Metformin pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention provides a metformin pharmaceutical composition. The pharmaceutical composition comprises: (1) a therapeutically effective amount of metformin; and (2) a cream carrier; the cream carrier comprises an emollient, a humectant, an emulsifier, an emulsion stabilizer, a thickener, a preservative, a pH regulator and a solvent, and the mass percentage of the metformin in the metformin pharmaceutical composition is 2-7wt%. The metformin pharmaceutical composition can significantly reduce the content of AGEs, and further reduce the expression of skin tissue inflammatory factors hs-CRP, IL-1 and IL-6, so that the inflammatory response of a wound surface is relieved, tissue healing and regeneration are promoted, and the effects of improving the diabetic skin microenvironment and promoting the healing speed of the diabetic wound surface are achieved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a metformin pharmaceutical composition and a preparation method and application thereof. Background Art

[0002] Wound healing is a complex process controlled by multiple factors, including orderly biological steps such as inflammation, cell migration, proliferation, and remodeling, which requires good functionality and integrity of tissues and cells. When diabetes occurs, the wound healing process is disturbed by high sugar factors, making it difficult for the skin to repair and heal for a long period of time after the trauma. Refractory diabetic wounds are one of the common serious complications of diabetes. They are often accompanied by bacterial infections or other complications, leading to wound failure and are one of the main causes of disability and even death in patients. Despite various intervention measures, such as wound care and surgery, refractory diabetic wounds remain a major problem that plagues clinical treatment.

[0003] Advanced glycation end products (AGEs) are a group of complex products produced by non-enzymatic glycosylation of biological macromolecules. Based on their sources, they can be divided into exogenous AGEs and endogenous AGEs. Exogenous AGEs mainly refer to AGEs ingested from food, while endogenous AGEs are AGEs formed in human organs, tissues or body fluids. It is currently believed that AGEs are mainly generated through the Mailard reaction: first, carbonyl-containing reducing sugars react reversibly with free amino groups of proteins and nucleic acids within a few hours to form unstable Schiff base structures, which are converted into relatively stable Amadori products, also called early glycosylation products, through reactions such as cyclization and intramolecular rearrangement within a few weeks; secondly, some Amadori products are directly oxidized and hydrolyzed to generate AGEs through the Hodge pathway, and other Amadori products can be converted into AGE precursor compounds such as glyoxal (GO), methylglyoxal (MGO), 3-deoxyglucosone (3-DG), etc. through dehydration, oxidative cleavage, rearrangement, etc.; finally, these active dicarbonyl compounds react again with residues on proteins or amino acids to form stable and irreversible AGEs products. [][] These AGEs products accumulate in the human body and interact with the receptor of advanced glycation end products (RAGE), causing oxidative stress (OS) response and releasing inflammatory factors such as C-reactive protein, IL-1, TNF-α, IL-6, etc. The long-term presence of these inflammatory factors in skin tissue is one of the main causes of chronic damage to diabetic skin tissue, spontaneous ulcers of skin tissue, or difficulty in healing after wounds occur.

[0004] Therefore, there is an urgent need in the art to develop a series of cream products that have an inhibitory effect on AGEs to improve the diabetic skin microenvironment and promote diabetic wound healing. Summary of the invention

[0005] The present invention aims to provide a metformin pharmaceutical composition and a preparation method and application thereof. The cream can improve the microenvironment state of diabetic skin tissue and promote wound healing.

[0006] In a first aspect of the present invention, a metformin pharmaceutical composition is provided, comprising:

[0007] (1) a therapeutically effective amount of metformin; and

[0008] (2) a cream carrier; the cream carrier comprises: a moisturizer, an emollient, an emulsifier, a thickener, a solvent, and optionally an auxiliary agent selected from the following group: a preservative, an emulsion stabilizer, a pH adjuster; wherein the mass percentage of metformin in the metformin pharmaceutical composition is 2-7wt%.

[0009] In another preferred embodiment, the pharmaceutical composition comprises:

[0010]

[0011] In another preferred embodiment, the emollient is selected from the following group: shea butter, liquid paraffin, polydimethylsiloxane, polydimethylsiloxane alcohol or a combination thereof.

