CN110522723A - A kind of Metformin hydrochloride percutaneous drug administration preparation and preparation method thereof - Google Patents

A kind of Metformin hydrochloride percutaneous drug administration preparation and preparation method thereof Download PDF

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CN110522723A
CN110522723A CN201910791315.5A CN201910791315A CN110522723A CN 110522723 A CN110522723 A CN 110522723A CN 201910791315 A CN201910791315 A CN 201910791315A CN 110522723 A CN110522723 A CN 110522723A
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metformin hydrochloride
preparation
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following
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林山
王松
杨云松
朱明哲
朱荣成
孟文静
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Jiangsu Shan Xin Pharmaceutcal Corp Ltd
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Jiangsu Shan Xin Pharmaceutcal Corp Ltd
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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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    • 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
    • A—HUMAN NECESSITIES
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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Abstract

The invention belongs to the transdermal drug delivery formulation art in pharmacy, providing a kind of Metformin hydrochloride percutaneous drug administration preparation, it is the preparation being prepared by Metformin hydrochloride, amphiphilic substance and pharmaceutically acceptable auxiliary material.Invention describes a kind of transdermal more efficient technological means, more traditional cream, patch have higher transdermal effect, the technological means can be applied to more exterior-applied formulations, it can be made the exterior-applied formulations such as ointment, aerosol, spray, liniment, gelling agent, patch, and raw material can be saved to reduce cost.

Description

A kind of Metformin hydrochloride percutaneous drug administration preparation and preparation method thereof
Technical field
The invention belongs to the transdermal drug delivery formulation arts in pharmacy, and in particular to a kind of Metformin hydrochloride is percutaneously given Medicine preparation and preparation method thereof.
Background technique
Diabetes B (T2DM) is the multiple-factor inheritance disease formed by inherent cause and environmental factor collective effect Disease is a kind of complicated heterogeneous glycometabolism disease, mainly includes that hyperglycemia is reacted, islet function is impaired and (or) pancreas islet Plain paracrisis is different substantiality disease of the insufficient insulin with insulin resistance.
Metformin hydrochloride is the fiest-tire medication and connection for the control hyperglycemia recommended in multiple National Diabetes treatment guidelines Share the basic medication in medicine.Good affinity can be used in combination with any other class antidiabetic drug.For example, melbine is slow Release piece can with sulfonylurea drugs, visit the use in conjunction such as Tang Ping, insulin.Melbine is by improving insulin resistance, increasing Basal glucose utilizes, reduces the protein kinase (AMPK) etc. that liver glucose produces and exports, activate adenosine monophosphate activation The blood glucose level of number of mechanisms reduction type 2 diabetic patient.At home and abroad, Metformin hydrochloride preparation type has oral administration solution Agent, oral solid formulation.Oral solid formulation mainly has quick-release tablet, enteric coatel tablets, sustained-release tablet and sustained-release micro-pill capsules agent, salt The oral specific disadvantage of sour melbine includes: that oral dose is big, and when kidney excretion is reduced, melbine is possible to stimulation cream The generation of acid；The patient of oral administration of metformin, which is up to 20%, will appear anorexia, nausea, vomiting, and abdominal discomfort and diarrhea etc. are secondary to be made With.
Metformin hydrochloride can be used as a kind of effective alternative medicine through skin absorption.Percutaneous dosing can avoid drug liver Dirty " first pass effect ", the destruction of gastrointestinal tract；Blood concentration is stablized, and poisonous side effect of medicine is reduced；It longer action time, mentions High bioavilability；It is easy to use, it is easy to operate, reduce administration number of times etc.；Patient dependence can be improved with self administration.I am public Application No. is 201711385865.4 and 201711386995.X patent of invention for department, describe Metformin hydrochloride percutaneous absorbtion Cream and patch, invention describes a kind of transdermal more efficient technological means, which be can be applied to more Exterior-applied formulation.
Although transdermal administration routes, which are that one kind is promising, substitutes oral and hypodermic administration mode, can use It is extremely limited in the medication amount of percutaneous dosing, main reason is that the skin barrier function of cuticula (SC) has pharmaceutical preparation It is strict with, whether semisolid, gel, emulsifiable paste, suspension, the dosage forms such as microemulsion and dressing, the drug discharged from dosage form Molecule requires to get to body circulation by continuous multilayer skin texture, the process include by the diffusion of lipophilicity SC, Through water content epidermis abundant, the capillary network of skin corium is finally entered, and is considered as drug molecule by SC diffusion The rate-limiting step of transdermal delivery, excessively hydrophilic salt cannot easily penetrate SC and after excessively lipophilic molecules cannot penetrate into downwards The continuous epidermis rich in moisture.
Amphiphatic nanometer formulation has potential advantage as carrier for transdermal delivery.Nanometer formulation small, phase with partial size The physical characteristic big to surface area, can come into full contact with skin surface, and it is amphiphilic can promote Cutaneous permeation, change cuticula Structure and mobility in addition the interaction of fusion mechanism, aquation influences each other, and make drugs through skin play whole body Effect.Alternative nano-carrier includes liposome, micro emulsion (microemulsion) and nanoparticle.
