CN112472660A - Azelaic acid-containing microneedle patch and preparation method thereof - Google Patents
Azelaic acid-containing microneedle patch and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a microneedle patch containing azelaic acid, and a solution formula for preparing a microneedle tip comprises: active ingredient, matrine and water-soluble matrix material; the active component comprises azelaic acid, and the mass percentage content of the azelaic acid in the needlepoint solution is 0.1-10%. The azelaic acid in the microneedle patch has high bioavailability and good skin mildness, avoids the irritation of the local skin of the azelaic acid and does not influence the antibacterial activity effect of the azelaic acid. The invention also discloses a preparation method of the microneedle patch.
Description
Technical Field
The invention relates to the technical field of medicines. And more particularly, to a microneedle patch containing azelaic acid and a method of manufacturing the same.
Background
Azelaic acid has good effects of resisting bacteria and oxidation, inhibiting grease secretion, inhibiting melanin generation, inhibiting cell proliferation, preventing excessive keratinization of hair follicles and the like, and has wide application in the fields of medicines, cosmetics and health care: has obvious curative effect on common acne, melanoma, malignant freckle, chloasma, acne rosacea and other diseases; plays an important role in improving skin aging, brightening skin, reducing pigmentation and the like. In addition, azelaic acid has higher safety and no adverse reaction of the whole body, has good human body tolerance compared with common antibiotic and hormone anti-acne medicines, is not easy to generate drug resistance and teratogenic action and potential endocrine imbalance problems through mucosa and skin, and has wide application prospect in the fields of medical treatment and cosmetology, so azelaic acid medicines and cosmetic products are developed by domestic and foreign pharmaceutical enterprises in succession. In 1989, azelaic acid cream developed by German schering AC company was officially released, in 1996, the American FDA approved azelaic acid as a therapeutic drug for skin diseases such as acne, erythema and the like, in 2003, azelaic acid cream preparation developed by Zhejiang Conenbei group under the trade name of "Dou" was sold on the market, and the hot trend of research on relevant preparations of azelaic acid by domestic research institutions and pharmaceutical enterprises was raised.
The currently marketed dosage forms of azelaic acid include: the usage modes of the cream, the gel and the mucilage are local application, the azelaic acid in the preparation penetrates through the horny layer of the skin to reach the epidermis layer and the dermis layer through the permeation effect so as to exert the drug effect, but the effective utilization rate of the drug is low due to the limited permeation amount, so the effect is achieved by increasing the concentration of the azelaic acid (the content of the azelaic acid in the products on the market is 10-20 percent), but the local skin irritation such as erythema, pruritus, scale, burning sensation and the like is easily caused. In addition, the water solubility of the azelaic acid is poor, so that the prescription development of the azelaic acid has certain difficulty.
Chinese patent CN106420787A discloses a method for preparing acne cream containing azelaic acid, which blends active ingredients such as azelaic acid with oleaginous base material to improve the solubility and skin permeability of azelaic acid, but for acne skin with vigorous sebum secretion, the use of a large amount of oleaginous base is undoubtedly snow frosting, which is easy to block skin pores, slow down skin metabolism rate and aggravate skin disease deterioration. In contrast, a non-greasy, highly breathable water-soluble matrix formulation is more suitable for improving skin symptoms while increasing the comfort of the skin for the patient.
Chinese patent CN108553411A discloses a preparation method of azelaic acid gel, and the prescription composition is as follows: 15% azelaic acid, 1% salicylic acid, 2% ZEN, 70% 1, 3-propanediol and 12% deionized water. The use of the high-concentration 1, 3-propylene glycol can improve the solubility of azelaic acid, and can increase the absorption of active ingredients by skin as a penetration enhancer, but the use of a large amount of alcohol reagents has certain stimulation to the skin, the pH of the 2% ZEN hydrogel is about 5.8, the hydrogel is an acidic environment, and a large amount of acidic drugs such as azelaic acid, salicylic acid and the like are added, so that the gel has larger overall acidity and can cause certain stimulation to the skin.
Chinese patent CN108187070A discloses a preparation method of azelaic acid hydroxypropyl-beta-cyclodextrin inclusion compound, which has the advantages of improving the solubility of azelaic acid and enhancing the stability of the drug, but the preparation process is complicated, two steps of mixing at high temperature in a reaction kettle and then spray drying are needed, the time consumption is long, and the industrial production of novel azelaic acid preparation is not facilitated.
