Riptacaine emulsifiable paste and preparation process thereof

Abstract

The invention provides a ripdicaine emulsifiable paste and a preparation process thereof. According to the invention, a new cream formula is selected, the transdermal absorption is faster than that of a preparation without a penetration enhancer, the anesthesia time is shortened, and the waiting time of a patient is reduced. Compared with the prior art, the new penetration enhancer has the advantages that the irritation of damaged skin is greatly reduced, the sensitivity of sensitive skin to products can be reduced, and for local anesthesia application of small surgeries such as puncture on subsequent patients, the irritation feeling of the skin after being damaged to the applied local anesthesia medicine is reduced, and better compliance is achieved. The preparation process of the cream provided by the invention is simple and stable to operate, and can meet the requirements of industrial large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a prilocaine cream and a preparation process thereof. BACKGROUND

[0002] Lidocaine is an amide local anesthetic, and has obvious excitatory and inhibitory biphasic effects on central nervous system after blood absorption or intravenous administration. It is widely used in infiltration anesthesia, epidural anesthesia, surface anesthesia and nerve conduction block.

[0003] Prilocaine is also an amide local anesthetic, and has local anesthetic effect by blocking the ion flow required for the generation and conduction of nerve impulses to stabilize the nerve cell membrane. The anesthetic strength and speed are similar to those of lidocaine, but the duration is longer, the vasodilating effect is weaker, and the toxicity is lower than that of lidocaine. Because of its fast metabolism, it also has less accumulation.

[0004] The eutectic mixture of lidocaine and prilocaine in a 1:1 ratio is an oil-in-water cream, which is called prilocaine cream, and is a skin surface anesthetic. It is commonly used for analgesia in intravenous puncture, intravenous cannulation and various surgical operation. It can be applied to intact skin under closed dressing, and the amide local anesthetic lidocaine and prilocaine are released from the cream into the epidermis and dermis, and then absorbed through the skin into the nerve tissue, and accumulated near the dermal pain receptors and nerve endings. The sodium influx of nerve fiber cell membrane is blocked, the membrane depolarization and action potential generation are inhibited, and the conduction impulse is blocked, thereby producing local anesthetic effect.

[0005] However, because the prilocaine cream needs to pass through the barrier function of the stratum corneum, it has the defects of slow transdermal absorption, long onset time, and short action time, which cannot meet the needs of clinical application. Chinese patent document CN101209250A discloses a new prescription using azone as a penetration enhancer to improve the transdermal rate. However, azone can cause loose skin structure and stimulate sensitive damaged skin. At present, there are also reports on the use of microemulsion technology to improve the transdermal absorption of prilocaine. Microemulsion is a homogeneous, transparent and thermodynamically stable dispersion system composed of oil phase, water phase, surfactant and co-surfactant mixed uniformly in appropriate proportions. It can significantly improve the solubility and local concentration of poorly soluble drugs, promote the transdermal penetration and absorption of drugs, and improve the bioavailability of drugs. However, the preparation of microemulsion requires complex excipients, and the safety and cost limit its practical application. In addition, microemulsion also has the problem of stability, and is prone to creaming, flocculation and other demulsification. SUMMARY

[0006] In view of the slow onset time of the existing art propylhexedrine cream, the present application provides a new preparation prescription, which can realize high transdermal amount of propylhexedrine cream, small skin irritation, thereby achieving the technical effects of faster onset and safety.

[0007] The specific prescription of the propylhexedrine cream of the present application is as follows:

[0008] Per 1000g:

[0009]

[0010] The specific prescription of the propylhexedrine cream of the present application is as follows:

[0011] Per 1000g:

[0012]

[0013] The specific prescription of the propylhexedrine cream of the present application is as follows:

[0014] Per 1000g:

[0015]

[0016] Another object of the present application is to provide a preparation process of the above cream, and the specific steps are as follows:

[0017] Step 1: soak carbomer in water;

[0018] Step 2: lidocaine and prilocaine are stirred into transparent liquid at room temperature for standby;

[0019] Step 3: polyoxyethylene hydrogenated castor oil is added to the mixture of step 2 and stirred to become water-in-oil oil phase mixture;

[0020] Step 4: add menthol to the mixture of step 3 and continue to stir evenly;

[0021] Step 5: stir the pre-soaked carbomer with the mixture in step 4 to form an oil-in-water mixture;

[0022] Step 6: add 10% sodium hydroxide solution to the stirring container to make the pH value of the mixture reach 8-9;

[0023] Step 7: add the remaining purified water to the stirring container to the formula amount and stir evenly into cream.

