CN111991371B - Pharmacosome hydrogel patch for treating hyperthyroidism in response to GSH concentration and preparation method thereof - Google Patents

Pharmacosome hydrogel patch for treating hyperthyroidism in response to GSH concentration and preparation method thereof Download PDF

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CN111991371B
CN111991371B CN202010878234.1A CN202010878234A CN111991371B CN 111991371 B CN111991371 B CN 111991371B CN 202010878234 A CN202010878234 A CN 202010878234A CN 111991371 B CN111991371 B CN 111991371B
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pharmacosome
methimazole
hydrogel patch
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CN111991371A (en
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戴红莲
代悦
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Wuhan University of Technology WUT
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
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    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
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    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones

Abstract

The invention relates to a pharmacome hydrogel patch for treating hyperthyroidism by GSH concentration responsiveness and a preparation method thereof.

Description

Pharmacosome hydrogel patch for treating hyperthyroidism in response to GSH concentration and preparation method thereof
Technical Field
The invention relates to a methimazole pharmacome hydrogel patch, in particular to a preparation method and application of a GSH concentration responsive methimazole pharmacome hydrogel patch.
Background
Methimazole (MMI) is an imidazole antithyroid drug, and the action mechanism of the Methimazole is to inhibit thyroid endoperoxidase, prevent the oxidation of the iodothyronine absorbed into the thyroid and the coupling of tyrosine, and further prevent the synthesis of thyroxine (T4) and triiodothyronine (T3). MMI does not influence the absorption of iodine and the release of synthesized hormone, and researches show that MMI is accumulated in thyroid after oral absorption and can only enter the thyroid to play the therapeutic effect of inhibiting the synthesis of thyroxine, and the strength of the effect depends on the local drug concentration in the thyroid. As MMI has stronger hydrophilicity and is difficult to penetrate thyroid cyst membrane, the concentration of oral medication in thyroid is not high, the treatment effect of the medication is reduced, and the serious side effect can be caused by simply increasing the dosage. Common adverse reactions (ADR) of methimazole include drug-induced liver damage, anaphylactic reaction, damage of olfactory system and damage of hematopoietic system; rare ADRs, including nephrotic syndrome and bronchial asthma, induce leukemia and drug-induced aplastic anemia, which can have serious consequences when not cured in time. The treatment course of the hyperthyroidism conservative treatment is 6 months to 2 years, and the current dosage forms on the market are mainly oral tablets and capsules. Because the biological half-life of the methimazole is short, the oral dosage of the medicine is large, the taking frequency is frequent, and serious consequences can be caused, so that the death of acute liver failure caused by the methimazole is reported at present. Therefore, there is a need for developing new drug delivery systems, such as transdermal drug delivery systems, which can increase the drug concentration at the thyroid lesion, reduce the adverse reaction of the drug, increase the compliance of long-term administration, and provide patients with better medication options.
Transdermal Drug Delivery System (TDDS) refers to a route of delivering drugs through the skin to achieve local or systemic therapeutic effects. It is one of the major areas of third generation pharmaceutical formulation research, second only to oral and injectable drugs. The reasons are that the route of administration of the drug is convenient, easy to use, non-invasive and also improves patient compliance. It also reduces fluctuations in drug concentration in the blood, provides stable plasma levels, reduces the chance of drug overdose and ease of detection. At the same time, it avoids the interference of the gastrointestinal environment, such as pH, enzyme activity, drug and food interactions, with drug efficacy and "first pass effect". These conditions prolong the therapeutic effect of the shorter half-life drug and improve the long-term stability of the drug. Administration may be stopped at any time after the stimulus is removed from the site.
The transdermal drug delivery system is adopted, so that the medication way of the drug can be changed, and the targeting property of the drug is improved; transdermal drug delivery, however, requires that the drug have a good ability to cross the plasma membrane barrier. As MMI is a drug with strong hydrophilicity, the principle of pharmacosomes is necessary to modify the MMI in a hydrophobic way to form an amphiphilic pharmacosomes so as to improve the permeability of the MMI. Pharmacosomes are compounds which are inactive or less active in vitro and release active substances to produce pharmacological action by enzymatic or non-enzymatic action in vivo. One key factor that must be considered in pharmacosome design is that the carrier to which the drug is chemically attached should be biocompatible, non-toxic or low-toxic in vivo. The aliphatic alcohol (except methanol) has low toxicity, and the ester formed by the aliphatic alcohol and the carboxylic acid has good hydrophobicity, so that the aliphatic alcohol becomes the first choice for the design of the pharmacosome.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provides a GSH stimulation-responsive methimazole pharmacome hydrogel patch with a simple process and a preparation method thereof.
The scheme adopted by the invention for solving the technical problems is as follows:
a methimazole pharmacosome hydrogel patch for GSH concentration responsive treatment of hyperthyroidism comprises a polymer matrix, a pharmacosome and auxiliary materials, wherein the pharmacosome has the following structure:
Figure BDA0002653296230000021
wherein R is C 2-30 Alkyl group of (1).