Disclosure of Invention
Based on the above facts, it is an object of the present invention to provide a microneedle patch containing azelaic acid, which has high bioavailability, is excellent in skin mildness, avoids local skin irritation by azelaic acid, and does not affect the antibacterial activity effect of azelaic acid.
A second object of the present invention is to provide a method for preparing a microneedle patch containing azelaic acid.
In order to achieve the first purpose, the invention adopts the following technical scheme:
a microneedle patch containing azelaic acid, the formulation of a solution for preparing the tip of a microneedle comprising: active ingredient, matrine and water-soluble matrix material;
the active component comprises azelaic acid, and the mass percentage content of the azelaic acid in the needlepoint solution is 0.1-10%.
Further, the matrine accounts for 0.13-20% of the needle tip solution by mass percent.
Further, the molar ratio of the azelaic acid to the matrine is 1:1-1: 1.5.
Further, the water-soluble matrix material is selected from one or a mixture of more of polyvinyl alcohol, polyvinylpyrrolidone, chitosan derivatives, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyglutamic acid, chondroitin sulfate, sodium alginate, sodium hyaluronate, collagen, pullulan, dextran, trehalose, sucrose, lecithin, xylitol, mannitol, sorbitol, glycerol, polyethylene glycol and sodium glycerophosphate.
Further, the chitosan derivative is selected from the group consisting of polyethylene glycol modified chitosan, guanidinoacetic acid modified chitosan, chitosan grafted with guanidino and carbonylmethoxypolyethylene glycol, chitosan grafted with guanidino and amino acid groups, chitosan grafted with basic amino acids or oligomers thereof and hydrophobic amino acids or oligomers thereof.
Further, the mass percentage of the water-soluble matrix material in the needle point solution is 1-80%.
Further, the mass percentage of the water-soluble matrix material in the needle point solution is 2% -50%.
Further, the active ingredient also comprises a functional substance.
Further, the functional substance is selected from one or more of madecassoside, licorice extract, tea polyphenol, salicylic acid, tanshinone, fruit acid, totarol, chlorogenic acid, beta-1, 3-glucan, tranexamic acid, resveratrol, nicotinamide, arbutin, licoflavone, squalane, allantoin, vitamin C ethyl ether, vitamin E, refined nicotinamide, panthenol, microorganism B6, inositol, silk peptide, minoxidil, diaminopyrimidine oxide, pyrrolidinyl diaminopyrimidine oxide, bletilla striata extract, rhubarb extract and witch hazel extract.
Further, the mass percentage of the functional substance in the needle point solution is 0.001% -10%.
Further, the mass percentage of the functional substance in the needle point solution is 0.001% -5%.
In order to achieve the second object, the present invention provides a method for preparing a microneedle patch containing azelaic acid, the method comprising at least a step of preparing a tip solution, and specifically comprising the steps of:
mixing the water solution of azelaic acid and matrine, adding water-soluble matrix material at room temperature, and dissolving completely to obtain the needle tip solution.
The invention has the following beneficial effects:
the microneedle patch containing azelaic acid solves the problems of poor skin permeability and low bioavailability of the existing azelaic acid preparation. The microneedle patch can be used at one time, can effectively pierce the stratum corneum of the skin, enables the active ingredient of azelaic acid to directly act on the epidermis layer or the dermis layer of the skin, has the advantages of quick response, reduced administration concentration, improved effective utilization rate of medicaments, convenient use for patients, no cross infection and the like. Meanwhile, in the components of the microneedle patch, the combination of azelaic acid and matrine can synergistically play a role in treating acne.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 is a photograph showing the deposition of the formulations 1 to 5 in the test examples under a fluorescence microscope.
Fig. 2 shows a topographical view of the microneedle patch prepared in example 1.
In fig. 3, a and b are graphs of the surface topography of the skin after the microneedle patch of example 2 and comparative example 1 is applied to the human body for 10 minutes in sequence.
Fig. 4 shows the surface topography of the microneedle patch in example 2 after 10 minutes of application to the human body.
In fig. 5, a and b are height profile diagrams of the tips of the microneedles before and after the microneedle patch in example 2 acts on a human body for 10 minutes.
FIG. 6 shows an SEM image of layered microneedles prepared in example 4
Fig. 7 shows the surface topography of the microneedle patch in example 9 after 10 minutes of application to the human body.
