CN115531293A - Micro-emulsified high-viscosity stable gel plaster matrix and preparation method thereof - Google Patents

Micro-emulsified high-viscosity stable gel plaster matrix and preparation method thereof Download PDF

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CN115531293A
CN115531293A CN202211226373.1A CN202211226373A CN115531293A CN 115531293 A CN115531293 A CN 115531293A CN 202211226373 A CN202211226373 A CN 202211226373A CN 115531293 A CN115531293 A CN 115531293A
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stirring
parts
refining
water
mixing
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韩斌
丁坚英
王新娜
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Beijing Yi Cheng Medical Science And Technology Co ltd
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Beijing Yi Cheng Medical Science And Technology Co ltd
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    • 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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    • A61K31/404—Indoles, e.g. pindolol
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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
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract

The invention discloses a micro-emulsified high-viscosity stable gel plaster matrix and a preparation method thereof
Figure DDA0003879901850000011
The gel plaster matrix of the invention not only ensures the fusion of active ingredients and the matrix, but also enhances the water and moisture retention of the plaster matrix, and improves the adhesion with skin, comfort and sample stability, thereby promoting the transdermal absorption of the medicine and improving the treatment effect. The plaster substrate has simple production process and is suitable for industrial mass production.

Description

Micro-emulsified high-viscosity stable gel plaster matrix and preparation method thereof
The application is application number: 202110634955.2, filing date: 2021.06.08, title of invention: the invention discloses a micro-emulsified high-viscosity stable gel plaster substrate and a preparation method thereof, which are divided into separate application cases of Chinese invention patents.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a micro-emulsified high-viscosity stable gel plaster matrix and a preparation method thereof.
Background
The administration routes for human bodies are mainly divided into injection administration, oral administration and transdermal administration. The injection belongs to forced administration by external force, and directly enters blood circulation or tissue fluid of a human body, so the absorption speed is fastest, but the injection can cause wound to the human body, can generate irritant pain to tissues such as blood vessels, muscles and the like, and can possibly cause strong side effect reaction of the human body. The oral administration is convenient and safe, but the oral administration is absorbed by gastrointestinal tract, so that the gastrointestinal tract stimulation and the liver loss are caused, and the liver first-pass effect is realized. The transdermal drug delivery is transdermal drug delivery, absorption, safe and convenient drug delivery, has no problems of gastrointestinal tract liver stimulation injury and the like, slow drug release, low drug delivery frequency, durable drug delivery, directional drug delivery and higher drug delivery efficiency. The skin administration is mainly absorbed by human body through transdermal drug delivery, the drug forms are cream, plaster and patch, compared with cream, patch, traditional rubber paste, black plaster and the like, the gel plaster has the following advantages of (1) good biocompatibility with skin, high water content, comfort and ventilation, no sensitization and no irritation. (2) Large drug loading, good drug release performance, strong skin affinity, improved hydration of horny layer, and transdermal absorption of drug. (3) The transdermal absorption controlled release technology is applied, so that the blood concentration is stable and the drug effect is durable. (4) Convenient use, no pollution to clothes, easy washing and repeated sticking. (5) In the production process, other organic solvents such as gasoline and the like are not used, so that the pollution to the environment is avoided.
The gel plaster is a novel external application plaster with high technological content, wide application range and convenient use in the world at present. In the early seventies of the last century, some countries in japan, the usa and europe have begun to develop medical hydrogel patches, and with the rapid development of the pharmaceutical industry, the variety of drugs increases and the application range of various administration methods is also expanding.
The gel plaster which is on the market at home comprises:
Figure BDA0003879901830000011
Figure BDA0003879901830000021
the patent documents of the gel plaster which are published in China include:
Figure BDA0003879901830000022
Figure BDA0003879901830000031
Figure BDA0003879901830000041
although gel plaster products are on the market at present, the unreasonable types, proportion and preparation process of the auxiliary materials lead to the problems that the process parameters are not easy to control in the production process, the forming property and the spreading property of the plaster are poor, the produced product is easy to permeate, the plaster is rotten, the plaster remains skin, loses water, volatile oil in the matrix is easy to float on the surface of the matrix, the adhesion is poor, the percutaneous absorption is poor and the like, so that the affinity, the comfort, the percutaneous absorption rate and the treatment effectiveness of the product and the skin are influenced.
Although pressure-sensitive adhesive (pressure-sensitive adhesive) bands are added to increase the adhesion, the sub-sensitive adhesive is sensitive to allergy, inconvenient to use and expensive to produce. The inventor finds that the defects of the prior art can be overcome by adopting the method.
