CN114569556A - Metformin hydrochloride ethosome and preparation method thereof - Google Patents

Metformin hydrochloride ethosome and preparation method thereof Download PDF

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CN114569556A
CN114569556A CN202210290025.4A CN202210290025A CN114569556A CN 114569556 A CN114569556 A CN 114569556A CN 202210290025 A CN202210290025 A CN 202210290025A CN 114569556 A CN114569556 A CN 114569556A
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metformin hydrochloride
ethosome
parts
alcohol
mixing
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朱晓亮
张菲茵
王莹哲
龙威
张美美
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Southern Hospital Southern Medical University
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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
    • 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)
    • 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
    • A61K47/08—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
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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 relates to the technical field of transdermal pharmaceutical preparations. The invention provides a metformin hydrochloride ethosome and a preparation method thereof, wherein the metformin hydrochloride ethosome is prepared from the following raw materials in parts by volume: 3-7 parts of metformin hydrochloride, 1-3 parts of lipid, 15-30 parts of alcohol and 60-75 parts of water. The invention takes the ethosome as the transdermal carrier of the metformin hydrochloride to prepare the metformin hydrochloride ethosome, and the product prepared by the invention has the characteristics of small particle size, high entrapment rate, high drug loading rate, strong transdermal permeability and good safety, and provides a safe and economic transdermal anti-fibrosis preparation for clinic.

Description

Metformin hydrochloride ethosome and preparation method thereof
Technical Field
The invention relates to the technical field of transdermal pharmaceutical preparations, in particular to a metformin hydrochloride ethosome and a preparation method thereof.
Background
Metformin hydrochloride is a first-line medicament for treating type 2 diabetes, a large number of basic researches prove that metformin hydrochloride plays a role in relieving cardiac, pulmonary, hepatic, renal and skin fibrosis, and most of the researches adopt a mode of orally taking metformin hydrochloride for intervention. The transdermal drug delivery has the characteristics of no wound, no pain, convenience and high patient compliance, and can supplement the defects of low bioavailability of oral drugs, gastrointestinal adverse reactions, liver and kidney toxicity, pain, skin ulcer, necrosis and the like caused by drug injection treatment.
Although the advantages of transdermal administration are prominent, the skin, the largest organ of the human body, has a barrier function, and transdermal administration means that a drug needs to penetrate the epidermis and the dermis layers of the skin to function, during which the skin can protect the body from penetrating substances by preventing further penetration of particles into the skin, neutralizing, attacking or degrading foreign substances, and other mechanisms, wherein the stratum corneum is the main barrier of the skin. The research on the metformin hydrochloride product for transdermal drug delivery has the advantages of better playing the role of metformin hydrochloride and reducing the pain of patients.
Disclosure of Invention
The invention aims to provide a metformin hydrochloride ethosome and a preparation method thereof, wherein the ethosome is used as a transdermal carrier of metformin hydrochloride to prepare the metformin hydrochloride ethosome, and a safe and economic novel preparation is provided.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a metformin hydrochloride ethosome, which is prepared from the following raw materials in parts by volume: 3-7 parts of metformin hydrochloride, 1-3 parts of lipid, 15-30 parts of alcohol and 60-75 parts of water.
Preferably, the lipid is soybean phospholipid or lecithin.
Preferably, the alcohol is ethanol or isopropanol.
Preferably, the ethanol is absolute ethanol.
The invention also provides a preparation method of the metformin hydrochloride ethosome, which comprises the following steps:
(1) mixing the lipid and the alcohol to obtain an alcohol phase;
(2) mixing metformin hydrochloride with water to obtain a water phase;
(3) and mixing the alcohol phase and the water phase, and performing ultrasonic treatment to obtain the metformin hydrochloride ethosome.
Preferably, the mixing in step (3) is performed under sealed conditions.
Preferably, the mixing method in the step (3) is as follows: the alcohol phase is heated at 150-250 μ L/min-1The velocity of (2) is injected into the aqueous phase.
Preferably, the method of the ultrasound in the step (3) is as follows: ultrasonic treatment is carried out for 4-6 seconds, and 2-4 seconds are stopped for 50-70 times.