In fig. 8, a and b sequentially show the VISIA imaging contrast images before and after one treatment of the acne-removing microneedle patch in example 16.
In fig. 9, a, b and c sequentially show the affected skin comparison chart before, after and after one week of treatment of the acne-removing microneedle patch of example 17.
In fig. 10, a, b and c sequentially show the affected skin comparison images before, once and twice treatments of the acne-removing microneedle patch in comparative example 2.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below with reference to preferred embodiments and the accompanying drawings. Similar parts in the figures are denoted by the same reference numerals. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
In the existing azelaic acid medicament dosage forms, the medicinal effect is exerted mainly by locally smearing, penetrating through a skin stratum corneum by a penetration effect and reaching an epidermal layer and a corium layer, but the effective utilization rate of the medicament is low due to limited penetration amount, and the local skin irritation such as erythema, pruritus, scale, burning sensation and the like is easily caused by increasing the concentration of azelaic acid in the medicament; and the solubility of azelaic acid in water is low, so that a water-soluble prescription which is mild, non-irritant and does not reduce the antibacterial effect of the azelaic acid is difficult to prepare. Accordingly, in order to improve bioavailability of azelaic acid, improve water solubility thereof, and reduce irritation thereof to the human body, an embodiment of the present invention provides a microneedle patch containing azelaic acid, in which a solution for preparing a microneedle tip is formulated comprising: active ingredient, matrine and water-soluble matrix material; the active component comprises azelaic acid, and the mass percentage content of the azelaic acid in the needlepoint solution is 0.1-10%.
It should be noted here that the microneedle of the present invention may be an integrated microneedle or a layered microneedle, that is, the needle point solution of the present invention may be used only for forming the needle point portion of the microneedle, or may be used for forming an integrated microneedle, and those skilled in the art may also prepare microneedles of other structural types based on the prescription of the microneedle needle point solution provided by the present invention, which is not limited further in the present invention.
In a preferred example, the molar ratio of azelaic acid to matrine is from 1:1 to 1: 1.5. In the microneedle patch, azelaic acid is used as dibasic acid, secondary ionization can be carried out, namely pKa1 is 4.53, and pKa2 is 5.33, partial ionization of azelaic acid is realized by regulating the proportion of matrine and azelaic acid, namely, the pH of the solution is controlled between a primary acidity coefficient and a secondary acidity coefficient, so that azelaic acid can exist in the solution in two forms of carboxylic acid molecules and ionic salt, the water solubility of azelaic acid can be increased, the bioavailability is improved, the normal exertion of the antibacterial activity of azelaic acid is not influenced, a normal skin comfortable acid-base environment with the pH of about 5 is prepared, the skin irritation is avoided, the safety of use of azelaic acid as an active ingredient is improved, and the microneedle forming can be ensured; meanwhile, the combination of the proportion of azelaic acid and matrine can more effectively and synergistically promote the effect of treating acne.
In a preferable example, the matrine accounts for 0.13 to 20 percent of the mass percentage of the needlepoint solution.
It will be appreciated that in the tip solution, water is also included.
In the present embodiment, the water-soluble matrix material is a matrix material for microneedle patch molding, and any matrix material that can be conventionally used for microneedle patches may be used. Exemplary water-soluble matrix materials include, but are not limited to, one or a mixture of several selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, chitosan derivatives, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyglutamic acid, chondroitin sulfate, sodium alginate, sodium hyaluronate, collagen, pullulan, dextran, trehalose, sucrose, lecithin, xylitol, mannitol, sorbitol, glycerol, polyethylene glycol, sodium glycerophosphate.
Further, exemplary chitosan derivatives are selected from the group consisting of polyethylene glycol modified chitosan, guanidinoacetic acid modified chitosan, chitosan grafted with guanidino and carbonylmethoxypolyethylene glycol, chitosan grafted with guanidino and amino acid groups, chitosan grafted with a basic amino acid or oligomer thereof and a hydrophobic amino acid or oligomer thereof.
Further, the mass percentage of the water-soluble matrix material in the needle point solution is 1-80%. Exemplary water-soluble matrix materials include, but are not limited to, 2-70%, 2-50%, 10-50%, 15-50%, etc., by weight of the tip solution.