Disclosure of Invention
The invention aims to provide a microemulsion high-viscosity stable gel plaster matrix which has a simple production process, can well form and lock water of a plaster body, prevents the plaster body from being dehydrated and hardened, has excellent biocompatibility, affinity and air permeability to skin, promotes transdermal absorption of medicaments, and improves the treatment effect, and a preparation method thereof. In order to realize the purpose, the technical scheme of the invention is as follows:
a micro-emulsified high-viscosity stable gel plaster matrix comprises the following components: the drug comprises active ingredients of drugs, hydrophilic polymer framework materials, a humectant, a microemulsion matrix, a filler, an excipient, a cross-linking agent, a cross-linking regulator, a pH regulator, a tackifier and deionized water; wherein the weight percentage of each component is as follows
Figure BDA0003879901830000042
Wherein, the drugs include but are not limited to flurbiprofen, loxoprofen sodium, lidocaine, diclofenac epolamine, ketoprofen, indomethacin and the like;
the hydrophilic polymer skeleton material comprises one or more than two of polyacrylic acid, sodium polyacrylate and partially neutralized sodium polyacrylate, and the dosage is 2-10%, preferably 4-8%.
The humectant comprises one or more of glycerol, propylene glycol, and 1, 3-butanediol. The amount is 10-40%, preferably glycerol, and the amount is 25-35%.
The microemulsion matrix comprises two or more of crotamiton, oleum Menthae Dementholatum, glycerol, polysorbate 80, menthol, and Mentholum. Preferably, the microemulsion matrix is prepared by emulsifying crotamiton, peppermint oil, polysorbate 80 and glycerin, and the emulsifying temperature is 25-35 ℃.
The filler comprises one or more of kaolin, talcum powder, titanium dioxide, superfine silica gel powder and kaolin. The dosage is 1-30%, preferably talcum powder, and the dosage is 3-7%.
The cross-linking agent comprises one or more of dihydroxyaluminum, aluminum hydroxide, aluminum oxide and aluminum chloride. The dosage is between 0 and 0.5 percent, preferably 0.03 to 0.08 percent of dihydroxyaluminum glycolate.
The crosslinking regulator is edetate disodium, and mainly plays a role in regulating and controlling the crosslinking speed. The amount is 0 to 0.5%, preferably 0.005 to 0.02%.
The pH regulator is tartaric acid, lactic acid, malic acid, the dosage is 0.1-2%, preferably tartaric acid, the dosage is 1.0-1.5%. The tackifier is one or more of polyvinyl alcohol, carbomer, gelatin, polyacrylic acid solution, polyvidone solution, sodium carboxymethylcellulose, and methyl acrylate-acrylic acid 2-ethylhexyl copolymer resin emulsion. The amount is 2-15%, preferably methyl acrylate-acrylic acid 2-ethylhexyl copolymer resin emulsion, and the amount is 5-10%.
The excipient is one or more of carbomer, gelatin, acrylic acid grafted starch and polymer thereof. The amount is 1-6%, preferably 3-5% of acrylic acid grafted starch.
Wherein the microemulsion matrix is prepared from an oil phase, an emulsifier and an auxiliary emulsion. The oil phase includes, but is not limited to: one or more of peppermint oil, crotamiton, menthol, etc.; emulsifiers include, but are not limited to: one or more of polysorbate 80, span 83, span 85, and the like; the auxiliary emulsion is selected from: one or two of glycerol, propylene glycol and 1, 3-butanediol.
Preferably, the gel plaster matrix of the invention consists of:
Figure BDA0003879901830000051
Figure BDA0003879901830000061
most preferably, the gel plaster matrix of the present invention consists of:
Figure BDA0003879901830000062
the name terms are explained below:
NP700 is partially neutralized sodium polyacrylate and is a matrix skeleton crosslinking material.
Mat1 is acrylic acid grafted starch and is an excipient. Is a copolymer of starch grafted acrylic acid, is a super absorbent and has excellent water absorption and retention functions. It can absorb several hundred times or even several thousand times of its own weight of water, it can absorb water but is insoluble in water, insoluble in organic solvent, and its viscosity is relatively high in aqueous solution, so that it can be used as thickening agent and diluting agent. The principle of water absorption is mainly the superposition of physical adsorption and chemical adsorption of the resin, namely physical adsorption by the network structure swelling of the product and the forming and water locking of the paste by the hydrophilic group in the product, so that the paste is prevented from being dehydrated and hardened.
Mat2 is methyl acrylate-acrylic acid 2-ethylhexyl copolymer resin emulsion as tackifier. Improve the adhesion of the gel plaster to the skin.
Sodium carboxymethyl cellulose as adhesive. Is a cellulose derivative obtained by chemically modifying natural cellulose and is an important water-soluble polymer.
Glycerin, as a humectant. Glycerol is used in topical preparations mainly as a moisturizer and emollient.
Tartaric acid as pH regulator. Mainly used for dissolving Al 3+ A compound is provided.
Disodium edetate is a cross-linking modifier. It forms metal chelate with polyvalent metal compound to control the cross-linking reaction speed. Disodium edetate to make Al in colloid 3+ The concentration of (b) is reduced over a period of time, so that the rate of crosslinking is slowed, and the formation of colloids is delayed until after application. But edetate disodium chelated Al 3+ The reaction of (A) is reversible, and the edetate disodium converts Al after the paste is formed 3+ The glue is gradually released so as to gradually increase and decrease the glue strength.