The invention provides a metformin hydrochloride ethosome and a preparation method thereof, wherein the metformin hydrochloride ethosome is prepared from the following raw materials in parts by volume: 3-7 parts of metformin hydrochloride, 1-3 parts of lipid, 15-30 parts of alcohol and 60-75 parts of water. The invention takes the ethosome as the transdermal carrier of the metformin hydrochloride to prepare the metformin hydrochloride ethosome, and the product prepared by the invention has the characteristics of small particle size, high entrapment rate, high drug loading rate, strong transdermal permeability and good safety, and provides a safe and economic transdermal anti-fibrosis preparation for clinic.
Drawings
FIG. 1 shows the cumulative transdermal absorption of metformin hydrochloride ethosome, liposome and alcohol aqueous solution.
Detailed Description
The invention provides a metformin hydrochloride ethosome, which is prepared from the following raw materials in parts by volume: 3-7 parts of metformin hydrochloride, 1-3 parts of lipid, 15-30 parts of alcohol and 60-75 parts of water.
In the present invention, the metformin hydrochloride is preferably used in an amount of 4 to 6 parts, and more preferably 5 parts.
In the present invention, the amount of the lipid is preferably 1.5 to 2.5 parts, and more preferably 2 parts.
In the present invention, the alcohol is preferably present in an amount of 18 to 28 parts, more preferably 20 to 25 parts.
In the present invention, the water is preferably 65 to 70 parts, and more preferably 67 to 68 parts.
In the present invention, the ethanol is preferably anhydrous ethanol.
The invention also provides a preparation method of the metformin hydrochloride ethosome, which comprises the following steps
(1) Mixing the lipid and the alcohol to obtain an alcohol phase;
(2) mixing metformin hydrochloride with water to obtain a water phase;
(3) and mixing the alcohol phase and the water phase, and performing ultrasonic treatment to obtain the metformin hydrochloride ethosome.
In the present invention, the method of mixing in step (1) is preferably: mixing soybean phospholipid and anhydrous ethanol, and stirring with magnetic stirrer to obtain yellowish transparent liquid as alcohol phase.
In the present invention, the method of mixing in step (2) is preferably: mixing metformin hydrochloride and water, and stirring on a magnetic stirrer to dissolve the medicine to form colorless transparent liquid, namely the water phase.
In the present invention, the stirring speed is preferably 600 to 800rpm, and more preferably 700 rpm.
In the present invention, the water is preferably double distilled water.
In the present invention, the mixing in step (3) is preferably performed under sealed conditions.
In the present invention, the method of mixing in step (3) is preferably: subjecting the alcohol phase to 150-250 μ L/min-1Is injected into the aqueous phase.
In the invention, the speed of the injection of the alcohol phase is preferably 180-220 mu L min-1More preferably 200. mu.L/min-1。
In the invention, after the alcohol phase is injected into the water phase, a magnetic stirrer is preferably used for stirring for 4-6 min under the condition of 600-800 rpm.
In the present invention, the stirring speed is preferably 600 to 800rpm, and more preferably 700 rpm.
In the present invention, the stirring time is preferably 5 min.
In the present invention, the method of the ultrasound in the step (3) is preferably: the ultrasonic treatment is performed for 50 to 70 times in a cycle of 4 to 6 seconds and stopping for 2 to 4 seconds, and the ultrasonic treatment is preferably performed for 60 times in a cycle of 5 seconds and stopping for 3 seconds.
In the invention, the power of the ultrasonic wave is preferably 170-200W, more preferably 180-190W, and more preferably 185-187.5W.
In the present invention, the metformin hydrochloride ethosome is preferably purified by a disposable syringe filter.