In practical application, functional substances such as one or more of madecassoside, licorice extract, tea polyphenol, salicylic acid, tanshinone, fruit acid, totarol, chlorogenic acid, beta-1, 3-glucan, tranexamic acid, resveratrol, nicotinamide, arbutin, licoflavone, squalane, allantoin, vitamin C ethyl ether, vitamin E, refined nicotinamide, panthenol, microorganism B6, inositol, silk peptide, minoxidil, diaminopyrimidine oxide, pyrrolidinyl diaminopyrimidine oxide, bletilla striata extract, rhubarb extract, witch hazel extract and the like can be added according to requirements. So as to endow the micro-needle patch with more functions, such as spot removal, melanoma treatment, skin whitening, hair care and hair growth and the like. Thereby playing a more important role in various skin-related diseases and health care fields.
The mass percentage of the functional substance in the needle point solution can be 0.001-10%. In some illustrative examples, but not limited to, 0.001% -8%, 0.001% -5%, 0.005% -5%, etc.
The microneedle patch containing azelaic acid provided in the present embodiment can solve the problems of (1) poor skin penetration property of the existing azelaic acid preparation; (2) is fat-soluble matrix, is greasy when in use, and is easy to cause acne; (3) the irritation problems such as skin red and swelling, pruritus and the like are easy to occur in use.
The microneedle patch can effectively pierce the stratum corneum of the skin, so that the active ingredient of azelaic acid directly acts on the epidermis layer or the dermis layer of the skin, and has the advantages of quick response, reduced administration concentration, improved effective utilization rate of the medicament, convenient use for patients, no cross infection and the like. In addition, matrine and azelaic acid are selected for compatibility. The matrine has strong alkaline tertiary amine group in the structure, is combined with azelaic acid to ensure that the azelaic acid is partially ionized, plays the role of a solubilizer, a pH regulator, an anti-allergy agent and a preservative while playing the anti-acne effect, and is refined by a prescription composition, so that the preparation process of the solution at the early stage is simpler, more convenient and quicker, and the industrial production efficiency is greatly improved.
The invention obtains the optimal proportion of the combination of azelaic acid and matrine by optimizing the prescription, and can ensure the microneedle molding while achieving the effects by mixing with a proper matrix material. The micro-needle patch disclosed by the invention can play an important role in the fields of acne removal, freckle removal, melanoma treatment, skin whitening and brightening, hair care and hair growth and other skin-related diseases and health care through the compatibility of the micro-needle patch and other effective active ingredients.
In another aspect, a further embodiment of the present invention provides a method for preparing a microneedle patch containing azelaic acid, the method at least comprising a step of preparing a solution for a needle tip, specifically, comprising the steps of:
mixing the water solution of azelaic acid and matrine, adding water-soluble matrix material at room temperature, and dissolving completely to obtain the needle tip solution.
The technical solution of the present invention is described below with reference to some specific examples:
the molar ratios mentioned in the tables below are the molar ratio of azelaic acid to matrine.
Test examples
Research on matching process of azelaic acid and matrine
The solution preparation method comprises the following steps: adding a certain amount of ultrapure water into a centrifugal tube, weighing a proper amount of azelaic acid by using an electronic balance, adding the azelaic acid into water, then placing the centrifugal tube in a water bath environment at 70 ℃ to promote the dissolution of the azelaic acid, after the azelaic acid is completely dissolved, weighing a proper amount of matrine by using the electronic balance, adding the matrine into the centrifugal tube, after the azelaic acid is completely dissolved, placing the centrifugal tube at room temperature for natural cooling, wherein the ratio of the azelaic acid to the matrine is shown in the following table 1.
(1) Evaluation of dissolution: after the solution is returned to room temperature, the dissolution condition of the solution in the test tube is visually observed, whether undissolved substances exist or not is firstly observed, then a pipette is used for sucking one drop of each solution, the solution is dripped on a clean glass sheet, after the solution is naturally volatilized, the solution is placed under a fluorescence microscope to observe whether crystals are separated out or not, and the separation conditions of the formulas 1 to 5 under the fluorescence microscope are shown as a to e in the figure 1 and table 1 in sequence.
(2) And (3) measuring the pH of the solution: the pH of each solution was measured using a pH meter and the results are shown in table 1 below.
The result shows that when the molar ratio of the azelaic acid to the matrine is lower than 1:1, no undissolved substance visible to the naked eye exists in the solution, and the microscopic expression shows that no azelaic acid crystal is separated out under a fluorescence microscope; when the molar ratio of azelaic acid to matrine reaches 1:1.8, the pH is 5.86 and is higher than 5.33, and the azelaic acid is in a completely ionized state, and the antibacterial activity of the azelaic acid is reduced in the completely ionized state, so that the azelaic acid cannot normally play pharmacological actions.
