CN106806338B - Compound lidocaine cream pharmaceutical composition and preparation method thereof - Google Patents
Compound lidocaine cream pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
The invention provides a compound lidocaine cream pharmaceutical composition and a preparation method thereof. The pharmaceutical composition is prepared by taking effective dose of lidocaine and prilocaine as main drug raw materials and taking polyoxyethylene hydrogenated castor oil, carbomer, sodium hydroxide and purified water as pharmaceutic adjuvants. The cream has the advantages of moistening, good spreadability, low impurity content, good quality and small irritation to skin.
Description
Technical Field
The invention relates to a compound lidocaine cream pharmaceutical composition and a preparation method thereof, belonging to the technical field of medicines.
Background
Local anesthetics refer to drugs that temporarily and reversibly block the generation and conduction of nerve fiber impulses within a defined area of the body without causing the patient to lose consciousness.
The local anesthetics are classified according to clinical application, and the following methods are used: superficial anesthesia, spinal anesthesia, infiltration and block anesthesia, epidural and caudal vertebra anesthesia, etc. The general use of local anesthetic and epinephrine can cause vasoconstriction, to increase local drug concentration, prolong and enhance drug action, and reduce systemic toxicity.
The first applied local anesthetic was cocaine, which was formally used clinically in 1884. Cocaine is highly toxic, addictive and unstable in aqueous solution. Procaine with excellent local anesthetic effect is synthesized in 1904, has stronger local anesthetic effect than cocaine and low toxicity, but has weak penetrating power, and cannot be used for surface anesthesia. Swedish chemist 1943
Lidocaine (2-diamylamine-N- (2,6-dimethyl phenyl) -acetamide) is synthesized for the first time, the local anesthetic action of the Lidocaine is 2-9 times stronger than that of procaine, the action maintenance time is long, and the effect taking is quick. Then a series of local anesthetics of the phthaleins are synthesized in sequence, such as tricaine, prilocaine, pyrrolcaine, bupivacaine and the like, which are different in local anesthetic action, onset time, stability and the like.
Lidocaine, also known as Xylocaine (Xylocaine) and Xylocaine (Lignocaine), belongs to local anesthetics of the phthalides class, is an organic weak base, and has a molecular structural formula shown as the following formula (i):
the lidocaine free alkali is white crystalline powder, has melting point of 66-70 deg.C, is easily soluble in ethanol, chloroform and dichloromethane, is soluble in ether, is insoluble in water, and is stable to acid, alkali, light and heat. The amido bond contained in the lipophilic part of the lidocaine is the weakest link in the molecule, is easy to break due to hydrolysis, but has stronger stability than the ester bond, and two methyl substituents are arranged on two ortho-positions of the benzene ring, so that the steric hindrance is increased, and the hydrolysis of the amido bond is stabilized. Just because lidocaine is not hydrolyzed and deactivated by cholinesterase as procaine in vivo, it has the advantages of strong drug effect and long duration of local anesthesia action. In addition, the hydrophilic part of the lidocaine is tertiary amine, so that the lidocaine has small irritation, and the local vasodilator effect is not obvious when the lidocaine is used, so that the lidocaine is more suitable for local anesthesia.
Prilocaine (Prilocaine), chemical name: n- (2-methylphenyl) -2-propylamine-propionamide, which has the chemical structural formula shown as the following formula (II):
prilocaine free base is needle crystal with melting point of 37-38 deg.C, and is easy to absorb moisture and store.
Prilocaine is also a local anesthetic, has better efficacy than procaine, has local anesthesia effect strength and speed similar to lidocaine, but has longer action time, lower toxicity, and smaller accumulation due to fast metabolism. Is suitable for epidural anesthesia, conduction anesthesia, infiltration anesthesia, etc.