[0012] In another preferred embodiment, the emulsifier is selected from the following group: cetearyl alcohol, glyceryl stearate, PEG-100 stearate, or a combination thereof.

[0013] In another preferred embodiment, the humectant is glycerin.

[0014] In another preferred embodiment, the emulsion stabilizer is selected from cetearyl olivate, sorbitan olivate, or a combination thereof.

[0015] In another preferred embodiment, the thickener is selected from the following group: polyacrylamine, C13-14 isoparaffin, laureth-7, carbomer or a combination thereof.

[0016] In another preferred embodiment, the preservative is selected from the group consisting of phenoxyethanol, methylparaben, propylparaben, or a combination thereof.

[0017] In another preferred embodiment, the pH adjuster is triethanolamine.

[0018] In another preferred embodiment, the solvent is water.

[0019] In another preferred embodiment, the pharmaceutical composition comprises:

[0020]

[0021] In another preferred embodiment, the metformin cream comprises:

[0022]

[0023]

[0024] In a second aspect of the present invention, there is provided a method for preparing the metformin pharmaceutical composition of the first aspect, the method comprising the steps of:

[0025] (1) heating and mixing an emollient, a humectant, an emulsifier, an emulsion stabilizer, a pH adjuster, a thickener, and a preservative to completely dissolve them to form a mixed solution;

[0026] (2) adding the aqueous phase to the above mixed solution and stirring for preliminary emulsification;

[0027] (3) fully emulsified; and

[0028] (4) Add metformin and mix well to prepare metformin cream.

[0029] In another preferred embodiment, the aqueous phase in step (2) is selected from water.

[0030] In the third aspect of the present invention, there is provided a use of the metformin pharmaceutical composition described in the first aspect for preparing a drug for improving the microenvironment of diabetic skin tissue, wherein the drug comprises the metformin pharmaceutical composition described in the first aspect and / or a common drug carrier.

[0031] In another preferred embodiment, the pharmaceutical composition is also used to treat or improve chronic wounds caused by diabetes.

[0032] In another preferred embodiment, the drug is also used to inhibit the synthesis of AGEs, thereby reducing the deposition of AGEs in skin tissue.

[0033] In another preferred embodiment, the drug is also used to reduce the expression of inflammatory factors in skin tissue.

[0034] In another preferred embodiment, the inflammatory factor is selected from the following group: hs-CRP, IL-1, IL-6 or a combination thereof.

[0035] In another preferred embodiment, the drug is used to promote wound healing.

[0036] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The results showed the effect of metformin on GO-AGEs. Figure 1 A shows the fluorescence intensity of metformin on GO-AGEs. Figure 1 B shows the effect of metformin on the synthetic increment rate of AGEs.

[0038] Figure 2 The contents of AGEs in the skin tissues of mice in each group are shown.

[0039] Figure 3 The hs-CRP level, an inflammatory factor, in skin tissue is shown.

[0040] Figure 4 Shows the content of inflammatory factor IL-1 in skin tissue.

[0041] Figure 5 The content of inflammatory factor IL-6 in skin tissue is shown.

[0042] Figure 6 The wound healing status of mice is shown.

[0043] Figure 7 The figure shows the healing trend of mouse wounds. DETAILED DESCRIPTION

[0044] The present inventors have unexpectedly developed a metformin pharmaceutical composition for the first time after extensive and in-depth research and a large number of screenings. The pharmaceutical composition is a cream, and the metformin pharmaceutical composition comprises: (1) a therapeutically effective amount of metformin; and (2) a cream carrier; the cream carrier comprises: an emollient, a humectant, an emulsifier, an emulsion stabilizer, a thickener, a preservative, a pH adjuster, and a solvent, wherein the mass percentage of metformin in the metformin pharmaceutical composition is 2-7wt%.

[0045] The metformin pharmaceutical composition prepared by the present invention can significantly reduce the content of AGEs, thereby reducing the expression of skin tissue inflammatory factors hs-CRP, IL-1, and IL-6, thereby alleviating the inflammatory reaction of the wound surface and promoting tissue healing and regeneration, thereby achieving the effect of improving the diabetic skin microenvironment and promoting the healing speed of the diabetic wound surface. On this basis, the present invention was completed.