And in the formula 4, since azelaic acid was not completely dissolved, it could not be used in the preparation of a needle tip solution and thus could not be used in the preparation of microneedles.
Therefore, the optimal ratio of the needed azelaic acid to the matrine is determined to be 1:1-1: 1.5.
TABLE 1 different proportions of azelaic acid and matrine
Example 1
Layered microneedle preparation containing azelaic acid
1. The preparation process comprises the following steps:
(1) preparation of needle tip solution
Adding 9.885mL of ultrapure water into a centrifugal tube, weighing 0.05g of azelaic acid in dissolved water by using an electronic balance, then placing the centrifugal tube in a water bath environment at 70 ℃ to promote the dissolution of azelaic acid, adding 0.065g of matrine after the azelaic acid is completely dissolved, wherein the molar ratio of azelaic acid to matrine is 1:1, adding 0.1g of sodium carboxymethylcellulose (CMC) after the temperature of the solution is reduced to room temperature, weighing 0.1g of trehalose, stirring for dissolution, and then placing the solution in a centrifuge to remove bubbles, thus obtaining the microneedle tip solution.
(2) Preparation of base solutions
Adding 7.8mL of ultrapure water into a centrifuge tube, weighing 2g of hydroxyethyl cellulose and 2g of PVP K900.2g by using an electronic balance, adding into the centrifuge tube, and placing into a centrifuge to remove bubbles after the materials are completely dissolved, thus obtaining the microneedle substrate solution.
(3) Microneedle prepared by adding sample
Sucking a quantitative microneedle tip solution by using a continuous sample adding gun, dripping the microneedle tip solution on a clean and dried PDMS mold, promoting the microneedle tip solution to enter a pinhole unit in a negative pressure vacuumizing mode, sucking a quantitative drug-free substrate solution after the microneedle tip solution is dried completely to form a film, dripping the drug-free substrate solution on each pinhole unit, drying the pinhole unit under a blowing condition, and demoulding after the needle tip solution is completely dried to obtain the layered microneedle patch containing azelaic acid, wherein the appearance diagram of the layered microneedle patch is shown in figure 2.
Example 2
A layered needle microneedle patch was prepared as in example 1, except that the formulation of the tip solution was different, and the formulation, dissolution and pH were as shown in table 2 (in table 2, the balance of the composition not shown was water).
The prepared microneedle patch acts on the arm of a sensitive skin volunteer for 10 minutes, then is taken down to observe whether the skin has an allergic condition, and the effect is shown as a in figure 3, wherein the skin is slightly reddened (the acting area of the microneedle is a normal phenomenon due to the puncture of the microneedle on the skin cuticle), and after about 2 hours, the redness is gradually faded, and no irritation reaction such as pruritus, swelling, diffuse allergy and the like exists; the surface topography of the resulting microneedle patch after 10 minutes of exposure is shown in figure 4.
The height of the micro-needle patch and the height of the residual needle after the micro-needle patch is applied to human skin for 10min are respectively shown as a and b in fig. 5.
TABLE 2 microneedle formulation using matrine, arginine solubilized azelaic acid, respectively (in g/-mL)
| Molar ratio of | Azelaic acid | Matrine | Arginine | CMC | Trehalose | Dissolution behavior | pH of the solution | |
| Example 2 | 1:1 | 0.5％ | 0.65％ | - | 1％ | 1％ | Completely dissolve | 4.83 |
| Comparative example 1 | 1:1 | 0.5％ | - | 0.5％ | 1％ | 1％ | Completely dissolve | 4.92 |
Comparative example 1
A layered needle was prepared as in example 1, except that the formulation of the tip solution was varied and the formulation and dissolution and pH were as shown in Table 2.
The prepared microneedle patch is acted on the arm of a sensitive skin volunteer for 10 minutes, and then taken down to observe whether the skin is allergic or not, wherein the effect is shown as b in fig. 3. Comparative example 1 effect as shown in b of fig. 3, the subject fed back skin itch, diffuse redness, and allergic reactions such as swelling, etc. at the microneedle action site.