The compound lidocaine cream is a compound cream preparation of lidocaine and prilocaine, is successfully developed and marketed (trade name EMLA, Enna) by Astra company in the eighties of the last century, and is marketed in more than ten countries including China, America and the like. The drug is mainly used for solving the problems that the existing narcotics (including injection, latex and solution) are difficult to penetrate through the stratum corneum and the epidermis of the intact skin and enter the dermis where nerve endings of sensory diseases are located, so that the analgesic effect is exerted, and the like, and becomes the first effective surface anesthetic capable of penetrating through the intact skin.
The formula of the EMLA is as follows: each 1000g of the cream contains 25g of lidocaine and prilocaine, 8019 g of polysorbate, 10g of carboxypolymethylene, NaOH for adjusting the pH value to 9.0 and the balance of purified water.
CN101209250A provides a compound lidocaine emulsifiable paste, the auxiliary materials of which comprise carbomer 934, tween-80 and penetration enhancer azone; the preparation method comprises the following steps: preparing lidocaine prilocaine eutectic, purifying water swelling carbomer 934, stirring uniformly to obtain transparent colloid, adjusting pH to 8-10 with sodium hydroxide solution, adding tween-80, stirring uniformly, adding eutectic and azone, stirring until emulsification is uniform, and adding water and stirring until emulsification is uniform.
CN101816642A provides a compound lidocaine emulsifiable paste, the auxiliary materials of which comprise polyoxyethylene hydrogenated castor oil and carbomer, and the preparation steps comprise: adding polyoxyethylene hydrogenated castor oil into lidocaine prilocaine eutectic, stirring to obtain water-in-oil phase mixture, mixing with purified water-soaked carbomer, stirring to obtain oil-in-water mixture, adjusting pH to above 9, replenishing water, and stirring to obtain cream.
When the formula and process research of the existing lidocaine cream is carried out, the content of o-toluidine which is a related substance of prilocaine in a sample is higher and reaches more than 2%, and the content of the related substance is higher than 2% after the inspection that the impurity is not controlled by a commercial product enna. O-toluidine, also known as 2-methylaniline, is easy to invade the human body through the skin, respiratory tract and digestive tract of a human body to cause a series of poisoning symptoms of the human body, light patients can feel scorching on the face, severe headache, dizziness and dyspnea, cyanosis appears, serious patients can have a series of damages to the central nervous system, cardiovascular system and other organs, the development is fast after poisoning, and the patients must be rescued actively. The allergic reaction of the compound lidocaine cream in clinical use, particularly in long-term use, is usually related to impurities, so how to control the content of related substances of the compound lidocaine cream is a problem to be solved in the field.
Disclosure of Invention
Aiming at the defects and shortcomings of the compound lidocaine cream in the prior art, the invention provides a compound lidocaine cream pharmaceutical composition and a preparation method thereof, wherein the content of a related substance, namely o-toluidine, can be as low as about 0.1 percent, and the maximum unknown single impurity content is 0.02 to 0.05 percent; the cream has good moistening and smearing properties, low impurity content, good quality, and low irritation to skin.
The invention is realized by the following technical scheme:
the compound lidocaine cream pharmaceutical composition provided by the invention contains the following components in each 10kg of cream:
further, the polyoxyethylene hydrogenated castor oil is selected from polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil, polyoxyethylene 80 hydrogenated castor oil, and the carbomer is selected from carbomer 974P, carbomer 971P, carbomer 934P, carbomer 980, carbomer 981, carbomer 941, carbomer 940, carbomer 934, and carbomer PES.
