CN114948862A - Compound tetracaine cream and preparation method thereof - Google Patents
Compound tetracaine cream and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
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Abstract
The invention discloses a compound tetracaine emulsifiable paste, which comprises the following components in parts by weight with a pH value of 7.6-8.5: lidocaine accounts for 1-10% of the total weight of the cream, tetracaine accounts for 1-10% of the total weight of the cream, myricetin accounts for 3-7% of the total weight of the cream, cadherine terpene accounts for 2-6% of the total weight of the cream, and other transdermal enhancers account for 2.2-3.5% of the total weight of the cream; the oil phase composition accounts for 8-12% of the total weight of the emulsifiable paste, the water phase composition accounts for 6-10% of the total weight of the emulsifiable paste, and 2mol of sodium hydroxide solution and tween-80 account for 3-9% of the total weight of the emulsifiable paste. The invention can be used for epidermal anesthesia before puncture, has quick effect and long slow release time, can effectively relieve the pain of a patient and makes the body feel comfortable.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to compound tetracaine cream and a preparation method thereof.
Background
Currently, patients need to be injected for local anesthesia in clinical puncture (puncture examination such as bone marrow puncture or liver puncture), and then puncture examination is performed after injection; the injection punctures the skin, although the pain of subsequent puncture is relieved, the injection is locally numb, inconvenient, short in action time and slow in effect taking; subcutaneous injection is prone to severe allergic reactions.
In order to solve the serious allergic reaction generated by local anesthesia during injection, the commonly used emulsifiable paste and gel for epidermal anesthesia are the composition of lidocaine and prilocaine, the composition can be used for superficial analgesia and oral local anesthesia, both of the lidocaine and the prilocaine are amide local anesthetics, and the composition can block the generation and conduction of nerve impulse by blocking a sodium ion channel, limiting the sodium ion channel and limiting the internal flow of sodium ions, thereby playing the role of local anesthesia or analgesia. The lidocaine and the prilocaine can form an oily eutectic substance in a certain proportion, the acting time is 1 hour, compared with the single use of two medicines, the eutectic substance has better transdermal absorption effect, the drug effects of the lidocaine and the prilocaine are improved to a certain extent, the combined use reduces the using amount of the lidocaine and the prilocaine, the adverse reaction and toxic and side effect occurrence rate of the lidocaine and the prions are reduced, the medication safety is improved, the occurrence probability of anaphylactic reaction is reduced, but the acting is slow, and the local anesthesia effect can not be achieved after the lidocaine and the prilocaine are erased, so the lidocaine and the prilocaine are less used for emergency examination type anesthesia.
Disclosure of Invention
The invention aims to provide a compound tetracaine emulsifiable paste and a preparation method thereof, and aims to solve the technical problems of how to provide an emulsifiable paste which can be used for epidermal anesthesia before puncture, has quick response and long slow release time, can effectively relieve the pain of a patient and ensure comfortable body feeling; and how to prepare the cream.
In order to achieve the purpose, the invention adopts the following technical scheme; the invention provides a compound tetracaine emulsifiable paste, which comprises the following components in parts by weight with a pH value of 7.6-8.5: lidocaine accounts for 1-10% of the total weight of the cream, tetracaine accounts for 1-10% of the total weight of the cream, myricetin accounts for 3-7% of the total weight of the cream, cadherine terpene accounts for 2-6% of the total weight of the cream, and other transdermal enhancers account for 2.2-3.5% of the total weight of the cream; the oil phase composition accounts for 8-12% of the total weight of the emulsifiable paste, the water phase composition accounts for 6-10% of the total weight of the emulsifiable paste, and 2mol of sodium hydroxide solution and tween-80 account for 3-9% of the total weight of the emulsifiable paste.
Preferably, the cream with the pH value of 7.6-8.5 comprises the following components: lidocaine accounts for 7% of the total weight of the cream, tetracaine accounts for 7% of the total weight of the cream, myricetin accounts for 3% of the total weight of the cream, daphnetin accounts for 3% of the total weight of the cream, and other skin penetration enhancers account for 2.8% of the total weight of the cream; the oil phase composition accounts for 8.6 percent of the total weight of the emulsifiable paste, the water phase composition accounts for 6.5 percent of the total weight of the emulsifiable paste, 2mol of sodium hydroxide solution and tween-80 accounts for 3 to 9 percent of the total weight of the emulsifiable paste.
Preferably, the water phase composition consists of the following raw materials in parts by weight: 0.2-1.5 parts of high-substituted hydroxypropyl cellulose, 1-3.5 parts of glycerol, 0.08-0.095 part of xanthan gum, 0.5-0.8 part of triethanolamine and 5-10 parts of sterile deionized water.
Preferably, the oil phase composition consists of the following raw materials in parts by weight: 2.1-5.3 parts of yellow vaseline and 2.5-5.8 parts of lanolin.
Preferably, the other transdermal enhancer is terpineol and/or alpha-bisabolol.
Tetracaine belongs to ester local anesthetics, is a long-acting local anesthetic, has strong penetrating power, is mainly used for mucous membrane surface anesthesia in operations of stomatology, otolaryngology, ophthalmology and the like, and has stronger local anesthetic action than procaine and is 10 times larger than the procaine. It is also more toxic, 10-12 times more than procaine. Can permeate mucosa, has quick action and takes effect within 1-3 minutes. And can be maintained for 2-3 hours. Dissolving in ethanol.