Preferably, the auxiliary materials comprise a humectant, a cross-linking agent, an emulsifier, a cross-linking regulator, a pH regulator, a solvent and a penetration enhancer.
Preferably, the polymer matrix material is sodium polyacrylate.
Preferably, the humectant is glycerin, the cross-linking agent is aluminum glycollate, the emulsifier is beeswax, the cross-linking regulator is EDTA, the pH regulator is citric acid, the solvent is UP water, and the penetration enhancer is any one or more of propylene glycol, menthol and azone.
Preferably, the preparation method of the pharmacosome is as follows:
(1) Adding methylimidazole methyl sulfide into methanol, adding sodium methoxide, stirring until the methylimidazole methyl sulfide is completely dissolved, and adding propiolic acid, wherein the molar ratio of the methylimidazole methyl sulfide to the propiolic acid is (0.1-10): 1, the molar ratio of methanol to sodium methoxide is (1-100): 1; carrying out reflux reaction on the obtained mixed solution for 1 to 200 hours at the temperature of between 10 and 100 ℃ under the protection of nitrogen; after the reaction is finished, rotationally evaporating the reaction solution for 10-120min at the temperature of 1-80 ℃ by using a rotary evaporator to obtain thick white liquid; freeze-drying the obtained thick white liquid for 10-120 hours to obtain white flaky solid methylthioimidazole acrylic acid;
(2) According to the formula of methylthioimidazole acrylic acid: EDC: NSH =1: (0.7-6): (0.6-15) activating the carboxyl stable intermediate in a molar ratio to obtain a methyl thioimidazole acrylic acid solution; the resulting methimazole acrylic acid solution was prepared according to the following ratio of methimazole acrylic acid: two to thirty alcohols = (0.1 to 100): 1, reacting for 1-200 h at 10-100 ℃; after the reaction is finished, the reaction solution is placed into ultrapure water with the temperature of 1-100 ℃ for ultrasonic washing for 1-120min, the reaction solution is centrifuged for 1-30min under the condition that the rotating speed is 1000-10000r/min, the supernatant is taken and then dissolved into the ultrapure water with the temperature of 1-100 ℃ for centrifugation, the supernatant is taken, the above steps are repeated for 1-10 times, and finally the supernatant is freeze-dried for 10-120 hours, so that the target pharmacosome product, namely the dimethylimidazole acrylic acid di-triacontyl ester, is obtained.
Preferably, R is C12 alkyl.
The invention also aims to provide a preparation method of the methimazole pharmacosome hydrogel patch for treating hyperthyroidism in a GSH concentration response manner, which comprises the following steps:
(1) A clean enamel plate is taken, a PE breathable pressure-sensitive adhesive tape is laid, and a silica gel mold is covered on a PE film for standby;
(2) Mixing a polymer matrix material with auxiliary materials and a pharmacosome, quickly stirring the mixture, injecting the mixture into the mold obtained in the step (1), and solidifying the auxiliary materials to form gel, wherein the pharmacosome has the structure:
Figure BDA0002653296230000031
wherein R is C 2-30 Alkyl groups of (a);
(3) Putting the solidified gel into an oven at 30-90 ℃ for 1-60 hours to remove air bubbles in the auxiliary materials;
(4) After bubble removal, the gel is placed into a refrigerator for shaping for 1 to 120 hours at the temperature of between 40 ℃ below zero and 4 ℃;
(5) Taking out the enamel plate, removing the mould, and pasting a layer of PE (polyethylene) breathable pressure-sensitive adhesive tape on the surface of the gel to obtain the patch;
(6) The obtained patch was placed in an aluminum foil bag and stored at 4 ℃.
Preferably, the step (2) specifically comprises:
mixing a polymer matrix, a humectant, a cross-linking agent and an emulsifier to obtain an oil phase A; mixing a crosslinking regulator, a pH regulator, a solvent and a penetration enhancer to obtain a water phase B; respectively placing the oil phase A and the water phase B into a 60 ℃ water bath kettle, stirring at constant temperature, placing the phase A into a beaker, then placing the pharmacosome, then placing the phase B, continuously stirring, rapidly injecting into a mold, and waiting for the auxiliary materials to solidify.
Preferably, the polymer matrix material is sodium polyacrylate.
Preferably, the humectant is glycerin, the cross-linking agent is aluminum glycollate, the emulsifier is beeswax, the cross-linking regulator is EDTA, the pH regulator is citric acid, the solvent is UP water, and the penetration enhancer is one or a mixture of two of propylene glycol and menthol.
The methimazole pharmacome hydrogel patch provided by the invention can be used for transdermal administration through a thyroid lesion part, and the pharmacome in the patch has better GSH responsiveness, can respond to stimulation of intracellular glutathione concentration, and realizes intelligent release of a medicament. The methimazole pharmacome and hydrogel are mixed to prepare a pharmacome hydrogel patch for treating hyperthyroidism, a transdermal drug delivery system is formed, and the transdermal drug delivery system is used for local treatment of hyperthyroidism and has the following advantages:
(1) The penetration enhancer is added to make the methimazole pharmacosome easier to penetrate the skin barrier.
