CN114617859A - Tropisetron hydrochloride ethosome gel plaster and preparation method thereof - Google Patents
Tropisetron hydrochloride ethosome gel plaster and preparation method thereof Download PDFInfo
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- CN114617859A CN114617859A CN202210313716.1A CN202210313716A CN114617859A CN 114617859 A CN114617859 A CN 114617859A CN 202210313716 A CN202210313716 A CN 202210313716A CN 114617859 A CN114617859 A CN 114617859A
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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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
- A61K47/02—Inorganic compounds
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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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
- A61K47/36—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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- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
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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
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
Abstract
The invention relates to a hydrochloric acid baseAlsetron ethosome gel plaster and a preparation method thereof. The tropisetron hydrochloride ethosome gel plaster comprises a plaster-containing layer and a medicine-containing layer, wherein the medicine-containing layer comprises: tropisetron hydrochloride, yolk lecithin, cholesterol, gelatin, sodium carboxymethylcellulose, sodium polyacrylate, dihydroxyaluminum glycolate and EDTA-Na2Titanium dioxide, kaolin, glycerol, ethanol and purified water. The tropisetron hydrochloride ethosome gel plaster has smooth and fine paste, good biocompatibility, convenient administration, small toxic and side effects and high skin permeation quantity, and can be slowly released.
Description
Technical Field
The invention relates to the technical field of medicinal preparations, in particular to tropisetron hydrochloride ethosome gel plaster and a preparation method thereof.
Background
The chemical name of Tropisetron Hydrochloride (TRO) is: 3-indolecarboxylic acid (8-methyl-8-azabicyclo [ 3.2.1)]-3 α -octyl) ester hydrochloride of the formula: c17H20N2O2HCl. As 5-HT3The high-efficiency and high-selectivity antagonist of the receptor is mainly used for preventing and treating CINV, has definite and effective effect on nausea and vomiting caused by moderate and severe emetogenic drugs, and has the complete control rate of 75 percent and 47 to 73 percent respectively. Tropisetron hydrochloride can selectively inhibit presynaptic 5-HT of peripheral neurons in emesis reflex3Stimulation of receptors and possibly direct effects on the central nervous system 5-HT3Receptor-mediated vagal afferent posterior region, which can block the chemical transmission of neuro-mediators during the vomiting reflex, thereby treating emesis induced by chemotherapy and radiotherapy. With other 5-HT3Receptor antagonists, compared to tropisetron hydrochloride, also have the advantages of low side effects, low incidence of drug interactions and long action time, and are therefore widely used.
The traditional tropisetron hydrochloride administration mode is intravenous injection for the first day and oral administration from the second day to the sixth day. Intravenous administration can only take effect for a short time, while patients with cancer and undergoing surgery experience severe pain after intravenous administration and have difficulty taking orally due to gastrointestinal dysfunction, limiting their clinical use to some extent. Because the oral administration has the problems of gastrointestinal adverse reaction, poor intravenous administration compliance and the like, the development of a Transdermal Drug Delivery System (TDDS) has significant significance.
Disclosure of Invention
In order to solve the technical problems, the invention provides a tropisetron hydrochloride ethosome gel plaster and a preparation method thereof.
The tropisetron hydrochloride ethosome gel emplastrum comprises a back lining layer, a paste-containing layer and an anti-sticking layer, wherein the paste-containing layer comprises: ethosome, tackifier, framework material, cross-linking agent, cross-linking regulator, filler, humectant and purified water. The ethosome has a vesicle structure and consists of water/alcohol or water/alcohol/phospholipid with relatively high ethanol concentration, and cholesterol is added to increase the toughness of the vesicle material. The ethosome in the tropisetron hydrochloride ethosome gel plaster comprises tropisetron hydrochloride, yolk lecithin, cholesterol, ethanol and purified water.
The plaster-containing layer further comprises by weight: 10-20 parts of ethosome, 6.3-8.3 parts of tackifier, 6.3-10.3 parts of framework material, 0.1-0.2 part of cross-linking agent, 0.2 part of cross-linking regulator, 1.3 parts of filler, 24-34 parts of humectant and 30-40 parts of purified water.
Further, the tropisetron hydrochloride ethosol gel plaster comprises a plaster-containing layer and a medicine-containing layer, wherein the medicine-containing layer comprises: tropisetron hydrochloride, yolk lecithin, cholesterol, gelatin, sodium carboxymethylcellulose, sodium polyacrylate, dihydroxyaluminum glycolate and EDTA-Na2Titanium dioxide, kaolin, glycerol, ethanol and purified water.
The viscosity enhancer can be selected from one or two of gelatin, sodium carboxymethylcellulose, polyvidone K90, carbomer 934 and carbomer 940, and preferably selected from one or two of gelatin and sodium carboxymethylcellulose.
The backbone material may be selected from the group consisting of polypropylene, preferably Viscomate NP-700 or NP-800, more preferably Viscomate NP-700.
The cross-linking agent can be one of aluminum hydroxide, aluminum chloride or aluminum glycollate, and is preferably aluminum glycollate.
The crosslinking regulator is selected from tartaric acid, citric acid or EDTA-Na2Is preferably EDTA-Na2。
The filler can be selected from one or two of micropowder silica gel, zinc oxide, diatomite, calcium carbonate, titanium dioxide or kaolin, preferably one or two of titanium dioxide or kaolin.
The humectant can be one selected from sorbitol, propylene glycol, polyethylene glycol or glycerol, preferably glycerol.
The backing layer may be selected from non-woven fabrics and the like.