The lidocaine belongs to amide local anesthetics, is a middle-effect local anesthetic, has the anesthesia time of 60-90 minutes, and has the advantages of quick response, wide dispersion, no obvious blood vessel dilation effect and increased toxicity along with the increase of the concentration of the drugs. The clinical application is mainly used for local anesthesia, conduction block anesthesia, epidural anesthesia and arrhythmia resistance. Lidocaine has a slightly longer duration of action, less accumulation and lower toxicity. Dissolving in ethanol.
Myricetin is a flavonol natural compound, a yellow needle crystal, has a melting point of 324.0-325.5 ℃, is dissolved in methanol, ethanol, acetone or ethyl acetate, is slightly soluble in water and insoluble in chloroform and petroleum ether, and is easily oxidized and turns green when placed in the air. Myricetin has effects of scavenging free radicals, resisting oxidation, resisting thrombosis, resisting tumor, diminishing inflammation, resisting bacteria, and having nerve inhibition, and scientists begin to research the use of myricetin in medicine, food, health product and cosmetic. The American health product FYI is prepared by using myricetin as additive for preventing and treating arthritis and various inflammations, especially for pregnant and lactating women and infants, and is expected to be used as anti-inflammatory agent for special people to reduce toxic and side effects of western antibiotics.
The main components of the juniperberry terpene include sabinene, p-cymene, alpha-terpinene, alpha-pinene, etc. The ledum terpene also has remarkable transdermal promotion effect on fluocinolone acetonide, isoniazid, propranolol hydrochloride, diazepam and the like. The inventor finds that the ledumene has the effect of promoting the transdermal promotion of tetracaine in the research process.
Highly substituted hydroxypropyl cellulose: white or slightly yellowish or grey granules or fibrous powders. No odor, no smell, combustibility and thermoplasticity. Swelling in water to obtain transparent to milky viscous colloidal solution; thickening and stabilizing effects in aqueous dispersion systems; its water absorption is characterized by a low equilibrium moisture content.
Glycerin is a colorless, odorless, sweet, clear, thick liquid, chemically known as "glycerol". Glycerin is usually extracted from fats and oils. The glycerol has strong hygroscopicity, and pure glycerol can absorb 40% of water, so that a film can be formed when the glycerol is applied on the skin, the effects of isolating air and preventing water evaporation are achieved, and the water in the air can be absorbed. Therefore, people usually wear the glycerin on the skin surface exposed in the air such as hands, faces and the like in winter, so that the glycerin can keep the skin soft and elastic, is not damaged by dust, weather and the like and is dry, and plays a role in preventing the skin from being frostbitten. The glycerin and the high-substituted hydroxypropyl cellulose are crosslinked to form a gel matrix, so that the reaction time is shortened, and the production efficiency is improved.
The xanthan gum has the characteristics of thickening, suspending, emulsifying and stabilizing, and is the biological gum with the best performance. The property of xanthan gum is greatly influenced by the amount of pyruvate groups contained at the molecular side chain terminal. Xanthan gum has more functional groups than general polymers and exhibits unique properties under specific conditions. It has diverse conformations in aqueous solution and shows different characteristics under different conditions. Has the advantages of suspension property and emulsibility, good water solubility, thickening property, stability to heat, stability to acid and alkali, stability to enzymolysis reaction and the like.
Triethanolamine is used as a fiber treatment agent, an anticorrosive additive, a plasticizer, a photographic developer additive, an engine carbon deposition preventive, etc. As additives or anticorrosive agents for plasticizers, neutralizers, lubricants, and dispersants for dyes, resins, and the like. It can also be used as synthetic surfactant and stabilizer.
Yellow vaseline is a yellowish or yellow uniform cream-shaped substance, is odorless or almost odorless, has a greasy feeling when being contacted with skin, and has certain stringiness. Is easily soluble in benzene at about 35 deg.C, soluble in chloroform at about 35 deg.C, slightly soluble in diethyl ether, and hardly soluble in ethanol or water; can be used for preparing medicinal ointment and skin protecting ointment.
Lanolin: is a secreted grease attached to wool, is a yellowish or brownish yellow cream-shaped substance, and has stickiness, greasiness, faint and specific odor. It is easily soluble in chloroform or diethyl ether, and can be dissolved in hot ethanol. Can be rapidly absorbed by mucosa and skin, and has the advantages of good adhesion, stable property, water absorption, and no rancidity. Is an excellent cream matrix and emulsifier of water-in-oil emulsion, and the dosage is 5%. Because of its high viscosity, it is not suitable to be used as a base material alone because of the discomfort when applied to the local area, and it is often used in combination with vaseline to increase the water absorption and penetration of vaseline.
Terpineol: colorless viscous liquid or low melting point transparent crystal, is soluble in ethanol, and slightly soluble in water and glycerol. 1 part terpineol can be dissolved in 2 parts by volume of a 70% ethanol solution. Has lilac taste.
α -bisabolol: is a component existing in chamomile, and the anti-inflammatory effect of chamomile is mainly from alpha-bisabolol. Alpha-bisabolol has stability and good skin compatibility, and not only has anti-inflammatory property, but also has antibacterial activity. Can increase the penetrability of other medicines and improve the skin penetrability.
