CN109985000B

CN109985000B - Kelibuo microemulsion composition

Info

Publication number: CN109985000B
Application number: CN201711471716.XA
Authority: CN
Inventors: 田广辉; 杨汝磊; 徐新早; 魏中元; 田军峰
Original assignee: Suzhou Vigonvita Life Sciences Co ltd
Current assignee: Suzhou Vigonvita Life Sciences Co ltd
Priority date: 2017-12-29
Filing date: 2017-12-29
Publication date: 2022-09-02
Anticipated expiration: 2037-12-29
Also published as: CN109985000A

Abstract

The invention discloses a Cliboro microemulsion composition, which comprises the following components in part by weight: comprises the following components in percentage by weight: 0.5-5.0 percent of Kreiron, 5-20 percent of oil phase, 10-40 percent of emulsifier, 5-30 percent of auxiliary emulsifier and 30-70 percent of water, wherein the oil phase is one or a combination of more of C10-C18 fatty acid monoester and tricarboxyglycerin ester, and the emulsifier is Tween emulsifier. The Cliboron microemulsion solution has good stability, has ideal microemulsion particle size, and can effectively improve the skin permeability of the medicament; compared with the Cliborox microemulsion solution, the Cliborox microemulsion gel can further improve the skin permeability and the retention, improve the compliance of the clinical treatment of the allergic dermatitis and play a slow release effect.

Description

Kelibuo microemulsion composition

Technical Field

The invention belongs to the field of biological medicine, and particularly relates to a Cliborol microemulsion solution and a microemulsion gel and a preparation method thereof.

Background

Allergic Dermatitis (AD), commonly known as eczema. Is a skin inflammatory disease closely related to genetic allergic diathesis, and is widely distributed in patients. Is characterized by pruritus, multiforme rash and associated exudation tendencies. Besides the clinical manifestations of eczema, the medicine also has the following characteristics: the family tendency of easily suffering from asthma, allergic rhinitis and eczema; allergy to foreign proteins; serum immunoglobulin e (ige) is elevated and eosinophilia is found in the blood.

The etiology and pathogenesis of allergic dermatitis are not completely understood. It is generally considered that the onset of disease is caused by various internal and external factors, including genetic factors, immune factors, environmental factors, etc. Allergic dermatitis has obvious familial aggregation, 60-90% of patients are obviously affected by seasons, and the patients have severe winter and mild summer. Sudden and large sweating may also be a worsening or inducing factor in rapid changes in cold, heat and ambient climate. Occupational morbidity from exposure to wool, textiles, dust and high temperature jobs is also high. Allergic dermatitis is distributed in all ages, infants and teenagers are abundant, and statistics show that 60% of allergic dermatitis is characterized by early occurrence and is accompanied by final growth. At present, in developed countries, the incidence rate of allergic dermatitis is maintained at 10-20%, and the tendency of the allergic dermatitis is increased year by year.

According to the characteristics of diseases and the research results of the current disease causes, the treatment modes of allergic dermatitis mainly comprise systemic drug therapy, physical therapy and local drug therapy. 1) Systemic drug therapy: systemic administration based on the immunological pathogenesis of allergic dermatitis includes oral administration and injection administration. The oral medicine mainly comprises cyclosporine A (CyA), Mycophenolate Mofetil (MMF) and the like, and is characterized by definite and reliable curative effect, and has the characteristics of being used as an immunosuppressant, liver and kidney toxicity, serious gastrointestinal tract reaction and neutropenia which greatly limit the application of the oral medicine, and the other oral medicine mainly takes antibacterial and antifungal medicines and has the main limitations of drug resistance and disease repeatability; the injection medicine is mainly an immunomodulator, represents a medicine containing interferon-gamma and immunoglobulin (HdIVIG), and has the characteristics of quick response and obvious effect, but has incomplete safety data after long-term administration. 2) Physical therapy: based on pathological research, the external physical intervention mode aiming at the focus part of the allergic dermatitis is represented by phototherapy (medium and high dose ultraviolet illumination), and the external physical intervention mode is characterized by safety without obvious adverse reaction, but the exact curative effect greatly limits the clinical application of the external physical intervention mode. 3) Topical drug therapy: allergic dermatitis is a local lesion, and local drug therapy (external drugs) is the preferred treatment scheme due to the disease characteristics. At present, the medicines for local treatment mainly comprise tacrolimus, pimecrolimus, capsaicin and doxepin liniment. The limitations of local therapeutic drugs are poor drug permeability, limited efficacy, undefined mechanism of action and easy recurrence.