[0024] Compared with the prior art, the cream of the present application is absorbed through the skin faster, more quickly, shortens the anesthesia time, and reduces the waiting time of the patient. Compared with the formulation added with atransdermal enhancer, the irritation of damaged skin is greatly reduced, the sensitivity of sensitive skin to the product can be reduced, and the irritation of the skin after damage to the local anesthetic drug that has been applied can be reduced, with better compliance for subsequent patients after puncture and local anesthesia for minor surgery.

[0025] And the process provided by the present application is simple, easy to scale up production, reasonable and stable in formula and process. DETAILED DESCRIPTION

[0026] The following is only a preferred embodiment of the present application and is not intended to limit the present application. Those skilled in the art can make several improvements, refinements, equivalent replacements without departing from the principles of the present application, which should be included in the protection scope of the present application.

[0027] Example 1

[0028] The prescription composition is as follows:

[0029]

[0030] The preparation process is as follows:

[0031] Step 1: Weigh the amount of carbomer in the formula and soak in purified water for 10-12 hours;

[0032] Step 2: Weigh the amount of lidocaine and prilocaine in the formula and put them into a stirring container. Stir at room temperature to make a transparent liquid for standby;

[0033] Step 3: Weigh the amount of polyoxyethylene hydrogenated castor oil in the formula and add it directly into the above stirring container to mix with the lidocaine and prilocaine mixture to make a water-in-oil oil phase mixture;

[0034] Step 4: Mix the pre-soaked carbomer with the oil phase mixture formed in Step 3 to stir into an oil-in-water mixture;

[0035] Step 5: Add 10% sodium hydroxide solution to the above stirring container to make the pH value of the mixture reach 8.5;

[0036] Step 6: Add the remaining amount of purified water to the stirring container to the formula amount and stir evenly into a cream;

[0037] Step 7: Fill and package.

[0038] Example 2

[0039] The prescription composition is as follows:

[0040] The prescription composition is as follows:

[0041] The preparation process is as follows:

[0042] Step 1: Take the formula amount of carbomer and purified water and soak for 10-12 hours;

[0043] Step 2: Take the formula amount of lidocaine and prilocaine and put it into the stirring container, stir at room temperature to become a transparent liquid for standby;

[0044] Step 3: Take the formula amount of polyoxyethylene hydrogenated castor oil, directly add it into the above stirring container, and stir it with the mixture of lidocaine and prilocaine to become a water-in-oil oil phase mixture;

[0045] Step 4: Take the formula amount of azone and add it to the mixture of step 3, continue to stir evenly;

[0046] Step 5: Stir the pre-soaked carbomer with the mixture in step 4 to form an oil-in-water mixture;

[0047] Step 6: Add 10% sodium hydroxide solution to the above stirring container to make the pH value of the mixture reach 8.5;

[0048] Step 7: Add the remaining amount of purified water to the formula amount in the stirring container, and stir evenly to form a cream;

[0049] Step 8: Fill and package.

[0050] Example 3

[0051] The prescription composition is as follows:

[0052]

[0053]

[0054] The preparation process is as follows:

[0055] Step 1: Take the formula amount of carbomer and purified water and soak for 10-12 hours;

[0056] Step 2: Take the formula amount of lidocaine and prilocaine and put it into the stirring container, stir at room temperature to become a transparent liquid for standby;

[0057] Step 3: Take the formula amount of polyoxyethylene hydrogenated castor oil, directly add it into the above stirring container, and stir it with the mixture of lidocaine and prilocaine to become a water-in-oil oil phase mixture;

[0058] Step 4: Take the formula amount of menthol and add it to the mixture of step 3, continue to stir evenly;

[0059] Step 5: The pre-soaked carbomer is stirred with the mixture in Step 4 to form an oil-in-water mixture;

[0060] Step 6: 10% sodium hydroxide solution is added to the above stirring container to make the pH value of the mixture reach 8.5;

[0061] Step 7: The remaining purified water is added to the stirring container to the formulation amount, and stirred to form a cream;

[0062] Step 8: Filling and packaging.