[0046] the term

[0047] As used herein, the term "therapeutically effective amount" refers to an amount that produces a function or activity in humans and / or animals and is acceptable to humans and / or animals. It should be understood by those skilled in the art that the "therapeutically effective amount" may vary depending on the route of administration, the adjuvants of the drug used, the severity of the disease, and the combination of other drugs.

[0048] As used herein, the term "comprising" includes not only closed definitions, but also semi-closed and open definitions. In other words, the term includes "consisting of...", "consisting essentially of...".

[0049] In the present invention, "metformin pharmaceutical composition" and "metformin cream" are used interchangeably.

[0050] Metformin pharmaceutical composition

[0051] The present invention provides a metformin pharmaceutical composition, comprising:

[0052] (1) a therapeutically effective amount of metformin; and

[0053] (2) a cream carrier; the cream carrier comprises: an emollient, a humectant, an emulsifier, an emulsion stabilizer, a thickener, a preservative, a pH adjuster, and a solvent, wherein the mass percentage of metformin in the metformin pharmaceutical composition is 2-7 wt %.

[0054] In the present invention, the emollient is selected from the group consisting of shea butter, liquid paraffin, dimethicone, dimethiconol or a combination thereof.

[0055] In the present invention, the emulsifier is selected from the following group: cetearyl alcohol, glyceryl stearate, PEG-100 stearate, or a combination thereof.

[0056] In the present invention, the humectant is selected from glycerin.

[0057] In the present invention, the emulsion stabilizer is selected from cetearyl olivate, sorbitan olivate, or a combination thereof.

[0058] In the present invention, the thickener is selected from the following group: polyacrylamine, C13-14 isoparaffin, laureth-7, carbomer or a combination thereof.

[0059] In the present invention, the preservative is selected from the group consisting of phenoxyethanol, methylparaben, propylparaben, or a combination thereof.

[0060] In the present invention, the pH adjuster is selected from triethanolamine.

[0061] In the present invention, the solvent is selected from water.

[0062] Emulsifier

[0063] The emulsifier in the present invention plays an emulsifying role. The emulsifier has both hydrophilic and lipophilic groups, and can surround the dispersed oil phase or water phase to prevent the oil phase or water phase from regrouping, thereby preparing an oil-in-water cream or an oil-in-water cream. The outer phase of the oil-in-water cream is a water phase, and the inner phase is an oil phase; the outer phase of the water-in-oil cream is an oil phase, and the inner phase is a water phase.

[0064] The "hydrophile-lipophile balance (HLB)" is used to indicate the difference in emulsification ability. The larger the HLB, the greater the hydrophilicity, which can stably form an oil-in-water cream; the smaller the HLB, the greater the lipophilicity, which can stably form an oil-in-water cream.

[0065] In the water-in-oil cream, an oil-in-water emulsifier is selected. The hydrophilic group of the water-in-oil emulsifier molecule is larger and stronger than the lipophilic group, and it belongs to a hydrophilic emulsifier, which is used to prepare the water-in-oil cream, and the HLB value of the water-in-oil emulsifier ranges from 8 to 18. The lipophilic group of the water-in-oil emulsifier molecule is larger and stronger than the hydrophilic group, and it belongs to a lipophilic emulsifier, which is used to prepare the water-in-oil cream, and the HLB value of the water-in-oil emulsifier ranges from 3 to 6.

[0066] In a preferred embodiment of the present invention, the emulsifier comprises oleic acid.

[0067] In the present invention, the inventor screened the amount of emulsifier in the cream. In a preferred embodiment, the amount of the emulsifier is 1.5-3wt%.

[0068] Preparation of metformin pharmaceutical composition

[0069] The present invention provides a method for preparing a metformin pharmaceutical composition, the method comprising the steps of:

[0070] (1) heating and mixing an emollient, a humectant, an emulsifier, an emulsion stabilizer, a pH adjuster, a thickener, and a preservative to completely dissolve them to form a mixed solution;

[0071] (2) adding the aqueous phase to the above mixed solution and stirring for preliminary emulsification;

[0072] (3) fully emulsified; and

[0073] (4) Add metformin and mix well to prepare metformin cream.

[0074] In another preferred embodiment, the aqueous phase in step (2) is water, sterile water, pure water, sterile water, distilled water, or physiological saline.

