CN118490615A - Soluble microneedle patch containing deoxycholic acid and preparation method and application thereof - Google Patents
Soluble microneedle patch containing deoxycholic acid and preparation method and application thereof Download PDFInfo
- Publication number
- CN118490615A CN118490615A CN202410584303.6A CN202410584303A CN118490615A CN 118490615 A CN118490615 A CN 118490615A CN 202410584303 A CN202410584303 A CN 202410584303A CN 118490615 A CN118490615 A CN 118490615A
- Authority
- CN
- China
- Prior art keywords
- deoxycholic acid
- soluble microneedle
- microneedle
- solid dispersion
- soluble
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 title claims abstract description 75
- 229960003964 deoxycholic acid Drugs 0.000 title claims abstract description 75
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000000843 powder Substances 0.000 claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 35
- 239000007962 solid dispersion Substances 0.000 claims abstract description 28
- 239000000560 biocompatible material Substances 0.000 claims abstract description 11
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 24
- 229920002674 hyaluronan Polymers 0.000 claims description 24
- 229960003160 hyaluronic acid Drugs 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000008367 deionised water Substances 0.000 claims description 16
- 229910021641 deionized water Inorganic materials 0.000 claims description 16
- 229920001661 Chitosan Polymers 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 238000009210 therapy by ultrasound Methods 0.000 claims description 9
- 238000009825 accumulation Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 3
- 238000007605 air drying Methods 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 230000001815 facial effect Effects 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- 238000000227 grinding Methods 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 29
- 230000000694 effects Effects 0.000 abstract description 10
- 238000004090 dissolution Methods 0.000 abstract description 7
- 238000004088 simulation Methods 0.000 abstract description 6
- 238000011282 treatment Methods 0.000 abstract description 5
- 238000013271 transdermal drug delivery Methods 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 3
- 239000000853 adhesive Substances 0.000 abstract description 2
- 230000001070 adhesive effect Effects 0.000 abstract description 2
- 230000000857 drug effect Effects 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000005540 biological transmission Effects 0.000 abstract 1
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 238000005516 engineering process Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 6
- 210000001789 adipocyte Anatomy 0.000 description 5
- 230000004888 barrier function Effects 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 206010052428 Wound Diseases 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 210000004877 mucosa Anatomy 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000643 oven drying Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- -1 insulin sensitizers Chemical compound 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 206010033675 panniculitis Diseases 0.000 description 2
- 230000037368 penetrate the skin Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000012466 permeate Substances 0.000 description 2
- 235000013406 prebiotics Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 210000004003 subcutaneous fat Anatomy 0.000 description 2
- 239000002344 surface layer Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 238000009827 uniform distribution Methods 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 206010040830 Skin discomfort Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- 206010043417 Therapeutic response unexpected Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002324 minimally invasive surgery Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000004482 other powder Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 230000036555 skin type Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A soluble microneedle patch containing deoxycholic acid and a preparation method and application thereof belong to the field of medicines. The invention provides a preparation and application of a soluble microneedle array patch containing deoxycholic acid in fat dissolution. Experimental results show that the microneedle patch is made of a biocompatible material and contains deoxycholic acid solid dispersion powder, and has double effects of dissolving fat and tightening skin. The research shows that the microneedle tip is uniform and has good mechanical strength and drug carrying capacity, and the effectiveness of the microneedle tip in transdermal drug delivery is verified through simulation and animal experiments. Therefore, the soluble microneedle array patch provides a new treatment scheme for the field of medicine, and has important clinical application prospect. Meanwhile, the embodiment optimizes the adjustment mass proportion, concentration, addition of adhesive and the like so as to improve the hardness and drug effect transmission efficiency of the microneedle, and provides important guidance and reference for further application of the preparation.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a soluble microneedle patch containing deoxycholic acid, and a preparation method and application thereof.