Summary of the invention
In view of the deficiencies of the prior art, more traditional the purpose of the present invention is to provide a kind of transdermal more efficient preparation Cream, patch have higher transdermal effect, which can be applied to more exterior-applied formulations, can be made ointment The exterior-applied formulations such as agent, aerosol, spray, liniment, gelling agent, patch, and raw material can be saved reduce cost.
The purpose of the present invention is to provide a kind of Metformin hydrochloride percutaneous drug administration preparations and preparation method thereof.
The present invention provides a kind of Metformin hydrochloride percutaneous drug administration preparations, it is by Metformin hydrochloride, amphiphilic object The nanometer formulation that matter and pharmaceutically acceptable auxiliary material are prepared.
Further, the amphiphilic substance of previous formulations is amphiphilic nano silica, cholic acid, PMA-SS, polyethylene glycol Octadecyl (tristearin) ether, amphiphilic chitosan, methyl acrylate, silk gum, hyaluronic acid, polyethylene glycol-polylactic acid-hydroxyl second The one such or two or more combination of sour, amphiphilic molybdenum dioxide.
Further, previous formulations are liposome gels, and liposome gel is made of the component of following parts by weight: 40-60 parts of Metformin hydrochloride, 72-108 parts of lecithin, 24-36 parts of cholesterol, 8-12 parts of amphiphilic nano silicon oxide, card wave 12-18 parts of nurse, 4-6 parts of glycerol, 1.6-2.4 parts of ethylparaben, 0.2-0.3 parts of triethanolamine, water for injection adds to 1000 parts.
Further, liposome gel is made of the component of following parts by weight: 50 parts of Metformin hydrochloride, lecithin 90 parts, 30 parts of cholesterol, 10 parts of amphiphilic nano silicon oxide, 15 parts of carbomer, 5 parts of glycerol, 2 parts of ethylparaben, three ethyl alcohol 0.25 part of amine, water for injection adds to 1000 parts.
Further, previous formulations are sprays, and spray is made of the component of following parts by weight: Metformin hydrochloride 40-60 parts, 75.2-112.8 parts of Tween-80,75.2-112.8 parts of dehydrated alcohol, 8-12 parts of peppermint oil, 8-12 parts of cholic acid, Buddhist nun 0.8-1.2 parts of tortoise beetle ester of pool, water for injection adds to 1000 parts.
Further, previous formulations are sprays, and spray is made of the component of following parts by weight: Metformin hydrochloride 50 parts, 94 parts of Tween-80,94 parts of dehydrated alcohol, 10 parts of peppermint oil, 10 parts of cholic acid, 1 part of methylparaben, water for injection adds to 1000 parts.
Further, previous formulations are aerosols, and aerosol is made of the component of following parts by weight: Metformin hydrochloride 40-60 parts, 44.8-67.2 parts of Tween-80,42.4-63.6 parts of glycerol, 8-12 parts of propylene glycol, 6.4-9.6 parts of peppermint oil, PMA- 9.6-14.4 parts of SS, 0.8-1.2 parts of methylparaben, 400-600 parts of third/butane mixture gase, water is added to be configured to 1000 parts.
Further, previous formulations are aerosols, and aerosol is made of the component of following parts by weight: Metformin hydrochloride 50 parts, 56 parts of Tween-80,53 parts of glycerol, 10 parts of propylene glycol, 8 parts of peppermint oil, 12 parts of PMA-SS, 1 part of methylparaben, third/ 500 parts of butane mixture gase, water is added to be configured to 1000 parts.
Further, previous formulations are liniments, and liniment is made of the component of following parts by weight: Metformin hydrochloride 40- 60 parts, 51.2-76.8 parts of Tween-80,52.8-79.2 parts of dehydrated alcohol, 6.4-9.6 parts of sesame oil, polyethylene glycol octadecyl 9.6-14.4 parts of (tristearin) ether, 0.8-1.2 parts of sodium benzoate, polyethylene glycol 400 adds to 1000 parts.
Further, previous formulations are liniments, and liniment is made of the component of following parts by weight: Metformin hydrochloride 50 Part, 64 parts of Tween-80,66 parts of dehydrated alcohol, 8 parts of sesame oil, 12 parts of ether of polyethylene glycol octadecyl (tristearin), sodium benzoate 1 Part, polyethylene glycol 400 adds to 1000 parts.
Further, previous formulations are nanoparticle gelling agents, and nanoparticle gelling agent is made of the component of following parts by weight: 40-60 parts of Metformin hydrochloride, 16-24 parts of sodium alginate, amphiphilic chitosan 0.8-1.2 parts, sodium carboxymethylcellulose 12-18 Part, 8-12 parts of carbomer, water is added to be formulated into 1000 parts.
