CN119033735A - External preparation for local anesthesia and preparation method thereof - Google Patents
External preparation for local anesthesia and preparation method thereof Download PDFInfo
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- CN119033735A CN119033735A CN202310616746.4A CN202310616746A CN119033735A CN 119033735 A CN119033735 A CN 119033735A CN 202310616746 A CN202310616746 A CN 202310616746A CN 119033735 A CN119033735 A CN 119033735A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- A—HUMAN NECESSITIES
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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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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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明提供一种局部麻醉外用制剂，其包含复方成膜基质、麻醉药剂以及填充剂，所述麻醉药剂为利多卡因或其盐以及丁卡因或其盐，相对于局部麻醉外用制剂总重量，以质量比计，利多卡因或其盐含量为3～7％，丁卡因或其盐含量为3～5％，复方成膜基质为聚乙烯醇和聚乙烯吡咯烷酮的组合物。本发明实现了基质的稳定性提升，并且提高了有效成分的稳定性。The present invention provides a local anesthetic external preparation, which comprises a composite film-forming matrix, an anesthetic agent and a filler, wherein the anesthetic agent is lidocaine or its salt and tetracaine or its salt, and relative to the total weight of the local anesthetic external preparation, by mass ratio, the content of lidocaine or its salt is 3-7%, the content of tetracaine or its salt is 3-5%, and the composite film-forming matrix is a composition of polyvinyl alcohol and polyvinyl pyrrolidone. The present invention realizes the improvement of the stability of the matrix and improves the stability of the active ingredient.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a local anesthetic external preparation for being coated on skin and a preparation method thereof.
Background
Local anesthetics are those drugs that temporarily, completely, and reversibly block nerve conduction within a defined range of the human body, i.e., lose sensation in a certain part of the human body without loss of consciousness, in order to facilitate surgical procedures. The local anesthetic and the general anesthetic are basically different in that after the local anesthetic is combined with certain specific parts on a sodium ion channel on a nerve membrane, the sodium ion passing through the sodium ion channel is reduced to change the nerve membrane potential, so that the conduction of nerve impulse is blocked, and finally, the anesthesia effect is realized, and the general anesthetic plays an anesthesia role by affecting the physical properties of the nerve membrane, such as the fluid property, permeability and the like of the membrane.
The lidocaine tetracaine compound cream (trade name Pliaglis) marketed in U.S. in 2006 contains the highest anesthetic component (lidocaine 7%, tetracaine 7%) among all local anesthetic cream products, and is mainly used for local anesthesia of intact skin prior to adult superficial skin surgery (e.g. dermal filler injection, pulsed dye laser treatment, facial laser resurfacing and laser-assisted tattoo removal). Lidocaine or a pharmaceutically acceptable salt thereof is an amide type local anesthetic which stabilizes the neuronal membrane by inhibiting ion flux generated by impulse initiation and conduction. After percutaneous administration, lidocaine or its medicinal salt penetrates into intact skin, the penetration amount is enough to produce analgesic effect but insufficient to produce intact nerve block, and tetracaine has stronger local anesthesia effect because of ester local anesthesia, can penetrate mucous membrane, and has quicker effect. Pliaglis has been marketed in multiple countries worldwide because of the superior effect achieved by the combination of the two formulations of Pliaglis. Pliaglis is characterized in that after being smeared on skin, the film can be formed along with the volatilization of surface moisture, and the film can be easily peeled off after 30 minutes without paste residue, thereby being convenient for clinical use and improving the compliance of patients.
However, the local anesthetic ingredients in this formulation are unstable, and in particular tetracaine is susceptible to hydrolysis, resulting in poor stability of the entire formulation. Various attempts to improve the stability of the prescription components often lead to a decrease in physical stability (thermodynamic stability), which is a topical patch that is difficult to use. In addition, pliaglis is more irritating, and the most common topical reactions noted in the specification are erythema (47%), skin discoloration (16%) and oedema (14%). The inventors found in the study that the cream formulated with reference to Pliaglis prescription (7% lidocaine +7% tetracaine) did have significant irritation, with a probability of 95% irritation after 60 minutes of application to the skin of volunteers after ear, whereas the blank cream was non-irritating, indicating that irritation is caused by the drug, requiring development of a more appropriate formulation for efficacy and irritation.
Therefore, how to develop the external preparation for local anesthesia with good thermodynamic stability, good formula component stability and good body adaptability is still a technical problem to be solved urgently.