In addition, the invention also provides a preparation method of the compound tetracaine cream, which comprises the following specific steps.
a. Preparing an aqueous phase: weighing high-substituted hydroxypropyl cellulose with corresponding weight, dividing the high-substituted hydroxypropyl cellulose into 3 parts, adding all sterile deionized water into a stirrer, gradually adding the high-substituted hydroxypropyl cellulose into the stirrer in multiple times at the rotating speed of 2.5 ten thousand revolutions per minute, stirring for 8-12 minutes to obtain a, adding the a into glycerol, xanthan gum and triethanolamine, and heating the mixture in a water bath at the temperature of 85-88.5 ℃ for 8-15 minutes to obtain a water phase;
b. preparing an oil phase: weighing yellow vaseline and lanolin; adding the mixture into a water bath stirring tank, and stirring for 15 minutes at the water bath temperature of 80-92 ℃ to obtain an oil phase;
c. mixing the oil phase and the water phase; adding the water phase in the step a into a water bath stirring tank at 82 ℃, pouring the oil phase in the step b into the stirring tank for a plurality of times while stirring, wherein the whole stirring process is 17-23 minutes;
d. adding a small amount of dolichones and other skin penetration enhancers into tween-80, stirring at room temperature to mix well;
e. dissolving myricetin in ethanol with the ethanol content of 75-83%;
f. uniformly mixing lidocaine and tetracaine with the products obtained in the steps c, d and e, and adjusting the pH value to 7.6-8.5 by using 2mol of sodium hydroxide solution to obtain an intermediate product;
g. and f, filling the intermediate product in the step f, and sterilizing to obtain the product.
Preferably, the temperature of the sterile deionized water is 65-83 ℃.
Compared with the prior art, the invention has the following beneficial effects.
1, the tetracaine and the lidocaine are used together, so that the anesthesia time is shortened, the permeability of the anesthetic is higher, the onset time of the existing anesthetic formed by combining the lidocaine and the prilocaine is 1 hour, the prilocaine is replaced by the tetracaine, the anesthesia effect can be improved, the components are stable, the irritation to the skin is small, the anesthesia effect can be quickly achieved, and the waiting time of a patient in the anesthesia process is shortened.
2, the invention adopts the dosage form of cream, which is convenient to carry and use; furthermore, the yellow vaseline and the lanolin are used as the matrix, so that the permeability of the medicine to the skin can be enhanced, the concentration of the medicine on the skin, the joint cavity and the like can be improved, and the vaseline can be greasy by adding a proper amount of lanolin, so that a patient feels more comfortable.
3, the myricetin used in the invention has a nerve inhibition effect, the combined use of the myricetin and the lidocaine improves the onset time of the anesthetic, and the 30-minute onset time of the single combined use of the tetracaine and the lidocaine is reduced to 20 minutes and is improved by 10 minutes. The transdermal absorption efficiency of the medicine is improved; in addition, the anaphylactic reaction of the patients can be reduced.
4, the dolichol terpene is added in the invention, so that the onset time of the anesthetic can be further reduced, the transdermal absorption rate of the medicine can be improved, and the pain and the waiting time of a patient during puncture examination can be reduced.
6, the invention does not contain hormone components; tetracaine, lidocaine, myricetin, dolichol and other transdermal enhancers accumulate ion flow required by blocking nerve impulse generation and conduction at a cortical pain receptor and nerve endings to stabilize nerve cells, so that the anesthesia effect of the cortex is achieved, no corrosion and no stimulation are caused to the skin, and the clinical use safety is enhanced.
7, the cream of the invention has less preparation processes and short time, and reduces the labor cost of production to a certain extent.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention. The primary objects and other advantages of the invention may be realized and attained by the instrumentalities particularly pointed out in the specification.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
A first part: pharmaceutical formulation part
Example 1
The embodiment relates to compound tetracaine cream, and the cream with the pH value of 8.5 comprises the following components: lidocaine accounts for 10% of the total weight of the cream, tetracaine accounts for 10% of the total weight of the cream, myricetin accounts for 7% of the total weight of the cream, cadherine terpene accounts for 6% of the total weight of the cream, and other skin penetration enhancer accounts for 3.5% of the total weight of the cream; the oil phase composition accounts for 12% of the total weight of the cream, the water phase composition accounts for 10% of the total weight of the cream, 2mol of sodium hydroxide solution and tween-80 accounts for 9% of the total weight of the cream.
The water phase composition consists of the following raw materials in parts by weight: 1.5 parts of high-substituted hydroxypropyl cellulose, 3.5 parts of glycerol, 0.095 part of xanthan gum, 0.8 part of triethanolamine and 10 parts of sterile deionized water.
The oil phase composition is composed of the following raw materials in parts by weight: 5.3 parts of yellow vaseline and 5.8 parts of lanolin.
Other skin penetration enhancers are terpineol.
A preparation method of compound tetracaine cream comprises the following specific steps.
a. Preparing an aqueous phase: weighing high-substituted hydroxypropyl cellulose with corresponding weight, dividing the high-substituted hydroxypropyl cellulose into 3 parts, adding all sterile deionized water into a stirrer, gradually adding the high-substituted hydroxypropyl cellulose into the stirrer in multiple times at the rotating speed of 2.5 ten thousand revolutions per minute, stirring for 8-12 minutes to obtain a, adding the a into glycerol, xanthan gum and triethanolamine, and heating the mixture in a water bath at the temperature of 85-88.5 ℃ for 8-15 minutes to obtain a water phase;
b. preparing an oil phase: weighing yellow vaseline and lanolin; adding the mixture into a water bath stirring tank, and stirring for 15 minutes at the water bath temperature of 80-92 ℃ to obtain an oil phase;
c. mixing the oil phase and the water phase; adding the water phase in the step a into a water bath stirring tank at 82 ℃, pouring the oil phase in the step b into the stirring tank for a plurality of times while stirring, wherein the whole stirring process is 17-23 minutes;
d. adding a small amount of dolichones and other skin penetration enhancers into tween-80, stirring at room temperature to mix well;
e. dissolving myricetin in 75-83% ethanol;
f. dissolving lidocaine and tetracaine in ethanol, uniformly mixing the lidocaine and the tetracaine with the products obtained in the steps c, d and e, and adjusting the pH value to 7.6-8.5 by using 2mol of sodium hydroxide solution to obtain an intermediate product;
g. and f, filling the intermediate product in the step f, and sterilizing to obtain the product.