The anti-sticking layer can be selected from polyethylene film, etc.
The tropisetron hydrochloride ethosome gel plaster can be prepared by the following method:
weighing tropisetron hydrochloride, dissolving the tropisetron hydrochloride in purified water, adding egg yolk lecithin and cholesterol, placing on a magnetic stirrer, heating in a constant-temperature water bath, dispersing to obtain a colloid dispersion liquid, slowly adding ethanol at a constant speed by using an injector, and continuously stirring, wherein the method is carried out according to the proportion that 100-500 mg egg yolk lecithin, 10-20 mg cholesterol, 2-5 ml ethanol and 5-10 ml purified water are added in every 100mg tropisetron hydrochloride; the whole preparation process is kept at a constant temperature, the obtained solution is homogenized under a high-shear homogenizing emulsifying machine, and the alcohol plastid solution of the tropisetron hydrochloride is obtained and stored by filtering with a microporous filter membrane;
dissolving sodium carboxymethylcellulose in glycerol and purified water to obtain phase A;
heating gelatin to dissolve in purified water, stirring to obtain transparent colloid to obtain phase B;
sequentially adding EDTA-Na into glycerol2Uniformly stirring aluminum glycoxide and Viscomate NP-700 to obtain a C phase;
dissolving titanium dioxide and kaolin in purified water to obtain a phase D;
adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into the phase C, fully stirring to obtain a gel phase E, adding the tropisetron hydrochloride ethosome solution, uniformly stirring, coating the mixture on non-woven fabrics at room temperature, and covering an anti-sticking layer to obtain the tropisetron hydrochloride ethosome gel plaster.
Through a large number of experimental researches, the tropisetron hydrochloride is prepared into an ethosome solution, and then the ethosome solution is further prepared into a gel plaster.
Advantageous effects
Experiments show that the tropisetron hydrochloride ethosome gel plaster has obvious slow release effect and remarkable permeation effect. The ethosome gel plaster is prepared by adopting a hydrophilic high polymer material with better safety and viscosity as a gel framework and matching with a cross-linking agent, a humectant, a tackifier and the like, not only is the paste smooth and fine, has good biocompatibility, convenient administration and small toxic and side effects, but also compared with the common hydrogel plaster, the ethosome technology can not only ensure that the tropisetron hydrochloride achieves the effect of slow release, but also can obviously improve the penetration of the drug on the skin and promote the skin penetration, and has good application prospect when being used as a new dosage form of a chemotherapy antiemetic.
The tropisetron hydrochloride ethosome gel plaster can avoid the first-pass effect through transdermal administration, is convenient to administer, and enhances the medication compliance of patients. Moreover, the traditional Chinese medicine composition has the remarkable advantages of convenient administration, good biocompatibility, small toxic and side effects and high transdermal rate.
Drawings
FIG. 1: two tropisetron hydrochloride gel plaster in-vitro release curves.
FIG. 2 is a schematic diagram: an in vitro percutaneous permeation curve of 3 tropisetron hydrochloride gel plasters.
FIG. 3: the time course of different administration forms of the tropisetron hydrochloride.
Detailed Description
The present invention will be further illustrated by the following examples and test examples, but the present invention is not limited thereto.
Example 1 preparation of tropisetron hydrochloride Alosol gel Patches
Accurately weighing 100mg of tropisetron hydrochloride raw material medicine, dissolving the tropisetron hydrochloride raw material medicine in 6mL of purified water, adding 500mg of egg yolk lecithin and 20mg of cholesterol, placing the mixture on a magnetic stirrer, heating the mixture in a constant-temperature water bath at 50 ℃, dispersing the mixture to obtain a colloid dispersion liquid, slowly adding 4mL of ethanol into the mixture at a constant speed by using an injector, continuously stirring the mixture for 30min, keeping the temperature of the whole preparation process at 50 ℃ constant, homogenizing the obtained liquid for 30s at 8000rpm in a high-shear homogenizing emulsifying machine, filtering the homogenized liquid by using a 0.22 mu m microporous filter membrane to respectively obtain tropisetron hydrochloride ethosome solution, and storing the tropisetron hydrochloride ethosome solution at 4 ℃ for later use;
800mg of CMC-Na was dissolved in 1.6g of glycerol and 4.67g of purified water as phase A; dissolving 600mg gelatin in 1.33g purified water under heating, and stirring to obtainObtaining phase B from transparent colloid; EDTA-Na was added to 4g of glycerin in this order243.6mg, 30mg of dihydroxyaluminum glycinate and Viscomate NP-7001200 mg, and uniformly stirring to obtain a phase C; 50mg of titanium dioxide and 200mg of kaolin were dissolved in 0.67g of purified water to obtain a D phase; adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into the phase C, stirring to obtain gel phase E, adding 4g of tropisetron hydrochloride ethosome solution, stirring uniformly, and adding the mixture at a speed of 5mm s-1The mixture is coated on non-woven fabrics at room temperature, the coating thickness is controlled to be (2.0 +/-0.1) mm, and a polyethylene film is covered to obtain the tropisetron hydrochloride ethosome gel plaster.