Further, nanoparticle gelling agent is made of the component of following parts by weight: 50 parts of Metformin hydrochloride, alginic acid 20 parts of sodium, 1 part of amphiphilic chitosan, 10 parts of carbomer, adds water to be formulated into 1000 parts by 15 parts of sodium carboxymethylcellulose.
Further, previous formulations are ointments, and ointment is made of the component of following parts by weight: Metformin hydrochloride 40-60 parts, 64-96 parts of ethyl cellulose, 40-60 parts of methyl acrylate, 24-36 parts of sorbester p17, Macrogol 4000 112- 168 parts, 520-780 parts of polyethylene glycol 400 add to 1000 parts.
Further, previous formulations are ointments, and ointment is made of the component of following parts by weight: Metformin hydrochloride 50 parts, 80 parts of ethyl cellulose, 50 parts of methyl acrylate, 30 parts of sorbester p17,140 parts of Macrogol 4000, polyethylene glycol 400 650 parts add to 1000 parts.
Further, previous formulations are patches, and patch is made of the component of following parts by weight: Metformin hydrochloride 40- 60 parts, PMMA72-108 parts, 24-36 parts of PLGA, PVA8-12 parts, 40-60 parts of silk gum, 24-36 parts of propylene glycol, water soluble acrylic acid 520-780 parts of pressure sensitive adhesive.
Further, previous formulations are patches, and patch is made of the component of following parts by weight: Metformin hydrochloride 50 Part, PMMA90 parts, PLGA30 parts, 10 parts of PVA, 50 parts of silk gum, 30 parts of propylene glycol, 650 parts of water soluble acrylic acid pressure sensitive adhesive.
The present invention also provides a kind of methods for preparing previous formulations, it includes the following steps:
A, the raw material of each weight proportion is weighed；
B, pharmaceutically acceptable auxiliary material is added or complementary ingredient is prepared.
Further, purposes of the preparation in preparation treatment diabetes B drug.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention The technology realized all belongs to the scope of the present invention.
Specific embodiment
Embodiment 1 prepares the Metformin hydrochloride liposome gel containing amphiphilic nano silica
Metformin hydrochloride 50g, lecithin 90g, cholesterol 30g, amphiphilic nano silicon oxide 10g, carbomer 15g are sweet Oily 5g, ethylparaben 2g, triethanolamine 0.25g, water for injection add to 1000g, by the above proportion accurate weighing, process for preparation It is as follows:
1) according to lecithin: cholesterol: amphiphilic nano silicon oxide: Metformin hydrochloride=9:3:1:5 ratio takes Four kinds of substances are stated, are dissolved in a small amount of ethyl alcohol；The appropriate phosphate buffer solution that pH value is 6.8 is configured, is set in 50 DEG C of waters bath with thermostatic control, It mixes slowly, slowly injects said mixture, stir 2 hours, liposome solutions are both obtained after ethyl alcohol volatilizes.
2) it takes carbomer to be placed in the appropriate phosphate buffer solution that appropriate pH value is 6.8, is swollen it sufficiently overnight, adds Enter glycerol to stir evenly, blank clear gel matrix is made, it is spare.
3) take liposome solutions appropriate, mix slowly it is lower be added slowly in gel-type vehicle respectively, while nipalgin is added Appropriate phosphate buffer solution is added to full dose in ethyl ester, and instillation triethylamine, which withers, saves pH value to 6.8 to get lipidosome gel.
The preparation of embodiment 2 contains the Metformin hydrochloride liposome gel of amphiphilic hyaluronic acid
Metformin hydrochloride 50g, lecithin 90g, cholesterol 30g, hyaluronic acid 10g, carbomer 15g, glycerol 5g, Ni Bo Golden ethyl ester 2g, triethanolamine 0.25g, water for injection add to 1000g, and by the above proportion accurate weighing, process for preparation is as follows:
1) according to lecithin: cholesterol: hyaluronic acid: Metformin hydrochloride=9:3:1:5 ratio takes above-mentioned four kinds of objects Matter is dissolved in a small amount of ethyl alcohol；The appropriate phosphate buffer solution that pH value is 6.8 is configured, sets in 50 DEG C of waters bath with thermostatic control, stirs at a slow speed It mixes, slowly injects said mixture, stir 2 hours, liposome solutions are both obtained after ethyl alcohol volatilizes.
2) it takes carbomer to be placed in the appropriate phosphate buffer solution that appropriate pH value is 6.8, is swollen it sufficiently overnight, adds Enter glycerol to stir evenly, blank clear gel matrix is made, it is spare.
3) take liposome solutions appropriate, mix slowly it is lower be added slowly in gel-type vehicle respectively, while nipalgin is added Appropriate phosphate buffer solution is added to full dose in ethyl ester, and instillation triethylamine, which withers, saves pH value to 6.8 to get lipidosome gel.