[0075] In the cream preparation method of the present invention, in the step (1), the heating temperature is controlled within an appropriate range, preferably the heating temperatures are the same. In a preferred embodiment of the present invention, the heating temperature is 50-90°C, preferably 60-85°C.

[0076] After the preliminary emulsification in step (2), the step (3) of fully emulsifying is required. In one example of the present invention, the step (3) is homogenized and emulsified at a speed of 10000-23000 rpm, preferably using a homogenizer for full emulsification.

[0077] After sufficient emulsification in step (3), metformin is added to the blank cream prepared by sufficient emulsification in step (3), mixed, and a topical metformin cream is prepared. In a preferred embodiment of the present invention, before adding metformin, the temperature of the blank cream after emulsification in step (3) is controlled at 30-50°C.

[0078] Method of application and use

[0079] The cream of the present invention is an external preparation, and a typical method of use is to apply the cream to the skin complications of diabetic patients.

[0080] In the cream of the present invention, the dosage of the active ingredient is a therapeutically effective amount, for example, about 1 μg / kg body weight-20 mg / kg body weight per day. When using the pharmaceutical composition, the safe and effective amount of the drug is suitable for humans or mammals, wherein the safe and effective amount is at least 10 μg / kg body weight, and in most cases does not exceed 10 mg / kg body weight, preferably 10 μg / kg body weight-5 mg / kg body weight. Of course, the specific dosage also needs to consider factors such as the route of administration and the health status of the patient, which are all within the skill range of skilled physicians. In addition, the cream of the present invention can also be used with other therapeutic agents such as transdermal agents (including before, during or after).

[0081] In the present invention, the cream is used to prepare a drug for preventing and / or treating diabetic skin complications. Representatively, the diabetic skin complications are skin itching, thinning of subcutaneous fat, thinning of skin, paresthesia, diabetic bullous disease, diabetic xanthomas, diabetic rash, and skin susceptibility to infection.

[0082] Methods for preventing and / or treating diabetic skin complications

[0083] The present invention provides a method for preventing and / or treating diabetic skin complications, comprising the step of applying the cream of the present invention to a subject in need thereof (typically the subject is a human or non-human mammal).

[0084] In the present invention, the cream improves the microenvironment of diabetic skin tissue, thereby promoting the healing of wound surface of traumatized skin tissue.

[0085] Compared with the prior art, the present invention has the following beneficial effects:

[0086] 1. The metformin cream of the present invention can reduce the deposition of AGEs in skin tissue.

[0087] 2. The metformin cream of the present invention can reduce the expression of inflammatory factors in skin tissue, thereby promoting the healing and regeneration of skin tissue.

[0088] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0089] Example 1 Preparation of Metformin Cream

[0090] In this experiment, metformin cream was prepared according to the formula in Table 1.

[0091] Table 1: Preparation ratio of metformin cream

[0092]

[0093]

[0094]

[0095] The steps for preparing metformin cream are as follows:

[0096] (1) According to the formula in Table 1, the emollient, humectant, emulsifier, emulsion stabilizer, pH adjuster, thickener, and preservative are heated to 70° C. and mixed until they are completely dissolved to form a mixed solution;

[0097] (2) adding the aqueous phase to the above mixed solution and stirring for preliminary emulsification;

[0098] (3) After stirring for a few minutes, homogenize with a homogenizer at 10,000 to 23,000 rpm for a few minutes to fully emulsify; and

[0099] (4) After emulsification, when the temperature drops to 40°C, add the prepared metformin and mix well to prepare metformin cream.

[0100] Example 2 Verification of metformin's inhibition of AGEs synthesis in vitro

[0101] 2.1 Experimental Purpose

[0102] According to the fluorescence intensity simulation system, the effects of different concentrations of metformin inhibitor on GO-AGEs were verified to verify that metformin can effectively inhibit the synthesis of AGEs in vitro.

[0103] 2.2 Experimental process

[0104] 1) Filter the metformin solution, GO solution and HSA solution through a filter head and set aside.

[0105] 2) Prepare 5 ml of 0.5 mM GO-HSA control group.