Example 2 preparation of tropisetron hydrochloride Alosol gel Patch
Accurately weighing 100mg of tropisetron hydrochloride raw material medicine, dissolving the tropisetron hydrochloride raw material medicine in 7mL of purified water, adding 100mg of yolk lecithin and 20mg of cholesterol, placing the mixture on a magnetic stirrer, heating the mixture in a thermostatic water bath at 50 ℃, dispersing the mixture to obtain a colloid dispersion liquid, slowly adding 3mL of ethanol into the mixture at a constant speed by using an injector, continuously stirring the mixture for 30min, keeping the temperature of the whole preparation process at 50 ℃ constant, homogenizing the obtained liquid for 30s at 8000rpm under a high-shear homogenizing emulsifying machine, filtering the homogenized liquid by using a 0.22-micrometer microporous filter membrane to respectively obtain tropisetron hydrochloride ethosome solution, and storing the tropisetron hydrochloride ethosome solution at 4 ℃ for later use;
608mg of CMC-Na was dissolved in 1.6g of glycerol and 4.67g of purified water as phase A; heating 600mg gelatin to dissolve in 1.33g purified water, stirring well to obtain transparent colloid to obtain phase B; adding 43.6mg tartaric acid, 20.4mg aluminum chloride and Viscomate NP-8001200 mg into 3.02g glycerol in sequence, and stirring to obtain phase C; 50mg of zinc oxide and 200mg of kaolin were dissolved in 1.68g of purified water to obtain a D phase; adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into the phase C, stirring to obtain gel phase E, adding 2g of tropisetron hydrochloride ethosome solution, stirring uniformly, and adding the mixture at a speed of 5mm s-1The mixture is coated on non-woven fabrics at room temperature, the coating thickness is controlled to be (2.0 +/-0.1) mm, and a polyethylene film is covered to obtain the tropisetron hydrochloride ethosome gel plaster.
Example 3 preparation of tropisetron hydrochloride Alosol gel Patches
Accurately weighing 100mg of tropisetron hydrochloride raw material medicine, dissolving the tropisetron hydrochloride raw material medicine in 8mL of purified water, adding 300mg of egg yolk lecithin and 10mg of cholesterol, placing the mixture on a magnetic stirrer, heating the mixture in a constant-temperature water bath at 50 ℃, dispersing the mixture to obtain a colloid dispersion liquid, slowly adding 2mL of ethanol into the mixture at a constant speed by using an injector, continuously stirring the mixture for 30min, keeping the temperature of the whole preparation process at 50 ℃ constant, homogenizing the obtained liquid for 30s at 8000rpm in a high-shear homogenizing emulsifying machine, filtering the homogenized liquid by using a 0.22 mu m microporous filter membrane to respectively obtain tropisetron hydrochloride ethosome solution, and storing the tropisetron hydrochloride ethosome solution at 4 ℃ for later use;
992mg of CMC-Na was dissolved in 2.54g of glycerol and 4.67g of purified water as phase A; heating 600mg gelatin to dissolve in 1.33g purified water, stirring well to obtain transparent colloid to obtain phase B; EDTA-Na was added to 4g of glycerin in this order243.6mg of dihydroxyaluminum glycolate, 39.6mg of dihydroxyaluminum glycolate and NP-7001969 mg of Viscomate, and uniformly stirring to obtain a phase C; 50mg of calcium carbonate and 200mg of diatomaceous earth were dissolved in 0.67g of purified water to obtain a D phase; adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into the phase C, stirring to obtain gel phase E, adding 4g of tropisetron hydrochloride ethosome solution, stirring uniformly, and adding the mixture at a speed of 5mm s-1The mixture is coated on non-woven fabrics at room temperature, the coating thickness is controlled to be (2.0 +/-0.1) mm, and a polyethylene film is covered to obtain the tropisetron hydrochloride ethosome gel plaster.
Example 4 preparation of tropisetron hydrochloride Alosol gel Patches
Accurately weighing 100mg of tropisetron hydrochloride raw material medicine, dissolving the tropisetron hydrochloride raw material medicine in 6mL of purified water, adding 500mg of egg yolk lecithin and 15mg of cholesterol, placing the mixture on a magnetic stirrer, heating the mixture in a constant-temperature water bath at 50 ℃, dispersing the mixture to obtain a colloid dispersion liquid, slowly adding 4mL of ethanol into the mixture at a constant speed by using an injector, continuously stirring the mixture for 30min, keeping the temperature of the whole preparation process at 50 ℃ constant, homogenizing the obtained liquid for 30s at 8000rpm in a high-shear homogenizing emulsifying machine, filtering the homogenized liquid by using a 0.22 mu m microporous filter membrane to respectively obtain tropisetron hydrochloride ethosome solution, and storing the tropisetron hydrochloride ethosome solution at 4 ℃ for later use;
800mg of povidone K90 was dissolved in 1.6g of glycerin and 3.76g of purified water as phase A; heating 600mg gelatin to dissolve in 1.33g purified water, and stirring to obtain transparent colloid as phase B; in 4g of glycerol in that orderAdding 43.6mg of citric acid, 30mg of aluminum hydroxide and Viscomate NP-7001585 mg, and uniformly stirring to obtain a phase C; 50mg of titanium dioxide and 200mg of kaolin were dissolved in 0.67g of purified water to obtain phase D; adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into the phase C, stirring to obtain gel phase E, adding tropisetron hydrochloride ethosome solution 3g, stirring uniformly, and adding the mixture at a speed of 5mm s-1The mixture is coated on non-woven fabrics at room temperature, the coating thickness is controlled to be (2.0 +/-0.1) mm, and a polyethylene film is covered to obtain the tropisetron hydrochloride ethosome gel plaster.