In the present invention, the disposable tip filter preferably has a gauge of 0.2 to 0.4 μm, and more preferably 0.22 μm.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
A preparation method of metformin hydrochloride ethosome comprises the following steps:
(1) weighing the raw materials according to the volume ratio of 3 parts of metformin hydrochloride, 1 part of soybean phospholipid, 15 parts of ethanol and 60 parts of double distilled water;
(2) mixing soybean phospholipid and ethanol, and stirring on a magnetic stirrer to obtain a light yellow transparent liquid to obtain an alcohol phase;
(3) mixing metformin hydrochloride with water, and stirring on a magnetic stirrer to dissolve the medicine to form colorless transparent liquid to obtain a water phase;
(4) the alcohol phase was kept under sealed conditions at 150. mu.L.min-1The aqueous phase was injected, stirred with a magnetic stirrer at 600rpm for 6min, sonicated at 170W for 6S, stopped for 4S for 50 cycles, and filtered with a 0.20 μm disposable syringe filter to obtain metformin hydrochloride ethosome.
Example 2
A preparation method of metformin hydrochloride ethosome comprises the following steps:
(1) weighing raw materials according to the volume ratio of 7 parts of metformin hydrochloride, 3 parts of lecithin, 30 parts of isopropanol and 75 parts of double distilled water;
(2) mixing lecithin and isopropanol, and stirring on a magnetic stirrer to obtain a light yellow transparent liquid to obtain an alcohol phase;
(3) mixing metformin hydrochloride with water, and stirring on a magnetic stirrer to dissolve the medicine to form colorless transparent liquid to obtain a water phase;
(4) the alcohol phase was kept under a sealed condition at 250. mu.L.min-1The aqueous phase was injected, stirred with a magnetic stirrer at 800rpm for 4min, sonicated at 200W for 4S, stopped for 2S for 70 cycles, and filtered with a 0.24 μm disposable syringe filter to obtain metformin hydrochloride ethosome.
Example 3
A preparation method of metformin hydrochloride ethosome comprises the following steps:
(1) weighing raw materials according to the volume ratio of 5 parts of metformin hydrochloride, 2 parts of soybean phospholipid, 25 parts of ethanol and 70 parts of double distilled water;
(2) mixing soybean phospholipid and ethanol, and stirring on a magnetic stirrer to obtain a light yellow transparent liquid to obtain an alcohol phase;
(3) mixing metformin hydrochloride with water, and stirring on a magnetic stirrer to dissolve the medicine to form colorless transparent liquid to obtain a water phase;
(4) The alcohol phase was kept under sealed conditions at 200. mu.L.min-1The aqueous phase was injected, stirred with a magnetic stirrer at 700rpm for 5min, sonicated at 187.5W for 5S, stopped for 60 cycles with 3S, and filtered with a 0.22 μm disposable syringe filter to obtain metformin hydrochloride ethosome.
Test example 1 preparation of metformin hydrochloride ethosome
1) Weighing raw materials according to the volume ratio of 0.2g of metformin hydrochloride, 0.044g of soybean phospholipid, 1.108mL of ethanol and 2.892mL of double distilled water;
(2) mixing soybean phospholipid and ethanol, and stirring on a magnetic stirrer to obtain a light yellow transparent liquid to obtain an alcohol phase;
(3) mixing metformin hydrochloride with water, and stirring on a magnetic stirrer to dissolve the medicine to form colorless transparent liquid to obtain a water phase;
(4) the alcohol phase was kept under sealed conditions at 200. mu.L.min-1The aqueous phase was injected, stirred with a magnetic stirrer at 700rpm for 5min, sonicated at 187.5W for 5S, stopped for 60 cycles with 3S, and filtered with a 0.22 μm disposable syringe filter to obtain metformin hydrochloride ethosome.
Test example 2 measurement of particle diameter and Dispersion coefficient of ethosome
1mL of metformin hydrochloride ethosome prepared in example 3 was placed in a Malvern particle size sample cell, and after air bubbles were removed, the particle size and dispersion coefficient of metformin hydrochloride ethosome were measured by dynamic light scattering at a 90-degree scattering angle.
Test example 3 establishment of a metformin hydrochloride standard curve
(1) Chromatographic condition of metformin hydrochloride
And (3) chromatographic column: hypersil ODS2C18250 4.6mm5 μm; mobile phase: methanol: phosphate buffer (PH 3.5, 100mL of phosphate buffer containing 0.1g SDS) 40: 60; column temperature: 40 ℃; flow rate: 1.0 mL/min; detection wavelength: 234 nm; sample introduction amount: 20 μ L.