The preparation of embodiment 3 contains the Metformin hydrochloride lipidosome gel of amphiphilic polyethylene glycol-polylactic acid-hydroxyacetic acid Agent
Metformin hydrochloride 50g, lecithin 90g, cholesterol 30g, polyethylene glycol-polylactic acid-hydroxyacetic acid 10g, card wave Nurse 15g, glycerol 5g, ethylparaben 2g, triethanolamine 0.25g, water for injection add to 1000g, match accurate weighing by above, Process for preparation is as follows:
1) according to lecithin: cholesterol: polyethylene glycol-polylactic acid-hydroxyacetic acid: Metformin hydrochloride=9:3:1:5 Ratio takes above-mentioned four kinds of substances, is dissolved in a small amount of ethyl alcohol；The appropriate phosphate buffer solution that pH value is 6.8 is configured, 50 DEG C of perseverances are set It in tepidarium, mixes slowly, slowly injects said mixture, stir 2 hours, liposome solutions are both obtained after ethyl alcohol volatilizes.
2) it takes carbomer to be placed in the appropriate phosphate buffer solution that appropriate pH value is 6.8, is swollen it sufficiently overnight, adds Enter glycerol to stir evenly, blank clear gel matrix is made, it is spare.
3) take liposome solutions appropriate, mix slowly it is lower be added slowly in gel-type vehicle respectively, while nipalgin is added Appropriate phosphate buffer solution is added to full dose in ethyl ester, and instillation triethylamine, which withers, saves pH value to 6.8 to get lipidosome gel.
Embodiment 4 prepares the Metformin hydrochloride liposome gel containing high dose amphiphilic nano silica
Metformin hydrochloride 50g, lecithin 90g, cholesterol 30g, amphiphilic nano silicon oxide 12g, carbomer 15g are sweet Oily 5g, ethylparaben 2g, triethanolamine 0.25g, water for injection add to 1000g, by the above proportion accurate weighing, process for preparation It is as follows:
1) according to lecithin: cholesterol: amphiphilic nano silicon oxide: Metformin hydrochloride=9:3:1.2:5 ratio takes Above-mentioned four kinds of substances, are dissolved in a small amount of ethyl alcohol；The appropriate phosphate buffer solution that pH value is 6.8 is configured, 50 DEG C of waters bath with thermostatic control are set In, it mixes slowly, slowly injects said mixture, stir 2 hours, liposome solutions are both obtained after ethyl alcohol volatilizes.
2) it takes carbomer to be placed in the appropriate phosphate buffer solution that appropriate pH value is 6.8, is swollen it sufficiently overnight, adds Enter glycerol to stir evenly, blank clear gel matrix is made, it is spare.
3) take liposome solutions appropriate, mix slowly it is lower be added slowly in gel-type vehicle respectively, while nipalgin is added Appropriate phosphate buffer solution is added to full dose in ethyl ester, and instillation triethylamine, which withers, saves pH value to 6.8 to get lipidosome gel.
Embodiment 5 prepares the Metformin hydrochloride liposome gel containing low dosage amphiphilic nano silica
Metformin hydrochloride 50g, lecithin 90g, cholesterol 30g, amphiphilic nano silicon oxide 8g, carbomer 15g, glycerol 5g, ethylparaben 2g, triethanolamine 0.25g, water for injection add to 1000g, and by the above proportion accurate weighing, process for preparation is such as Under:
1) according to lecithin: cholesterol: amphiphilic nano silicon oxide: Metformin hydrochloride=9:3:0.8:5 ratio takes Above-mentioned four kinds of substances, are dissolved in a small amount of ethyl alcohol；The appropriate phosphate buffer solution that pH value is 6.8 is configured, 50 DEG C of waters bath with thermostatic control are set In, it mixes slowly, slowly injects said mixture, stir 2 hours, liposome solutions are both obtained after ethyl alcohol volatilizes.
2) it takes carbomer to be placed in the appropriate phosphate buffer solution that appropriate pH value is 6.8, is swollen it sufficiently overnight, adds Enter glycerol to stir evenly, blank clear gel matrix is made, it is spare.
3) take liposome solutions appropriate, mix slowly it is lower be added slowly in gel-type vehicle respectively, while nipalgin is added Appropriate phosphate buffer solution is added to full dose in ethyl ester, and instillation triethylamine, which withers, saves pH value to 6.8 to get lipidosome gel.
The preparation of embodiment 6 contains the Metformin hydrochloride micro emulsion spray of amphiphilic cholic acid
Metformin hydrochloride 50g, Tween-80 94g, dehydrated alcohol 94g, peppermint oil 10g, cholic acid 10g, methylparaben 1g, water for injection add to 1000g, and by the above proportion accurate weighing, process for preparation is as follows:
1) Tween-80, dehydrated alcohol, cholic acid, peppermint oil are mixed in proportion, in turning for magnetic stirring apparatus 400rmin Speed is lower to stir 2min, then the Metformin hydrochloride of recipe quantity is added in mixed system, stirs 20min under same revolving speed to obtain the final product Colostric fluid.