EXAMPLE 5 preparation of tropisetron hydrochloride Alosol gel Patches
Accurately weighing 100mg of tropisetron hydrochloride raw material medicine, dissolving the tropisetron hydrochloride raw material medicine in 8mL of purified water, adding 300mg of egg yolk lecithin and 15mg of cholesterol, placing the mixture on a magnetic stirrer, heating the mixture in a constant-temperature water bath at 50 ℃, dispersing the mixture to obtain a colloid dispersion liquid, slowly adding 2mL of ethanol into the mixture at a constant speed by using an injector, continuously stirring the mixture for 30min, keeping the temperature of the whole preparation process at 50 ℃ constant, homogenizing the obtained liquid for 30s at 8000rpm in a high-shear homogenizing emulsifying machine, filtering the homogenized liquid by using a 0.22 mu m microporous filter membrane to respectively obtain tropisetron hydrochloride ethosome solution, and storing the tropisetron hydrochloride ethosome solution at 4 ℃ for later use;
800mg of CMC-Na was dissolved in 2.54g of glycerol and 4.67g of purified water as phase A; heating 600mg gelatin to dissolve in 1.33g purified water, stirring well to obtain transparent colloid to obtain phase B; EDTA-Na was added to 4g of glycerin in order230mg, 39.6mg of aluminum hydroxide and Viscomate NP-8001200 mg, and uniformly stirring to obtain a phase C; 50mg of zinc oxide and 200mg of kaolin were dissolved in 1.68g of purified water to obtain a D phase; adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into the phase C, stirring to obtain gel phase E, adding tropisetron hydrochloride ethosome solution 3g, stirring uniformly, and adding the mixture at a speed of 5mm s-1The mixture is coated on non-woven fabrics at room temperature, the coating thickness is controlled to be (2.0 +/-0.1) mm, and a polyethylene film is covered to obtain the tropisetron hydrochloride ethosome gel plaster.
Example 6 preparation of tropisetron hydrochloride Alosol gel Patches
Accurately weighing 100mg of tropisetron hydrochloride raw material medicine, dissolving the tropisetron hydrochloride raw material medicine in 6mL of purified water, adding 100mg of yolk lecithin and 10mg of cholesterol, placing the mixture on a magnetic stirrer, heating the mixture in a constant-temperature water bath at 50 ℃, dispersing the mixture to obtain a colloid dispersion liquid, slowly adding 4mL of ethanol into the mixture at a constant speed by using an injector, continuously stirring the mixture for 30min, keeping the temperature of the whole preparation process at 50 ℃ constant, homogenizing the obtained liquid for 30s at 8000rpm in a high-shear homogenizing emulsifying machine, filtering the homogenized liquid by using a 0.22 mu m microporous filter membrane to respectively obtain tropisetron hydrochloride ethosome solution, and storing the tropisetron hydrochloride ethosome solution at 4 ℃ for later use;
800mg of CMC-Na was dissolved in 2.54g of glycerol and 4.67g of purified water as phase A; heating 600mg gelatin to dissolve in 1.33g purified water, stirring well to obtain transparent colloid to obtain phase B; EDTA-Na was added to 4g of glycerin in this order243.6mg, 30mg of dihydroxyaluminum glycinate and Viscomate NP-7001200 mg, and uniformly stirring to obtain a phase C; 50mg of titanium dioxide and 200mg of diatomaceous earth were dissolved in 1.68g of purified water to obtain a D phase; adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into the phase C, stirring to obtain gel phase E, adding 2g of tropisetron hydrochloride ethosome solution, stirring uniformly, and adding the mixture at a speed of 5mm s-1The mixture is coated on non-woven fabrics at room temperature, the coating thickness is controlled to be (2.0 +/-0.1) mm, and a polyethylene film is covered to obtain the tropisetron hydrochloride ethosome gel plaster.
Example 7 preparation of tropisetron hydrochloride Alosol gel Patches
Accurately weighing 100mg of tropisetron hydrochloride raw material medicine, dissolving the tropisetron hydrochloride raw material medicine in 7mL of purified water, adding 500mg of egg yolk lecithin and 20mg of cholesterol, placing the mixture on a magnetic stirrer, heating the mixture in a constant-temperature water bath at 50 ℃, dispersing the mixture to obtain a colloid dispersion liquid, slowly adding 3mL of ethanol into the mixture at a constant speed by using an injector, continuously stirring the mixture for 30min, keeping the temperature of the whole preparation process at 50 ℃ constant, homogenizing the obtained liquid for 30s at 8000rpm in a high-shear homogenizing emulsifying machine, filtering the homogenized liquid by using a 0.22-micron microporous membrane to respectively obtain tropisetron hydrochloride ethosome solution, and storing the tropisetron hydrochloride ethosome solution at 4 ℃ for later use;
992mg of CMC-Na was dissolved in 1.6g of glycerol and 3.76g of purified water as phase A; heating 600mg gelatin to dissolve in 1.33g purified water, stirring well to obtain transparent colloid to obtain phase B; EDTA-Na was added to 3.02g of glycerin in this order243.6mg of aluminum chloride 20.4mg and Viscomate NP-7001585 mg, stirring well to obtain phase C; dissolving 50mg of calcium carbonate and 200mg of kaolin in 0.67g of purified water to obtain a D phase; adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into the phase C, stirring to obtain gel phase E, adding 4g of tropisetron hydrochloride ethosome solution, stirring uniformly, and adding the mixture at a speed of 5mm s-1The mixture is coated on non-woven fabrics at room temperature, the coating thickness is controlled to be (2.0 +/-0.1) mm, and a polyethylene film is covered to obtain the tropisetron hydrochloride ethosome gel plaster.