Comparing the results of example 2 and comparative example 1, it can be seen that the matrine-containing microneedle can alleviate the skin irritation of azelaic acid to intolerant users, has good skin safety, and increases the number of people to whom azelaic acid is applied.
Examples 3 to 8
A layered needle microneedle patch was prepared as in example 1, except that the tip solution formulation was different and is shown in table 3. An SEM image of the layered microneedle prepared in example 4 is shown in fig. 6.
TABLE 3 prescription of tip solution and prescription of matrix material for the layered microneedle patch containing azelaic acid (where tip solution means a prescription consisting of active ingredient and matrix material) Table (in g/ml, and the balance of the prescription is water)
Example 9
Preparation of unitary microneedles containing azelaic acid
(1) Microneedle solution formulation
According to the molar ratio of azelaic acid to matrine of 1:1 preparing a solution, adding 7.3mL of ultrapure water into a centrifugal tube, weighing 2g of polyvinyl alcohol by using an electronic balance, adding the polyvinyl alcohol into the centrifugal tube, dissolving the polyvinyl alcohol in an oven at 80 ℃, taking out the polyvinyl alcohol after the polyvinyl alcohol is completely dissolved, using a medicine spoon to dissolve 0.5g of azelaic acid, then placing the centrifugal tube in a water bath environment at 70 ℃ to promote the dissolution of azelaic acid, adding 0.65 matrine after the azelaic acid is completely dissolved, adjusting the pH value of the solution, increasing the solubility of the azelaic acid, weighing 0.5g of carboxymethyl chitosan after the temperature of the solution is reduced to room temperature, stirring and dissolving, and then placing the solution in a centrifuge to remove bubbles, thereby obtaining the microneedle solution containing the azelaic acid.
(2) Microneedle prepared by adding sample
And (3) sucking a quantitative microneedle tip solution by using a continuous sample adding gun, dripping the microneedle tip solution on a clean and dried PDMS (polydimethylsiloxane) mould, promoting the solution to enter a pinhole unit in a negative pressure vacuumizing mode, and demolding after the solution is completely dried to obtain the integrated microneedle patch containing azelaic acid.
The prepared microneedle patch acts on the arm of a sensitive skin volunteer, the surface appearance of the obtained microneedle patch after acting for 10 minutes is shown in figure 7, and the acting part of the skin microneedle of the subject has no anaphylactic reaction.
Examples 10 to 15
A one-piece microneedle patch was prepared as in example 9, except that the formulation of the microneedle solution was different, and the formulation is shown in table 4. The skin safety test of the microneedles prepared by different prescriptions shows that no anaphylactic reaction occurs.
Table 4 prescription composition table of integrated microneedle patch containing azelaic acid
Examples 16 to 21
The microneedle preparation method was referred to example 1 except that a specific tip solution was formulated as shown in table 5.
The acne-removing microneedle patch containing azelaic acid prepared by examples 16-21 had very good acne-removing effect and no skin allergy.
Recruiting a patient suffering from moderate acne for pharmacodynamic evaluation, performing VISIA imaging on the skin of the acne part of the patient before use, then attaching the acne-removing microneedle patch of the embodiment 16 to the acne part of the patient, pressing forcibly for 20 seconds, continuously applying for 20 minutes, then taking off for one treatment, performing VISIA imaging on the skin of the acne part of the patient at an interval of 24 hours after the treatment, and comparing with an effect chart before use. Before and after one-time treatment, VISIA imaging contrast images of the acne-removing microneedle patch in example 16 are shown as a and b in fig. 8 in sequence.
The comparison graphs of the affected skin before, after and after two times of treatment and one week of treatment of the acne-removing microneedle patch of example 17 are shown as a, b and c in fig. 9. The pictures show that the acne type of the patient is pustule type and pain is caused by light touch, the acne removing microneedle patch in the embodiment 17 is attached to the acne position of the patient, the acne is pressed for 20 seconds with strength, the acne removing microneedle patch is continuously applied for 20 minutes and then taken off as one treatment, the acne removing microneedle patch is used again after 24 hours, the pustule on the affected part is obviously reduced and shrunken after two patches, the pustule completely disappears after one week, the skin of the affected part is well healed, and no obvious acne mark is left.
Table 5 prescription composition table of acne-removing microneedle patch containing azelaic acid
Examples 22 to 27
Preparation of whitening microneedle patch containing azelaic acid
The microneedle preparation method was referred to example 1 except that a specific tip solution was formulated as shown in table 6.