2) methylparaben is dissolved in appropriate purified water, be added in colostric fluid, continue moisturizing to 1000mL, stirring to mixing Uniformly to obtain the final product.
The preparation of embodiment 7 contains the Metformin hydrochloride microemulsion aerosol of amphiphilic PMA-SS
Metformin hydrochloride 50g, Tween-80 56g, glycerol 53g, propylene glycol 10g, peppermint oil 8g, PMA-SS 12g, Buddhist nun Tortoise beetle ester 1g is moored, third/butane mixture gase 500g is configured to 1000g, and by the above proportion accurate weighing, process for preparation is as follows:
1) Tween-80, glycerol, PMA-SS, peppermint oil are mixed in proportion, in the revolving speed of magnetic stirring apparatus 400rmin Lower stirring 2min, then the Metformin hydrochloride of recipe quantity is added in mixed system, 20min is stirred under same revolving speed up to just Lotion.
2) methylparaben, propylene glycol are dissolved in appropriate purified water, are added in colostric fluid, continue moisturizing to 500mL, stirring It is extremely uniformly mixed to obtain the final product.
3) plunging is taken, according to medical fluid: the ratio of propellant (1:1) is filling.
The preparation of embodiment 8 contains the Metformin hydrochloride micro emulsion liniment of amphiphilic polyethylene glycol octadecyl (tristearin) ether
Metformin hydrochloride 50g, Tween-80 64g, dehydrated alcohol 66g, sesame oil 8g, polyethylene glycol octadecyl (tristearin) Ether 12g, sodium benzoate 1g, polyethylene glycol 400 add to 1000g, and by the above proportion accurate weighing, process for preparation is as follows:
1) Tween-80, dehydrated alcohol, polyethylene glycol octadecyl (tristearin) ether, sesame oil are mixed in proportion, in magnetic force 2min is stirred under the revolving speed of blender 400rmin, then the Metformin hydrochloride of recipe quantity is added in mixed system, on an equal basis 20min is stirred under revolving speed up to colostric fluid.
2) be adjusted to 1 000mL with polyethylene glycol 400, filter, packing to get.
The preparation of embodiment 9 contains the Metformin hydrochloride nanoparticle gelling agent of amphiphilic chitosan
Metformin hydrochloride 50g, sodium alginate 20g, amphiphilic chitosan 1g, sodium carboxymethylcellulose 15g, carbomer 10g adds water to be formulated into 1000g, and by the above proportion accurate weighing, process for preparation is as follows:
1) Metformin hydrochloride of weighing, sodium alginate and amphiphilic chitosan are dissolved in 1000ml water, stirring is mixed It is outstanding.
2) suspension is spray-dried to obtain drug containing amphiphilic nano grain with spray dryer.
3) it takes the carbomer of recipe quantity, sodium carboxymethylcellulose to be sufficiently swollen in water, nano particle is added, sufficiently stirs It mixes, moisturizing to 1000g, and continues to be stirred until homogeneous.
The preparation of embodiment 10 contains the Metformin hydrochloride nanoparticle ointment of amphiphilic methyl acrylate
Metformin hydrochloride 50g, ethyl cellulose 80g, methyl acrylate 50g, sorbester p17 30g, Macrogol 4000 140g, polyethylene glycol 400 600g, by the above proportion accurate weighing, process for preparation is as follows:
1) ethyl cellulose, methyl acrylate are dissolved into first in 800mL methanol, ultrasound after ten minutes, by recipe quantity salt After sour melbine is dissolved in 200mL methanol, it is added in polymer solution and stirs 30 minutes.Arlacel-80, electromagnetism are added later Blender is stirred continuously under the revolving speed of 500rpm.
2) it stirs molding suspension and is spray-dried to obtain amphiphilic nano grain with spray dryer again.
3) amphiphilic nano grain, polyethylene glycol 400, Macrogol 4000 mixing, 75 DEG C of thawings are stirred evenly, are persistently stirred Mix to room temperature to get.
The preparation of embodiment 11 contains the Metformin hydrochloride nanoparticle patch of amphiphilic silk gum
Metformin hydrochloride 50g, PMMA90g, PLGA30g, PVA 10g, silk gum 50g, propylene glycol 30g, water soluble acrylic acid Pressure sensitive adhesive 650g, by the above proportion accurate weighing, process for preparation is as follows:
1) Metformin hydrochloride of weighing, PMMA, PLGA and silk gum are dissolved in 600g methylene chloride, are dropwisely added In water phase containing PVA5%, and using homogenizer 24000 turns/min homogeneous 15min, then carry out magnetic agitation 3 hours.
2) by centrifugation, per minute 25,000 turn after 15 minutes, is washed three times, freezing is dry the amphiphilic nano particle formed It is dry.
3) drug containing nanoparticle is added in water and propylene glycol solution, addition water soluble acrylic acid pressure sensitive adhesive is uniformly mixed.