Kribotron marketed in 2016 is used as an external small-molecule boron medicament and has great significance for treating allergic dermatitis. Based on the research of the pathogenesis of the allergic dermatitis, the effects of inhibiting the activity of various inflammatory mediators and degrading cyclic adenosine monophosphate are achieved by inhibiting two inflammatory targets, namely phosphodiesterase 4(PDE4) and proinflammatory cytokines, so that the effect of treating the allergic dermatitis is achieved.

The marketed preparation of Cliborol is a cream (trade name: EUCRISA) and is administered 2 times a day. According to the characteristics of allergic dermatitis diseases, the clinical compliance of long-time continuous administration is poor, the cream is mainly an oily substrate, the greasy feeling on the surface of the skin after administration is strong, the cream is difficult to clean after contacting with clothes and the like, the clinical administration compliance is poor, the production process of the cream is complex, the drug preparation and sub-packaging need to be subjected to heat treatment, and special packaging materials are needed.

The ideal external preparation promotes the medicine to penetrate through the horny layer of the skin in a physical way by means of a preparation technology and a simple and stable prescription process, improves the permeability so as to achieve the aim of improving the treatment efficiency, reduces the toxic and side effects of the medicine, improves the safety and improves the clinical compliance of the medicine.

Micro Emulsion (ME) is an isotropic, transparent, thermodynamically stable dispersion system formed spontaneously by mixing water, oil, surfactant and co-surfactant in appropriate proportions. Microemulsions were first discovered and named by schulman et al. It is known that the drug is prepared into a microemulsion transdermal delivery preparation, so that the drug loading and stability of the preparation can be improved, the action time of the drug is prolonged, and the bioavailability is improved, and the microemulsion has low surface tension and is easy to moisten the skin, so that the structure of the stratum corneum is changed, and the drug is easy to penetrate through the stratum corneum and be absorbed by a human body. The microemulsion transdermal drug delivery preparation has been successful in the market at present. However, the effect of the microemulsion preparation is closely related to the specific pharmaceutical ingredients, the surfactant used and the size of the microemulsion particles, and in addition, the stability of the microemulsion preparation itself is very important, and the oil phase in the emulsion or cream appearing in the prior art is generally vaseline or fatty alcohol, but the preparation using the oil phase has poor stability and poor transdermal permeability. It is unexpected that a microemulsion preparation having excellent stability and remarkably improved effect can be obtained for a specific drug.

Disclosure of Invention

Problems to be solved by the invention

The invention aims to provide a Cliboron microemulsion composition with good stability and ideal microemulsion particle size aiming at the defects of the prior art.

Means for solving the problems

A krebs microemulsion composition comprising: the weight percentage of the emulsion is 0.5-5.0 percent of Cliborol, 5-20 percent of oil phase, 10-40 percent of emulsifier, 5-30 percent of auxiliary emulsifier and 30-70 percent of water, wherein the oil phase is one or a combination of more of fatty acid monoester selected from C10-C18 and tricarboxyglycerol, and the emulsifier is selected from Tween emulsifier. The fatty acid monoester is fatty acid ester formed by esterification of 1mol of fatty acid and 1mol of alcohol, and the glycerol tricarboxylate is glycerol tricarboxylate formed by esterification of 3mol of carboxylic acid and 1mol of glycerol.

Further, the kreb luo micro emulsion composition is kreb luo micro emulsion solution or kreb luo micro emulsion gel, wherein the kreb luo micro emulsion solution comprises the following components in percentage by weight: 0.5-5.0% of kresoxim, 5-20% of oil phase, 10-40% of emulsifier, 5-30% of co-emulsifier and 30-70% of water, wherein the oil phase is one or more of C10-C18 fatty acid monoester and triglyceride, and the emulsifier is one or more of Tween 80 and Tween 60; the Cliboron microemulsion gel comprises the Cliboron microemulsion solution and a gel material.

Further, the Cliboroluo microemulsion solution comprises, by weight, 1.0-2.0% of Cliboroluo, 8-15% of an oil phase, 15-30% of an emulsifier, 10-25% of a co-emulsifier, 40-60% of water, preferably 1.5-2.0% of Cliboroluo, 8-10% of an oil phase, 20-30% of an emulsifier, 10-20% of a co-emulsifier, and 40-50% of water.