The microneedle patches containing azelaic acid prepared by examples 22-27 had very good whitening effects.
Table 6 prescription composition table for whitening microneedle patch containing azelaic acid
Examples 28 to 33
Preparation of speckle-removing microneedle patch containing azelaic acid
The microneedle preparation method was referred to example 9 except that a specific tip solution was formulated as shown in table 7.
The microneedle patches containing azelaic acid prepared by examples 28-33 had very good depigmenting effects.
TABLE 7 composition table of speckle-removing microneedle patch containing azelaic acid
Examples 34 to 39
Preparation of Hair growing microneedle Patch containing azelaic acid
The microneedle preparation method was referred to example 9 except that a specific tip solution was formulated as shown in table 8.
The microneedle patches containing azelaic acid prepared by examples 34-39 had very good hair growth effects.
Table 8 composition table of hair growing microneedle patch containing azelaic acid
Comparative example 2
Microneedle tip solutions were prepared according to the molar ratio of azelaic acid to matrine 1:1.8 as mentioned in formulation 5 in table 1 above, and the specific formulation is shown in table 9 below. Microneedle substrate solution formulations are shown in example 1. Preparing the microneedle.
Table 9 specific microneedle tip solution recipe table is shown in the following table
Before use, the skin of the acne part of a patient is photographed, the prepared microneedle patch is attached to the acne part of the patient, the patient is pressed with force for 20 seconds, the microneedle patch is continuously attached for 20 minutes and then taken off for primary treatment, the patient is photographed at an interval of 24 hours after treatment, one prepared microneedle patch is attached to the acne part of the patient again, the patient is pressed with force for 20 seconds, the microneedle patch is continuously attached for 20 minutes and taken off for secondary treatment, the patient is photographed at an interval of 24 hours after treatment, and the comparison picture of the effect before and after treatment is shown in fig. 10.
In fig. 10, a, b and c sequentially show a comparison graph of affected skin before, after and after treatment for one time and two times of the acne treatment of the acne-removing microneedle patch in the formula 5, and the result shows that the pustule condition of an acne part is not obviously improved, which indicates that the antibacterial and acne-removing effects of the microneedle patch prepared in the formula 5 are not significant, because the pH value of the solution is 5.86 and the secondary dissociation coefficient of azelaic acid is 5.33 under the condition that the molar ratio of azelaic acid to matrine is 1:1.8, which indicates that under the condition, the carboxylic acid group of azelaic acid is completely ionized and exists in the solution in the form of ionic salt, so that the antibacterial activity of the azelaic acid is reduced and the acne-removing effect is not obvious.
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention, and it will be obvious to those skilled in the art that other variations or modifications may be made on the basis of the above description, and all embodiments may not be exhaustive, and all obvious variations or modifications may be included within the scope of the present invention.
Claims (9)
1. A microneedle patch containing azelaic acid, wherein a solution formulation for preparing a microneedle tip comprises: active ingredient, matrine and water-soluble matrix material;
the active component comprises azelaic acid, and the mass percentage content of the azelaic acid in the needlepoint solution is 0.1-10%.
2. The microneedle patch containing azelaic acid according to claim 1, wherein the matrine is contained in the needlepoint solution in an amount of 0.13 to 20% by mass.
3. A microneedle patch containing azelaic acid according to claim 1, wherein the molar ratio of azelaic acid to matrine is 1:1-1: 1.5.
4. The microneedle patch containing azelaic acid as claimed in claim 1, wherein the water-soluble base material is selected from one or a mixture of several of polyvinyl alcohol, polyvinylpyrrolidone, chitosan derivative, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, polyglutamic acid, chondroitin sulfate, sodium alginate, sodium hyaluronate, collagen, pullulan, dextran, trehalose, sucrose, lecithin, xylitol, mannitol, sorbitol, glycerin, polyethylene glycol, sodium glycerophosphate.
5. A microneedle patch containing azelaic acid according to claim 4, wherein said chitosan derivative is selected from polyethylene glycol-modified chitosan, guanidinoacetic acid-modified chitosan, chitosan grafted with guanidino and carbonylmethoxypolyethylene glycol, chitosan grafted with guanidino and amino acid groups, chitosan grafted with basic amino acids or oligomers thereof and hydrophobic amino acids or oligomers thereof.