[0063] Example 4

[0064] The prescription composition is as follows:

[0065]

[0066] The preparation process is as follows:

[0067] Step 1: The formulation amount of carbomer is weighed and soaked in purified water for 10-12 hours;

[0068] Step 2: The formulation amount of lidocaine and prilocaine is weighed and put into a stirring container, and stirred at room temperature to form a transparent liquid for standby;

[0069] Step 3: The formulation amount of polyoxyethylene hydrogenated castor oil is weighed and directly added to the above stirring container, and stirred with the mixture of lidocaine and prilocaine to form an oil-in-water oil phase mixture;

[0070] Step 4: The formulation amount of menthol is weighed and added to the mixture in Step 3, and continue to stir evenly;

[0071] Step 5: The pre-soaked carbomer is stirred with the mixture in Step 4 to form an oil-in-water mixture;

[0072] Step 6: 10% sodium hydroxide solution is added to the above stirring container to make the pH value of the mixture reach 8.5;

[0073] Step 7: The remaining purified water is added to the stirring container to the formulation amount, and stirred to form a cream;

[0074] Step 8: Filling and packaging.

[0075] Example 5

[0076] The prescription composition is as follows:

[0077]

[0078] The preparation process is as follows:

[0079] Step 1: Take the amount of carbomer in the formula and soak in purified water for 10-12 hours;

[0080] Step 2: Take the amount of lidocaine and prilocaine in the formula and put into the stirring container, stir at room temperature until transparent liquid is obtained for standby;

[0081] Step 3: Take the amount of polyoxyethylene hydrogenated castor oil in the formula and directly add into the above stirring container, stir with the mixture of lidocaine and prilocaine until uniform, becoming water-in-oil oil phase mixture;

[0082] Step 4: Take the amount of menthol in the formula and add into the mixture of Step 3, continue to stir until uniform;

[0083] Step 5: Stir the pre-soaked carbomer with the mixture in Step 4 to form oil-in-water mixture;

[0084] Step 6: Add 10% sodium hydroxide solution into the above stirring container to make the pH value of the mixture reach 8.5;

[0085] Step 7: Add the remaining amount of purified water into the stirring container to the formula amount, stir until uniform;

[0086] Step 8: Fill and package.

[0087] Example 6

[0088] In vitro transdermal penetration experiment

[0089] Test scheme:

[0090] Healthy adult guinea pigs were selected, dislocated and killed, and then skinned and depilated for standby. The in vitro transdermal penetration experiment was carried out by using intelligent transdermal experimental instrument. The specific operation was as follows: the guinea pig skin was taken out, washed repeatedly with physiological saline, fixed between the supply pool and the receiving pool, and the stratum corneum was faced to the supply pool. The transdermal receiving liquid (20% ethanol-normal saline) was added to the receiving pool, 0.8g of the test sample was evenly applied on the surface of the skin in the supply pool, covered with a lid, and sealed with a layer of preservative film. The temperature of the intelligent transdermal experimental instrument was set at 37±0.1℃, and the rotation speed was set at 350r / min. At 1h, 2h and 4h of the experiment, 2mL of transdermal receiving liquid was taken out, and 2mL of isothermal and freshly prepared 20% ethanol-normal saline was supplemented to the receiving pool. The transdermal receiving liquid was filtered through a 0.22μm microporous filter, and the drug content was determined.

[0091] Test results:

[0092] Table 1 Cumulative penetration amount of main drugs in rat skin (μg / cm 2 )

[0093]

[0094] Experimental conclusion:

[0095] The ointments in Examples 2-5 with added penetration enhancers had a faster penetration rate and higher penetration volume than those in Example 1 without added penetration enhancers.