Talcum powder is used as filler. The emulsion is mainly used for shaping paste, and can increase the stability of the shape of a product and increase the tensile strength. Aluminum glycollate as cross-linking agent. The cross-linking agent (aluminium ion) reacts with free carboxylic acid groups in the high molecular polymer, so that the macromolecular hydrophilic high molecular polymer is further cross-linked into a pseudoplastic gel with certain strength and elasticity, and the stability and viscoelasticity of the preparation are improved.
Oleum Menthae Dementholatum as penetration enhancer. After acting on the skin, the physical and chemical properties of the skin and the normal physiological structure of the skin can be changed to different degrees, so that the permeability of the skin is increased, and the blood circulation of subcutaneous capillaries is stimulated, thereby playing a role in promoting the penetration of skin in external preparations. Crotamiton, an anti-pruritic agent. Can be used for resisting allergy caused by partial active ingredients.
Polysorbate-80 as emulsifier. Is an oil/water emulsifier, and can be used as a solubilizer, a wetting agent, a dispersant, a stabilizer, etc. Deionized water as a solvent.
The invention further provides a preparation method of the gel plaster matrix, which comprises the following steps:
(1) Adding water into a pH value regulator, and stirring for dissolving;
(2) Dissolving active medicine in water under stirring;
(3) Mixing the oil phase, emulsifier and auxiliary emulsion at 25-35 deg.C, slowly adding water, and stirring to obtain microemulsion matrix;
(4) Adding a tackifier into deionized water, stirring and dispersing, and adding a cross-linking agent, stirring and dispersing;
(5) Taking hydrophilic polymer skeleton material, excipient, crosslinking regulator, filler, humectant and adhesive, stirring at a low speed, and mixing uniformly, and then increasing the stirring speed to mix uniformly; adding the step (1) and the step (2), uniformly mixing at a low speed, and then increasing the mixing speed to uniformly mix; adding the microemulsion matrix obtained in the step (3) for uniform mixing, and increasing the mixing speed for uniform mixing to form O/W type emulsifiable paste; finally adding the mixture obtained in the step (4) for uniform mixing;
(6) And after the refining is finished, coating by using an upper coating machine.
(7) Cutting, bagging and packaging.
Preferably, the preparation method comprises the following steps:
(1) 1.0-1.5 parts of tartaric acid is taken, added with water and stirred for dissolution;
(2) Adding water into the active drug, stirring and dissolving;
(3) Taking 1-3 parts of crotamiton, 0.3-0.7 part of polysorbate, 0.3-0.7 part of glycerol and 1-3 parts of deionized water, stirring at 25-35 ℃, slowly adding water, and uniformly stirring to obtain a microemulsion matrix;
(4) Adding 5-10 parts of Mat into deionized water, stirring and dispersing, and then adding 0.03-0.08 part of dihydroxyaluminum glycolate, stirring and dispersing;
(5) Taking 4-8 parts of NP, 1-5 parts of Mat, 0.005-0.02 part of edetate disodium, 3-7 parts of talcum powder, 25-35 parts of glycerol, 0.1-1 part of sodium carboxymethylcellulose and 0.1-0.3 part of titanium dioxide, stirring and mixing uniformly at a slow speed (10-15HZ, 2-4 min), and then increasing the stirring speed to mix uniformly (30-45Hz, 8-12 min); adding the step (1) and the step (2), uniformly mixing at a low speed (10-15Hz, 1-3 min), and then increasing the mixing speed to uniformly mix (30-45Hz, 8-12 min); then adding the microemulsion matrix obtained in the step (3) for uniformly mixing (10-15Hz, 1-3 min), and then improving the mixing speed for uniformly mixing (30-45Hz, 6-10 min) to form O/W type emulsifiable paste; finally, adding the mixture obtained in the step (4) for uniformly refining (30-45Hz, 8-12 min);
(6) And after the refining is finished, coating by using an upper coating machine.
(7) Cutting, bagging and packaging.
Most preferably, the preparation method of the invention comprises the following steps:
(1) 1.2 parts of tartaric acid is taken, added with water and stirred to be dissolved;
(2) Adding water into the active drug, stirring and dissolving;
(3) (3) stirring 2 parts of crotamiton, 0.5 part of polysorbate, 0.5 part of glycerol and 2 parts of deionized water at 25-35 ℃, slowly adding water, and uniformly stirring to obtain a micro-emulsion matrix;
(4) Adding 2 parts of Mat into deionized water, stirring and dispersing, and then adding 0.05 part of aluminum glyceroxide, stirring and dispersing;
(5) Taking 700 parts of NP, 1 part of Mat, 0.01 part of edetate disodium, 5 parts of talcum powder, 29.5 parts of glycerol, 0.5 part of sodium carboxymethylcellulose and 0.2 part of titanium dioxide, stirring and mixing uniformly at a slow speed (12HZ, 3min), and then increasing the stirring speed to mix uniformly (40Hz, 10min); adding the raw materials in the step (1) and the step (2), uniformly mixing at a low speed (12Hz, 2min), and then increasing the mixing speed to uniformly mix (40Hz, 10min); then adding the microemulsion matrix obtained in the step (3) for uniformly mixing (12Hz, 2min), and then increasing the mixing speed for uniformly mixing (40Hz, 8min) to form O/W type emulsifiable paste; finally, adding the mixture obtained in the step (4) for uniform refining (40Hz, 10min);
(6) After the completion of the refining, the coating is performed by an applicator.