(2) The methimazole pharmacome hydrogel patch provided by the invention has the characteristics of economy, convenience, no leakage, no drug loss, good stability, high encapsulation rate, targeting property, controllable release, convenience for non-invasiveness, avoidance of systemic toxic and side effects, high compliance and timely drug withdrawal.
(3) The methimazole pharmacosome can respond to the stimulation of glutathione concentration in cells, and intelligent release of the drug is realized through Michael elimination reaction.
(4) The methimazole pharmacosome can be made into transdermal drug delivery system, and can increase local concentration of medicine at thyroid gland focus part, prolong action time of medicine in focus tissue, thereby improving therapeutic effect of medicine. The drug delivery system directly acts on the focus part, so that the damage to normal tissues is reduced, and the adverse reaction of the drug is reduced; in addition, the system improves the compliance of long-term medication, improves the use safety of the medicine, and provides a better medication choice for patients.
Drawings
FIG. 1 illustrates a methimazole pharmacosome hydrogel patch mold prepared in accordance with the present invention;
FIG. 2 is a finished product of a methimazole pharmacosome hydrogel patch prepared by the present invention;
FIG. 3 shows the transdermal permeation rate of methimazole pharmacosome hydrogel patch prepared by the present invention without a penetration enhancer;
FIG. 4 shows the transdermal penetration rate of 2% Azone (Azone) in the methimazole pharmacosome hydrogel patch prepared by the present invention;
FIG. 5 shows the transdermal penetration rate of the methimazole pharmacosome hydrogel patch prepared by the present invention with 1-5% Propylene Glycol (PG) and 1% Menthol (MOH);
FIG. 6 shows that the methimazole pharmacosome hydrogel patch prepared by the present invention has a pharmacosome transdermal permeation rate of 1-5% Propylene Glycol (PG) and 2% Menthol (MOH);
FIG. 7 shows the transdermal penetration rate of the methimazole pharmacosome hydrogel patch prepared by the present invention with 1-5% Propylene Glycol (PG) and 3% Menthol (MOH);
FIG. 8 shows the transdermal penetration rate of methimazole pharmacosome containing 1-5% Propylene Glycol (PG) and 4% Menthol (MOH) in the preparation of methimazole pharmacosome hydrogel patch of the present invention;
FIG. 9 shows the transdermal penetration rate of the methimazole pharmacosome hydrogel patch prepared by the present invention containing 1-5% Propylene Glycol (PG) and 5% Menthol (MOH).
Detailed Description
The following examples are provided to further illustrate the present invention for better understanding, but the present invention is not limited to the following examples.
Example 1 preparation of pharmacosomes:
(1) Preparation of 3- [ (1-methyl-1H-imidazol-2-yl) thio ] -2-propenoic acid (methylthio imidazole propenoic acid, MMI-AA)
Methimazole (30 mmol) was dissolved in methanol (0.5 mol), sodium methoxide (10 mmol) was added thereto under stirring until methimazole was completely dissolved, and propiolic acid (10 mmol) was added thereto. Reaction temperature: reacting for 100 hours at 50 ℃ under the protection of nitrogen and in a reflux state. After the reaction is finished, carrying out rotary evaporation on the reaction liquid for 60min at 32 ℃ by using a rotary evaporator to obtain thick white liquid; and (3) freeze-drying the thick white liquid for 50 hours to obtain MMI-AA (white flaky solid).
(2) Preparation of 3- [ (1-methyl-1H-imidazol-2-yl) thio ] -2-propenoic acid-dodecyl ester (methylthioimidazole acrylic dodecyl ester, MMI-AA-OLa)
Methylthioimidazole acrylic acid (9 mmol) and EDC (27 mmol) were dissolved in DMF (260 mmol), activated for 20min and 20min under stirring, and then NHS (45 mmol) was added and stabilized under stirring for 1 hour. And (3) dissolving dodecanol (0.3 mmol) in DMF (260 mmol), and adding the treated methylthioimidazole acrylic acid solution into the dodecanol solution while stirring at the reaction temperature of 30 ℃ under the protection of nitrogen for 50 hours. And after the reaction is finished, putting the reaction solution into ultrapure water at 4 ℃ for ultrasonic washing, centrifuging for 15min under the condition that the rotating speed is 5000r/min after the ultrasonic washing is carried out for 60min, taking the supernatant, dissolving the supernatant into the ultrapure water at 4 ℃ again, centrifuging, taking the supernatant, repeating the steps for 5 times, finally freeze-drying the supernatant for 60 hours, and freeze-drying to obtain the midyellow liquid MMI-AA-OLa of the dodecyl methyl imidazolium acrylate.
Example 2
The preparation method is the same as that of example 1, except that n-octanol and methylthioimidazole acrylic acid are used to obtain methylthioimidazole acrylic acid n-octyl ester MMI-AA-OCa.