In this example, the temperature of the sterile deionized water was 68 ℃.
Example 2
The embodiment relates to a compound tetracaine cream, which is characterized in that the cream with the pH value of 8.2 comprises the following components in parts by weight: lidocaine accounts for 7% of the total weight of the cream, tetracaine accounts for 7% of the total weight of the cream, myricetin accounts for 3% of the total weight of the cream, daphnetin accounts for 3% of the total weight of the cream, and other skin penetration enhancers account for 2.8% of the total weight of the cream; the oil phase composition accounts for 8.6 percent of the total weight of the cream, the water phase composition accounts for 6.5 percent of the total weight of the cream, 2mol of sodium hydroxide solution and tween-80 accounts for 8 percent of the total weight of the cream.
The water phase composition consists of the following raw materials in parts by weight: 0.8 part of high-substituted hydroxypropyl cellulose, 1.8 parts of glycerol, 0.095 part of xanthan gum, 0.6 part of triethanolamine and 8 parts of sterile deionized water.
The oil phase composition is composed of the following raw materials in parts by weight: 3.7 parts of yellow vaseline and 3.8 parts of lanolin.
Other skin penetration enhancers are terpineol and alpha-bisabolol.
A preparation method of compound tetracaine cream comprises the following specific steps.
a. Preparing an aqueous phase: weighing high-substituted hydroxypropyl cellulose with corresponding weight, dividing the high-substituted hydroxypropyl cellulose into 3 parts, adding all sterile deionized water into a stirrer, gradually adding the high-substituted hydroxypropyl cellulose into the stirrer in multiple times at the rotating speed of 2.5 ten thousand revolutions per minute, stirring for 8-12 minutes to obtain a, adding the a into glycerol, xanthan gum and triethanolamine, and heating the mixture in a water bath at the temperature of 85-88.5 ℃ for 8-15 minutes to obtain a water phase;
b. preparing an oil phase: weighing yellow vaseline and lanolin; adding the mixture into a water bath stirring tank, and stirring for 15 minutes at the water bath temperature of 80-92 ℃ to obtain an oil phase;
c. mixing the oil phase and the water phase; adding the water phase in the step a into a water bath stirring tank at 82 ℃, pouring the oil phase in the step b into the stirring tank for a plurality of times while stirring, wherein the whole stirring process is 17-23 minutes;
d. adding a small amount of dolichones and other skin penetration enhancers into tween-80, stirring at room temperature to mix well;
e. dissolving myricetin in ethanol with the ethanol content of 75-83%;
f. dissolving lidocaine and tetracaine in ethanol, uniformly mixing the lidocaine and the tetracaine with the products obtained in the steps c, d and e, and adjusting the pH value to 7.6-8.5 by using 2mol of sodium hydroxide solution to obtain an intermediate product;
g. and f, filling the intermediate product in the step f, and sterilizing to obtain the product.
In this example, the temperature of the sterile deionized water was 78 ℃.
Example 3
The embodiment relates to a compound tetracaine cream, which comprises the following components in parts by weight, wherein the cream has a pH value of 7.6-8.5: lidocaine accounts for 5% of the total weight of the cream, tetracaine accounts for 5% of the total weight of the cream, myricetin accounts for 4.5% of the total weight of the cream, cadherine terpene accounts for 4.2% of the total weight of the cream, and other skin penetration enhancer accounts for 3.0% of the total weight of the cream; the oil phase composition accounts for 10% of the total weight of the cream, the water phase composition accounts for 7% of the total weight of the cream, 2mol of sodium hydroxide solution and Tween-80 accounts for 5% of the total weight of the cream.
The water phase composition consists of the following raw materials in parts by weight: 1 part of high-substituted hydroxypropyl cellulose, 2 parts of glycerol, 0.085 part of xanthan gum, 0.6 part of triethanolamine and 8 parts of sterile deionized water.
The oil phase composition is composed of the following raw materials in parts by weight: 3.8 parts of yellow vaseline and 3.2 parts of lanolin.
Other skin penetration enhancers are terpineol and alpha-bisabolol.
A preparation method of compound tetracaine cream comprises the following specific steps.
a. Preparing an aqueous phase: weighing high-substituted hydroxypropyl cellulose with corresponding weight, dividing the high-substituted hydroxypropyl cellulose into 3 parts, adding all sterile deionized water into a stirrer, gradually adding the high-substituted hydroxypropyl cellulose in steps at a rotating speed of 2.5 ten thousand revolutions per minute, stirring for 8-12 minutes to obtain a, adding the a into glycerol, xanthan gum and triethanolamine, and heating in a water bath at 85-88.5 ℃ for 8-15 minutes to obtain a water phase;
b. preparing an oil phase: weighing yellow vaseline and lanolin; adding the mixture into a water bath stirring tank, and stirring for 15 minutes at the water bath temperature of 80-92 ℃ to obtain an oil phase;
c. mixing the oil phase and the water phase; adding the water phase in the step a into a water bath stirring tank at 82 ℃, pouring the oil phase in the step b into the stirring tank for a plurality of times while stirring, wherein the whole stirring process is 17-23 minutes;
d. adding a small amount of dolichones and other skin penetration enhancers into tween-80, stirring at room temperature to mix well;
e. dissolving myricetin in ethanol with the ethanol content of 75-83%;
f. dissolving lidocaine and tetracaine in ethanol, uniformly mixing the lidocaine and the tetracaine with the products obtained in the steps c, d and e, and adjusting the pH value to 7.6-8.5 by using 2mol of sodium hydroxide solution to obtain an intermediate product;
g. and f, filling the intermediate product in the step f, and sterilizing to obtain the product.