4) rubber cement of mixing is applied to back lining materials, area 1000cm2, heating, drying, then cover up-protective layer.As needed Metformin hydrochloride nanoparticle transdermal patch is made in size cutting, packaging.
The preparation of the traditional cream of comparative example 1
Metformin hydrochloride 50g, albolene 20g, glycerin monostearate 20g, 16 or octadecyl alcolol 50g, carbomer 5g, atoleine 80g, polysorbate60 60g, azone 50g, glycerol 50g, methyl p-hydroxybenzoate 1g, benzyl alcohol 5g, injection Water adds to 1000g, and by the above proportion accurate weighing, emulsifiable paste process for preparation is as follows:
1) polysorbate60, methyl p-hydroxybenzoate, glycerol distillation water are mixed and heated to 70 DEG C；
2) Metformin hydrochloride of recipe quantity and carbomer are soluble in water；
3) 16 or octadecyl alcolol, benzyl alcohol, albolene, glycerin monostearate, atoleine, the azone of recipe quantity add Heat is slowly added to mixture that step 1) obtains quickly after mixing evenly to 75 DEG C, and the Metformin hydrochloride that step 2) is added is molten Liquid mixes, is condensed into cream.
The preparation of the traditional matrix-type transdermal patch of comparative example 2
Metformin hydrochloride 50g, propylene glycol 200g, silicon rubber pressure sensitive adhesive 700g.
It is prepared by following preparation processes:
1. Metformin hydrochloride is dissolved in propylene glycol solution, silicon rubber pressure sensitive adhesive is added and is uniformly mixed.
2. the rubber cement of mixing is applied to back lining materials, area 10000cm2, heating, drying, then cover up-protective layer.
3. size is cut as needed, the matrix-type transdermal patch of drug containing compositions is made in packaging.
Below by way of specific percutaneous abilities experiments have shown that beneficial effects of the present invention.
1 percutaneous abilities of test example compare
The miniature pig of Metformin hydrochloride nanometer formulation containing amphiphilic substance of the invention and traditional cream is in vitro Skin in vitro transdermal test.
The processing of miniature pig isolated skin: taking small-sized pigskin, removes subcutaneous fat, refrigerated storage is standby after physiological saline is cleaned With.
The transdermal measurement of miniature swine skin is fixed: carrying out penetrating absorption using Franz Transdermal diffusion cell, when use consolidates skin Due on diffusion cell, smearing appropriate embodiment 1-7, traditional cream, patch, transdermal 2.8 ± 0.1cm of area respectively2, water-bath temperature 35 DEG C, mixing speed 300rpm, reception tank volume 6ml of degree, receiving liquid are 0.9% normal saline solution.Respectively at 2,4,6,8, 10, it samples within 12 hours, every 200 μ L of sub-sampling, and supplements isometric 35 DEG C of physiological saline immediately.Sample uses high performance liquid chromatography Method is analyzed.
Receive liquid processing method: 200 μ L of acceptable solution being taken to be placed in centrifuge tube, 200 μ L mobile phases are added, vibrates 2min, 10000rpm is centrifuged 10min, takes 20 μ L sample detection of supernatant.
Transdermal accumulation infiltration capacity is calculated as follows:
Qi=(CiV+ ∑ Ci-1 × Vi)/S
V is to receive building volume；Vi is each sample volume；Ci is drug concentration when i-th samples in receiving liquid；S is Transdermal contact area.
Using unit area accumulation infiltration capacity Qi as ordinate, time t is abscissa mapping, obtains drug accumulation penetration curve. The straight line portion of curve obtained is returned, slope, as steady-state permeation rate J (the μ g.cm of drug are found out-2.h-1)。
Penetrating absorption detection method of content:
Mobile phase: 0.05% heptane sulfonic acid sodium salt (10% phosphoric acid adjusts pH=4.0): acetonitrile=84:16；
Chromatographic column: Inertsil ODS-SP C18,4.6mm × 250mm, 5 μm；
Detection wavelength: 233nm；Column temperature: 30 DEG C；Flow velocity: 1.0ml/min；Sample volume: 20 μ L；
Test result shows to be shown in Table 1.
Penetrating absorption result (n=6) of 1 present invention of table on miniature swine skin
It can be seen from the results above that the external preparation of the invention containing amphiphilic nano material, percutaneous abilities have It significantly improves.