Example 3
The preparation method is the same as in example 1, except that stearyl alcohol and methylthio imidazole acrylic acid are used to obtain methylthio imidazole acrylic acid octadecyl ester MMI-AA-OSt.
Example 4
A piece of clean enamel disc is taken, a PE breathable pressure sensitive adhesive tape is laid, and a silica gel mold is covered on a PE film for standby. And (3) placing the oil phase (A) and the water phase (B) into a 60 ℃ water bath kettle, stirring at constant temperature, taking the phase A, placing the phase A into a beaker, then placing 10mg of the methimazole pharmacosome obtained in example 1, then placing the phase B (the mass ratio of the phase A to the phase B is =7.03, and quickly injecting into a mold under continuous stirring until the auxiliary materials are solidified. The solidified auxiliary materials are put into an oven at 60 ℃ for 2 hours to remove air bubbles in the auxiliary materials. Then placing the mixture into a refrigerator at the temperature of-20 ℃ for shaping for 24 hours. Taking out the enamel plate after 24 hours, removing the mould, pasting a layer of PE breathable pressure sensitive adhesive tape on the auxiliary material, putting the patch into an aluminum foil bag, and storing the patch in a refrigerator at 4 ℃ for later use. The hydrogel patch comprises the following auxiliary materials:
TABLE 1 Patch adjuvant formulation containing 2% azone
Figure BDA0002653296230000061
Example 5:
and (3) paving a PE (polyethylene) breathable pressure-sensitive adhesive tape on a clean enamel plate, and covering a silica gel mold on a PE film for later use. And (3) putting the oil phase (A) and the water phase (B) into a 60 ℃ water bath kettle, stirring at constant temperature, taking the phase A, putting the phase A into a beaker, then putting 10mg of methimazole pharmacosome, putting the phase B (the mass ratio of the phase A to the phase B = 7.03.97), continuously stirring, and quickly injecting into a mold until the auxiliary materials are solidified. The solidified auxiliary materials are put into an oven at 60 ℃ for 2 hours to remove air bubbles in the auxiliary materials. Then placing the mixture into a refrigerator at the temperature of-20 ℃ for shaping for 24 hours. Taking out the enamel plate after 24 hours, removing the mould, sticking a layer of PE breathable pressure-sensitive adhesive tape on the auxiliary material, putting the patch into an aluminum foil bag, and storing in a refrigerator at 4 ℃ for later use. The hydrogel patch comprises the following auxiliary materials:
TABLE 2 Patch adjuvant formulation containing 1% propylene glycol 1% menthol
Figure BDA0002653296230000062
Figure BDA0002653296230000071
Example 6:
and (3) paving a PE (polyethylene) breathable pressure-sensitive adhesive tape on a clean enamel plate, and covering a silica gel mold on a PE film for later use. And (3) placing the oil phase (A) and the water phase (B) into a 60 ℃ water bath kettle, stirring at a constant temperature, taking the phase A, placing the phase A into a beaker, then placing 10mg of methimazole pharmacosome, then placing the phase B (the mass ratio of the phase A to the phase B = 7.03) into the beaker, continuously stirring, and quickly injecting into a mold until the auxiliary materials are solidified. The solidified auxiliary materials are put into an oven at 60 ℃ for 2 hours to remove air bubbles in the auxiliary materials. Then placing the mixture into a refrigerator at the temperature of-20 ℃ for shaping for 24 hours. Taking out the enamel plate after 24 hours, removing the mould, pasting a layer of PE breathable pressure sensitive adhesive tape on the auxiliary material, putting the patch into an aluminum foil bag, and storing the patch in a refrigerator at 4 ℃ for later use. The auxiliary material formula of the hydrogel patch is as follows:
TABLE 3 Patch adjuvant formulation containing 2% propylene glycol 1% menthol
Figure BDA0002653296230000072
Example 7:
and (3) paving a PE (polyethylene) breathable pressure-sensitive adhesive tape on a clean enamel plate, and covering a silica gel mold on a PE film for later use. And (3) placing the oil phase (A) and the water phase (B) into a 60 ℃ water bath kettle, stirring at a constant temperature, taking the phase A, placing the phase A into a beaker, then placing 10mg of methimazole pharmacosome, then placing the phase B (the mass ratio of the phase A to the phase B = 7.03) into the beaker, continuously stirring, and quickly injecting into a mold until the auxiliary materials are solidified. The solidified auxiliary materials are put into an oven at 60 ℃ for 2 hours to remove air bubbles in the auxiliary materials. Then placing the mixture into a refrigerator with the temperature of-20 ℃ for shaping for 24 hours. Taking out the enamel plate after 24 hours, removing the mould, sticking a layer of PE breathable pressure-sensitive adhesive tape on the auxiliary material, putting the patch into an aluminum foil bag, and storing in a refrigerator at 4 ℃ for later use. The auxiliary material formula of the hydrogel patch is as follows:
TABLE 4 Patch adjuvant formulation containing 3% propylene glycol 1% menthol
Figure BDA0002653296230000073
Figure BDA0002653296230000081
Example 8:
and (3) paving a PE (polyethylene) breathable pressure-sensitive adhesive tape on a clean enamel plate, and covering a silica gel mold on a PE film for later use. And (3) placing the oil phase (A) and the water phase (B) into a 60 ℃ water bath kettle, stirring at a constant temperature, taking the phase A, placing the phase A into a beaker, then placing 10mg of methimazole pharmacosome, then placing the phase B (the mass ratio of the phase A to the phase B = 7.03) into the beaker, continuously stirring, and quickly injecting into a mold until the auxiliary materials are solidified. The solidified auxiliary materials are put into an oven at 60 ℃ for 2 hours to remove air bubbles in the auxiliary materials. Then placing the mixture into a refrigerator with the temperature of-20 ℃ for shaping for 24 hours. Taking out the enamel plate after 24 hours, removing the mould, sticking a layer of PE breathable pressure-sensitive adhesive tape on the auxiliary material, putting the patch into an aluminum foil bag, and storing in a refrigerator at 4 ℃ for later use. The auxiliary material formula of the hydrogel patch is as follows:
TABLE 5 Patch adjuvant formulation with 4% propylene glycol 1% menthol
Figure BDA0002653296230000082
Example 9:
a piece of clean enamel disc is taken, a PE breathable pressure sensitive adhesive tape is laid, and a silica gel mold is covered on a PE film for standby. And (3) placing the oil phase (A) and the water phase (B) into a 60 ℃ water bath kettle, stirring at a constant temperature, taking the phase A, placing the phase A into a beaker, then placing 10mg of methimazole pharmacosome, then placing the phase B (the mass ratio of the phase A to the phase B = 7.03) into the beaker, continuously stirring, and quickly injecting into a mold until the auxiliary materials are solidified. The solidified auxiliary materials are put into an oven at 60 ℃ for 2 hours to remove air bubbles in the auxiliary materials. Then placing the mixture into a refrigerator with the temperature of-20 ℃ for shaping for 24 hours. Taking out the enamel plate after 24 hours, removing the mould, pasting a layer of PE breathable pressure sensitive adhesive tape on the auxiliary material, putting the patch into an aluminum foil bag, and storing the patch in a refrigerator at 4 ℃ for later use. The hydrogel patch comprises the following auxiliary materials:
TABLE 6 Patch adjuvant formulation with 5% propylene glycol 1% menthol
Figure BDA0002653296230000091
Example 10:
a piece of clean enamel disc is taken, a PE breathable pressure sensitive adhesive tape is laid, and a silica gel mold is covered on a PE film for standby. And (3) placing the oil phase (A) and the water phase (B) into a 60 ℃ water bath kettle, stirring at a constant temperature, taking the phase A, placing the phase A into a beaker, then placing 10mg of methimazole pharmacosome, then placing the phase B (the mass ratio of the phase A to the phase B = 7.03) into the beaker, continuously stirring, and quickly injecting into a mold until the auxiliary materials are solidified. The solidified auxiliary materials are put into an oven at 60 ℃ for 2 hours to remove air bubbles in the auxiliary materials. Then placing the mixture into a refrigerator at the temperature of-20 ℃ for shaping for 24 hours. Taking out the enamel plate after 24 hours, removing the mould, sticking a layer of PE breathable pressure-sensitive adhesive tape on the auxiliary material, putting the patch into an aluminum foil bag, and storing in a refrigerator at 4 ℃ for later use. The auxiliary material formula of the hydrogel patch is as follows:
TABLE 7 Patch adjuvant formulation with 1-5% propylene glycol 2-5% menthol
Figure BDA0002653296230000092
The methimazole pharmacosome hydrogel patch prepared in the above example was subjected to an in vitro transdermal test using a vertical Franz diffusion cell (RYJ-6 b, huangghai). The diffusion cell included two opposing glass receiving chambers equipped with a magnetic stirrer and a water bath jacket. Each receiving chamber has a volume of 6.5 +/-0.1 mL and a transdermal diffusion area of 2.8cm 2 The effective skin penetration area is 1.7671cm 2 . The methimazole pharmacosome patch sample was applied to the rat skin stratum corneum side, carefully held between the delivery chamber and the receiving chamber with the stratum corneum side facing the delivery chamber and the dermis side facing the receiving chamber and placed on a diffusion cell. Each set of experiments contained five parallel samples. After the diffusion chambers on both sides were clamped, 6.5. + -. 0.1mL of a receiving solution was injected into the receiving chamber. The receiving solution used in the experiment was cell PBS containing 20% ethanol, which was prepared in advance and degassed by ultrasound. In the experiment, the rotation speed of a stirrer is 500r.p.m, and the water bath temperature is 37 +/-0.5 ℃. 4ml samples were taken from the receiving chamber at 1, 2, 3, 4, 5, 6, 7, 8 and 24h, followed by the addition of the same volume of blank receiving solution, centrifugation of the resulting diffusion solution, supernatant collection, filtration through a 0.45 μm microporous membrane filter, subsequent filtration, and quantitative analysis of the methimazole pharmacosome content of the patch using an ultraviolet-visible spectrophotometer (UV-2600, shimadzu instruments, ltd.). After the content measurement, the unit area (cm) was calculated by the following formula 2 ) Cumulative amount of drug permeation Q:
Figure BDA0002653296230000101
wherein, Q: cumulative transdermal permeation amount of drug, S: effective skin penetration area, V: volume of receiving liquid in the receiving chamber, V n : the volume of receiving solution taken out, C, at each time i : concentration of drug in the receiving fluid, C, from the 1 st to the last sampling n : the sub-sampling receives the concentration of the drug in the fluid. The steady-state part of the drug permeation curve (the curve of the cumulative transdermal permeation amount of the drug versus time) is tangent, and the slope of the tangent is the transdermal permeation rate of the drug.