In this example, the temperature of the sterile deionized water was 80 ℃.
Example 4
The embodiment relates to a compound tetracaine cream, which comprises the following components in parts by weight, wherein the cream has a pH value of 7.6-8.5: lidocaine accounts for 1-10% of the total weight of the cream, tetracaine accounts for 1% of the total weight of the cream, myricetin accounts for 3% of the total weight of the cream, cadherine terpene accounts for 2% of the total weight of the cream, and other transdermal enhancers account for 2.2% of the total weight of the cream; the oil phase composition accounts for 8% of the total weight of the emulsifiable paste, the water phase composition accounts for 6% of the total weight of the emulsifiable paste, 2mol of sodium hydroxide solution and tween-80 accounts for 3% of the total weight of the emulsifiable paste.
The water phase composition consists of the following raw materials in parts by weight: 0.2 part of high-substituted hydroxypropyl cellulose, 1 part of glycerol, 0.08 part of xanthan gum, 0.5 part of triethanolamine and 5 parts of sterile deionized water.
The oil phase composition is composed of the following raw materials in parts by weight: 2.1 parts of yellow vaseline and 2.5 parts of lanolin.
Other skin penetration enhancers are alpha-bisabolol.
A preparation method of compound tetracaine cream comprises the following specific steps.
a. Preparing an aqueous phase: weighing high-substituted hydroxypropyl cellulose with corresponding weight, dividing the high-substituted hydroxypropyl cellulose into 3 parts, adding all sterile deionized water into a stirrer, gradually adding the high-substituted hydroxypropyl cellulose into the stirrer in multiple times at the rotating speed of 2.5 ten thousand revolutions per minute, stirring for 8-12 minutes to obtain a, adding the a into glycerol, xanthan gum and triethanolamine, and heating the mixture in a water bath at the temperature of 85-88.5 ℃ for 8-15 minutes to obtain a water phase;
b. preparing an oil phase: weighing yellow vaseline and lanolin; adding the mixture into a water bath stirring tank, and stirring for 15 minutes at the water bath temperature of 80-92 ℃ to obtain an oil phase;
c. mixing the oil phase and the water phase; adding the water phase in the step a into a water bath stirring tank at 82 ℃, pouring the oil phase in the step b into the stirring tank for a plurality of times while stirring, wherein the whole stirring process is 17-23 minutes;
d. adding a small amount of dolichones and other skin penetration enhancers into tween-80, stirring at room temperature to mix well;
e. dissolving myricetin in ethanol with the ethanol content of 75-83%;
f. dissolving lidocaine and tetracaine in ethanol, uniformly mixing the lidocaine and the tetracaine with the products obtained in the steps c, d and e, and adjusting the pH value to 7.6-8.5 by using 2mol of sodium hydroxide solution to obtain an intermediate product;
g. and f, filling the intermediate product in the step f, and sterilizing to obtain the product.
In this example, the temperature of the sterile deionized water was 72 ℃.
Example 5
The embodiment relates to a compound tetracaine cream, which comprises the following components in parts by weight, wherein the cream has a pH value of 7.6-8.5: lidocaine accounts for 8% of the total weight of the cream, tetracaine accounts for 7% of the total weight of the cream, myricetin accounts for 5% of the total weight of the cream, cadherin terpene accounts for 5% of the total weight of the cream, and other skin penetration enhancer accounts for 3.2% of the total weight of the cream; the oil phase composition accounts for 11.5% of the total weight of the cream, the water phase composition accounts for 9% of the total weight of the cream, 2mol of sodium hydroxide solution and tween-80 accounts for 8.2% of the total weight of the cream.
The water phase composition consists of the following raw materials in parts by weight: 0.82 part of high-substituted hydroxypropyl cellulose, 2.3 parts of glycerol, 0.085 part of xanthan gum, 0.7 part of triethanolamine and 8 parts of sterile deionized water.
The oil phase composition is composed of the following raw materials in parts by weight: 4.3 parts of yellow vaseline and 3.8 parts of lanolin.
Other skin penetration enhancers are terpineol and alpha-bisabolol.
A preparation method of compound tetracaine cream comprises the following specific steps.
a. Preparing an aqueous phase: weighing high-substituted hydroxypropyl cellulose with corresponding weight, dividing the high-substituted hydroxypropyl cellulose into 3 parts, adding all sterile deionized water into a stirrer, gradually adding the high-substituted hydroxypropyl cellulose into the stirrer in multiple times at the rotating speed of 2.5 ten thousand revolutions per minute, stirring for 8-12 minutes to obtain a, adding the a into glycerol, xanthan gum and triethanolamine, and heating the mixture in a water bath at the temperature of 85-88.5 ℃ for 8-15 minutes to obtain a water phase;
b. preparing an oil phase: weighing yellow vaseline and lanolin; adding the mixture into a water bath stirring tank, and stirring for 15 minutes at the water bath temperature of 80-92 ℃ to obtain an oil phase;
c. mixing the oil phase and the water phase; adding the water phase in the step a into a water bath stirring tank at 82 ℃, pouring the oil phase in the step b into the stirring tank for a plurality of times while stirring, wherein the whole stirring process is 17-23 minutes;
d. adding a small amount of dolichones and other skin penetration enhancers into tween-80, stirring at room temperature to mix well;
e. dissolving myricetin in ethanol with the ethanol content of 75-83%;
f. dissolving lidocaine and tetracaine in ethanol, uniformly mixing the lidocaine and the tetracaine with the products obtained in the steps c, d and e, and adjusting the pH value to 7.6-8.5 by using 2mol of sodium hydroxide solution to obtain an intermediate product;
g. and f, filling the intermediate product in the step f, and sterilizing to obtain the product.