Further, the oil phase is one or more selected from oleate, triglyceride, palmitate and myristate, preferably, the oleate is alkyl oleate, the alkyl is C1-C6 alkyl, the triglyceride is C1-C6 carboxylic acid, the palmitate is alkyl palmitate, the alkyl is C1-C6 alkyl, the myristate is alkyl myristate, and the alkyl is C1-C6 alkyl.

Further, the oil phase is one or more of ethyl oleate, glyceryl triacetate, isopropyl palmitate and isopropyl myristate.

Further, the coemulsifier is one or more of methanol, ethanol, propanol, isopropanol, propylene glycol and polyethylene glycol 400.

Further, the oil phase is ethyl oleate, the emulsifier is tween 80, and the co-emulsifier is ethanol, preferably absolute ethanol.

Further, the gel material is one or more of carbomer, methylcellulose or sodium carboxymethylcellulose, preferably carbomer 940, carbomer 934 and carbomer 941, and more preferably carbomer 940, and the adding weight of the gel material is 0.5-2.5% of that of the kreb microemulsion solution.

Furthermore, the particle diameter of the microemulsion particles in the Cliboro microemulsion solution is 5-50 nm.

Furthermore, the particle diameter of the microemulsion particles in the Cliboro microemulsion solution is 5-30 nm.

The invention also provides a preparation method of the krebs microemulsion composition, which comprises the following steps: (1) taking the oil phase, the emulsifier and the co-emulsifier, stirring uniformly, adding the Cliboroluo, stirring, and adding water to obtain a Cliboroluo microemulsion solution, (2) optionally adding a gel material, fully swelling, and mixing uniformly to obtain the Cliboroluo microemulsion gel.

Further, the step (1) is that the oil phase, the emulsifier and the co-emulsifier are taken and stirred uniformly, Cliboron is added, stirring is continued until the mixture is dissolved, purified water is added, stirring is carried out until the mixture is clear, and a clear transparent solution is obtained after bubbles are eliminated, namely the Cliboron microemulsion solution, wherein when the purified water is added, a mechanical stirrer is used for stirring, and the stirring speed is 500-5000 rpm

Further, the reaction temperature of the reaction is 20-100 ℃, preferably 20-80 ℃.

ADVANTAGEOUS EFFECTS OF INVENTION

1) The Cliborox microemulsion solution has good stability, has ideal microemulsion particle size, and the microemulsion ion surface has positive charge, and experiments prove that the skin permeability of the pharmaceutical composition can be effectively improved, and the treatment effect of the Cliborox can be expected to be improved;

2) the Keliboro microemulsion gel provided by the invention improves the problems of skin adhesion, spreadability and retention time of the microemulsion on the basis of a Keliboro microemulsion solution, increases the adhesion of a medicament on the skin surface, improves the skin retention amount of the medicament, can improve the compliance of clinical treatment of allergic dermatitis, can prevent the medicament in the microemulsion from being separated out, improves the medicament stability, prolongs the release time of the medicament, realizes a slow release effect, and achieves the purpose of reducing the medicament frequency.

3) The Cliboroluo microemulsion or the microemulsion gel is an O/W system, and the drug system has the advantages of adhesion, spreadability, permeability and the like, has the advantages of easy cleaning, no pollution to clothes and the like, and has good clinical application compliance.

4) The Cliboro microemulsion solution or the microemulsion gel is simple to prepare and controllable in process.

Drawings

Figure 1 stability of particle size distribution of krebs microemulsion solutions of examples 1-3.

Figure 2 stability of particle size distribution of krebs microemulsion solutions of examples 4-6 and comparative example 1.

Detailed Description

Kriborol, under the name Crisabiole, was approved by the U.S. FDA in 2016 and marketed as a phosphodiesterase-4 (PDE-4) inhibitor.