(7) Cutting, bagging and packaging.
Compared with the gel plaster substrate in the prior art, the invention has the following advantages:
the invention selects the types and the proportion of the auxiliary materials, has easily controlled production process parameters, good paste formability and good spreadability, and is suitable for industrial mass production.
The gelatin, polyvinyl alcohol, sodium carboxymethylcellulose or povidone and the like adopted in the prior art have the defects of insufficient water absorption, poor water retention and moisture retention, poor adhesion and poor formability. In the production process, water spheres are formed after water phase is added, the phenomenon of solid-water two-phase separation is generated, the forming state is very different every time, and the stirring speed and the stirring time are not easy to control.
The invention adopts acrylic acid grafted starch with good water absorption and excellent water-locking and moisture-keeping properties, and after adding deionized water, the acrylic acid grafted starch can absorb water rapidly by means of hydrophilic groups to form and lock water, and has the advantages of good shaping effect, bubble-free paste, good coating and spreading properties, simple production process and easy operation.
The auxiliary materials selected by the invention are of the same type and proportion, so that the water-locking and moisture-preserving property is good, and the adhesion effect is strong; the coating and spreading performance is good.
The invention adopts the microemulsion matrix, reduces the volatilization of volatile oil, and ensures the constant release and transdermal absorption of the medicament. The volatile oil is used as a transdermal absorption enhancer in the gel plaster preparation, but the addition mode of the volatile oil has great influence on the transdermal absorption effect and the stability of the medicinal preparation. In the prior art, the volatile oil is usually directly added, but the volatile oil has the problems of easy volatilization, easy oxidation and the like, is easy to lose and deteriorate in the preparation and storage processes, and even has the phenomenon that the volatile oil floats on the surface of a matrix, so that the problems of poor adhesion, poor sensory comfort, poor transdermal absorption and the like of a gel plaster are caused. The matrix is prepared from volatile oil into microemulsion, so that the stability of the matrix is improved, and the therapeutic effect of the drug is improved.
The invention adopts hydrophilic pharmaceutic adjuvant, has no allergy and irritation to skin, and improves the medication safety of patients.
The solvent adopted by the invention is water, and no organic solvent is adopted, so that the method is safe and environment-friendly, and is beneficial to protecting the ecological environment.
Therefore, the technical scheme of the invention solves the problems of easy dehydration, insufficient viscosity, poor stability and the like of the gel plaster, and improves the compliance and the treatment effect of clinical use.
The most preferred gel plaster matrix composition of the present invention is obtained by screening.
Optimization and innovation are carried out by referring to the prescription composition of the marketed instruction of loxoprofen sodium gel plaster (trade name LOXONIN PAP) co-produced by Japan. The prescription composition is as follows: aluminum hydroxide, glycerin, talcum powder, partially neutralized sodium polyacrylate, sodium carboxymethylcellulose, tartaric acid, edetate disodium, peppermint oil, polysorbate 80, crotamiton, water, unknown 1 and unknown 2; wherein part of the sodium polyacrylate is a cross-linked framework material; aluminum hydroxide is used as a cross-linking agent; disodium edetate is a crosslinking regulator; tartaric acid as pH regulator; sodium carboxymethylcellulose is used as a tackifier; glycerin is used as a humectant; water as solvent and talcum powder as excipient; polysorbate-80 as emulsifier; peppermint oil is used as a penetrant; crotamiton is an anti-pruritic agent. The prescription composition list basically meets the types of substrates for preparing the emplastrum, but the common problems of the gel emplastrum at present are insufficient viscosity, even viscosity loss, poor skin following performance and poor stability, thereby causing poor effectiveness. At present, products on the market in China adopt pressure-sensitive adhesive bandage to assist samples to adhere to skin, which is inconvenient in clinical use and poor in medication compliance, and secondly, the pressure-sensitive adhesive is very easy to cause allergy and is easy to generate allergic reactions such as red, swelling, itching and the like after being used. Therefore, the existing gel plaster substrate needs to be optimized and innovated, the problems are solved, and finally, the product has good adhesion, good stability, good treatment effect and no allergy.
The direction of optimization and improvement is mainly performed according to the prescription (including composition and dosage) and the production process. First, we screened and examined the substrates of the commonly used thickening agents and viscosity increasing agents, such as carbomer, partially neutralized sodium polyacrylate, gelatin, polyvinyl alcohol, mat1, mat2, and the like.