In this example, the temperature of the sterile deionized water was 76 ℃.
A second part: pharmacodynamic moiety
Control group 1
The embodiment relates to a cream for stopping bleeding and relieving pain of anus, which comprises the following components in parts by weight: lidocaine accounts for 10% of the total weight of the cream, tetracaine accounts for 10% of the total weight of the cream, myricetin accounts for 7% of the total weight of the cream, daphnetin accounts for 6% of the total weight of the cream, the oil phase composition accounts for 12% of the total weight of the cream, the water phase composition accounts for 10% of the total weight of the cream, 2mol of sodium hydroxide solution and tween-80 accounts for 9% of the total weight of the cream.
The water phase composition consists of the following raw materials in parts by weight: 1.5 parts of high-substituted hydroxypropyl cellulose, 3.5 parts of glycerol, 0.095 part of xanthan gum, 0.8 part of triethanolamine and 10 parts of sterile deionized water.
The oil phase composition is composed of the following raw materials in parts by weight: 5.3 parts of yellow vaseline and 5.8 parts of lanolin.
A preparation method of compound tetracaine cream comprises the following specific steps.
a. Preparing an aqueous phase: weighing high-substituted hydroxypropyl cellulose with corresponding weight, dividing the high-substituted hydroxypropyl cellulose into 3 parts, adding all sterile deionized water into a stirrer, gradually adding the high-substituted hydroxypropyl cellulose into the stirrer in multiple times at the rotating speed of 2.5 ten thousand revolutions per minute, stirring for 8-12 minutes to obtain a, adding the a into glycerol, xanthan gum and triethanolamine, and heating the mixture in a water bath at the temperature of 85-88.5 ℃ for 8-15 minutes to obtain a water phase;
b. preparing an oil phase: weighing yellow vaseline and lanolin; adding the mixture into a water bath stirring tank, and stirring for 15 minutes at the water bath temperature of 80-92 ℃ to obtain an oil phase;
c. mixing the oil phase and the water phase; adding the water phase in the step a into a water bath stirring tank at 82 ℃, pouring the oil phase in the step b into the stirring tank for a plurality of times while stirring, wherein the whole stirring process is 17-23 minutes;
d. adding a small amount of dolichol into tween-80, and stirring at room temperature to mix well;
e. dissolving myricetin in ethanol with the ethanol content of 75-83%;
f. dissolving lidocaine and tetracaine in ethanol, uniformly mixing the lidocaine and the tetracaine with the products obtained in the steps c, d and e, and adjusting the pH value to 7.6-8.5 by using 2mol of sodium hydroxide solution to obtain an intermediate product;
g. and f, filling the intermediate product in the step f, and sterilizing to obtain the product.
In this example, the temperature of the sterile deionized water was 69 ℃.
Control group 2
The embodiment relates to compound tetracaine cream, and the cream with the pH value of 8.5 comprises the following components: lidocaine accounts for 10% of the total weight of the cream, tetracaine accounts for 10% of the total weight of the cream, the oil phase composition accounts for 12% of the total weight of the cream, the water phase composition accounts for 10% of the total weight of the cream, 2mol of sodium hydroxide solution, and tween-80 accounts for 9% of the total weight of the cream.
The water phase composition consists of the following raw materials in parts by weight: 1.5 parts of high-substituted hydroxypropyl cellulose, 3.5 parts of glycerol, 0.095 part of xanthan gum, 0.8 part of triethanolamine and 10 parts of sterile deionized water.
The oil phase composition is composed of the following raw materials in parts by weight: 5.3 parts of yellow vaseline and 5.8 parts of lanolin.
A preparation method of compound tetracaine cream comprises the following specific steps.
a. Preparing an aqueous phase: weighing high-substituted hydroxypropyl cellulose with corresponding weight, dividing the high-substituted hydroxypropyl cellulose into 3 parts, adding all sterile deionized water into a stirrer, gradually adding the high-substituted hydroxypropyl cellulose into the stirrer in multiple times at the rotating speed of 2.5 ten thousand revolutions per minute, stirring for 8-12 minutes to obtain a, adding the a into glycerol, xanthan gum and triethanolamine, and heating the mixture in a water bath at the temperature of 85-88.5 ℃ for 8-15 minutes to obtain a water phase;
b. preparing an oil phase: weighing yellow vaseline and lanolin; adding the mixture into a water bath stirring tank, and stirring for 15 minutes at the water bath temperature of 80-92 ℃ to obtain an oil phase;
c. mixing the oil phase and the water phase; adding the water phase in the step a into a water bath stirring tank at 82 ℃, pouring the oil phase in the step b into the stirring tank for a plurality of times while stirring, wherein the whole stirring process is 17-23 minutes;
d. dissolving lidocaine and tetracaine in ethanol, uniformly mixing the lidocaine and the tetracaine with the product obtained in the step c, and adjusting the pH value to 7.6-8.5 by using 2mol of sodium hydroxide solution to obtain an intermediate product;
e. and d, filling the intermediate product in the step d, and sterilizing to obtain the product.