Disclosure of Invention
The invention aims to overcome the defects of the existing pharmaceutical preparation in treatment and use, and provides a local anesthetic external preparation with good thermodynamic stability, good formula component stability and good body adaptability, and particularly provides a local anesthetic external preparation which comprises a compound film forming matrix, an anesthetic agent and a filler, wherein the anesthetic agent is lidocaine or salt thereof and tetracaine or salt thereof, and the content of the lidocaine or salt thereof is 3-7% and the content of the tetracaine or salt thereof is 3-5% in terms of mass ratio relative to the total weight of the local anesthetic external preparation, and the compound film forming matrix is a composition of polyvinyl alcohol and polyvinylpyrrolidone. In a preferred embodiment of the present invention, the polyvinyl alcohol content is 6 to 15% and the polyvinylpyrrolidone content is 0 to 9% by mass relative to the total weight of the external preparation for local anesthesia.
The filler is one or more selected from calcium sulfate, calcium carbonate, calcium bicarbonate, calcium phosphate, calcium hydrophosphate, aluminum hydroxide, titanium pigment, mica powder, talcum powder, kaolin, diatomite and microcrystalline cellulose.
Therefore, in a preferred embodiment of the present invention, the filler is calcium sulfate, and the content of calcium sulfate is 15 to 35% by mass relative to the total weight of the external preparation for local anesthesia.
The film-forming matrix of the present invention may further contain various pharmaceutically acceptable additives, without affecting the effect of the present invention. Examples of such additives include a preservative, a humectant, an emulsifier, and a filler. For example, as the preservative, one or more of parabens, sorbic acid and its salts, hydroxybenzoic acid and its esters (e.g., methylparaben, ethylparaben, propylparaben, etc.), and benzalkonium chloride may be used, and generally, the content may be 0.05 to 0.2% by mass based on the total weight of the external preparation for local anesthesia, but the content is not limited thereto, and whether or not it is contained and the content may be selected as required by those skilled in the art.
The humectant may be, for example, one or more of glycerin, propylene glycol, butylene glycol, hexylene glycol, vaseline, and hyaluronic acid, and may be contained in an amount of 3 to 10% by mass based on the total weight of the external preparation for local anesthesia, but the content is not limited thereto, and whether or not the content is contained or the content is selected as required by those skilled in the art.
The emulsifier may be, for example, one or more of tween, span, polyoxyethylene castor oil, polyethylene glycol 54-hydrogenated castor oil, and polyethylene glycol 15-hydroxystearate, and the content is 3 to 6% by mass relative to the total weight of the external preparation for local anesthesia, but the content is not limited, and whether or not it is contained and the content can be selected by those skilled in the art as required.
The topical preparations of the present invention are useful for local analgesia and/or for local anesthesia. The method is used for local pain relief in skin surface surgery, wherein the skin surface surgery comprises the steps of skin filler injection, pulse dye laser treatment, facial laser surface reconstruction or laser assisted tattoo removal, the local anesthesia comprises the step of local anesthesia of a cortex, the step of local anesthesia of the cortex comprises the step of needle puncture or shallow surgery, and the step of needle puncture comprises the step of placing a catheter or taking a blood sample.
In another aspect of the present invention, there is provided a method for preparing a local anesthetic external preparation, comprising the steps of:
A drug-carrying granule forming step of heating and mixing lidocaine or a salt thereof, tetracaine or a salt thereof to form a eutectic mixture, and then adding an emulsifier to obtain a mixture 1;
A compound film forming matrix forming process, namely mixing polyvinyl alcohol with water, heating and stirring the mixture to dissolve the mixture at a temperature below 100 ℃, cooling the mixture to room temperature, adding polyvinylpyrrolidone, stirring the mixture to dissolve the mixture, adding a filler, a preservative and a humectant which are optional components, and forming a mixture 2;
and a mixing step of mixing the mixture 1 and the mixture 2 to homogenize the mixture, thereby obtaining a local anesthetic external preparation.
Compared with the prior art, the invention has the following advantages:
1. The physical stability (i.e. thermodynamic stability) of the medicament can be improved by adopting the compound film forming agent.
2. Calcium sulfate is used as a medicine filling agent, so that the chemical stability of the medicine is improved.
3. The stability of the formulation of the present invention is superior to the marketed product Pliaglis.
Detailed Description
In the present invention, lidocaine or its salt and tetracaine or its salt are not different from the prior art, and commonly used lidocaine hydrochloride, tetracaine hydrochloride and the like can be used, but are not limited to these specific salts. The weight content of lidocaine and tetracaine is calculated as the actual content of lidocaine and tetracaine in the salt (i.e., if tetracaine hydrochloride is used, the weight of the hydrochloric acid portion of tetracaine hydrochloride is not calculated in the content of tetracaine).
In the present invention, in order to reduce the irritation of tetracaine, the concentration is preferably controlled to 5% or less, and in view of the principle that the local anesthetic effect is better as the drug concentration is higher, the compound ratio is preferably 3 to 7% of lidocaine or its salt and 3 to 5% of tetracaine or its salt.