Background
The fat-dissolving technology comprises a radio-frequency fat-dissolving technology, an ultrasonic fat-dissolving technology, a minimally invasive surgery and injection of traditional fat-dissolving medicines. Common traditional lipid-dissolving drugs include, but are not limited to, deoxycholic acid, insulin sensitizers, epinephrine drugs, and the like. Deoxycholic acid is a substance naturally existing in bile, and can accurately destroy cell membranes of fat cells by local injection, so that the fat cells are cracked, and the flowing fat is cleared by macrophages; the surface of the cell membrane of tissue cells such as skin and muscle contains a large amount of protein, so that the tissue cells cannot be cracked, and the skin can be compacted while fat is dissolved, and the problem of skin relaxation after fat dissolution is prevented. The main administration mode of deoxycholic acid is local smearing or local injection. The local application can directly apply deoxycholic acid preparation on the skin surface needing fat reduction, and then promote the deoxycholic acid preparation to permeate into subcutaneous adipose tissue by means of massage and the like to take effect. Local injection is to inject deoxycholic acid solution directly onto the fat region to be treated. However, these two common modes of administration also each have some drawbacks. For topical application, deoxycholic acid molecules may not penetrate the skin barrier sufficiently due to permeability limitations, resulting in an undesirable effect in subcutaneous adipose tissue. Meanwhile, the application may cause uneven absorption, so that the therapeutic effect is unstable or not ideal. In addition, allergy or irritation may be generated to the ingredients of the deoxycholic acid formulation applied, resulting in skin discomfort or other adverse reactions. In contrast, the manner of local injection may be accompanied by injection-related risks, such as pain, swelling, bleeding, local infection, etc., and risks of potential nerve or vessel damage. Local discomfort, such as pain, swelling, hard mass, etc., may occur after injection, affecting patient comfort and quality of life. Furthermore, the effectiveness of the injection may be affected by the injection technique, resulting in an unstable or unexpected therapeutic effect. Deoxycholic acid, on the other hand, is a poorly soluble drug with limited bioavailability. Therefore, in order to solve the drawbacks of the conventional administration methods and the limited bioavailability of deoxycholic acid, there is a need for an efficient administration method that can effectively utilize deoxycholic acid. the fat-soluble microneedle patch containing deoxycholic acid has an innovative design and can effectively solve the problem of fat accumulation. The microneedle patch adopts a soluble design, and deoxycholic acid is released to the deep layer of the skin through the penetration of the microneedle on the surface of the skin so as to achieve the effect of dissolving fat. The main advantages of such patches include: 1. the fat dissolving effect is remarkable. Deoxycholic acid is used as an active ingredient, and can effectively dissolve fat cells and reduce fat accumulation. 2. Microneedle penetration technology. By adopting the microneedle technology, the microneedles in the patch can penetrate the skin surface to directly release the medicine into the deep skin, so that the permeability and absorption efficiency of the medicine are improved. 3. The safety is high. Because the microneedle patch adopts a soluble design, residues are not left in the use process, the risks of infection and allergy are reduced, and the microneedle patch is suitable for various skin types. 4. Has high bioavailability. The cyclodextrin is used as a carrier, and the amorphous solid dispersion powder of deoxycholic acid is prepared by a spray drying technology. The powder can effectively inhibit recrystallization of deoxycholic acid, prolong the time of maintaining supersaturation of the drug in skin, and is beneficial to loading of insoluble drug in hollow microneedle and high bioavailability. 5. The operation is simple and convenient: only the microneedle patch is attached to the skin, the microneedle is completely permeated by gentle massage, and then the drug can be released after waiting for a period of time, so that no additional professional operation is required. The soluble microneedle patch containing deoxycholic acid combines advanced drug delivery technology and fat-dissolving components, and provides an innovative solution for solving the fat accumulation problem.
The skin serves as the largest organ of the human body and is one of the largest defending barriers of the human body, so that the entry of external microorganisms is blocked. In order to maximize the therapeutic effect of the prebiotics, the proper mode of administration must be selected to break through this barrier. At the same time, the wound surface is ensured to be as small as possible so as to prevent other bacteria or fungi from being infected in the process of delivering the medicine. Microneedle arrays have been developed in recent years as a new way of facilitating drug delivery, consisting of many tiny needles, for penetrating the skin or mucosa and delivering drugs or performing other treatments. These microneedles, typically having a size on the order of nanometers or sub-millimeters, can penetrate the surface layers of the skin or mucosa, creating tiny channels that allow the drug to penetrate into the deep tissues of the skin. The microneedle array has the advantages of improving the drug permeability, reducing the dosage and side effects, providing personalized treatment, improving the compliance of patients and the like, and is the most suitable administration mode for carrying prebiotics, adjusting oral mucosa or skin wound surface flora.
Disclosure of Invention
The invention designs and prepares the soluble microneedle array patch containing deoxycholic acid, and the microneedle penetrates through skin mucosa on the premise of ensuring tiny wound surface, thereby playing the role of deoxycholic acid fat dissolution to the maximum extent.
The technical scheme adopted by the invention is as follows:
A soluble microneedle patch containing deoxycholic acid comprises a microneedle substrate and a soluble microneedle body, wherein the soluble microneedle body is made of a biocompatible material, and the microneedle body contains deoxycholic acid solid dispersion powder.
Further, the biocompatible material is selected from the group consisting of chitosan, hyaluronic acid, and pvp k-90.
The soluble microneedle array patch containing deoxycholic acid is prepared by the following method:
(1) And (3) putting deoxycholic acid into a round-bottomed flask containing an ethanol aqueous solution, carrying out ultrasonic treatment until the deoxycholic acid is completely dissolved, carrying out rotary evaporation, carrying out air drying at room temperature, and then grinding to obtain uniform powder.