In this example, the temperature of the sterile deionized water was 82 ℃.
Control group 3
The embodiment relates to a compound tetracaine cream, which is characterized in that the cream with the pH value of 8.2 comprises the following components in parts by weight: lidocaine accounts for 7% of the total weight of the cream, tetracaine accounts for 7% of the total weight of the cream, cadinene accounts for 3% of the total weight of the cream, and other skin penetration enhancers account for 2.8% of the total weight of the cream; the oil phase composition accounts for 8.6 percent of the total weight of the cream, the water phase composition accounts for 6.5 percent of the total weight of the cream, 2mol of sodium hydroxide solution and tween-80 accounts for 8 percent of the total weight of the cream.
The water phase composition consists of the following raw materials in parts by weight: 0.8 part of high-substituted hydroxypropyl cellulose, 1.8 parts of glycerol, 0.095 part of xanthan gum, 0.6 part of triethanolamine and 8 parts of sterile deionized water.
The oil phase composition is composed of the following raw materials in parts by weight: 3.7 parts of yellow vaseline and 3.8 parts of lanolin.
Other skin penetration enhancers are terpineol and alpha-bisabolol.
A preparation method of compound tetracaine cream comprises the following specific steps.
a. Preparing an aqueous phase: weighing high-substituted hydroxypropyl cellulose with corresponding weight, dividing the high-substituted hydroxypropyl cellulose into 3 parts, adding all sterile deionized water into a stirrer, gradually adding the high-substituted hydroxypropyl cellulose into the stirrer in multiple times at the rotating speed of 2.5 ten thousand revolutions per minute, stirring for 8-12 minutes to obtain a, adding the a into glycerol, xanthan gum and triethanolamine, and heating the mixture in a water bath at the temperature of 85-88.5 ℃ for 8-15 minutes to obtain a water phase;
b. preparing an oil phase: weighing yellow vaseline and lanolin; adding the mixture into a water bath stirring tank, and stirring for 15 minutes at the water bath temperature of 80-92 ℃ to obtain an oil phase;
c. mixing the oil phase and the water phase; adding the water phase in the step a into a water bath stirring tank at 82 ℃, pouring the oil phase in the step b into the stirring tank for a plurality of times while stirring, wherein the whole stirring process is 17-23 minutes;
d. adding a small amount of dolichones and other skin penetration enhancers into tween-80, stirring at room temperature to mix well;
e. dissolving lidocaine and tetracaine in ethanol, uniformly mixing the lidocaine and the tetracaine with the steps c and d, and adjusting the pH value to 7.6-8.5 by using 2mol of sodium hydroxide solution to obtain an intermediate product;
f. and e, filling the intermediate product in the step e, and sterilizing to obtain the product.
In this example, the temperature of the sterile deionized water was 72 ℃.
2.1 test of skin irritation by Compound Tetracaine cream
2.1.1 test animals
30 rabbits with the weight of 2 kg-4 kg are taken, 15 rabbits are respectively used for male and female, the temperature in a laboratory is 25 +/-1 ℃, and the relative humidity is 65%.
2.1.2 test methods
Skin preparation: removing hair from two sides of spine of rabbit 24h before administration, wherein the area of hair removal is 15cm 2 After unhairing, checking whether the unhaired skin is scratched due to unhairing or not 24h, if the skin is injured, the rabbit is not suitable for performing an irritation experiment; removing with the tip of a sterilizing needleThe skin of rabbit with hair disinfection is lacerated into cross shape, and the wound size is no more than 10mm 2 The bleeding stopped, and the rabbits were used as a test for irritation of damaged skin.
The rabbits are fasted for 24h, subjected to clysis, and after the intestines are emptied, the rabbits' anus is wiped and sterilized.
Cutting the dehaired and sterilized rabbit anus with the tip of a sterilizing needle to form a cross-shaped wound with a size not more than 1mm 2 When blood exudation stops; the rabbit treated as described above was used for the irritation test.
In the test, the rabbits are divided into three groups, each group comprises 10 rabbits, and each group comprises five male rabbits and five female rabbits; 2g of compound tetracaine cream is smeared on a back wound of the rabbit, the state of the anus of the rabbit is recorded at 1 hour, 2 hours, 6 hours, 24 hours and 48 hours respectively, and the rabbit is not fed with water or fasted in the experimental process.
Selecting the largest amount of example 1 in parts by weight, adding no other transdermal enhancer on the basis of the example 1 to form a control group 1, adding no myricetin, cadherine terpene and other transdermal enhancer on the basis of the example 1 to form a control group 2, adding no myricetin on the basis of the example 2 to form a control group 3, and observing the administration of three groups of rabbits; the first group was applied to the affected part on the back of the rabbit using example 1 and control group 1, respectively, and the second group was applied to the affected part on the back of the rabbit using control group 1 and control group 2, respectively; the third group is applied to the affected part of rabbit anus and the affected part of rabbit back by using the control group 1 and the control group 3 respectively; test results the results of the rabbit back skin test are shown in table 1. Wherein, the back is coated with two drugs on the left and right sides of the anus respectively, and the left side is coated with the same drug as the anus.
TABLE 1 test results of irritation of Compound Tetracaine cream to dorsal skin
Therefore, compared with other compound tetracaine creams added with myricetin, the control group 2 and the control group 3 which are not added with myricetin are easy to generate anaphylactic reaction, are not beneficial to wound healing and are easy to cause inflammatory reaction on wounds.
2.2 drug efficacy test
2.2.1 test subjects
Randomly selecting 20 patients for a drug effectiveness test, wherein the age of the patients is 18-50 years, and 10 men and 10 women in the test.