The invention provides a Clibororo microemulsion composition. Specifically, the composition is a Cribono microemulsion solution or a Cribono microemulsion gel, wherein the Cribono microemulsion solution comprises the following raw materials in percentage by weight: 1.0-2.0% of kresoxim, 8-15% of oil phase, 15-30% of emulsifier, 10-25% of co-emulsifier and 40-60% of water, wherein the oil phase is one or more of ethyl oleate, glyceryl triacetate, isopropyl palmitate and isopropyl myristate, the emulsifier is one or more of tween 80 and tween 60, and the co-emulsifier is one or more of absolute ethyl alcohol, propylene glycol and polyvinyl alcohol 400; the formula of the raw materials of the Cliboro microemulsion gel comprises a Cliboro microemulsion solution and a gel material.

In a preferred embodiment, the krebs microemulsion solution has the following raw material formula: 1.5-2.0 percent of Clibuo, 8-10 percent of oil phase, 20-30 percent of emulsifier, 10-20 percent of co-emulsifier and 40-50 percent of water phase.

In a preferred embodiment, the oil phase is ethyl oleate, the emulsifier is tween 80, and the co-emulsifier is absolute ethanol. Under the condition of the formula, the prepared Cliboro microemulsion solution has the advantages of most excellent particle size and stability, best corresponding skin permeability and no side effect. Further, the formula of the krebs microemulsion solution comprises the following raw materials: about 2.0% of kresoxim, about 8% of oil phase, about 30% of emulsifier, about 10% of coemulsifier and about 50% of water phase.

The kreb's microemulsion solution of the present invention can be prepared according to the general method of microemulsion solutions known in the art, however, preferably, the kreb's microemulsion solution of the present invention is prepared by the following steps: taking the oil phase, the emulsifier and the co-emulsifier according to the formula amount, uniformly stirring at room temperature or under a heating condition, adding the Clibolol according to the formula amount, continuously stirring until the Clibolol is dissolved, then continuously adding the purified water under the condition of continuous stirring, continuously stirring until the solution is clear, and obtaining a clear and transparent solution after bubbles are completely eliminated, namely the Clibolol microemulsion solution. The Cliboro microemulsion solution prepared by the method is an oil-in-water microemulsion, and the surface of the microemulsion liquid drop is charged.

In a preferred embodiment, when adding purified water, a mechanical stirrer is used for stirring, and the stirring speed is 500-5000 rpm, under the condition, the micro-emulsion particles obtained have ideal particle size and good uniformity.

In a preferred embodiment, the particle size of the microemulsion particles in the kreb's microemulsion solution is between 5 and 50nm, preferably between 5 and 30nm, and more preferably between 5 and 20 nm. The testing method of the particle size distribution comprises the following steps: taking the microemulsion solution, diluting with purified water by one time, and determining the particle size distribution by adopting a Nicomp388 laser particle size analyzer. The p.i value is the Variance (Variance) which is the coefficient of variation of multiple measurements, and is the same as the average particle size as the reported result.

As a further preferable scheme of the invention, the Clibono microemulsion composition is a Clibono microemulsion gel, compared with a Clibono microemulsion solution, the drug precipitation in the microemulsion can be prevented through a stable net structure of a gel material, and meanwhile, the adhesiveness and the spreadability of the drug system on the skin surface are improved, the drug retention time is prolonged, and the drug compliance is improved.

Furthermore, in the kreb luo micro emulsion gel, the adding weight of the gel material is 0.5-2% of the adding weight of the kreb luo micro emulsion solution.

Preferably, the gel material is a carbomer, such as carbomer 940.

A simple preparation method of the Clibororo microemulsion gel comprises the following steps: and adding a gel material into the Cliboroluo microemulsion solution, fully swelling, and uniformly mixing to obtain the Cliboroluo microemulsion.

According to another aspect of the invention, the preparation method of the krebs microemulsion solution comprises the following steps: 1) taking the formula amount of the Clibolol, the oil phase, the emulsifier and the co-emulsifier, and dissolving at room temperature or heating to 60-80 ℃; 2) and under the condition of continuous stirring, continuously adding the water phase into the oil phase, and continuously stirring until bubbles are eliminated to obtain a clear and transparent micro-emulsion solution.

Furthermore, common bacteriostatic agents, essence and the like can be added into the microemulsion composition provided by the invention.

The technical solution of the present invention will be further described with reference to specific examples. It should be understood that the following examples are only for illustrating and explaining the present invention and are not intended to limit the scope of the present invention. Unless otherwise indicated, the instruments, materials, reagents and the like used in the following examples are all available by conventional commercial means.