Of the invention contains the transdermal amount linear equation of accumulation of the Metformin hydrochloride preparation capable of permeating skin on miniature swine skin:
Embodiment 1:y=411.62x-956.35, R2=0.9892
Embodiment 2:y=279.62x-584.87, R2=0.9957
Embodiment 3:y=121.19x-200.79, R2=0.9987
Embodiment 4:y=270.83x-527.45, R2=0.9977
Embodiment 5:y=401.44x-857.46, R2=0.9962
Embodiment 6:y=457.24x-1059.9, R2=0.9879
Embodiment 7:y=383.70x-970.75, R2=0.9813
Embodiment 8:y=264.58x-599.75, R2=0.9860
Embodiment 9:y=419.61x-774.9, R2=0.9978
Embodiment 10:y=331.71x-629.56, R2=0.9962
Embodiment 11:y=374.47x-668.86, R2=0.9998
Traditional cream: y=190.00x-415.09, R2=0.9839
Traditional patch: y=72.936x-137.27, R2=0.9714
Wherein, for liposome gel, the present invention is in following consumption proportion: 40-60 parts of Metformin hydrochloride, lecithin 72-108 parts of rouge, 24-36 parts of cholesterol, 8-12 parts of amphiphilic nano silicon oxide, 12-18 parts of carbomer, 4-6 parts of glycerol, Ni Bo Golden ethyl ester 1.6-2.4 parts, 0.2-0.3 parts of triethanolamine；40-60 parts of Metformin hydrochloride, 72-108 parts of lecithin, cholesterol 24-36 parts, amphiphilic hyaluronic acid 8-12 parts, 12-18 parts of carbomer, 4-6 parts of glycerol, 1.6-2.4 parts of ethylparaben, three second 0.2-0.3 parts of hydramine；40-60 parts of Metformin hydrochloride, 72-108 parts of lecithin, 24-36 parts of cholesterol, amphiphilic nano titanium dioxide 9.6-14.4 parts of silicon, 12-18 parts of carbomer, 4-6 parts of glycerol, 1.6-2.4 parts of ethylparaben, 0.2-0.3 parts of triethanolamine In the case of, effect is better than traditional cream, wherein it is preferred that the technical side that amphiphilic substance is amphiphilic nano silicon oxide 8-12 parts Case.In following dosage model are as follows: 50 parts of Metformin hydrochloride, 90 parts of lecithin, 30 parts of cholesterol, amphiphilic nano silicon oxide 10 Part, 15 parts of carbomer, 5 parts of glycerol, 2 parts of ethylparaben, 0.25 part of triethanolamine；50 parts of Metformin hydrochloride, lecithin 90 Part, 30 parts of cholesterol, 10 parts of amphiphilic hyaluronic acid, 15 parts of carbomer, 5 parts of glycerol, 2 parts of ethylparaben, triethanolamine 0.25 part；50 parts of Metformin hydrochloride, 90 parts of lecithin, 30 parts of cholesterol, 12 parts of amphiphilic nano silicon oxide, carbomer 15 Part, in the case where 5 parts of glycerol, 2 parts of ethylparaben, 0.25 part of triethanolamine, effect is better than traditional cream, wherein it is preferred that double The technical solution that parent's property substance is 10 parts of amphiphilic nano silicon oxide.
To sum up, the transdermal more efficient technological means of one kind prepared by the present invention, more traditional cream, patch have more High transdermal effect, the technological means can be applied to more exterior-applied formulations, can be made ointment, aerosol, spray, The exterior-applied formulations such as liniment, gelling agent, patch, and raw material can be saved reduce cost.

Claims (11)

1. a kind of Metformin hydrochloride percutaneous drug administration preparation, it is characterised in that: it be by Metformin hydrochloride, amphiphilic substance with And the nanometer formulation that pharmaceutically acceptable auxiliary material is prepared.
2. preparation according to claim 1, which is characterized in that the amphiphilic substance be amphiphilic nano silica, Cholic acid, PMA-SS, polyethylene glycol octadecyl (tristearin) ether, amphiphilic chitosan, methyl acrylate, silk gum, hyaluronic acid, poly- second The one such or two or more combination of glycol-poly lactic-co-glycolic acid, amphiphilic molybdenum dioxide.
3. preparation according to claim 2, it is characterised in that: the preparation is liposome gel, liposome gel It is made of the component of following parts by weight: 40-60 parts of Metformin hydrochloride, 72-108 parts of lecithin, 24-36 parts of cholesterol, double Close nano silica 8-12 parts, 12-18 parts of carbomer, 4-6 parts of glycerol, 1.6-2.4 parts of ethylparaben, triethanolamine 0.2- 0.3 part, water for injection adds to 1000 parts；Preferably, liposome gel is made of the component of following parts by weight: hydrochloride 50 parts of biguanides, 90 parts of lecithin, 30 parts of cholesterol, 10 parts of amphiphilic nano silicon oxide, 15 parts of carbomer, 5 parts of glycerol, nipalgin 2 parts of ethyl ester, 0.25 part of triethanolamine, water for injection adds to 1000 parts.
4. preparation according to claim 2, it is characterised in that: the preparation is spray, and spray is by following parts by weight Several components is constituted: 40-60 parts of Metformin hydrochloride, 75.2-112.8 parts of Tween-80,75.2-112.8 parts of dehydrated alcohol, thin 8-12 parts of lotus oil, 8-12 parts of cholic acid, 0.8-1.2 parts of methylparaben, water for injection adds to 1000 parts；Preferably, spray by The component of following parts by weight is constituted: 50 parts of Metformin hydrochloride, 94 parts of Tween-80, and 94 parts of dehydrated alcohol, 10 parts of peppermint oil, 10 parts of cholic acid, 1 part of methylparaben, water for injection adds to 1000 parts.