Figure 1 is a methimazole pharmacosome hydrogel patch mold prepared in accordance with the present invention. The silica gel plate is 20cm long, 3cm wide, 1mm thick, and the round hole diameter is 1.5cm, and the round hole interval is 2cm, and the round hole is placed in the middle.
FIG. 2 shows the preparation of methimazole pharmacosome hydrogel patch of the present invention. The methimazole pharmacosome hydrogel patch has diameter of 1.5cm, thickness of 1mm, and effective skin penetration area of 1.7671cm 2 。
FIG. 3 is a graph showing the transdermal permeation rate of methimazole pharmacosome hydrogel patch prepared by the present invention without a permeation enhancer.
Transdermal permeabilities (μ g cm) of MMI-AA-OCa (0% PE, 80.3200. + -. 1.3455), MMI-AA-OLa (0% PE, 75.5554. + -. 1.6173), MMI-AA-OSt (0% PE, 70.1730. + -. 1.0926) and MMI (0% PE, 4.4175. + -. 0.6006) -2 *h -1 ) Contrast, respectively increase18.1822, 17.1037 and 15.8852 times of the modified methimazole pharmacosome show that the modified methimazole pharmacosome has good effect of promoting the penetration of the drug into the skin. Transdermal permeabilities (. Mu.g.. Cm.) of MMI-AA-OCa (0% PE, 80.3200. + -. 1.3455), MMI-AA-OLa (0% PE, 75.5554. + -. 1.6173) and MMI-AA-OSt (0% PE, 70.1730. + -. 1.0926) -2 *h -1 ) In contrast, there is a significant difference, possibly related to the size of the molecular weight.
FIG. 4 is the transdermal penetration rate of 2% Azone (Azone) containing pharmacosome in methimazole pharmacosome hydrogel patch prepared by the present invention.
Transdermal permeability (. Mu.g. Cm) of MMI-AA-OLa (0% PE) to MMI-AA-OLa (2% Azone) -2 *h -1 ) In contrast, the transdermal permeability of 2% of the azo (214.5860. + -. 1.1849) was 2.8401 times that of MMI-AA-OLa (0% PE, 75.5554. + -. 1.6173) without a penetration enhancer, indicating that 2% of the azo had a good effect of promoting the penetration of MMI-AA-OLa into the skin.
FIG. 5 shows the transdermal penetration rate of methimazole pharmacosome containing 1-5% Propylene Glycol (PG) and 1% Menthol (MOH) in the preparation of methimazole pharmacosome hydrogel patch of the present invention.
Drug permeation rate (μ g cm) of MMI pharmacosome (MMI-AA-OLa) hydrogel patch containing 1-5% Propylene Glycol (PG) and 1% Menthol (MOH) was calculated from the drug permeation curve -2 *h -1 ) The% of PG +1% MOH (167.9140. + -. 2.0161)>3％PG+1％MOH(135.3840±1.9088)>4％PG+1％MOH(123.4200±2.3228)>1％PG+1％MOH(117.8040±1.5080)>5％PG+1％MOH(111.2040±1.5122)>Control MMI-AA-OLa (0% PE, 75.5554. + -. 1.6173). The results show that as the PG content in the hydrogel patch increased and the MOH content remained unchanged, the transdermal permeation rate of MMI-AA-OLa showed a tendency to increase first and then decrease, with a maximum at 2% PG +1% MOH but less than 2% Azone (214.5860. + -. 1.1849).
FIG. 6 shows the transdermal penetration rate of the methimazole hydrogel patch prepared according to the present invention with 1-5% Propylene Glycol (PG) and 2% Menthol (MOH).