[0096] In Example 2, azone was added, and in Examples 3-5, menthol was added as a penetration enhancer. The penetration-enhancing effects were comparable, with Example 5 showing a better penetration-enhancing effect than Example 2.

[0097] Example 7

[0098] Skin irritation test

[0099] Test protocol:

[0100] Rabbits were randomly divided into a normal skin group and a damaged skin group, with 4 rabbits in each group. They were fed normally for 3 days in the experimental environment.

[0101] Preparation of normal skin: 24 hours before administration, use a razor to shave the hair on both sides of the spine on the back of the rabbit, with a hair removal area of ​​approximately 2×2cm on each side. 2 Check the hair removal area for any damage; if there is no damage, it is considered normal skin.

[0102] Preparation of broken skin: Shave the hair on both sides of the spine on the back of the rabbit according to the above procedure. After disinfecting the skin surface with 75% alcohol, use a sterile needle to draw a "well" pattern on the hairless skin surface, just enough to break the epidermis.

[0103] Before administration, the test skin was cleaned with warm water. 0.6g of the cream from Examples 1-5 was applied evenly to both the normal skin group and the damaged skin group.

[0104] After administration, each rabbit's administration site was covered with sterile medical gauze and secured with medical tape to prevent leakage. Four hours after topical application of the test substance to the skin, the medical gauze was removed, and the skin was gently rinsed and wiped with warm water to remove any residual cream. At 1 hour, 24 hours, 48 ​​hours, and 72 hours after rinsing, the skin at the test site was visually observed for erythema, edema, etc. According to Table 2, the skin erythema and edema reaction scores for each group of test animals at each time point were recorded. The average score of the skin irritation reaction was calculated using the following formula, and the skin irritation intensity level was determined according to Table 3.

[0105]

[0106] Table 2 Skin Irritation Scoring Criteria

[0107]

[0108] Table 3 Skin Irritation Intensity Grading

[0109]

[0110] Test Results

[0111] The results of the test are shown in Table 4 and Table 5. The results of the test showed that the erythema and edema scores of the normal skin were 0 at 1 h, 24 h, 48 h and 72 h after the application of the cream samples of Examples 2-5 and the removal of the residual test substances, indicating that the cream samples of Examples 2-5 had no irritation to the normal skin.

[0112] The skin irritation scores of the damaged skin treated with the cream of Example 2 at 1 h, 24 h, 48 h and 72 h were 1.25, 1, 0.75 and 0.25, respectively, and the skin irritation intensity grades were mild, mild, mild and none, respectively. The skin irritation intensity grades of the cream samples of Examples 3-5 at 1 h, 24 h, 48 h and 72 h were mild, mild, none and none, respectively. The above results showed that the skin irritation of Example 2 was stronger than that of Examples 3-5.

[0113] Table 4 Skin irritation scores

[0114]

[0115] Table 5 Skin irritation intensity grades

[0116]

Claims

1. A liposome dicaine cream, characterized in that, The specific composition formulation is as follows: Per 1000g:

2. The lipofuscin cream according to claim 1, characterized in that, The specific composition formula is as follows: per 1000g:

3. The lipofuscin cream according to claim 1, characterized in that, The specific composition formula is as follows: per 1000g:

4. The preparation process of the cream according to claims 1-3, characterized in that, Includes the following steps: Step 1: Soak the carbomer in water; Step 2: Mix lidocaine and prilocaine at room temperature until a clear liquid is formed and set aside. Step 3: Add the polyoxyethylene hydrogenated castor oil to the mixture from Step 2 and stir to form a water-in-oil mixture. Step 4: Add menthol to the mixture from Step 3 and continue stirring until well combined; Step 5: Stir the pre-soaked carbomer with the mixture from Step 4 to form an oil-in-water mixture; Step 6: Add 10% sodium hydroxide solution to the above-mentioned stirring container to make the pH value of the mixture reach 8-9; Step 7: Add the remaining purified water to the mixing container to the formula volume, and stir until it forms an emulsion.

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