Test example 1 tropisetron hydrochloride ethosome gel patch for in vitro release and transdermal test
1.1 Experimental instruments
1.2 materials and reagents
1.3 Experimental animals
BALB/c nude mice Changzhou Kavens laboratory animals Co., Ltd
1.4 preparation of test articles
Preparing tropisetron hydrochloride ethosome gel plaster: prepared according to example 1
Preparing tropisetron hydrochloride aqueous solution gel plaster: 0.800g of sodium carboxymethylcellulose was dissolved in 1.6g of glycerol and 4.67g of purified water as phase A; heating and dissolving 0.600g of gelatin in 1.33g of purified water, and uniformly stirring to prepare transparent colloid to obtain a phase B; EDTA-Na was added to 4g of glycerin in order20.0436 g, 0.0300g of dihydroxyaluminum glycinate and 0.8978 g of Viscomate NP-7001.200 g, and uniformly stirring to obtain a phase C; dissolving titanium dioxide 0.050g and kaolin 0.200gDissolving in 0.67g of purified water to obtain a D phase; adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into phase C, stirring to obtain gel phase E, adding 4g of 1% aqueous solution, stirring, and mixing at 5mm s-1Coating on a non-woven fabric at room temperature, controlling the coating thickness to be (2.0 +/-0.1) mm, and covering a polyethylene film to obtain the tropisetron hydrochloride aqueous solution gel plaster.
Preparing tropisetron hydrochloride and blank ethosome auxiliary material gel plaster: 0.800g of sodium carboxymethylcellulose was dissolved in 1.6g of glycerol and 4.67g of purified water as phase A; heating and dissolving 0.600g of gelatin in 1.33g of purified water, and uniformly stirring to prepare transparent colloid to obtain a phase B; EDTA-Na was added to 4g of glycerin in order20.0436 g, 0.0300g of dihydroxyaluminum glycinate and 0.8978 g of Viscomate NP-7001.200 g, and uniformly stirring to obtain a phase C; dissolving 0.050g of titanium dioxide and 0.200g of kaolin in 0.67g of purified water to obtain a D phase; sequentially adding the phase A and the phase B into the phase D, and fully stirring to obtain a mixed phase; slowly adding the mixed phase into phase C, stirring to obtain gel phase E, adding 1% tropisetron hydrochloride adjuvant solution 4g (5% egg yolk lecithin, 40% ethanol, 0.2% cholesterol and appropriate amount of water), stirring, and mixing at 5mm s-1The mixture is coated on non-woven fabrics at room temperature, the coating thickness is controlled to be (2.0 +/-0.1) mm, and a polyethylene film is covered to obtain the tropisetron hydrochloride and blank ethosome auxiliary material gel plaster.
1.5 in vitro Release assay
The test method comprises the following steps: the modified Franz cell method was used, with the upper chamber being the diffusion chamber and the lower chamber being the receiving chamber. Respectively taking tropisetron hydrochloride ethosome gel plaster and tropisetron hydrochloride aqueous solution gel plaster (1.767 cm) with different drug-loading rates2) Removing the anti-sticking layer, attaching to Cuprophan semi-permeable membrane, and flatly fixing the semi-permeable membrane on the diffusion interface of Franz vertical diffusion cell, wherein the receiving cell volume is 12ml, and the effective diffusion area is 1.767cm2Heating in constant temperature water bath at 32 + -0.5 deg.C, filling preheated release medium (0.01M phosphate buffer solution, pH 7.4) into the receiving tank, exhausting bubbles, placing electromagnetic stirring piece in the tank, and rotating at 600rpmAnd (6) moving. 4.5ml samples were taken at 1, 2, 3, 6, 9, 12, 18 and 24h (supplemented with the same temperature equivalent release medium at the same time), and the receiver was analyzed under the following chromatographic conditions to calculate the cumulative amount of drug released (Q)n/μg·cm-2) And cumulative Release Rate (Q)n/％)。
Chromatographic conditions are as follows: Welch-C18 reverse phase column (250 mm. times.4.6 mm, 5 μm), mobile phase: KH2PO4 buffer (pH 4.5) -acetonitrile (75: 25), flow rate: 1mL/min, sample size: 20 μ L, column temperature: 30 ℃, detection wavelength: 285 nm.
And (3) test results: in vitro cumulative release (Q) of tropisetron hydrochloride ethosome gel plaster and tropisetron hydrochloride aqueous solution gel plastern/μg·cm-2)-t1/2The curve is shown in FIG. 1, and the release model parameters are shown in Table 1. The release processes of the two conform to Higuchi equations (correlation coefficients are 0.9978 and 0.9984 respectively), and compared with tropisetron hydrochloride aqueous solution gel plaster, the tropisetron hydrochloride ethosome gel plaster has a slower release rate (30.665 mu g cm)-2·h-1/2vs.47.281μg·cm-2·h-1/2). Therefore, the tropisetron hydrochloride in the tropisetron hydrochloride ethosome gel plaster can be slowly released.