The material selection of the compound film forming matrix is an important characteristic of the invention, and in the invention, the inventor unexpectedly discovers that the compound film forming agent can improve the thermodynamic stability of the medicine, and the chemical stability of the medicine with active ingredients can be obviously improved by taking calcium sulfate as the filler of lidocaine and tetracaine. In the high-speed centrifugation experiment, compared with the single film forming agent, the medicine of the compound film forming agent is not easy to phase separate. The inventors speculate that it may be the reason that polyvinyl alcohol in combination with polyvinylpyrrolidone, in addition to being a film former, is also a commonly used surfactant or stabilizer, which is more favorable for oil droplet stabilization than polyvinyl alcohol alone, thereby effectively preventing the oil phase from aggregating.
The filler plays a role in shaping in the present invention, so that the physical properties of the matrix of polyvinyl alcohol and polyvinyl pyrrolidone can be adjusted to a range of physicochemical parameters suitable for the external preparation for skin. However, the inventors have further found that the use of a specific filler, calcium sulfate, not only allows adjustment of the physicochemical parameters, but also improves stability. In the high-temperature acceleration experiment, the stability of the formula using calcium sulfate as the filler is obviously improved compared with the formula using other fillers such as common calcium hydrophosphate as the filler. The filler is generally inert, the situation that the stability of the formula is obviously affected is rare, and the eutectic mixture of the anesthetic agent can possibly react with calcium hydrophosphate, and further the problem that the effective components are easily degraded to generate impurities is found out, while the calcium sulfate used as the filler can not cause the acceleration of chemical degradation, so that the drug is not easily degraded, thereby obviously improving the stability of the drug. The calcium sulfate content is 15-35% in terms of mass ratio relative to the total weight of the local anesthetic external preparation, so that the external preparation has a good drug stability effect. When the compound matrix of the invention is further matched, good thermodynamic stability and prescription chemical stability can be realized, and the compound matrix is the most preferable implementation mode of the invention.
The film-forming matrix of the present invention may further contain various pharmaceutically acceptable additives without affecting the effect of the present invention. Examples of such additives include a preservative, a humectant, an emulsifier, and a filler. For example, the preservative may be one or more of nipagin, sorbic acid and its salts, hydroxybenzoic acid and its salts/esters, and benzalkonium chloride, and in general, the content may be 0.05 to 0.2% by mass relative to the total weight of the external preparation for local anesthesia, but the content is not limited thereto, and whether or not the content is contained and the content may be selected as required by those skilled in the art.
The reagent for dissolving the drug may be, for example, one or more of methanol, ethanol, isopropanol, and chloroform.
The humectant may be, for example, one or more of glycerin, propylene glycol, butylene glycol, hexylene glycol, vaseline, and hyaluronic acid, and may be contained in an amount of 3 to 10% by mass based on the total weight of the external preparation for local anesthesia, but the content is not limited thereto, and whether or not the content is contained or the content is selected as required by those skilled in the art.
The emulsifier may be, for example, one or more of tween, span, polyoxyethylene castor oil, polyethylene glycol 54-hydrogenated castor oil, and polyethylene glycol 15-hydroxystearate, and the content is 3 to 6% by mass relative to the total weight of the external preparation for local anesthesia, but the content is not limited, and whether or not it is contained and the content can be selected by those skilled in the art as required.
As a method for producing a local anesthetic external preparation, there can be mentioned a method for producing a local anesthetic external preparation comprising the steps of:
A drug-carrying granule forming step of heating and mixing lidocaine or a salt thereof, tetracaine or a salt thereof to form a eutectic mixture, and then adding an emulsifier to obtain a mixture 1;
A compound film forming matrix forming process, namely mixing polyvinyl alcohol with water, heating and stirring the mixture to dissolve the mixture at a temperature below 100 ℃, cooling the mixture to room temperature, adding polyvinylpyrrolidone, stirring the mixture to dissolve the mixture, adding a filler, a preservative and a humectant which are optional components, and forming a mixture 2;
and a mixing step of mixing the mixture 1 and the mixture 2 to homogenize the mixture, thereby obtaining a local anesthetic external preparation.
The invention provides a local anesthesia external preparation with good thermodynamic stability, good formula component stability and good body adaptability, which can be used for external local anesthesia and local pain relief in any form, and the local pain relief can be used for local pain relief in skin surface surgery.
In order to further explain the elements of the present invention, the following examples are given, but the scope of the present invention is not limited to the following examples.
Examples
Example 1-screening of Compound film Forming agent ratio, stability improvement
Prescriptions were designed wherein the total weight per prescription sample was 100g.