Furthermore, the compound lidocaine cream pharmaceutical composition contains the following components in each 10kg of cream:
the invention also provides a preparation method of the compound lidocaine cream pharmaceutical composition, which comprises the following steps:
(1) preparation of an aqueous phase: weighing carbomer according to the prescription amount, weighing purified water according to the prepared 0.5-2% carbomer aqueous solution, slowly adding carbomer into the purified water, and stirring for more than 1 hour to completely dissolve the carbomer to obtain a water phase;
(2) preparing an oil phase: weighing lidocaine and prilocaine according to a formula, putting the lidocaine and the prilocaine in a main pot, stirring and mixing uniformly at 40-50 ℃, and melting to obtain a transparent liquid, namely a lidocaine-prilocaine eutectic solution; completely melting the polyoxyethylene hydrogenated castor oil in the formula amount at 60 ℃, adding the melted polyoxyethylene hydrogenated castor oil into the eutectic mixture, and uniformly stirring to obtain an oil phase for later use;
(3) preparing 5-40% sodium hydroxide solution by using purified water according to the prescription amount;
(4) emulsification: measuring the balance of purified water, adding the purified water into the oil phase prepared in the step (2), setting the slow stirring and wall scraping stirring speed to be 50 revolutions per minute, starting emulsification after stirring for 5 minutes and keeping the slow stirring and wall scraping stirring speed unchanged, wherein the speed is 2000 revolutions per minute, the high-speed emulsification is carried out for 3 minutes every 1 minute, and the accumulated time is not less than 12 minutes;
(5) and (3) adding the water phase prepared in the step (1) into the emulsion prepared in the step (4), stirring for 10 minutes, then setting the slow stirring and wall scraping stirring to 60 revolutions per minute, slowly adding the sodium hydroxide solution prepared in the step (3), continuously stirring for half an hour, discharging, and performing a subsequent filling process to obtain the compound lidocaine cream pharmaceutical composition.
Further, the quality of the cream intermediate can be controlled during the above preparation by monitoring the following items:
(1) the characteristics are as follows: white or off-white creams;
(2) pH value: directly measuring the emulsifiable paste, wherein the pH value is 8.7-9.7 (appendix VIH of the 2010 version two parts of Chinese pharmacopoeia);
(3) granularity: according to the first method of the appendix IXE of the 2010 version of the Chinese pharmacopoeia, emulsion drops and particles larger than 180 mu m cannot be detected;
(4) centrifugal stability: taking 5g of cream in a centrifugal tube, centrifuging at 4000r/min for 15min at a high speed, and avoiding oil-water stratification;
(5) mixing uniformity: taking 10 parts of cream, calculating the theoretical content relative to the labeled amount by peak area according to an external standard method, wherein the relative standard deviation of the content of 10 parts of samples is not more than 3.0%.
The invention has the following beneficial effects:
(1) on the basis of the prior art of the compound lidocaine emulsifiable paste, the content of the related substance o-toluidine is controlled by improving the prescription and the preparation method, so that the content of the related substance o-toluidine is reduced to about 0.1 percent from 2 percent in the prior art, the quality of the compound lidocaine emulsifiable paste is greatly improved, and the occurrence of side reactions in clinical use is reduced.
(2) The unknown single impurity is also controlled, the content is as low as 0.02 to 0.05 percent, and the product quality is good.
(3) Compared with the compound lidocaine emulsifiable paste provided by CN101816642A, the invention greatly reduces the usage amount of sodium hydroxide, reduces the alkalinity in preparation, simultaneously reduces the usage amount of carbomer, and reduces the production cost.
(4) The prepared cream has the advantages of moistening, good spreadability, convenient administration, little skin irritation, good curative effect and stable quality.
(5) The preparation method is simple to operate, the main drug is uniformly dispersed in the oil-in-water matrix, and the quality of the drug is good.
Detailed Description
The invention will now be further described by way of the following examples, which are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that the equivalent substitutions and modifications made in the present disclosure are within the scope of the present invention.