2.2.2 Experimental procedures and results
Applying the ointment to ears and hands of a patient to be tested for 7 days, applying the ointment to the ears and the hands of the patient once every 12 hours, and recording the time of paralytic feelings of the patient; during the test, the patient normally takes food and water, and the patient with excessively long hair is combed. The patients were divided into two groups, 10 patients each, 5 men and 5 women, the first group of patients were applied with example 2 on the left hand and behind the left ear, the other side was applied with control group 3, the second group of patients were applied with example 1 on the left hand and behind the left ear, and the other side was applied with control group 2.
As a result of the experiment, the first group of patients had an average paralytic sensation on one side of example 2 for 8 to 10 minutes, and the control group 3 had an average paralytic sensation for 20 to 22 minutes.
The second group of patients had an average paralytic effect on one side of example 1 for 12-15 minutes, and on control group 2 for 30-35 minutes.
The patients had no skin damage except for red spots and slight red swelling on one side of the control group 3 and the control group 2.
It can be seen that the time for paralytic sensation is short and no wound red and swelling occurs in example 1 and example 2 compared to the two control groups, and the pharmaceutical composition is the same in example 1 and example 2, which shows that example 2 has faster onset of action, less irritation to the skin and no greater allergic reaction. Therefore, the anesthetic added with myricetin, cadherine and other transdermal enhancers can accelerate the paralysis generation time of patients and reduce the waiting time of patients in the puncture examination process.
In summary, the present invention is only a preferred embodiment, and not intended to limit the scope of the invention, and all equivalent changes and modifications in the shape, structure, characteristics and spirit of the present invention described in the claims should be included in the scope of the present invention.
Claims (7)
1. The compound tetracaine cream is characterized in that the cream with the pH value of 7.6-8.5 comprises the following components: lidocaine accounts for 1-10% of the total weight of the cream, tetracaine accounts for 1-10% of the total weight of the cream, myricetin accounts for 3-7% of the total weight of the cream, cadherine terpene accounts for 2-6% of the total weight of the cream, and other transdermal enhancers account for 2.2-3.5% of the total weight of the cream; the oil phase composition accounts for 8-12% of the total weight of the emulsifiable paste, the water phase composition accounts for 6-10% of the total weight of the emulsifiable paste, and 2mol of sodium hydroxide solution and tween-80 account for 3-9% of the total weight of the emulsifiable paste.
2. The compound tetracaine cream as claimed in claim 1, wherein the cream with the pH value of 7.6-8.5 comprises the following components: lidocaine accounts for 7% of the total weight of the cream, tetracaine accounts for 7% of the total weight of the cream, myricetin accounts for 3% of the total weight of the cream, daphnetin accounts for 3% of the total weight of the cream, and other skin penetration enhancers account for 2.8% of the total weight of the cream; the oil phase composition accounts for 8.6 percent of the total weight of the emulsifiable paste, the water phase composition accounts for 6.5 percent of the total weight of the emulsifiable paste, 2mol of sodium hydroxide solution and tween-80 accounts for 3 to 9 percent of the total weight of the emulsifiable paste.
3. The compound tetracaine cream as claimed in claim 2, wherein the aqueous phase composition is composed of the following raw materials in parts by weight: 0.2-1.5 parts of high-substituted hydroxypropyl cellulose, 1-3.5 parts of glycerol, 0.08-0.095 part of xanthan gum, 0.5-0.8 part of triethanolamine and 5-10 parts of sterile deionized water.
4. The compound tetracaine cream as claimed in claim 3, wherein the oil phase composition is composed of the following raw materials in parts by weight: 2.1-5.3 parts of yellow vaseline and 2.5-5.8 parts of lanolin.
5. The compound tetracaine cream of claim 4, wherein the other transdermal enhancer is terpineol and/or alpha-bisabolol.
6. A method for preparing a compound tetracaine cream as claimed in any one of claims 1-5, comprising the steps of:
a. preparing an aqueous phase: weighing high-substituted hydroxypropyl cellulose with corresponding weight, dividing the high-substituted hydroxypropyl cellulose into 3 parts, adding all sterile deionized water into a stirrer, gradually adding the high-substituted hydroxypropyl cellulose into the stirrer in multiple times at the rotating speed of 2.5 ten thousand revolutions per minute, stirring for 8-12 minutes to obtain a, adding the a into glycerol, xanthan gum and triethanolamine, and heating the mixture in a water bath at the temperature of 85-88.5 ℃ for 8-15 minutes to obtain a water phase;
b. preparing an oil phase: weighing yellow vaseline and lanolin; adding the mixture into a water bath stirring tank, and stirring for 15 minutes at the water bath temperature of 80-92 ℃ to obtain an oil phase;
c. mixing the oil phase and the water phase; adding the water phase in the step a into a water bath stirring tank at 82 ℃, pouring the oil phase in the step b into the stirring tank for a plurality of times while stirring, wherein the whole stirring process is 17-23 minutes;
d. adding a small amount of dolichones and other skin penetration enhancers into tween-80, stirring at room temperature to mix well;
e. dissolving myricetin in ethanol with the ethanol content of 75-83%;
f. uniformly mixing lidocaine and tetracaine with the products obtained in the steps c, d and e, and adjusting the pH value to 7.6-8.5 by using 2mol of sodium hydroxide solution to obtain an intermediate product;
g. and f, filling the intermediate product in the step f, and sterilizing to obtain the product.
7. The method for preparing a compound tetracaine cream as claimed in claim 6, wherein the temperature of the sterile deionized water is 65-83 ℃.
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