Example 1-1: preparation of Clibororo microemulsion solution

The krebs microemulsion solution was prepared according to the formulation composition in table 1 and the following preparation steps:

1) at room temperature, taking oleic acid ethyl ester, tween 80 and absolute ethyl alcohol, uniformly stirring by adopting a high-efficiency mechanical stirrer at the stirring speed of 500rpm, adding kresoxim, and continuously stirring until the materials are dissolved;

2) continuously adding purified water into the oil phase under the condition of continuous stirring, continuously stirring until the mixture is clear, and obtaining colorless to light yellow clear transparent solution after bubbles are eliminated.

TABLE 1

The average particle size of the resulting microemulsion solution was 16.5. + -. 0.6nm, P.I.0.127.

Examples 1 to 2: preparation of Clibororo microemulsion solution

This example is substantially the same as example 1-1 except that, in the case where Tween 80 is replaced with Tween 60 and absolute ethanol is replaced with polyethylene glycol 400, the resulting microemulsion solution has an average particle size of 23.4. + -. 0.7nm and P.I.0.185.

Examples 1 to 3: preparation of Clibororo microemulsion solution

This example is essentially the same as example 1-1 except that, where Tween 80 is replaced by lecithin and absolute ethanol is replaced by propylene glycol, the resulting microemulsion solution has an average particle size of 22.5. + -. 0.8nm, P.I.0.215.

Example 2: preparation of Clibororo microemulsion solution

The krebs microemulsion solution was prepared according to the formulation composition in table 2 and the following preparation steps:

1) at room temperature, taking oleic acid ethyl ester, tween 80 and absolute ethyl alcohol, uniformly stirring by adopting a high-efficiency mechanical stirrer at the stirring speed of 2500rpm, adding kresoxim, and continuously stirring until the materials are dissolved;

TABLE 2

The average particle size of the resulting microemulsion solution was 7.7 ± 0.3nm, p.i.0.251.

Example 3: preparation of Clibororo microemulsion solution

The krebs microemulsion solution was prepared according to the formulation composition in table 3 and the following preparation steps:

1) at room temperature, taking isopropyl myristate, tween 80, polyethylene glycol 400 and absolute ethyl alcohol, uniformly stirring by adopting a high-efficiency mechanical stirrer at the stirring speed of 3000rpm, adding Cliborol, and continuously stirring until the isopropyl myristate, the tween 80, the polyethylene glycol 400 and the absolute ethyl alcohol are dissolved;

TABLE 3

The average particle size of the resulting microemulsion solution was 16.8 + -0.5 nm, P.I.0.225.

Example 4: preparation of Clibororo microemulsion solution

The krebs microemulsion solution was prepared according to the formulation composition in table 4 and the following preparation steps:

1) at room temperature, taking glyceryl triacetate, tween 80 and absolute ethyl alcohol, uniformly stirring by adopting a high-efficiency mechanical stirrer at the stirring speed of 4000rpm, adding kresoxim, and continuously stirring until the mixture is dissolved;

2) continuously adding purified water into the oil phase under the condition of continuous stirring, continuously stirring until the mixture is clear, and obtaining a colorless to yellow clear transparent solution after bubbles disappear.

TABLE 4

The resulting microemulsion solution had an average particle size of 19.8 + -0.8 nm, P.I.0.187.

Comparative example 1Preparation of Clibororo microemulsion solution

The krebs microemulsion solution was prepared according to the formulation composition in table 5 and the following preparation steps:

1) taking isopropyl palmitate, polyoxyethylene hydrogenated castor oil 40 and absolute ethyl alcohol, heating to 45 ℃ in an oil bath, uniformly stirring by adopting a high-efficiency mechanical stirrer at the stirring speed of 4000rpm, adding Clibolo, and continuously stirring until the isopropyl palmitate, the polyoxyethylene hydrogenated castor oil and the absolute ethyl alcohol are dissolved;

TABLE 5

The average particle size of the obtained micro-emulsion solution is 257.0 +/-19.4 nm and P.I.0.388, and after standing for 24 hours, the solution is layered, and partial oil drops are deposited and crystals are separated out.

Example 5: preparation of Clibororo microemulsion solution

The krebs microemulsion solution was prepared according to the formulation composition in table 6 and the following preparation steps:

1) taking ethyl oleate, tween 80 and absolute ethyl alcohol, uniformly stirring by adopting a high-efficiency mechanical stirrer at a stirring speed of 5000rpm, heating to 60-80 ℃, adding kresoxim, and continuously stirring until the kresoxim is dissolved;

TABLE 6

The resulting microemulsion solution had an average particle size of 17.4 + -0.6 nm, P.I.0.158.