Example 1 preparation of Compound Lidocaine cream pharmaceutical composition
Prescription composition (preparation of 10kg cream):
the preparation method comprises the following steps:
(1) preparation of an aqueous phase: weighing carbomer 974P according to the prescription amount, weighing purified water according to the amount of a prepared 1.2% carbomer 974P water solution, slowly adding carbomer 974P into the purified water, and stirring for more than 1 hour to completely dissolve to obtain a water phase;
(2) preparing an oil phase: weighing lidocaine and prilocaine according to a formula, putting the lidocaine and the prilocaine in a main pot, stirring and mixing uniformly at 40-50 ℃, and melting to obtain a transparent liquid, namely a lidocaine-prilocaine eutectic solution; completely melting polyoxyethylene 40 hydrogenated castor oil in a prescription amount at 60 ℃, adding the melted polyoxyethylene 40 hydrogenated castor oil into the eutectic mixture, and uniformly stirring to prepare an oil phase for later use;
(3) preparing 10% sodium hydroxide solution by using purified water according to the prescription amount;
(4) emulsification: measuring the balance of purified water, adding the purified water into the oil phase prepared in the step (2), setting the slow stirring and wall scraping stirring speed to be 50 revolutions per minute, starting emulsification after stirring for 5 minutes and keeping the slow stirring and wall scraping stirring speed unchanged, wherein the speed is 2000 revolutions per minute, the high-speed emulsification is carried out for 3 minutes every 1 minute, and the accumulated time is not less than 12 minutes;
(5) and (3) adding the water phase prepared in the step (1) into the emulsion prepared in the step (4), stirring for 10 minutes, then setting the slow stirring and wall scraping stirring to 60 revolutions per minute, slowly adding the sodium hydroxide solution prepared in the step (3), continuously stirring for half an hour, discharging, and performing a subsequent filling process to obtain the compound lidocaine cream pharmaceutical composition.
The following items were monitored simultaneously during the preparation to control the quality of the cream intermediate:
(1) the characteristics are as follows: white or off-white creams;
(2) pH value: directly measuring the emulsifiable paste, wherein the pH value is 8.7-9.7 (appendix VIH of the 2010 version two parts of Chinese pharmacopoeia);
(3) granularity: according to the first method of the appendix IXE of the 2010 version of the Chinese pharmacopoeia, emulsion drops and particles larger than 180 mu m cannot be detected;
(4) centrifugal stability: taking 5g of cream in a centrifugal tube, centrifuging at 4000r/min for 15min at a high speed, and avoiding oil-water stratification;
(5) mixing uniformity: taking 10 parts of cream, calculating the theoretical content relative to the labeled amount by peak area according to an external standard method, wherein the relative standard deviation of the content of 10 parts of samples is not more than 3.0%.
Example 2 preparation of Compound Lidocaine cream pharmaceutical composition
Prescription composition (preparation of 45kg cream):
the preparation method comprises the following steps:
(1) preparation of an aqueous phase: slowly adding the carbomer 940 with the prescription amount into 18525g of purified water, and stirring for more than 1 hour to completely dissolve the carbomer 940 to obtain a water phase;
(2) preparing an oil phase: weighing lidocaine and prilocaine according to a formula, putting the lidocaine and the prilocaine into a main pot, stirring and mixing uniformly at 40-50 ℃, and melting to obtain a transparent liquid, namely a lidocaine-prilocaine eutectic solution; completely melting polyoxyethylene 80 hydrogenated castor oil in a prescription amount at 60 ℃, adding the melted polyoxyethylene 80 hydrogenated castor oil into the eutectic mixture, and uniformly stirring to prepare an oil phase for later use;
(3) preparing 10% sodium hydroxide solution by using purified water according to the prescription amount;
(4) emulsification: measuring the balance of purified water, adding the purified water into the oil phase prepared in the step (2), setting the slow stirring and wall scraping stirring speed to be 50 revolutions per minute, starting emulsification after stirring for 5 minutes and keeping the slow stirring and wall scraping stirring speed unchanged, wherein the speed is 2000 revolutions per minute, the high-speed emulsification is carried out for 3 minutes every 1 minute, and the accumulated time is not less than 12 minutes;
(5) and (3) adding the water phase prepared in the step (1) into the emulsion prepared in the step (4), stirring for 10 minutes, then setting the slow stirring and wall scraping stirring to 60 revolutions per minute, slowly adding the sodium hydroxide solution prepared in the step (3), continuously stirring for half an hour, discharging, and performing a subsequent filling process to obtain the compound lidocaine cream pharmaceutical composition.