[0106] 3) Prepare 5ml GO-I: The concentration of metformin ranges from 9.5mM to 10.5mM in one bottle and 47.5-52.5mM in one bottle. Take 10mM and 50mM metformin concentrations as examples: 10mM (50μL metformin + 12.5μL GO + 2.5ml BSA + 2437.5μL PBS) for a total of 5ml; 50mM (250μL metformin + 12.5μL GO + 2.5ml BSA + 2237.5μL PBS) for a total of 5ml. The final concentrations and addition amounts of each component in the preparation system are shown in Tables 3 and 4.

[0107] 4) All prepared solutions were placed in 15 ml centrifuge tubes, placed in an incubator for incubation and sampled according to the schedule, as shown in Table 2.

[0108] Table 2: System Experiment Operation Schedule

[0109]

[0110] Table 3: Final concentration of each component in the system

[0111]

[0112] Table 4: Amount of each component added in the system

[0113]

[0114] 5) Collect samples from days 0, 1, and 2: Take 1 ml of each sample and freeze it in an EP tube.

[0115] 6) Aliquot the specimens and send them for fluorescence detection: add 150 μL of retained specimens to each well of a 96-well plate for fluorescence detection.

[0116] 2.3 Experimental Results

[0117] like Figure 1As shown in Figure A, it can be found from the data results that the fluorescence intensity of GO-AGEs incubated with metformin inhibitor in the system after 3 days is lower than that without adding metformin inhibitor, indicating that metformin has an inhibitory effect on the formation of GO-AGEs. Figure 1 As shown in B, the effect of metformin on the incremental synthesis ratio of AGEs, where the inhibitory effect of metformin in the concentration range of 9.5mM-10.5mM is better than that in the concentration range of 47.5-52.5mM, which preliminarily verifies that metformin can effectively inhibit the synthesis of GO-AGEs in vitro.

[0118] Example 3 Effect of metformin cream on wound healing in diabetic mice

[0119] 3.1 Verify the effect of metformin cream on the microenvironment of the back skin tissue of diabetic mice and its promoting effect on the healing of diabetic wounds.

[0120] 3.2 Experimental Grouping

[0121] A. Diabetic mice,

[0122] B. Diabetic mice + metformin solution wet compress on the back,

[0123] C. Diabetic mice + cream intervention (without metformin),

[0124] D. Diabetic mice + cream intervention (containing metformin).

[0125] 3.3 Experimental process

[0126] 3.3.1 Establishment of diabetic mouse model

[0127] Mice in groups A, B, C, and D were injected with streptozotocin (STZ, Sigma, USA) to induce diabetic mouse models. After one week, the blood sugar of mice increased, and the blood sugar value was maintained at 16.7-30mmol / L, which was considered a successful model induction. From the second cycle, mice in group B began to apply metformin solution to their backs, and mice in groups C and D began to intervene with topical creams. From the 12th week after successful induction, samples were taken to observe the content of AGEs in skin tissue, the expression of inflammatory factors and related growth factors. At the same time, in the 12th week, the four groups A, B, C, and D were made into mice with shallow second-degree burn models, and the healing of the wounds on the 7th, 14th, and 21st days were observed respectively. The wound at the beginning of the burn was used as the baseline area of ​​the wound, and the wound healing rate was expressed as (baseline wound area - wound area at that time) ÷ baseline wound area to evaluate the wound healing rate.

[0128] 3.3.2 Circumcision of mouse back skin

[0129] Use depilatory cream and a shaver to remove the hair on the mouse collar and back where samples are to be collected. After disinfecting the skin collection site, use an ophthalmic trephine to remove the local skin. After the skin is removed, put the mouse back into the cage and continue to be raised. After the skin sample is trimmed to an appropriate size, it is immediately placed in 10% neutral formaldehyde for fixation and preservation.

[0130] 3.4 Experimental Results

[0131] 3.4.1. Induction of diabetic mouse model

[0132] One week after STZ induced diabetic mice, the nutritional status of diabetic mice began to deteriorate, their hair became dry and dull, they became irritable, they drank more, ate more, and urinated more, and their body weight decreased significantly compared with the control group during the same period. The blood sugar level was significantly higher than that of the control group (normal group: 7±0.2; diabetic group: 26.2±1.78; p<0.01). As the course of diabetic mice prolonged, the weight of the mice increased slowly, indicating that the model was successfully induced.