Table 1 release model parameters for two tropisetron hydrochloride gel patches (n ═ 3)
1.6 in vitro transdermal test
The test method comprises the following steps: the conditions were the same as for the in vitro release test except that the Cuprophan semi-permeable membrane was replaced with treated nude mouse skin. Taking a healthy BALB/c nude mouse, removing the neck, killing, separating out abdominal skin, carefully removing subcutaneous fat and connective tissue, cleaning with normal saline, cutting a proper size of complete undamaged skin, flatly paving and fixing the skin on a diffusion interface of a Franz vertical diffusion cell, wherein the horny layer faces one side of a diffusion chamber. Respectively putting tropisetron hydrochloride ethosome gel plaster, tropisetron hydrochloride aqueous solution gel plaster and tropisetron hydrochloride + blank ethosome auxiliary material gel plaster (1.767 cm)2) Sticking to horny layer of nude mouse skin, sampling for 3, 6, 9, 12, 18 and 24 hr for 4.5ml (simultaneously adding release medium with same temperature and same amount), analyzing the received solution, and calculating the cumulative transdermal amount (Q) of the drug according to the following formulan/μg·cm-2) Cumulative skin penetration (Q)n/%) and steady state transdermal rate (J)ss/μg·cm-2·h-1)。
QnThe cumulative permeation amount per unit area at the nth time point, A is the effective permeation area, CnThe mass concentration of the drug measured at the nth point, V is the volume of the receiving tank, CiThe mass concentration of the drug, V, measured at the (n-1) th pointiFor each sample volume. Qn％＝QnThe cumulative permeability at the nth time point is/W, Q/% is the effective permeation area, and W is the actual total drug-containing amount per unit area.
Chromatographic conditions are as follows: Welch-C18 reverse phase column (250 mm. times.4.6 mm, 5 μm), mobile phase: KH2PO4 buffer (pH 4.5) -acetonitrile (75: 25), flow rate: 1mL/min, sample size: 20 μ L, column temperature: 30 ℃, detection wavelength: 285 nm.
And (3) test results: the in vitro transdermal permeation curves of 3 tropisetron hydrochloride gel plasters are shown in figure 2. As can be seen from FIG. 2, the mean cumulative permeation volume of the tropisetron hydrochloride ethosome gel patch in 24h is (92.45 +/-6.85) mu g/cm-2The permeability is 21.66 percent, is 3.88 times of tropisetron hydrochloride aqueous solution gel plaster and 3.24 times of tropisetron hydrochloride and blank ethosome auxiliary material gel plaster, and the difference has statistical significance (P)<0.05). And the calculated steady transdermal speed of the tropisetron hydrochloride ethosome gel plaster is (3.52 +/-0.28) mu g.cm < -2 >. h-1Is tropisetron hydrochloride aqueous solution gel plaster [ (0.69 +/-0.10) mu g cm-2·h-1]Gel plaster with tropisetron hydrochloride and blank ethosome auxiliary material [ (0.78 +/-0.12) mu g cm-2·h-1]5.10 times and 4.52 times. Thus, the tropisetron hydrochloride is proved to be encapsulated in ethosome and only tropisetron hydrochloride is added or only tropisetron hydrochloride and ethosome auxiliary materials are mixed and applied to the gel plasterCan play a role in promoting penetration.
Test example 2 pharmacokinetic study of Tropisetron hydrochloride Alosomal gel plaster
2.1 Experimental instruments
Model G7117B 1290 HPLC
API 6470 model Triplex quadrupole tandem Mass spectrometer applied biosystems, USA
Model GL21M Changshan Xiangzhi centrifuge Instrument Co., Ltd of high-speed refrigerated centrifuge
2.2 materials and reagents
2.3 Experimental animals
New Zealand white rabbit Shandong green leaf pharmaceutical Co Ltd animal experiment center
2.4 preparation of test articles
Preparing tropisetron hydrochloride ethosome gel plaster: prepared according to example 1
Preparing tropisetron hydrochloride aqueous solution gel plaster: 0.800g of sodium carboxymethylcellulose was dissolved in 1.6g of glycerol and 4.67g of purified water as phase A; heating and dissolving 0.600g of gelatin in 1.33g of purified water, and uniformly stirring to prepare transparent colloid to obtain a phase B; EDTA-Na was added to 4g of glycerin in order20.0436 g, 0.0300g of dihydroxyaluminum glycinate and 0.8978 g of Viscomate NP-7001.200 g, and uniformly stirring to obtain a phase C; dissolving 0.050g of titanium dioxide and 0.200g of kaolin in 0.67g of purified water to obtain a D phase; adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into phase C, stirring to obtain gel phase E, adding 4g of 1% aqueous solution, stirring, and mixing at 5mm s-1Coating on a non-woven fabric at room temperature, controlling the coating thickness to be (2.0 +/-0.1) mm, and covering a polyethylene film to obtain the tropisetron hydrochloride aqueous solution gel plaster.
2.5 design of the experiment
Weighing 12 New Zealand white rabbits, and weighingThe resulting mixture was randomly divided into an Intravenous (IV) group, an ethosomal gel patch (EC) group and an aqueous gel patch (AC) group, each of which was 4 individuals (4. + -. 0.2 kg). Intravenous injection group, which is converted according to the maximum daily oral dose of human body to obtain intravenous administration dose of 0.275 mg/kg-1The tropisetron hydrochloride injection is intravenously administered to rabbit ear rims. Collecting blood from rabbit ear vein at 0min, 5min, 10min, 20min, 30min, 1h, 2h, 4h, 6h, 8h, and 12h after administration, placing in heparinized centrifuge tube, immediately centrifuging at 4 deg.C centrifuge at 5000rpm for 10min, collecting supernatant, and storing in-80 deg.C refrigerator. Gel patch group, administered at a dose of 20 mg/patch, New Zealand white rabbits were fixed, sheared on their backs, carefully sheared with eye scissors until close to the skin, and then applied with a small amount of depilatory cream to remove the back fluff, forming as smooth an area as possible, taking care not to damage the skin. Respectively sticking tropisetron hydrochloride ethosome gel plaster and tropisetron hydrochloride aqueous solution gel plaster to a shaving area, fixing the tropisetron hydrochloride ethosome gel plaster and the tropisetron hydrochloride aqueous solution gel plaster by using medical adhesive tapes, and removing the gel plaster after 24 hours. And collecting blood from rabbit ear vein at 0min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h and 48h after administration, placing in heparinized centrifuge tube, immediately centrifuging at 4 deg.C in centrifuge at 5000rpm for 10min, collecting upper layer plasma, and storing in refrigerator at-80 deg.C.