Examples 1 to 6
The weight percentages of the required components are shown in Table 1
Figure BDA0003879901830000101
Figure BDA0003879901830000111
As a result:
first, first evaluation of experiment
Sample preparation: examples 1-6 gel plasters
The method comprises the following steps: each of the samples of examples was applied to the wrist of each volunteer subject for 10 total, and evaluated for film residue, skin-following property, use comfort, skin irritation, skin allergy, tearing pain, etc.
The initial evaluation results are shown in Table 2 below:
Figure BDA0003879901830000112
the results show that: the samples prepared by using the auxiliary materials such as polyvinyl alcohol, gelatin, carbomer and the like are poorer than the samples prepared by using Mat1 and Mat2 auxiliary materials. Therefore, the gel plaster prepared by selecting Mat1 and Mat2 auxiliary materials has good skin following performance and does not have the problems of allergy, stimulation and tearing pain.
Experiment two, initial adhesion force performance test (30 degree slope rolling ball method)
Sample preparation: EXAMPLES 1-6 gel plasters
The method comprises the following steps: taking samples, and determining the adhesion force according to 0952 of the four-part general rules of the 2020 edition of Chinese pharmacopoeia
The results of the initial adhesion measurement are shown in Table 3
Figure BDA0003879901830000121
As a result: the test results show that with Mat 1 When used together with Mat2, the tackifier has better effect than other tackifiers which are used singly or in combination.
Experiment three, release test
Sample preparation: EXAMPLES 1-6 gel plasters
The method comprises the following steps: the samples of examples 1 to 6 of the present invention were each used to determine the degree of release.
The instrument comprises the following steps: percutaneous absorption diffusion instrument and liquid chromatograph
The testing steps are as follows:
(1) The membrane was cut to an appropriate size, the test sample was applied to the outside, fixed to a Franz diffusion cell, and the supply cell and the receiving cell were connected and fixed. The receiving liquid preheated to 32 ℃ is added into the receiving tank.
(2) The diffusion cell holding the sample was placed in a water bath of a transdermal diffusion apparatus pre-warmed to 32 ℃ and magnetically stirred at 50 rpm.
(3) Samples were taken at 1h, 2h, 4h, 6h, 8h, 10h, 12h, and 24h, respectively. 1ml of the receiving solution was taken out and the same volume of the receiving solution was replenished. Filtering with water phase needle type filter membrane (polyethersulfone, 0.45 μm).
(4) Sampling and putting on a high performance liquid chromatograph for sample injection to carry out test analysis.
Chromatographic conditions are as follows:
a chromatographic column: octadecylsilane chemically bonded silica gel as filler
Mobile phase: water-acetonitrile-phosphoric acid =690:310:1
Detection wavelength: 220nm
Sample injection amount: 10 μ l
Flow rate: 1.0ml/min
Solvent: receiving liquid
Column temperature: 40 deg.C
Operating time: 12min
The release results are shown in Table 4
Figure BDA0003879901830000131
And (4) conclusion: in example 1 and example 3, burst release occurs in 6 hours, and the burst release of the drug causes excessive local drug concentration, increases side effects, ensures no safety, and can not be continuously administered, thereby achieving slow treatment effect. In example 2, the drug release speed is too slow, and the effectiveness of clinical medication cannot be guaranteed. Only the samples of examples 4, 5 and 6 are slowly and stably released, so that the effective and lasting administration of the medicine can be ensured, and the safety and the effectiveness of clinical medication can be ensured. However, examples 4 and 5 have problems of easy agglomeration and caking during the mixing process, generation of a large amount of bubbles, insufficient initial adhesion after sample preparation, rapid water loss, poor stability and the like. Therefore, only the example 6 is simple and convenient in the trial production process, and the quality of the sample after trial production is better.
The formula of the matrix is continuously optimized on the basis of the example 6 (examples 7-11), and the invention is further verified and demonstrated to provide the high-viscosity and stable gel plaster matrix which is suitable for industrial mass production and has the advantages of simple production process, rapid forming and water locking, prevention of dehydration and hardening of the plaster body, excellent biocompatibility, affinity, air permeability and transdermal absorption effect on the skin and the preparation method.
Examples 7 to 11
The required weight percentages of the components are shown in table 5 below, wherein the active components are: the loxoprofen sodium comprises active ingredients such as flurbiprofen, diclofenac epolamine, ketoprofen, indomethacin, etc., and the dosage of deionized water is adjusted according to the product specification.
Figure BDA0003879901830000132
Figure BDA0003879901830000141
First, first evaluation of experiment
Sample preparation: examples 7 to 11 Patches
The method comprises the following steps: each of the samples of examples was applied to the wrist of a volunteer subject (30 total), and evaluated for film residue, skin-following property, comfort in use, skin irritation, skin allergy, tearing pain, etc.