Example 3 preparation of Compound Lidocaine cream pharmaceutical composition
Prescription composition (preparation of 10kg cream):
the preparation method comprises the following steps:
(1) preparation of an aqueous phase: weighing carbomer 934 according to the formula amount, weighing purified water according to the amount of a prepared 0.5% carbomer 934 aqueous solution, slowly adding carbomer 934 into the purified water, and stirring for more than 1 hour to completely dissolve to obtain a water phase;
(2) preparing an oil phase: weighing lidocaine and prilocaine according to a formula, putting the lidocaine and the prilocaine in a main pot, stirring and mixing uniformly at 40-50 ℃, and melting to obtain a transparent liquid, namely a lidocaine-prilocaine eutectic solution; completely melting polyoxyethylene 80 hydrogenated castor oil in a prescription amount at 60 ℃, adding the melted polyoxyethylene 80 hydrogenated castor oil into the eutectic mixture, and uniformly stirring to prepare an oil phase for later use;
(3) preparing 5% sodium hydroxide solution by using purified water according to the prescription amount;
(4) emulsification: measuring the balance of purified water, adding the purified water into the oil phase prepared in the step (2), setting the slow stirring and wall scraping stirring speed to be 50 revolutions per minute, starting emulsification after stirring for 5 minutes and keeping the slow stirring and wall scraping stirring speed unchanged, wherein the speed is 2000 revolutions per minute, the high-speed emulsification is carried out for 3 minutes every 1 minute, and the accumulated time is not less than 12 minutes;
(5) and (3) adding the water phase prepared in the step (1) into the emulsion prepared in the step (4), stirring for 10 minutes, then setting the slow stirring and wall scraping stirring to 60 revolutions per minute, slowly adding the sodium hydroxide solution prepared in the step (3), continuously stirring for half an hour, discharging, and performing a subsequent filling process to obtain the compound lidocaine cream pharmaceutical composition.
The following items were monitored simultaneously during the preparation to control the quality of the cream intermediate:
(1) the characteristics are as follows: white or off-white creams;
(2) pH value: directly measuring the emulsifiable paste, wherein the pH value is 8.7-9.7 (appendix VIH of the 2010 version two parts of Chinese pharmacopoeia);
(3) granularity: according to the first method of the appendix IXE of the 2010 version of the Chinese pharmacopoeia, emulsion drops and particles larger than 180 mu m cannot be detected;
(4) centrifugal stability: taking 5g of cream in a centrifugal tube, centrifuging at 4000r/min for 15min at a high speed, and avoiding oil-water stratification;
(5) mixing uniformity: taking 10 parts of cream, calculating the theoretical content relative to the labeled amount by peak area according to an external standard method, wherein the relative standard deviation of the content of 10 parts of samples is not more than 3.0%.
Example 4 preparation of Compound Lidocaine cream pharmaceutical composition
Prescription composition (preparation of 10kg cream):
the preparation method comprises the following steps:
(1) preparation of an aqueous phase: weighing carbomer 941 according to the amount of the prescription, weighing purified water according to the amount of a prepared 2% carbomer 934 aqueous solution, slowly adding carbomer 941 into the purified water, and stirring for more than 1 hour to completely dissolve the carbomer 941 to obtain a water phase;
(2) preparing an oil phase: weighing lidocaine and prilocaine according to a formula, putting the lidocaine and the prilocaine in a main pot, stirring and mixing uniformly at 40-50 ℃, and melting to obtain a transparent liquid, namely a lidocaine-prilocaine eutectic solution; completely melting polyoxyethylene 40 hydrogenated castor oil in a prescription amount at 60 ℃, adding the melted polyoxyethylene 40 hydrogenated castor oil into the eutectic mixture, and uniformly stirring to prepare an oil phase for later use;
(3) preparing 40% sodium hydroxide solution by using purified water according to the prescription amount;
(4) emulsification: measuring the balance of purified water, adding the purified water into the oil phase prepared in the step (2), setting the slow stirring and wall scraping stirring speed to be 50 revolutions per minute, starting emulsification after stirring for 5 minutes and keeping the slow stirring and wall scraping stirring speed unchanged, wherein the speed is 2000 revolutions per minute, the high-speed emulsification is carried out for 3 minutes every 1 minute, and the accumulated time is not less than 12 minutes;
(5) and (3) adding the water phase prepared in the step (1) into the emulsion prepared in the step (4), stirring for 10 minutes, then setting the slow stirring and wall scraping stirring to 60 revolutions per minute, slowly adding the sodium hydroxide solution prepared in the step (3), continuously stirring for half an hour, discharging, and performing a subsequent filling process to obtain the compound lidocaine cream pharmaceutical composition.