(2) Preparation of a standard substance: weighing 10mg of metformin hydrochloride standard substance, putting into a 10mL volumetric flask, fixing the volume by using the mobile phase mixed solution under the chromatographic condition in the step (1), and shaking up to obtain 1mg-1Metformin hydrochloride standard solution.
(3) Drawing of standard curve
Weighing metformin hydrochloride standard solution, diluting with mobile phase mixed solution under chromatographic condition in (1), and preparing into solution with concentration of 0.5, 1, 2, 5, 8, 10, 20, 50 μ g/mL-1After being filtered by a 0.22 mu m disposable syringe filter, the series of standard solutions are continuously injected according to the chromatographic conditions of (1), the peak areas of the standard solutions with different concentrations are recorded, linear regression is carried out by taking the concentration of the sample as the abscissa and the peak area as the ordinate, and a standard curve is drawn.
Test example 4 encapsulation efficiency measurement
The encapsulation efficiency of the metformin hydrochloride ethosome is determined by adopting an ultra-high speed centrifugation method, the metformin hydrochloride ethosome prepared in example 3 is moved into a high-speed centrifuge tube, the parameter of the ultra-high speed centrifuge is set to be 100000g, the centrifugation time is 90min, after the centrifugation is finished, the supernatant is diluted by 1000 times by double distilled water, the supernatant is centrifuged for 10min under 13000rmp condition by the centrifuge, a 0.22 mu m disposable needle filter is used for filtration, HPLC detection is carried out according to the chromatographic condition in experimental example 3(1), and the peak area of the supernatant is recorded. And meanwhile, diluting the suspension at the bottom of the high-speed centrifugal tube, performing demulsification, degreasing, centrifuging, filtering, performing HPLC (high performance liquid chromatography) detection, and recording the peak area of the suspension at the bottom. Calculating the mass W of the free drug and the bottom suspension by using the standard curve Swimming device、WBottom (C)。
The Encapsulation Efficiency (EE) was calculated as follows:
encapsulation efficiency WBottom (C)/(WSwimming device+WBottom) X 100% formula (1)
W in formula (1)Swimming deviceIs the mass of free drug in the ethosome, WBottomThe ethosome encapsulates the mass of the drug.
Test example 5 drug Loading Rate measurement
The encapsulation efficiency of the metformin hydrochloride ethosome is measured by adopting an ultra-high speed centrifugation method, the metformin hydrochloride ethosome is moved into a high-speed centrifuge tube, the parameter of the ultra-high speed centrifuge is set to be 100000g, the centrifugation time is 90min, after the centrifugation is finished, the supernatant is diluted 1000 times by using double distilled water, the supernatant is centrifuged for 10min under the condition of 13000rmp by using the centrifuge, a 0.22 mu m disposable syringe filter is used for filtration, the HPLC detection is carried out according to the chromatographic condition in the experimental example 3(1), and the peak area of the supernatant is recorded. Calculating the mass W of the free drug by using a metformin hydrochloride standard curveSwimming deviceAnd calculating the drug loading rate of the metformin hydrochloride ethosome by using the mass Wmost of the free drug.
The drug Loading Efficiency (LE) is calculated as follows:
drug loading rate (W)General assembly-WSwimming device)/WGeneral assemblyX 100% formula (2)
W in formula (2)Swimming deviceIs the mass of free drug in the ethosome, WGeneral assemblyIs the total mass of metformin hydrochloride ethosome.