Drug permeation rate (μ g cm) of MMI pharmacosome (MMI-AA-OLa) hydrogel patch containing 1-5% Propylene Glycol (PG) 2% Menthol (MOH) was calculated from the drug permeation curve -2 *h -1 ) Is a2％PG+2％MOH(189.6980±1.7281)>3％PG+2％MOH(147.0680±1.6941)>4％PG+2％MOH(131.2540±1.5756)>1％PG+2％MOH(123.7940±0.7955)>5％PG+2％MOH(115.9020±2.1297)>Control MMI-AA-OLa (0% PE, 75.5554. + -. 1.6173). The results show that as the PG content in the hydrogel patch increased and the MOH content remained unchanged, the transdermal permeation rate of MMI-AA-OLa showed a tendency to increase first and then decrease, with a maximum at 2% PG +2% MOH but less than 2% Azone (214.5860. + -. 1.1849).
FIG. 7 shows the transdermal penetration rate of methimazole pharmacosome containing 1-5% Propylene Glycol (PG) and 3% Menthol (MOH) in the preparation of methimazole pharmacosome hydrogel patch of the present invention.
Drug permeation rate (μ g cm) of MMI pharmacosome (MMI-AA-OLa) hydrogel patch containing 1-5% Propylene Glycol (PG) and 3% Menthol (MOH) was calculated from the drug permeation curve -2 *h -1 ) As 2% of the MOH PG +3% of>3％PG+3％MOH(162.3640±1.9650)>4％PG+3％MOH(149.0600±2.4879)>1％PG+3％MOH(145.9040±1.3307)>5％PG+3％MOH(138.0580±2.4848)>Control MMI-AA-OLa (0% PE, 75.5554. + -. 1.6173). The results revealed that the transdermal permeation rate of MMI-AA-OLa exhibited a tendency to increase and then decrease as the PG content in the hydrogel patch was increased and the MOH content remained unchanged, the maximum value appeared at 2% PG +3% MOH, the transdermal permeation rate value thereof was 1.4104 times as large as 2% Azone (214.5860. + -. 1.1849).
FIG. 8 shows the transdermal penetration rate of the methimazole pharmacosome hydrogel patch prepared by the present invention containing 1-5% Propylene Glycol (PG) and 4% Menthol (MOH).
Drug permeation rate (μ g cm) of MMI pharmacosome (MMI-AA-OLa) hydrogel patch containing 1-5% Propylene Glycol (PG) and 4% Menthol (MOH) was calculated from the drug permeation curve -2 *h -1 ) The content of 2% PG +4% of MOH (248.9440 + -1.7411)>3％PG+4％MOH(158.8960±1.9828)>4％PG+4％MOH(147.2220±1.7566)>1％PG+4％MOH(139.5900±2.5051)>5％PG+4％MOH(127.1520±1.7857)>Control MMI-AA-OLa (0% PE, 75.5554. + -. 1.6173). The results show that the transdermal permeation rate of MMI-AA-OLa increases and then decreases with increasing PG content and maintaining the MOH content in the hydrogel patchSmall trend, maximum at 2% PG +4% MOH, with a transdermal penetration rate value of 1.1601 times that of 2% Azone (214.5860. + -. 1.1849).
FIG. 9 shows the transdermal penetration rate of the methimazole pharmacosome hydrogel patch prepared by the present invention containing 1-5% Propylene Glycol (PG) and 5% Menthol (MOH).
Drug permeation rate (μ g cm) of MMI pharmacosome (MMI-AA-OLa) hydrogel patch containing 1-5% Propylene Glycol (PG) and 5% Menthol (MOH) was calculated from the drug permeation curve -2 *h -1 ) The% of PG +5% by MOH (191.6460. + -. 1.5851)>3％PG+5％MOH(156.6700±2.1886)>4％PG+5％MOH(132.7480±0.8197)>1％PG+5％MOH(128.4820±2.0932)>5％PG+5％MOH(120.9140±1.2117)>Control MMI-AA-OLa (0% PE, 75.5554. + -. 1.6173). The results show that as the PG content in the hydrogel patch increased and the MOH content remained unchanged, the transdermal permeation rate of MMI-AA-OLa showed a tendency to increase first and then decrease, with a maximum at 2% PG +5% MOH, but less than 2% Azone (214.5860. + -. 1.1849).
While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.

Claims (10)

1. The methimazole pharmacosome hydrogel patch for GSH concentration-responsive hyperthyroidism treatment is characterized by comprising a polymer matrix, a pharmacosome and auxiliary materials, wherein the pharmacosome has the following structure:
Figure 252843DEST_PATH_IMAGE001
，
wherein R is C 12 Or C 18 Alkyl or octyl.
2. The hydrogel patch of claim 1, wherein the adjuvant comprises a humectant, a cross-linking agent, an emulsifier, a cross-linking modifier, a pH modifier, a solvent, a penetration enhancer.
3. The hydrogel patch of claim 1, wherein the polymeric matrix material is sodium polyacrylate.
4. The hydrogel patch of claim 2, wherein the humectant is glycerin, the cross-linking agent is aluminum glycollate, the emulsifier is beeswax, the cross-linking modifier is EDTA, the pH modifier is citric acid, the solvent is UP water, and the penetration enhancer is any one or more of propylene glycol, menthol, and azone.