The following items were monitored simultaneously during the preparation to control the quality of the cream intermediate:
(1) the characteristics are as follows: white or off-white creams;
(2) pH value: directly measuring the emulsifiable paste, wherein the pH value is 8.7-9.7 (appendix VIH of the 2010 version two parts of Chinese pharmacopoeia);
(3) granularity: according to the first method of the appendix IXE of the 2010 version of the Chinese pharmacopoeia, emulsion drops and particles larger than 180 mu m cannot be detected;
(4) centrifugal stability: taking 5g of cream in a centrifugal tube, centrifuging at 4000r/min for 15min at a high speed, and avoiding oil-water stratification;
(5) mixing uniformity: taking 10 parts of cream, calculating the theoretical content relative to the labeled amount by peak area according to an external standard method, wherein the relative standard deviation of the content of 10 parts of samples is not more than 3.0%.
Example 5 preparation of Compound Lidocaine cream pharmaceutical composition
Prescription composition (preparation of 10kg cream):
the preparation method comprises the following steps:
(1) preparation of an aqueous phase: weighing carbomer 934P according to the formula amount, weighing purified water according to the prepared 1.5% carbomer 934P water solution, slowly adding carbomer 934P into the purified water, and stirring for over 1 hour to completely dissolve to obtain a water phase;
(2) preparing an oil phase: weighing lidocaine and prilocaine according to a formula, putting the lidocaine and the prilocaine in a main pot, stirring and mixing uniformly at 40-50 ℃, and melting to obtain a transparent liquid, namely a lidocaine-prilocaine eutectic solution; completely melting polyoxyethylene 60 hydrogenated castor oil in a prescription amount at 60 ℃, adding the melted polyoxyethylene 60 hydrogenated castor oil into the eutectic mixture, and uniformly stirring to prepare an oil phase for later use;
(3) preparing 25% sodium hydroxide solution by using purified water according to the prescription amount;
(4) emulsification: measuring the balance of purified water, adding the purified water into the oil phase prepared in the step (2), setting the slow stirring and wall scraping stirring speed to be 50 revolutions per minute, starting emulsification after stirring for 5 minutes and keeping the slow stirring and wall scraping stirring speed unchanged, wherein the speed is 2000 revolutions per minute, the high-speed emulsification is carried out for 3 minutes every 1 minute, and the accumulated time is not less than 12 minutes;
(5) and (3) adding the water phase prepared in the step (1) into the emulsion prepared in the step (4), stirring for 10 minutes, then setting the slow stirring and wall scraping stirring to 60 revolutions per minute, slowly adding the sodium hydroxide solution prepared in the step (3), continuously stirring for half an hour, discharging, and performing a subsequent filling process to obtain the compound lidocaine cream pharmaceutical composition.
The following items were monitored simultaneously during the preparation to control the quality of the cream intermediate:
(1) the characteristics are as follows: white or off-white creams;
(2) pH value: directly measuring the emulsifiable paste, wherein the pH value is 8.7-9.7 (appendix VIH of the 2010 version two parts of Chinese pharmacopoeia);
(3) granularity: according to the first method of the appendix IXE of the 2010 version of the Chinese pharmacopoeia, emulsion drops and particles larger than 180 mu m cannot be detected;
(4) centrifugal stability: taking 5g of cream in a centrifugal tube, centrifuging at 4000r/min for 15min at a high speed, and avoiding oil-water stratification;
(5) mixing uniformity: taking 10 parts of cream, calculating the theoretical content relative to the labeled amount by peak area according to an external standard method, wherein the relative standard deviation of the content of 10 parts of samples is not more than 3.0%.