(2) Dissolving deoxycholic acid solid dispersion powder and a biocompatible material obtained in the step (1) by deionized water;
(3) Stirring, and then carrying out ultrasonic treatment and standing;
(4) Filling the solution which is subjected to standing in the step (3) into a mould, and centrifuging;
(5) Adding the solution which is subjected to standing in the step (3) into a mould again until small bulges are formed;
(6) And (5) drying the product obtained in the step (5), and demoulding after drying to obtain the microneedle.
Further, the ratio of deoxycholic acid solid dispersion powder to biocompatible material in the step (2) is 1 (3-5.5) by mass; the pH value of the deionized water is 7.
Further, in the step (3), the stirring time is 3-4 hours.
Further, in the step (4), the centrifugal speed is 3000-4000rpm, the centrifugal times are 4-6 times, and the centrifugal time is about 10-15 minutes each time.
Further, in the step (6), the drying temperature is 35-40 ℃ and the drying time is 24-30 hours.
The invention provides application of the soluble microneedle patch containing deoxycholic acid in preparing a medicine for reducing fat accumulation of the face and neck. The facial and neck parts are parts with more fat accumulation, such as the face, the neck, the lower jaw and the like. Mandibular fatty increase, such as of moderate weight, is most suitable for treatment using the microneedle patches of the present invention.
The invention has the beneficial effects that:
The microneedle is made of biocompatible materials, and ensures that the materials and the skin can be fused into a whole. Deoxycholic acid is a poorly soluble drug with limited bioavailability, and the invention aims at the problem, and amorphous solid dispersion powder is prepared by using common cyclodextrin as a carrier and adopting a spray drying technology. The powder can effectively inhibit recrystallization of deoxycholic acid, prolong the time of maintaining supersaturation of the drug in skin, and is beneficial to loading of insoluble drug in hollow microneedle and high bioavailability.
The soluble microneedle array patch containing deoxycholic acid is simple in preparation and clear in mechanism. The invention ensures that the microneedle penetrates through the surface layer of the skin to reach the fat layer when in use by limiting the size of the microneedle body. The microneedle tips do not reach the deep skin layer with rich nerve endings, so that pain sense can not be generated. In addition, the microneedle body is made of biocompatible materials, can be integrated with skin, and cannot cause wounds and inflammations, so that the defect that insoluble microneedles can cause wounds is overcome, and the effect of effectively transferring deoxycholic acid solid powder to the skin can be achieved by breaking through the barrier function of the skin under the condition that a user does not have pain and bleeding.
The technology of the soluble microneedle array for conveying deoxycholic acid solid powder has no obvious skin irritation, and well solves the problems that deoxycholic acid is difficult to permeate into the skin and the solubility is low.
In conclusion, the invention provides a brand new theory and advanced solution for fat dissolution, also provides a promising strategy and exploration thought for the clinical application of deoxycholic acid, and has important scientific research value.
Drawings
FIG. 1 is a morphological observation of the microneedles prepared in example 1, which is a result of verifying uniform distribution of tips and drug loading ability of the microneedles by naked eyes, an inverted microscope, and a confocal microscope, in order from left to right;
FIG. 2 is a graph showing the results of mechanical strength measurement of the tips of the microneedles in example 6 of the present invention;
FIG. 3 is a simulated image of the diffusion of a simulated drug through the skin and the results of a 3D simulation of transdermal drug delivery in example 7 of the present invention.
Detailed Description
The foregoing of the invention is further illustrated by the following specific examples, which are not intended to limit the invention thereto.
Example 1: preparation of soluble microneedle array patch
Deoxycholic acid is a bile acid compound naturally occurring in the human body, usually metabolized by cholesterol. The cell membrane of the fat cells can be accurately destroyed by local injection, so that the fat cells are cracked, and the flowing fat is cleared by macrophages; the surface of the cell membrane of tissue cells such as skin and muscle contains a large amount of protein, so that the tissue cells cannot be cracked, and the skin can be compacted while fat is dissolved, and the problem of skin relaxation after fat dissolution is prevented.
In order to better exert the fat-dissolving effect of deoxycholic acid, we selected chitosan as the substrate of the microneedle array. The chitosan is a product of removing partial acetyl of natural polysaccharide chitin, has the characteristics of biodegradability, biocompatibility, no toxicity and the like, is widely applied to the field of pharmacy due to the guarantee of safety, and is a common auxiliary material in pharmacy. Deoxycholic acid is a poorly soluble drug and has limited bioavailability, and the invention aims at the problem that cyclodextrin which is commonly used is used as a carrier, and amorphous solid dispersion powder is prepared by a spray drying technology. The powder can effectively inhibit recrystallization of deoxycholic acid, prolong the time of maintaining supersaturation of the drug in skin, and is beneficial to loading of insoluble drug in hollow microneedle and high bioavailability.