The initial results are shown in Table 6 below:
Figure BDA0003879901830000142
Figure BDA0003879901830000151
the results show that: with the increase of Mat1 dosage, the paste becomes thicker and the slurry stirring is limited, and the paste fluidity is poorer and the spreadability is slightly poorer when the paste is coated in example 10. With the increase of Mat2 dosage, the emplastrum has better viscosity and obviously increased following performance with skin. The overall results show that: the product of the invention has no film residue, better following property with skin, high viscosity, no irritation, no allergy, comfortable adhesion, no pain when being torn, repeated tearing and sticking, and the like.
Experiment two, initial adhesion force performance test (30 degree slope rolling ball method)
Sample preparation: examples 7 to 11 Patches
The method comprises the following steps: taking samples, and determining the adhesion force according to 0952 of the four-part general rules of the 2020 edition of Chinese pharmacopoeia
Initial adhesion results are shown in Table 7
Figure BDA0003879901830000152
As a result: the test results show that the initial viscosity increases significantly with the increase of the amount of the Mat1 and Mat2 prescriptions, but when the amount of the Mat1 reaches more than 5% (example 10), the paste is too thick and the initial viscosity increases more gradually.
Experiment III, weightlessness test
Sample preparation: examples 7 to 11
The method comprises the following steps: a sample prepared in a trial way is taken, the weight loss of the sample is measured, and the water retention property and the stability of the sample are inspected.
The weight loss results are shown in Table 8
Figure BDA0003879901830000153
As a result: the sample of example 11 had a water loss of 1.25% at 30 days, less than 2%, and less than the other samples.
Experiment four, release test
Sample preparation: example 11 sample
The method comprises the following steps: the release rate was measured by taking the sample of example 11 of the present invention and a commercially available preparation from a domestic manufacturer or a commercially available preparation from a Japanese manufacturer.
The instrument comprises the following steps: percutaneous absorption diffusion instrument and liquid chromatograph
Sample formulation:
experimental group a: self-prepared experimental group B: formulation experimental group C on the market at home: japanese commercial preparations
The test steps are as follows:
(5) The membrane was cut to an appropriate size, the test sample was applied to the outside, fixed to a Franz diffusion cell, and the supply cell and the receiving cell were connected and fixed. The receiving liquid preheated to 32 ℃ is added into the receiving tank.
(6) The diffusion cell holding the sample was placed in a water bath of a transdermal diffusion apparatus pre-warmed to 32 ℃ and magnetically stirred at 50 rpm.
(7) Samples were taken at 1h, 2h, 4h, 6h, 8h, 10h, 12h, and 24h, respectively. 1ml of the receiving solution was taken out and the same volume of the receiving solution was replenished. Filtering with water phase needle type filter membrane (polyethersulfone, 0.45 μm).
(8) Sampling and placing on a high performance liquid chromatograph for sample introduction and test analysis.
Chromatographic conditions are as follows:
and (3) chromatographic column: octadecylsilane chemically bonded silica gel as filler
Mobile phase: water-acetonitrile-phosphoric acid =690:310:1
Detection wavelength: 220nm
Sample introduction amount: 10 μ l
Flow rate: 1.0ml/min
Solvent: receiving liquid
Column temperature: 40 deg.C
Operating time: 12min
The release results are shown in table 9:
Figure BDA0003879901830000161
Figure BDA0003879901830000171
as a result: the in vitro release rate of the sample of example 11 was substantially identical to that of the commercially available formulation in Japan, and was superior to that of the commercially available formulation in China.
Experiment five, percutaneous absorption test
Sample preparation: example 11 sample
The method comprises the following steps: the results of transdermal absorption were measured and compared with a commercially available preparation obtained from a domestic manufacturer or a Japanese manufacturer, using the sample of example 11 of the present invention.
The instrument comprises the following steps: percutaneous absorption diffusion instrument and liquid chromatograph
Sample formulation:
experimental group a: self-prepared experimental group B: formulation experimental group C on the market at home: japanese commercial preparations
The test steps are as follows:
(1) And (3) taking a processed skin sample of the small fragrant pig, and soaking the small fragrant pig in normal saline for 2 hours.
(2) The skin sample was cut to an appropriate size, the test sample was applied to the outer side, and the skin sample was fixed to the Franz diffusion cell (the inner side of the skin sample faces the diffusion liquid), and the supply cell and the receiving cell were connected and fixed. The receiving liquid preheated to 32 ℃ is added into the receiving tank.
(3) The diffusion cell holding the sample was placed in a water bath of a transdermal diffusion apparatus pre-warmed to 32 ℃ and magnetically stirred at 50 rpm.
(4) Samples were taken at 2h, 4h, 8h, 10h, 12h, 24h, respectively. 1ml of the receiving solution was taken out and the same volume of the receiving solution was replenished.
(9) Sampling and putting on a high performance liquid chromatograph for sample injection to carry out test analysis.
Chromatographic conditions are as follows:
and (3) chromatographic column: octadecylsilane chemically bonded silica gel as filler
Mobile phase: water-acetonitrile-phosphoric acid =690:310:1
Detection wavelength: 220nm
Sample injection amount: 10 μ l
Flow rate: 1.0ml/min
Solvent: receiving liquid
Column temperature: 40 deg.C
Operating time: 12min
The results of the transdermal absorption are shown in table 10:
Figure BDA0003879901830000181
as a result: example 11 the transdermal absorption rate was superior to that of the domestic and Japanese commercial preparations.