Example 6 substance examination
The compound lidocaine cream prepared by the embodiment of the invention is adopted to carry out long-term stability test investigation. The test was carried out for 18 months under the conditions of a long-term test (25. + -. 2 ℃ C., RH 40. + -. 5%) simulating a commercial package. The results of the detection of the relevant substances are shown in Table 1 below:
TABLE 1 records of the relevant substance investigation tests
As can be seen from Table 1, after the samples in the examples are placed for 18 months under the long-term test condition, the related substance o-toluidine is between 0.10% and 0.11%, the maximum unknown single impurity is between 0.02% and 0.05%, and other known impurities are not detected, which shows that the compound lidocaine cream has very low impurity content, the related substance o-toluidine is well controlled, the safety is good, and the product quality is greatly improved on the basis of the prior art.
Example 7 comparison of the Performance of several creams
The results of comparing the cream prepared in example 1 of the present invention with the cream prepared in example 1 and the commercially available EMLA in the preparation of the lidocaine cream prepared in example 1 of CN101209250A and CN101816642A, respectively, in terms of the shape of the product, the phase inversion temperature, the pH, whether the emulsion breaking and delamination occurs in the coating uniformity setting, and the like, are shown in the following table 2:
TABLE 2 comparison of the Properties of several creams
As can be seen from Table 2, the compound lidocaine cream prepared by the embodiment of the invention has the best combination property.
Example 8 allergy test and skin irritation test
Experimental materials:
test sample 1: in the compound lidocaine cream in this embodiment 1, the content of lidocaine and prilocaine are both 2.5%, the character is white cream, and the ph value is 8.9;
matrix control group: excipients without lidocaine or prilocaine, wherein the components are only auxiliary materials of the cream in the embodiment 1, and the cream is white in character;
③ comparison of commercial products: the content of lidocaine and prilocaine in the compound lidocaine emulsifiable paste EMLA sold in the market is 2.5%, the character is white emulsifiable paste, and the pH value is 9.7.
The purpose is as follows: and observing whether the local skin administration of the compound lidocaine emulsifiable paste has immunogenicity (anaphylaxis) and local irritation or not, evaluating the safety of the compound lidocaine emulsifiable paste, and providing a basis for clinical medication.
The method comprises the following steps:
(1) BT test:
60 guinea pigs were divided into 5 groups, namely, a test sample 1 group, a vehicle control group, a commercial product control group, a negative control group, and a positive control group, wherein the test sample 1 group contained 20 animals, and the remaining 4 control groups contained 10 animals. Animals were sensitized on days 1, 7, and 14, and challenged on day 14 after the last sensitization. The reaction at the site of application was observed immediately after removal of the drug, followed by visual observation and recording at 24, 48 and 72 hours after administration.
(2) Repeated administration skin irritation test:
the obvious stimulation phenomena such as erythema, edema and the like are not observed on the local appearance of the administration part of the animals with intact skin during the administration period and after the administration, and the average value of the skin irritation response scores of all groups is 0. The animals with damaged skin can see mild erythema and scabbing phenomena in the initial administration period (1-4 days), and no obvious difference exists among the groups. In the middle period of administration, erythema of each group except the commercial product control group gradually disappears, the healing time and degree of the skin are basically consistent, no obvious irritation reaction is seen on the skin after healing, and no obvious abnormality is seen on the skin in the observation period; the commercial control group had slower erythema disappearance and longer skin healing time.