6. A microneedle patch containing azelaic acid according to claim 1, wherein the water-soluble matrix material is present in the tip solution in an amount of 1-80% by mass, preferably 2-50% by mass.
7. A microneedle patch containing azelaic acid according to claim 1, wherein said active ingredient further comprises a functional substance; preferably, the functional substance is one or more of madecassoside, licorice extract, tea polyphenol, salicylic acid, tanshinone, fruit acid, totarol, chlorogenic acid, beta-1, 3-glucan, tranexamic acid, resveratrol, nicotinamide, arbutin, licoflavone, squalane, allantoin, vitamin C ethyl ether, vitamin E, refined nicotinamide, panthenol, microorganism B6, inositol, silk peptide, minoxidil, diaminopyrimidine oxide, pyrrolidinyl diaminopyrimidine oxide, bletilla striata extract, rhubarb extract and witch hazel extract.
8. A microneedle patch containing azelaic acid according to claim 7, wherein the content of said functional substance in the tip solution is 0.001% -10% by mass, preferably 0.001% -5%.
9. A preparation method of a microneedle patch containing azelaic acid is characterized by at least comprising a preparation step of a needle tip solution, and specifically comprises the following steps:
mixing the water solution of azelaic acid and matrine, adding water-soluble matrix material at room temperature, and dissolving completely to obtain the needle tip solution.
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| CN113248364A (en) * | 2021-05-27 | 2021-08-13 | 无锡元旭生物技术有限公司 | Method for solubilizing azelaic acid |
| CN114028264A (en) * | 2021-11-26 | 2022-02-11 | 广州贝奥吉因生物科技股份有限公司 | Microneedle patch for acne removal and repair and preparation method and application thereof |
| CN115414381A (en) * | 2022-11-07 | 2022-12-02 | 西南民族大学 | Composition with scar inhibition and/or wound healing promotion effects and preparation method and application thereof |
| WO2023001607A1 (en) * | 2021-07-22 | 2023-01-26 | Lts Lohmann Therapie-Systeme Ag | Microneedle array with antiseptics |
| CN115737532A (en) * | 2022-11-29 | 2023-03-07 | 华中科技大学 | Supermolecule salicylic acid composite microneedle patch, and preparation method and application thereof |
| CN115869411A (en) * | 2023-02-17 | 2023-03-31 | 中科微针（北京）科技有限公司 | Composition for treating acne, micro-needle for treating acne and preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113248364A (en) * | 2021-05-27 | 2021-08-13 | 无锡元旭生物技术有限公司 | Method for solubilizing azelaic acid |
| WO2023001607A1 (en) * | 2021-07-22 | 2023-01-26 | Lts Lohmann Therapie-Systeme Ag | Microneedle array with antiseptics |
| CN114028264A (en) * | 2021-11-26 | 2022-02-11 | 广州贝奥吉因生物科技股份有限公司 | Microneedle patch for acne removal and repair and preparation method and application thereof |
| CN115414381A (en) * | 2022-11-07 | 2022-12-02 | 西南民族大学 | Composition with scar inhibition and/or wound healing promotion effects and preparation method and application thereof |
| CN115414381B (en) * | 2022-11-07 | 2023-03-28 | 西南民族大学 | Composition with scar inhibition and/or wound healing promotion effects and preparation method and application thereof |
| CN115737532A (en) * | 2022-11-29 | 2023-03-07 | 华中科技大学 | Supermolecule salicylic acid composite microneedle patch, and preparation method and application thereof |
| CN115869411A (en) * | 2023-02-17 | 2023-03-31 | 中科微针（北京）科技有限公司 | Composition for treating acne, micro-needle for treating acne and preparation method |
| CN116869848A (en) * | 2023-09-08 | 2023-10-13 | 中科微针（北京）科技有限公司 | Scar-removing microneedle patch containing centella asiatica active ingredient |
| CN117567762A (en) * | 2023-11-15 | 2024-02-20 | 江南大学 | Method for improving azelaic acid water solubility and stability |
| CN117815113A (en) * | 2024-03-04 | 2024-04-05 | 北京青颜博识健康管理有限公司 | Soluble microneedle capable of being dried at high temperature and preparation method and application thereof |
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Inventor after: Gao Yunhua Inventor after: Xing Mengzhen Inventor after: Yang Guozhong Inventor before: Jiang Lin Inventor before: Xing Mengzhen Inventor before: Yang Guozhong Inventor before: Gao Yunhua |
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