Example 6: preparation of Clibororo microemulsion solution

The krebs microemulsion solution was prepared according to the formulation composition in table 7 and the following preparation steps:

1) taking ethyl oleate, tween 80 and absolute ethyl alcohol, uniformly stirring by adopting a high-efficiency mechanical stirrer at a stirring speed of 5000rpm, adding clitorium, and continuously stirring until the materials are dissolved;

TABLE 7

The average particle size of the resulting microemulsion solution was 26.5. + -. 0.8nm, P.I.0.271.

Example 7: preparation of Clibororo microemulsion gel

The krebs microemulsion gel was prepared according to the formulation composition in table 8 and the following preparation steps:

and (3) at room temperature, adding the formula amount of carbomer 940 into the Kelibuo microemulsion solution, and mixing uniformly after the mixture is fully swelled.

TABLE 8

The viscosity of the kreb ludox microemulsion gel obtained by the formula 1 is 3120 +/-60 mPa.s, the viscosity of the kreb ludox microemulsion gel obtained by the formula 2 is 8780 +/-80 mPa.s, and the viscosity of the kreb ludox microemulsion gel obtained by the formula 3 is 12370 +/-110 mPa.s.

Example 8: preparation of Clibororo microemulsion gel

The krebs microemulsion gel was prepared according to the formulation composition in table 9 and the following preparation steps:

TABLE 9

The viscosity of the kreb ludox microemulsion gel obtained by the formula 4 in the embodiment is 7960 +/-50 mPa.s, the viscosity of the kreb ludox microemulsion gel obtained by the formula 5 is 13890 +/-430 mPa.s, and the viscosity of the kreb ludox microemulsion gel obtained by the formula 6 is 23000 +/-800 mPa.s.

Example 9: preparation of Clibororo microemulsion gel

The krebs microemulsion gel was prepared according to the formulation composition in table 10 and the following preparation steps:

Watch 10

The viscosity of the Clibororo microemulsion gel obtained by the formula 7 is 14560 +/-290 mPa.s, the viscosity of the Clibororo microemulsion gel obtained by the formula 8 is 24380 +/-690 mPa.s, and the viscosity of the Clibororo microemulsion gel obtained by the formula 9 is 42000 +/-1100 mPa.s.

Example 10: percutaneous absorption test of Kelibuo microemulsion gel

In vitro skin penetration tests were performed using the kreb @ me microemulsion solution of example 1-1, the kreb @ me microemulsion solution of comparative example 1, the gelata of the particulate kreb @ me microemulsion prepared according to formulation 6 of example 8, and the 2% kreb @ me cream prepared according to the cream preparation method of the reference kreb @ me cream patent document (US20170152273a1), respectively.

The above samples were used for the artificial skin membrane permeation test. The artificial skin membrane was fixed in the supply chamber of the Franz diffusion cell, and 20% polyethylene glycol 400 in pH 7.4 phosphate buffer was added as release medium to the receiving chamber, keeping the inner lining of the artificial membrane in intimate contact with the solution. A fixed amount of the sample was placed in a room, the temperature of the jacket was controlled to 37. + -. 1 ℃ by adjusting the water bath, the stirring speed was 100r/min, and the content of the drug in the receiving room was measured, and the results are shown in Table 11.

TABLE 11

The results show that: the Cliboroluo microemulsion and the gel thereof have better transdermal permeability. Although the Kelibuo microemulsion solution can promote the transdermal absorption of the drug, the Kelibuo microemulsion solution can not be retained on the surface of the skin for a long time due to the particularity of the application part and needs to be continuously administered; although the Cribolol cream can meet the requirement of continuous administration, the skin permeability is inferior to that of microemulsion and gel thereof, and simultaneously, the Cribolol cream is composed of a large amount of oleaginous matrixes, so that the administration part and clothes are troublesome to clean, and the administration compliance is poor. Therefore, compared comprehensively, the krebs microemulsion gel has better skin adhesion and skin permeability, has a certain slow release effect, and the characteristics of the krebs microemulsion gel are favorable for improving the compliance of clinical medication.