And (4) conclusion: under the test condition, the BT test result of the compound lidocaine cream is negative; in the repeated administration skin irritation test, no obvious irritation is seen on normal and damaged skin of the white rabbit with big ears, and the irritation is weaker than that of a commercially available product.
Claims (2)
1. The preparation method of the compound lidocaine cream pharmaceutical composition is characterized in that each 10kg of the pharmaceutical composition contains:
the preparation method comprises the following steps:
(1) preparation of an aqueous phase: weighing carbomer according to the prescription amount, weighing purified water according to the prepared 0.5-2% carbomer aqueous solution, slowly adding carbomer into the purified water, and stirring for more than 1 hour to completely dissolve the carbomer to obtain a water phase;
(2) preparing an oil phase: weighing lidocaine and prilocaine according to a formula, putting the lidocaine and the prilocaine in a main pot, stirring and mixing uniformly at 40-50 ℃, and melting to obtain a transparent liquid, namely a lidocaine-prilocaine eutectic solution; completely melting the polyoxyethylene hydrogenated castor oil in the formula amount at 60 ℃, adding the melted polyoxyethylene hydrogenated castor oil into the eutectic mixture, and uniformly stirring to obtain an oil phase for later use;
(3) preparing 5-40% sodium hydroxide solution by using purified water according to the prescription amount;
(4) emulsification: weighing the residual purified water, adding the residual purified water into the oil phase prepared in the step (2), setting the slow stirring and wall scraping stirring speed to be 50 revolutions per minute, starting emulsification after stirring for 5 minutes at a constant slow stirring and wall scraping stirring speed of 2000 revolutions per minute at a high speed of 3 minutes every 1 minute, and keeping the cumulative time to be not less than 12 minutes;
(5) and (3) adding the water phase prepared in the step (1) into the emulsion prepared in the step (4), stirring for 10 minutes, then setting the slow stirring and wall scraping stirring to 60 revolutions per minute, slowly adding the sodium hydroxide solution prepared in the step (3), continuously stirring for half an hour, discharging, and performing a subsequent filling process to obtain the compound lidocaine cream pharmaceutical composition.
2. A process for the preparation of a compound lidocaine cream pharmaceutical composition as claimed in claim 1, wherein the following items are monitored during the preparation to control the quality of the cream intermediate:
(1) the characteristics are as follows: white or off-white creams;
(2) pH value: taking the product for direct measurement, wherein the pH value is 8.7-9.7;
(3) granularity: according to the first method of the appendix IXE of the 2010 version of the Chinese pharmacopoeia, emulsion drops and particles larger than 180 mu m cannot be detected;
(4) centrifugal stability: taking 5g of the product in a centrifugal tube, centrifuging at 4000r/min for 15min at a high speed, and avoiding oil-water stratification;
(5) mixing uniformity: taking 10 parts of the product, calculating the theoretical content relative to the labeled amount by peak area according to an external standard method, wherein the relative standard deviation of the content of the 10 parts of the sample is not more than 3.0%.
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| CN110585312A (en) * | 2019-10-18 | 2019-12-20 | 北京博达绿洲医药科技研究有限公司 | Liduodeoxyemulsion and preparation method and application thereof |
| CN112438963A (en) * | 2020-11-11 | 2021-03-05 | 长沙晶易医药科技有限公司 | External preparation of lidocaine-prilocaine pharmaceutical composition and application thereof |
| CN112704662B (en) * | 2021-02-05 | 2023-04-25 | 华熙生物科技股份有限公司 | Lidocaine emulsifiable paste, preparation method and application thereof |
| CN113398101B (en) * | 2021-07-30 | 2022-06-28 | 温州医科大学附属眼视光医院 | Compound lidocaine gel patch |
| CN114948862A (en) * | 2022-06-09 | 2022-08-30 | 北京中泰邦医药科技有限公司 | Compound tetracaine cream and preparation method thereof |
| CN116098882A (en) * | 2023-04-06 | 2023-05-12 | 山东诚创蓝海医药科技有限公司 | Composition containing lidocaine prilocaine and preparation method thereof |
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