The advantageous effects of the present invention are further illustrated by comparative experiments below.
Experiment six,
The gel plaster prepared by the method in the prior art in China has serious dehydration, and particularly has more obvious dehydration phenomenon after opening a bag, thereby causing sample viscosity loss and change of release rate. And the sample prepared by the technology applied by the inventor has better water locking and moisture retention. The water loss rate of the commercially available preparation from the purchased domestic manufacturer, the commercially available preparation from the Japanese manufacturer, and example 11 were measured. The experimental results prove that the sample in example 11 is not easy to lose water and has better stability.
The results are shown in Table 11:
Figure BDA0003879901830000182
experiment seven,
The gel plaster prepared by the prior art method in China has insufficient viscosity and needs additional pressure sensitive adhesive tape for assisting use. The samples prepared by the technique applied by the inventor have good viscosity. Commercially available preparations from domestic manufacturers, commercially available preparations from Japanese manufacturers, and example 11 were subjected to initial adhesion test according to the second method of 0952, the four Ministry of Japan pharmacopoeia 2020 edition. The experimental results prove that the initial adhesion of the sample in the example 11 is better.
The results of the experiment are shown in table 12 below:
Figure BDA0003879901830000191
sample trials were conducted with different active ingredients, such as flurbiprofen, epolamine diclofenac, and the like, in combination with the matrix formulation of example 11 (examples 12-13), further illustrating the effectiveness and versatility of the matrix of the present invention.
Examples 12 to 13
The weight percentages of the components are shown in Table 13
Figure BDA0003879901830000192
Figure BDA0003879901830000201
As a result:
first evaluation of experiment
Sample preparation: examples 12-13 gel plasters
The method comprises the following steps: each of the samples of examples was applied to the wrist of each volunteer subject for 10 total, and evaluated for film residue, skin-following property, comfort in use, skin irritation, skin allergy, tearing pain, etc.
The preliminary evaluation results are shown in Table 14 below:
Figure BDA0003879901830000202
the results show that: the initial evaluation results were all better after changing the different active ingredients using the base formula of example 11.
Experiment two, initial adhesion force performance test (30 degree slope rolling ball method)
Sample preparation: examples 12-13 gel plasters
The method comprises the following steps: taking samples, and determining the adhesion force according to 0952 of the four-part general rules of the 2020 edition of Chinese pharmacopoeia
Initial adhesion results are shown in Table 15
Figure BDA0003879901830000203
As a result: the results of the tests show that the initial tack results are good after changing the active ingredient with the base formulation of example 11.
Drawings
FIG. 1: comparative graph of initial adhesion between the formulation of example 11 and the formulation commercially available in China and the formulation commercially available in Japan
FIG. 2 is a schematic diagram: comparative graph of release curves of example 11 formulation and domestic and Japanese commercial formulations
FIG. 3: comparative graph of transdermal absorption curves of example 11 formulation, domestic commercial formulation and Japanese commercial formulation
Detailed Description
The present invention will be further described with reference to the following examples; it should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Examples 1 to 6
The weight percentages of the required components are given in Table 16
Composition of Example 1 Example 2 Example 3 Example 4 Example 5 Example 6
Loxoprofen sodium 1 1 1 1 1 1
NP700 6 6 6 6 6 6
Carbomer 0 3 0 0 0 0
Gelatin 0 0 3 0 0 0
Polyvinyl alcohol 2 2 2 2 2 0
Mat1 0 0 0 3 0 3
Mat2 0 0 0 0 3 3
Sodium carboxymethylcellulose 2 2 2 2 2 2
Glycerol 30 30 30 30 30 30
Tartaric acid 1.2 1.2 1.2 1.2 1.2 1.2
Edetate disodium 0.1 0.1 0.1 0.1 0.1 0.1
Talcum powder 5 5 5 5 5 5
Aluminium glycollate 0.05 0.05 0.05 0.05 0.05 0.05
Mint oil 0.5 0.5 0.5 0.5 0.5 0.5
Clomiton, a new preparation method 2 2 2 2 2 2
Polysorbate-80 0.5 0.5 0.5 0.5 0.5 0.5
Titanium dioxide 0.2 0.2 0.2 0.2 0.2 0.2
Deionized water 49.45 46.45 46.45 46.45 46.45 45.45
Examples 7 to 11
The required weight percentages of the components are shown in table 17 below, wherein the active components are: the loxoprofen sodium comprises active ingredients such as flurbiprofen, diclofenac epolamine, ketoprofen, indomethacin and the like, and the dosage of deionized water is adjusted according to the product specification.