The preparation process comprises the following steps:
1. mixing lidocaine and tetracaine with a prescription amount, heating and melting in water bath at 60 ℃, adding span 80, and stirring and mixing uniformly to obtain a mixture 1;
2. polyvinyl alcohol, methylparaben and propylparaben are added into the purified water, and the mixture is stirred and dissolved in water bath at 80 ℃. Cooling to room temperature, adding polyvinylpyrrolidone, stirring to dissolve, adding calcium hydrogen phosphate and vaseline, and stirring to obtain mixture 2.
3. Mixing the mixture 1 and the mixture 2, and stirring uniformly.
Discussion of results prescription 1, prescription 2, prescription 3 and prescription 4 were each filled with a small amount of paste and centrifuged at 10000rmp in a high speed centrifuge for 10min, with prescription 1 being significantly layered and prescription 2 being slightly layered, and prescription 3 and prescription 4 being not significantly layered. Taking a small amount of paste, centrifuging at 5000rmp for 10min in a high-speed centrifuge, wherein prescription 1 has layering, and prescriptions 2, 3 and 4 have no layering. The result shows that the thermodynamic stability of the system adopting the compound film forming agent is better than that of the single film forming agent.
Experiments further show that the film strength is weakened with the increase of the dosage of polyvinylpyrrolidone in the compound film forming agent. When the dosage exceeds 6%, the skin coating area exceeds 20cm 2, and the film is difficult to be removed at one time after film formation. Therefore, the amount of polyvinylpyrrolidone is preferably 0 to 6%.
Example 2-screening for additional fillers.
The recipe is designed as follows, wherein the total weight per recipe sample is 100g.
The preparation process is the same as in example 1.
And (3) respectively taking a small amount of paste of a marketed product Pliaglis, a prescription 1-2 and a prescription 5-9, sealing, and then placing in a 40 ℃ oven for an acceleration test. After 10 days, the sample was taken out and analyzed for its related substances by high performance liquid chromatography.
The analysis results were as follows:
| Prescription (filling agent) | 0 Day total impurity% | 40 ℃ To 10 days total impurity% | Impurity increase% compared to day 0 |
| Pliaglis (calcium hydrophosphate) | 4.14 | 6.99 | 2.85 |
| 1 (Calcium hydrophosphate) | 0.77 | 2.59 | 1.82 |
| 2 (Calcium hydrophosphate) | 0.70 | 2.47 | 1.77 |
| 5 (Calcium sulfate) | 0.55 | 1.46 | 0.91 |
| 6 (Calcium carbonate) | 0.85 | 2.37 | 1.52 |
| 7 (Calcium bicarbonate) | 1.04 | 3.17 | 2.13 |
| 8 (Talcum powder) | 0.96 | 3.35 | 2.39 |
| 9 (Kaolin) | 0.93 | 2.59 | 1.66 |
Discussion of results from the results of formulas 1 and 2, it is clear that the addition of polyvinylpyrrolidone has substantially no effect on the stability of the paste. The results of the formulas 5-9 show that the calcium sulfate is used as the filler, the paste has good stability, and the amount of impurities generated by degradation is minimum. Meanwhile, the prescription of the application has higher stability than the marketed products Pliaglis.
EXAMPLE 3 screening of calcium sulfate usage
Prescriptions were designed wherein the total weight per prescription sample was 100g.
The preparation process is the same as in example 1.
It was found in experiments that as the calcium sulfate content in the formulation increased, the cream viscosity increased. A small amount of paste is respectively applied on the backs of volunteers, and then the backs are laid flat or hung down, and the specific results are as follows:
| Prescription (calcium sulfate content) | Results after coating |
| 10(15%) | Flatly-placed back of hand, and paste slowly flows |
| 11(20%) | The ointment does not flow when the back of the hand is put flat, but can slowly flow when the ointment is put vertically |
| 12(25%) | Is not drool when being vertically placed |
| 13(30%) | The ointment is not drool when being dropped, but the ointment is slightly rough and astringent |
| 14(35%) | The ointment is coarse and astringent, and is coated with gravel feeling |
The result discussion shows that the calcium sulfate content is low, the paste is easy to flow, the calcium sulfate content is high, the paste is coarse, and the preferable content range of the calcium sulfate is 20-30%.
The present invention is described in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e., it does not mean that the present invention must be practiced depending on the above detailed methods. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (11)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310616746.4A CN119033735A (en) | 2023-05-29 | 2023-05-29 | External preparation for local anesthesia and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310616746.4A CN119033735A (en) | 2023-05-29 | 2023-05-29 | External preparation for local anesthesia and preparation method thereof |
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| Publication Number | Publication Date |
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| CN119033735A true CN119033735A (en) | 2024-11-29 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202310616746.4A Pending CN119033735A (en) | 2023-05-29 | 2023-05-29 | External preparation for local anesthesia and preparation method thereof |
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| CN (1) | CN119033735A (en) |
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2023
- 2023-05-29 CN CN202310616746.4A patent/CN119033735A/en active Pending
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