2.6LC-MS/MS method for determining drug content in rabbit blood
The chromatographic method comprises the following steps: adopting ZORBAX XDB-C18 chromatographic column (50mm × 2.1mm, 3.5 μm), and isocratic eluting with methanol-0.1% formic acid water solution (80: 20) for 3.5min at flow rate of 0.4 mL/min-1The column temperature was 40 ℃ and the amount of sample was 5. mu.L.
The mass spectrometry method comprises the following steps: electrospray ionization source (ESI) is adopted, scanning mode is Multiple Reaction Monitoring (MRM), and positive ion mode detection is adopted. The ion spray voltage was 5500V, the ion source temperature was 450 ℃, the gas curtain gas (CUR) was 10psi, the pressure of gas 1(GS1) in the source was 45psi, and the pressure of gas 2(GS2) in the source was 45 psi. Mass spectrometry parameters for the tropisetron hydrochloride control and IS are shown in Table 2.
TABLE 2 Mass Spectrometry parameters for tropisetron hydrochloride controls and IS
| Compound (I) | Q1Mass/Da | Q3Mass/Da | DP/volts | EP/volts | CE/volts | CXP/volts |
| Tropisetron hydrochloride | 284.9 | 124.1 | 106 | 10 | 33 | 8 |
| IS | 312.9 | 138.1 | 120 | 10 | 30 | 10 |
Preparation of control solution and IS solution: accurately weighing appropriate amount of tropisetron hydrochloride reference substance and IS reference substance, and dissolving into 0.2 mg/mL with methanol respectively-1The stock solution of (1). Precision sucking tropisetron hydrochlorideAppropriate amount of stock solution, 50% methanol water solution as diluent, gradually diluting to 1000, 400, 200, 100, 40, 20, 10, 4, 2 ng.mL-1The series of standard solutions of (4) was stored at-20 ℃ until use. Precisely sucking a proper amount of IS stock solution and 50% methanol aqueous solution as diluent, and diluting to 500 ng/mL-1The IS solution of (5) was stored at-20 ℃ until use.
Plasma sample treatment: treating the sample by liquid-liquid extraction, adding 100 μ L of plasma sample into 2mL EP tube, adding 5 μ LIS solution, and vortexing for 30 s; adding 1.5mL of ethyl acetate, carrying out vortex oscillation for 10min, centrifuging at 13000rpm for 10min, transferring all supernate to a 10mL clean glass centrifuge tube, and drying by nitrogen; adding 100 μ L of 50% methanol water solution for redissolution, vortexing and shaking for 10s, and taking supernatant into a sample bottle.
2.7 measurement of blood concentration in New Zealand white Rabbit
The blood concentration data of the tropisetron hydrochloride intravenous injection group, the tropisetron hydrochloride ethosome gel plaster group and the tropisetron hydrochloride aqueous solution gel plaster group are respectively shown in tables 3, 4 and 5, and the curve of the blood concentration (C) -time (t) is shown in FIG. 3. As can be seen from the figure, the absorption and elimination of the rabbit after intravenous injection are rapid, the absorption and elimination of the gel plaster are slow, the blood concentration fluctuation is small, the action time is prolonged, and a certain slow release effect is achieved. Under the same administration dosage, the blood concentration in the rabbits of the EC group (ethosome gel plaster group) is obviously higher than that of the rabbits of the AC group (aqueous gel plaster group) (. about.p <0.01), and the ethosome has the function of promoting skin penetration.
TABLE 3 blood concentration in rabbits following intravenous injection of tropisetron hydrochloride (n ═ 4)
TABLE 4 blood concentration of tropisetron hydrochloride in rabbits gel patch (n ═ 4)
TABLE 5 blood concentration of tropisetron hydrochloride in rabbits (n ═ 4)
2.8 pharmacokinetic parameters
The results of the pharmacokinetic studies are shown in table 6. As is clear from Table 6, t is for the ethosome gel patch group and the aqueous gel patch group1/212.0 and 19.4 times of the intravenous group, respectively, MRT0～tAre 7.4 times of intravenous injection group, and the T of ethosome gel plastermaxElongation, CmaxDecrease, AUC0～tAnd AUC0～∞3.2 times and 4.2 times of the intravenous group, respectively, the difference was statistically significant (. about.p)<0.01), which shows that the controlled release effect of the gel plaster is better, the transdermal administration can obviously prolong the action time of the medicine, and the penetration promoting effect of the ethosome can improve the absorption and utilization degree of the medicine. C of tropisetron hydrochloride ethosome gel paste compared with tropisetron hydrochloride aqueous solution gel pastemaxAnd AUC0～tSignificant increase, 5.0 fold and 6.2 fold respectively, the difference was statistically significant (. about.p)<0.01), which shows that the tropisetron hydrochloride in the ethosome gel emplastrum can maintain relatively high concentration in vivo, and the penetration of the medicine in the skin is obviously improved.
