mepivacaine hydrochloride aqueous gel.

8. A preparation method of mepivacaine hydrochloride aqueous gel according to claim 7, characterized in that: The pH regulator is hydrochloric acid.

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