5. The hydrogel patch of claim 1, wherein the pharmacosome is prepared by the method comprising:
(1) Adding methimazole into methanol, adding sodium methoxide, stirring until the methimazole is completely dissolved, and adding propiolic acid, wherein the molar ratio of the methimazole to the propiolic acid is (0.1 to 10): 1, the molar ratio of methanol to sodium methoxide is (1 to 100): 1; carrying out reflux reaction on the obtained mixed solution at 10-100 ℃ for 1-200h under the condition of nitrogen protection; after the reaction is finished, carrying out rotary evaporation on the reaction liquid for 10-120min at the temperature of 1-80 ℃ by using a rotary evaporator to obtain thick white liquid; freeze-drying the obtained thick white liquid for 10-120 hours to obtain white flaky solid methylthioimidazole acrylic acid;
(2) According to the formula of methylthioimidazole acrylic acid: EDC: NSH =1: (0.7 to 6): activating the carboxyl stable intermediate according to the molar ratio of (0.6-15) to obtain a methylthioimidazole acrylic acid solution; the resulting methimazole acrylic acid solution was prepared according to the following ratio of methimazole acrylic acid: alcohol = (0.1 to 100): 1, reacting at 10-100 ℃ for 1-200h; the alcohol is n-octanol, dodecanol or octadecanol; after the reaction is finished, the reaction solution is placed into ultrapure water with the temperature of 1-100 ℃ for ultrasonic washing for 1-120min, the centrifugal operation is carried out for 1-30min under the condition that the rotating speed is 1000-10000r/min, the supernatant is taken and then dissolved in the ultrapure water with the temperature of 1-100 ℃ for centrifugal operation, the supernatant is taken, the above operation is repeated for 1-10 times, and finally the supernatant is freeze-dried for 10-120 hours, so that the target pharmacosome product, namely the methylimidazolium methacrylate, is obtained.
6. The hydrogel patch according to any one of claims 1 to 5, wherein R is a C12 alkyl group.
7. A preparation method of a methimazole pharmacosome hydrogel patch for treating hyperthyroidism in a GSH concentration response mode is characterized by comprising the following steps:
(1) A clean enamel plate is taken, a PE breathable pressure-sensitive adhesive tape is laid, and a silica gel mold is covered on a PE film for standby;
(2) Mixing a polymer matrix material with auxiliary materials and a pharmacosome, quickly stirring the mixture, injecting the mixture into the mold obtained in the step (1), and solidifying the auxiliary materials to form gel, wherein the pharmacosome has the structure:
Figure 241528DEST_PATH_IMAGE001
，
wherein R is C 12 Or C 18 Alkyl or octyl of (a);
(3) Putting the solidified gel into an oven at the temperature of between 30 and 90 ℃ for 1 to 60 hours to remove air bubbles in the auxiliary materials;
(4) After bubble removal, putting the gel into a refrigerator for setting for 1-120 hours under the condition of minus 40 to 4 ℃;
(5) Taking out the enamel plate, removing the mould, and pasting a layer of PE (polyethylene) breathable pressure-sensitive adhesive tape on the surface of the gel to obtain the patch;
(6) The obtained patch was placed in an aluminum foil bag and stored at 4 ℃.
8. The preparation method according to claim 7, wherein the step (2) specifically comprises:
mixing a polymer matrix, a humectant, a cross-linking agent and an emulsifier to obtain an oil phase A; mixing a crosslinking regulator, a pH regulator, a solvent and a penetration enhancer to obtain a water phase B; respectively placing the oil phase A and the water phase B into a 60 ℃ water bath kettle, stirring at constant temperature, placing the phase A into a beaker, then placing the pharmacosome, then placing the phase B, continuously stirring, rapidly injecting into a mold, and waiting for the auxiliary materials to solidify.
9. A method as claimed in claim 7 or claim 8, wherein the polymeric matrix material is sodium polyacrylate.
10. The method according to claim 8, wherein the humectant is glycerin, the crosslinking agent is aluminum glycollate, the emulsifier is beeswax, the crosslinking modifier is EDTA, the pH modifier is citric acid, the solvent is UP water, and the penetration enhancer is one or a mixture of two of propylene glycol and menthol.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1857261A (en) * 2006-03-30 2006-11-08 华中科技大学 Aquogel type thiamazole plaster preparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1857261A (en) * 2006-03-30 2006-11-08 华中科技大学 Aquogel type thiamazole plaster preparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Microwave-promoted regio- and stereoselective vinylation of heterocyclic thiols;Nimmakuri Rajesh et al.;《RSC Advances》;20140106;第4卷;第7834-7837页 *
Synthesis of 3-(1-Methyl-1H-imidazol-2-ylthio)propanoic Acid and (E)-3-(1-Methyl-1H-imidazol-2-ylthio)acrylic Acid;Christopher M. Hattan et al.;《Synth. Commun.》;20120905;第43卷(第1期);第1-8页 *

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