Figure BDA0003879901830000211
Figure BDA0003879901830000221
The preparation process comprises the following steps:
the compositions were prepared as shown in Table 18
Figure BDA0003879901830000222
Figure BDA0003879901830000231
1. The components are prepared respectively.
2. Adding the component A and the component B into the component E, and stirring and refining the mixture uniformly to form viscous paste.
3. Adding the component C into the step 2, and stirring and refining the mixture uniformly to form viscous paste.
4. Adding the component D into the step 3, and stirring and refining the mixture uniformly to form viscous paste.
5. And (4) coating.
6. And (6) slicing.
7. And (6) packaging.
Wherein the coating method adopts the coating method of the conventional gel plaster.

Claims (4)

1. A micro-emulsified high-viscosity stable gel plaster matrix is characterized in that the weight percentages of the components are as follows:
Figure FDA0003879901820000011
wherein NP700 is a partially neutralized sodium polyacrylate,
wherein Mat1 is acrylic acid grafted starch,
wherein Mat2 is methyl acrylate-acrylic acid 2-ethylhexyl copolymer resin emulsion,
wherein the active ingredient is ketoprofen.
2. The gel plaster matrix according to claim 1, wherein the weight percentages of the components are as follows:
Figure FDA0003879901820000012
Figure FDA0003879901820000021
wherein the active ingredient is ketoprofen.
3. The preparation method of the gel plaster is characterized by comprising the following steps:
(1) 1.0-1.5 parts of tartaric acid is taken, added with water and stirred for dissolution;
(2) Adding water into the active drug, stirring and dissolving;
(3) Taking 1-3 parts of crotamiton, 0.3-0.7 part of polysorbate, 0.3-0.7 part of glycerol and 1-3 parts of deionized water, stirring at 25-35 ℃, slowly adding water, and uniformly stirring to obtain a microemulsion matrix;
(4) Adding 5-10 parts of methyl acrylate-acrylic acid 2-ethylhexyl copolymer resin emulsion into deionized water, stirring and dispersing, and then adding 0.03-0.08 part of dihydroxyaluminum glycolate, stirring and dispersing;
(5) Taking 4-8 parts of NP, 3-5 parts of Mat, 0.005-0.02 part of edetate disodium, 3-7 parts of talcum powder, 25-35 parts of glycerol, 0.1-1 part of sodium carboxymethylcellulose and 0.1-0.3 part of titanium dioxide, stirring at a low speed of 10-15HZ for 2-4min, uniformly mixing, increasing the stirring speed to 30-45Hz, and uniformly mixing for 8-12 min; adding the step (1) and the step (2), stirring at a low speed of 10-15Hz for 1-3min, uniformly mixing, and then increasing the mixing speed to 30-45Hz for mixing for 8-12min to ensure uniformity; adding the microemulsion matrix obtained in the step (3) and refining for 1-3min at 10-15Hz, and increasing the refining speed to 30-45Hz and refining for 6-10min to obtain O/W type cream; finally adding the components in the step (4) at 30-45Hz, and refining for 8-12min to be uniform;
(6) After the refining is finished, coating by using a coating machine;
(7) Cutting, bagging and packaging;
wherein NP700 is a partially neutralized sodium polyacrylate,
wherein Mat1 is acrylic acid grafted starch,
wherein Mat2 is methyl acrylate-acrylic acid 2-ethylhexyl copolymer resin emulsion,
wherein the active ingredient is ketoprofen.
4. The method of claim 3, comprising the steps of:
(1) 1.2 parts of tartaric acid is taken, added with water and stirred for dissolution;
(2) Adding water into the active drug, stirring and dissolving;
(3) Taking 2 parts of crotamiton, 80.5 parts of polysorbate, 0.5 part of glycerol and 2 parts of deionized water, stirring at 25-35 ℃, slowly adding water, and uniformly stirring to obtain a microemulsion matrix;
(4) Taking deionized water, adding 6 parts of methyl acrylate-acrylic acid 2-ethylhexyl copolymer resin emulsion, stirring and dispersing, and then adding 0.05 part of dihydroxyaluminum glycinate, stirring and dispersing;
(5) Taking 700 parts of NP, 1 part of Mat, 0.01 part of edetate disodium, 5 parts of talcum powder, 29.5 parts of glycerol, 0.5 part of sodium carboxymethylcellulose and 0.2 part of titanium dioxide, stirring at a low speed of 12HZ for 3min, uniformly mixing, and then increasing the stirring speed to 40Hz for 10min to uniformly mix; adding the step (1) and the step (2), mixing at a low speed of 12Hz for 2min to make the mixture uniform, and then increasing the mixing speed to 40Hz for mixing for 10min to make the mixture uniform; adding the microemulsion matrix obtained in the step (3) for refining at 12Hz for 2min, and after the mixture is uniform, increasing the refining speed to 40Hz for refining for 8min to form O/W type emulsifiable paste uniformly; finally adding the components in the step (4) for refining at 40Hz for 10min to make the components uniform;
(6) After the refining is finished, coating by using a coating machine;
(7) Cutting, bagging and packaging the mixture,
wherein the active ingredient is ketoprofen.
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