5. preparation according to claim 2, it is characterised in that: the preparation is aerosol, and aerosol is by following parts by weight Several components is constituted: 40-60 parts of Metformin hydrochloride, 44.8-67.2 parts of Tween-80, and 42.4-63.6 parts of glycerol, propylene glycol 8- 12 parts, 6.4-9.6 parts of peppermint oil, 9.6-14.4 parts of PMA-SS, 0.8-1.2 parts of methylparaben, third/butane mixture gase 400- 600 parts, water is added to be configured to 1000 parts；Preferably, aerosol is made of the component of following parts by weight: Metformin hydrochloride 50 Part, 56 parts of Tween-80,53 parts of glycerol, 10 parts of propylene glycol, 8 parts of peppermint oil, 12 parts of PMA-SS, 1 part of methylparaben, third/fourth 500 parts of alkane gaseous mixture, water is added to be configured to 1000 parts.
6. preparation according to claim 2, it is characterised in that: the preparation is liniment, and liniment is by following parts by weight Component is constituted: 40-60 parts of Metformin hydrochloride, 51.2-76.8 parts of Tween-80, and 52.8-79.2 parts of dehydrated alcohol, sesame oil 6.4-9.6 parts, 9.6-14.4 parts of polyethylene glycol octadecyl (tristearin) ether, 0.8-1.2 parts of sodium benzoate, polyethylene glycol 400 adds to 1000 parts；Preferably, liniment is made of the component of following parts by weight: 50 parts of Metformin hydrochloride, 64 parts of Tween-80, anhydrous 66 parts of ethyl alcohol, 8 parts of sesame oil, 12 parts of ether of polyethylene glycol octadecyl (tristearin), 1 part of sodium benzoate, polyethylene glycol 400 adds to 1000 Part.
7. preparation according to claim 2, it is characterised in that: the preparation is nanoparticle gelling agent, nanoparticle gelling agent It is made of the component of following parts by weight: 40-60 parts of Metformin hydrochloride, 16-24 parts of sodium alginate, amphiphilic chitosan 0.8- 1.2 parts, 12-18 parts of sodium carboxymethylcellulose, 8-12 parts of carbomer, water is added to be formulated into 1000 parts；Preferably, nanoparticle gelling agent It is made of the component of following parts by weight: 50 parts of Metformin hydrochloride, 20 parts of sodium alginate, 1 part of amphiphilic chitosan, carboxymethyl 15 parts of sodium cellulosate, 10 parts of carbomer, water is added to be formulated into 1000 parts.
8. preparation according to claim 2, it is characterised in that: the preparation is ointment, and ointment is by following parts by weight Several components is constituted: 40-60 parts of Metformin hydrochloride, 64-96 parts of ethyl cellulose, 40-60 parts of methyl acrylate, and sorbester p17 24-36 parts, 112-168 parts of Macrogol 4000,520-780 parts of polyethylene glycol 400 add to 1000 parts；Preferably, ointment It is made of the component of following parts by weight: 50 parts of Metformin hydrochloride, 80 parts of ethyl cellulose, 50 parts of methyl acrylate, sapn 80 30 parts, 140 parts of Macrogol 4000,650 parts of polyethylene glycol 400 add to 1000 parts.
9. preparation according to claim 2, it is characterised in that: the preparation is patch, and patch is by following parts by weight Component constitute: 40-60 parts of Metformin hydrochloride, PMMA72-108 parts, 24-36 parts of PLGA, PVA8-12 parts, 40-60 parts of silk gum, 24-36 parts of propylene glycol, 520-780 parts of water soluble acrylic acid pressure sensitive adhesive；Preferably, patch is made of the component of following parts by weight: 50 parts of Metformin hydrochloride, PMMA90 parts, PLGA30 parts, 10 parts of PVA, 50 parts of silk gum, 30 parts of propylene glycol, aqueous acrylamide acid fracturing 650 parts of quick glue.
10. a kind of prepare preparation described in claim 1~9 any one, it is characterised in that: it includes the following steps:
A, the raw material of each weight proportion is weighed；
B, pharmaceutically acceptable auxiliary material is added or complementary ingredient is prepared.
11. purposes of the preparation described in any one of claim 1 to 9 in preparation treatment diabetes B drug.
CN201910791315.5A 2019-08-26 2019-08-26 A kind of Metformin hydrochloride percutaneous drug administration preparation and preparation method thereof Pending CN110522723A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114569556A (en) * 2022-03-23 2022-06-03 南方医科大学南方医院 Metformin hydrochloride ethosome and preparation method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114569556A (en) * 2022-03-23 2022-06-03 南方医科大学南方医院 Metformin hydrochloride ethosome and preparation method thereof

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