Test example 6 in vitro transdermal test
The water in the Franz diffusion cell was preheated and maintained at 37 ℃, the total receiving cell volume was 7mL, and the actual receiving solution volume was 6 mL. The prepared in-vitro rat skin stratum corneum is upwards arranged between a receiving pool and supply pools, 1mL of metformin hydrochloride ethosome, liposome and alcohol aqueous solution prepared in example 1 are respectively added into each supply pool, the supply pools are covered by sealing films to avoid water evaporation and edge leakage, and the actual effective permeation area is 3.14cm2. In the experimental process, the water temperature of the diffusion cell is kept at 37 ℃, the rotor speed is 300rpm, 1mL of receiving liquid is taken by a 1mL syringe when the drug is administered for 0.5, 1, 2, 3, 4, 6 and 9 hours respectively, 1mL of preheated receiving liquid is supplemented immediately after sampling, the collected receiving liquid is diluted, centrifuged and filtered, and HPLC detection is carried out to compare the accumulated permeation amount and the transdermal permeation amount rate of three different metformin hydrochloride preparations.
The experimental results are as follows: the particle size of the metformin hydrochloride ethosome prepared in example 1 is 68.32nm, the dispersion coefficient is 0.140, the encapsulation efficiency is 49.5%, and the drug loading rate is 50.51%.
The skin permeation rate of the metformin hydrochloride ethosome is 999.6 mug cm-2·h-1(ii) a The skin permeation rate of the metformin hydrochloride liposome is 375.2 mug cm -2·h-1(ii) a Aqueous solution of metformin hydrochloride 319.1. mu.g-cm-2·h-1. It can be seen that the permeation rates of metformin hydrochloride liposomes are 2.72 and 3.18 times those of 5% metformin hydrochloride liposome and 5% metformin hydrochloride aqueous solution, respectively. Figure 1 is the cumulative permeation per unit area of optimally formulated 5% metformin hydrochloride ethosome, liposomes and aqueous alcohol solution.
The embodiment of the invention provides a metformin hydrochloride ethosome and a preparation method thereof, wherein the metformin hydrochloride ethosome is prepared from the following raw materials in parts by volume: 3-7 parts of metformin hydrochloride, 1-3 parts of lipid, 15-30 parts of alcohol and 60-75 parts of water. The invention takes the ethosome as the transdermal carrier of the metformin hydrochloride to prepare the metformin hydrochloride ethosome, and the product prepared by the invention has the characteristics of small particle size, high entrapment rate, high drug loading rate, strong transdermal permeability and good safety, and provides a safe and economic transdermal anti-fibrosis preparation for clinic.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (8)

1. The metformin hydrochloride ethosome is characterized by being prepared from the following raw materials in parts by volume: 3-7 parts of metformin hydrochloride, 1-3 parts of lipid, 15-30 parts of alcohol and 60-75 parts of water.
2. Metformin hydrochloride ethosomes according to claim 1, characterized in that the lipid is soya lecithin or lecithin.
3. Metformin hydrochloride ethosome according to claim 2, wherein said alcohol is ethanol or isopropanol.
4. The metformin hydrochloride ethosome according to any one of claims 1 to 3, wherein the ethanol is anhydrous ethanol.
5. The method for preparing metformin hydrochloride ethosome according to any one of claims 1 to 4, which comprises the following steps:
(1) mixing the lipid and the alcohol to obtain an alcohol phase;
(2) mixing metformin hydrochloride and water to obtain a water phase;
(3) mixing the alcohol phase and the water phase, and performing ultrasonic treatment to obtain the metformin hydrochloride ethosome.
6. The production method according to claim 5, wherein the mixing in the step (3) is performed under a sealed condition.
7. The method of claim 6, wherein the mixing in step (3) is performed by: subjecting the alcohol phase to 150-250 μ L/min -1Is injected into the aqueous phase.
8. The method according to any one of claims 5 to 7, wherein the ultrasonic treatment in step (3) comprises: ultrasonic treatment is carried out for 4-6 seconds, and 2-4 seconds are stopped for 50-70 times.
CN202210290025.4A 2022-03-23 2022-03-23 Metformin hydrochloride ethosome and preparation method thereof Pending CN114569556A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110522723A (en) * 2019-08-26 2019-12-03 江苏山信药业有限公司 A kind of Metformin hydrochloride percutaneous drug administration preparation and preparation method thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110522723A (en) * 2019-08-26 2019-12-03 江苏山信药业有限公司 A kind of Metformin hydrochloride percutaneous drug administration preparation and preparation method thereof

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