Example 11Stability test of Kelibuo microemulsion solution

The prepared krebs microemulsion solution is stored at room temperature (25 +/-2 ℃ and 65 +/-5% RH), and the stability of the microemulsion solution is inspected at 5 days, 10 days and 30 days respectively. The microemulsion solution properties and appearance change table 12, particle size distribution table 13, and fig. 1 and 2 were observed.

TABLE 12 stability of the Clibororo microemulsion solution

TABLE 13 stability of particle size distribution of Cliboro microemulsion solution

The results show that: the Cliboron microemulsion solution has better stability. The clear and transparent homogeneous system is kept under room temperature storage. The particle size distribution is stable, and emulsion drop aggregation and breakage do not occur. Therefore, the Clibororo emulsion prepared by the technology has good stability.

The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. The kreb microemulsion composition is a kreb microemulsion solution or a kreb microemulsion gel, wherein the kreb microemulsion solution consists of 0.5 to 5.0 percent of kreb, 5 to 20 percent of oil phase, 10 to 40 percent of emulsifier, 5 to 30 percent of auxiliary emulsifier and 30 to 70 percent of water in percentage by weight, wherein the oil phase is selected from one or more of oleate, tricarboxyglycerin ester and myristate, the emulsifier is selected from one or more of tween 80 and tween 60, and the auxiliary emulsifier is selected from one or more of methanol, ethanol, propanol, isopropanol, propylene glycol and polyethylene glycol 400; the particle size of the microemulsion particles in the Kelibuo microemulsion solution is 5-50 nm; the Cliboro microemulsion gel consists of the Cliboro microemulsion solution and a gel material, wherein the gel material is selected from one or more of carbomer, methylcellulose or sodium carboxymethylcellulose.

2. The kreb microemulsion composition as claimed in claim 1, wherein the kreb microemulsion solution consists of kreb 1.0-2.0 wt%, oil phase 8-15 wt%, emulsifier 15-30 wt%, co-emulsifier 10-25 wt%, and water 40-60 wt%.

3. The kreb microemulsion composition as claimed in claim 2, wherein the kreb microemulsion solution consists of kreb 1.5-2.0 wt%, oil phase 8-10 wt%, emulsifier 20-30 wt%, co-emulsifier 10-20 wt%, and water 40-50 wt%.

4. The kreb microemulsion composition as claimed in claim 1, wherein the oleate is an alkyl oleate, wherein the alkyl group is a C1-C6 alkyl group; the carboxylic acid in the tricarboxyglycerol is a carboxylic acid containing C1-C6; the myristic acid ester is alkyl myristate, wherein the alkyl is C1-C6 alkyl.

5. The kreb microemulsion composition as claimed in claim 1, wherein the oil phase is ethyl oleate.

6. The kreb microemulsion composition as claimed in claim 1, wherein the kreb microemulsion gel has a viscosity of 2000-30000 mpa.s.

7. The kreb microemulsion composition as claimed in claim 6, wherein the kreb microemulsion gel has a viscosity of 3000-25000 mPa.s.

8. The kreb microemulsion composition as claimed in claim 1, wherein the added weight of the gel material is 0.5-2.5% of the added weight of the kreb microemulsion solution.

9. The kreb's microemulsion composition as claimed in claim 1, wherein the particle diameter of the microemulsion particles in the kreb's microemulsion solution is 5-30 nm.

10. A process for the preparation of a kreb composition as claimed in any one of claims 1 to 9, which comprises the steps of: (1) taking the oil phase, the emulsifier and the co-emulsifier, stirring uniformly, adding Clibono, stirring, adding water to obtain a Clibono microemulsion solution, and (2) optionally adding a gel material, fully swelling, and mixing uniformly to obtain the Clibono microemulsion gel.

11. The method for preparing a kreb composition as claimed in claim 10, wherein the step (1) is to take the oil phase, the emulsifier and the co-emulsifier, stir them uniformly, add kreb, continue to stir until dissolved, add purified water, stir until clarified, obtain a clear and transparent solution after bubbles disappear, i.e. the kreb microemulsion solution, wherein when the purified water is added, a mechanical stirrer is used for stirring, the stirring speed is 500-5000 rpm, and the reaction temperature is 20-100 ℃.

12. A process for the preparation of a kreb composition according to claim 11 wherein the reaction temperature is from 20 to 80 ℃.