TABLE 6 pharmacokinetic study of different dosage forms of tropisetron hydrochloride (n ═ 4)
| Drug substitution parameters | IV | EC | AC |
| Cmax(μg/mL) | 40.11±10.34 | 12.19±2.40 | 2.41±0.72 |
| Tmax(h) | 0.083±0.000 | 4.000±0.000 | 4.500±1.000 |
| t1/2(h) | 1.91±0.34 | 22.87±5.20 | 38.05±17.92 |
| AUC0～t(μg·mL-1·h) | 66.23±20.22 | 211.76±48.97 | 34.02±7.72 |
| AUC0～∞(μg·mL-1·h) | 67.63±21.14 | 281.33±81.07 | 55.20±5.20 |
| MRT0～t(h) | 2.41±0.20 | 17.89±1.51 | 17.96±1.30 |
| MRT0～∞(h) | 2.64±0.35 | 32.55±7.04 | 52.75±21.96 |
2.9 bioavailability
Absolute bioavailability (F) of tropisetron hydrochloride gel patchAbs) The calculation formula is as follows: wherein AUCEC(AC)And dEC(AC)Respectively represents the area under the curve of the drug-hour curve and the administration dosage of the tropisetron hydrochloride ethosomes gel plaster or the tropisetron hydrochloride aqueous solution gel plaster, and the AUCIVAnd dIVRespectively represent the area under the curve of the time curve and the dosage of the tropisetron hydrochloride injection.
The absolute bioavailability of the tropisetron hydrochloride ethosome gel plaster and the absolute bioavailability of the tropisetron hydrochloride aqueous solution gel plaster are respectively 18.1% and 2.9% according to the formula, so that the tropisetron hydrochloride ethosome gel plaster has obvious advantages compared with the aqueous solution gel plaster after being prepared into the tropisetron hydrochloride ethosome gel plaster.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. The tropisetron hydrochloride ethosome gel plaster comprises a back lining layer, a plaster-containing layer and an anti-sticking layer, and is characterized in that the plaster-containing layer comprises: the medicament comprises an ethosome, a tackifier, a framework material, a cross-linking agent, a cross-linking regulator, a filling agent, a humectant and purified water, wherein the medicament-containing ointment layer comprises the following components in parts by weight: 5-20 parts of ethosome, 6.3-8.3 parts of tackifier, 6.3-10.3 parts of framework material, 0.1-0.2 part of cross-linking agent, 0.2 part of cross-linking regulator, 1.3 parts of filler, 24-34 parts of humectant and 30-40 parts of purified water;
wherein the ethosome comprises tropisetron hydrochloride, egg yolk lecithin, cholesterol, ethanol and purified water.
2. The gel patch as claimed in claim 1, wherein said viscosity increasing agent is selected from one or two of gelatin, sodium carboxymethylcellulose, povidone K90, carbomer 934, carbomer 940.
3. The gel patch as claimed in claim 1, wherein said matrix material is selected from the group consisting of polypropylene.
4. The gel patch as claimed in claim 1, wherein said cross-linking agent is selected from one of aluminium hydroxide, aluminium chloride or aluminium glycollate.
5. Gel patch according to claim 1, characterized in that the crosslinking modifier is selected from tartaric acid, citric acid or EDTA-Na2One kind of (1).
6. The gel patch as claimed in claim 1, wherein said filler is selected from one or two of aerosil, zinc oxide, diatomaceous earth, calcium carbonate, titanium dioxide or kaolin.
7. The gel patch as claimed in claim 1, wherein said humectant is selected from one of sorbitol, propylene glycol, polyethylene glycol or glycerin.
8. The gel patch as claimed in claim 1, wherein said layer containing said paste comprises: tropisetron hydrochloride, yolk lecithin, cholesterol, gelatin, sodium carboxymethylcellulose, sodium polyacrylate, dihydroxyaluminum glycolate and EDTA-Na2Titanium dioxide, kaolin, glycerol, ethanol and purified water.
9. The process for preparing a gel patch according to claim 8, wherein:
weighing a tropisetron hydrochloride raw material medicament, dissolving the tropisetron hydrochloride raw material medicament in purified water, adding egg yolk lecithin and cholesterol, placing the mixture on a magnetic stirrer, heating the mixture in a constant-temperature water bath, dispersing to obtain a colloid dispersion liquid, slowly adding ethanol into the mixture at a constant speed by using an injector, continuously stirring, keeping the temperature constant in the whole preparation process, homogenizing the obtained liquid under a high-shear homogenizing emulsifying machine, and filtering the mixture by using a microporous filter membrane to respectively obtain an ethosome solution of the tropisetron hydrochloride for storage;
dissolving sodium carboxymethylcellulose in glycerol and purified water to obtain phase A;
heating gelatin to dissolve in purified water, and stirring to obtain transparent colloid as phase B;
EDTA-Na is added into glycerol in sequence2Uniformly stirring aluminum glyceroxide and Viscomate NP-700 to obtain a phase C;
dissolving titanium dioxide and kaolin in purified water to obtain a phase D;
adding phase A and phase B into phase D in sequence, and stirring thoroughly to obtain mixed phase; slowly adding the mixed phase into the phase C, fully stirring to obtain a gel phase E, adding the tropisetron hydrochloride ethosome solution, uniformly stirring, coating the mixture on the non-woven fabric of the backing layer at room temperature, and covering an anti-sticking layer to obtain the tropisetron hydrochloride ethosome gel plaster.
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| US20040047901A1 (en) * | 2000-12-06 | 2004-03-11 | Cornelia Beier | Absorbing agents and cover layer which is impermeable to active substances and which contains channel-formers or removable protective layer of a transdermal therapeutic system |
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