[0133] 3.4.2 Determination of AGEs content in skin tissue: After homogenizing the skin tissue, measure the absorbance of ultraviolet light at 280nm to evaluate the AGEs content in the skin tissue. The results are as follows: Figure 2 shown.

[0134] The results showed that after topical application of metformin cream, the AGEs content in the skin tissue of group D mice was significantly decreased compared with groups A, B, and C, and the results of each group were statistically significant (P≤0.05), indicating that topical metformin cream can effectively reduce the deposition of AGEs in skin tissue.

[0135] 3.4.3 ELISA method was used to determine the expression of inflammatory factors in the skin tissue of each group: the skin tissue of diabetic mice at week 12 was homogenized and centrifuged at 1000 g to obtain the supernatant tissue. Protein quantification was performed on each specimen, and the ELISA method (according to the operating instructions of the kit) was used to detect the levels of inflammatory factors hs-CRP, IL-1, and IL-6 in the skin tissue.

[0136] like Figure 3 , Figure 4 and Figure 5 As shown in the figure, after the intervention of metformin cream, the levels of inflammatory mediators hs-CRP, IL-1, and IL-6 in the wound tissue of mice in group D were significantly lower than those in the other three groups A, B, and C, and the differences were statistically significant (P≤0.05). This shows that the use of metformin cream can reduce the inflammatory response of the wound surface and promote tissue healing.

[0137] like Figure 6 and Figure 7As shown, with the extension of observation days, the wounds of mice in each intervention group showed a healing trend. The healing rate of the wounds in group D using metformin cream was significantly higher than that in other diabetic groups, indicating that metformin cream can effectively promote wound healing.

[0138] Comprehensively evaluating the above experimental results, topical metformin cream has been proven in both system experiments and animal experiments to be able to effectively inhibit the formation of AGEs and reduce the expression of inflammatory mediators in diabetic skin wounds in mice, thereby promoting the healing and regeneration of skin tissue, thereby achieving the effect of improving the diabetic skin microenvironment and promoting the healing speed of diabetic wounds.

[0139] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A metformin pharmaceutical composition, characterized in that: The pharmaceutical composition comprises: (1) a therapeutically effective amount of metformin; and (2) a cream carrier; the cream carrier comprises: a moisturizer, an emollient, an emulsifier, a thickener, a solvent, and optionally an auxiliary agent selected from the following group: a preservative, an emulsion stabilizer, a pH adjuster; wherein the mass percentage of metformin in the metformin pharmaceutical composition is 2-7wt%.

2. The metformin pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition comprises:

3. The metformin pharmaceutical composition according to claim 1, characterized in that: The emollient is selected from the group consisting of shea butter, liquid paraffin, dimethicone, dimethiconol, or a combination thereof.

4. The metformin pharmaceutical composition according to claim 1, characterized in that: The emulsifier is selected from the group consisting of cetearyl alcohol, glyceryl stearate, PEG-100 stearate, or a combination thereof.

5. The metformin pharmaceutical composition according to claim 1, characterized in that: The humectant is glycerin.

6. The metformin pharmaceutical composition according to claim 1, characterized in that: The emulsion stabilizer is selected from cetearyl olivate, sorbitan olivate, or a combination thereof.

7. The metformin pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition comprises:

8. A method for preparing the metformin pharmaceutical composition according to claim 1, characterized in that: The method comprises the steps of: (1) heating and mixing an emollient, a humectant, an emulsifier, an emulsion stabilizer, a pH adjuster, a thickener, and a preservative to completely dissolve them to form a mixed solution; (2) adding the aqueous phase to the above mixed solution and stirring for preliminary emulsification; (3) fully emulsified; and (4) Add metformin and mix well to prepare metformin cream.

9. A use of the metformin pharmaceutical composition according to claim 1, characterized in that: Used for preparing a drug for improving the microenvironment of diabetic skin tissue, wherein the drug comprises the metformin pharmaceutical composition according to claim 1 and / or a common drug carrier.

10. The use according to claim 9, characterized in that The pharmaceutical composition is also used for treating or improving chronic wounds caused by diabetes.

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