The original prescription adopted by the invention is as follows:
Deoxycholic acid solid dispersion powder 10mg
Chitosan 30mg
Deionized water 1.5mL
The preparation method adopted by the invention comprises the following steps: adding a proper amount of deionized water into a beaker, adding 10mg of deoxycholic acid solid dispersion powder and 30mg of chitosan into a small bottle, and dissolving with 1.5mL of deionized water; adding a stirrer, stirring on an instrument for 3.5 hours, and then carrying out ultrasonic treatment and standing for 2 hours; putting the dissolved substance into a mould, and centrifuging for 4 times at 3000rpm for 15 minutes each time; taking out the die, and adding the dissolved matters again until small bulges are formed; drying at 37deg.C for 24 hr, and taking out the microneedle; and morphological observations were made. As a result, as shown in FIG. 1, the present invention successfully prepared soluble lipid-dissolving microneedles containing deoxycholic acid.
Example 2:
the soluble microneedle array patch prepared according to example 1 can exert a certain therapeutic effect. In order to further improve the therapeutic effect of the microneedles, it is decided to select a substance that can achieve physical isolation as an adjuvant to be added to the original prescription.
It is known from the literature that hyaluronic acid is an acidic mucopolysaccharide, which was first isolated from bovine vitreous from Meyer et al, professor Meyer, university of columbia, 1934. Hyaluronic acid shows various important physiological functions in the body by virtue of unique molecular structure and physicochemical properties, such as lubricating joints, regulating permeability of vascular walls, regulating diffusion and operation of proteins, water and electrolytes, promoting wound healing and the like.
The hyaluronic acid with a certain proportion is added into the original prescription to play the role of physical isolation of the hyaluronic acid, and the hyaluronic acid is matched with deoxycholic acid solid dispersion powder to the maximum extent, so that a better treatment effect is realized.
The prescription adjusted according to example 1 is as follows:
The preparation method adopted by the prescription comprises the following steps: adding a proper amount of deionized water into a beaker, adding 10mg of deoxycholic acid solid dispersion powder, 30mg of chitosan and 2mg of hyaluronic acid into a small bottle, and dissolving with deionized water; adding a stirrer, stirring for 3.5 hours on a magnetic stirrer, and then carrying out ultrasonic treatment and standing for 2 hours; putting the dissolved substance into a mould, and centrifuging for 4 times at 3000rpm for 15 minutes each time; taking out the die, and adding the dissolved matters again until small bulges are formed; oven-drying at 37deg.C for 24 hr, and taking out the micropins.
Example 3:
The soluble microneedle array patch prepared according to example 1 was selected to increase the concentration of hyaluronic acid in order to further increase its therapeutic effect, in combination with a better lipid-dissolving effect of deoxycholic acid solid dispersion powder.
The preparation method comprises the steps of preparing a series of hyaluronic acid solutions with gradient concentrations, adding the hyaluronic acid solutions into a microneedle mould, wherein the concentration of the hyaluronic acid is 0, 3.3mg/mL, 6.67mg/mL, 10mg/mL, 13.33mg/mL and 16.67mg/mL in sequence, and the addition amounts of the hyaluronic acid corresponding to each gradient concentration are 0mg, 5mg, 10mg, 15mg, 20mg and 25mg respectively. And drying under the same condition to obtain a series of blank microneedles with gradient concentration of hyaluronic acid.
Through researches, the therapeutic effect is improved along with the increase of the concentration of the hyaluronic acid in a certain concentration range, and the hyaluronic acid are positively correlated. However, when hyaluronic acid is out of a certain range, dissolution of deoxycholic acid solid dispersion powder is affected, resulting in insufficient content of main active ingredient. Experiments have shown that 10mg/mL is the most suitable concentration of hyaluronic acid.
The prescription adjusted according to example 1 is as follows:
The preparation method adopted by the prescription comprises the following steps: adding a proper amount of deionized water into a beaker, adding 10mg of deoxycholic acid solid dispersion powder, 30mg of chitosan and hyaluronic acid with the gradient mass into a small bottle, and dissolving with deionized water; adding a stirrer, stirring on an instrument for 3.5 hours, and then carrying out ultrasonic treatment and standing for 2 hours; putting the dissolved substance into a mould, and centrifuging for 4 times at 3000rpm for 15 minutes each time; taking out the die, and adding the dissolved matters again until small bulges are formed; and drying the mixture for 24 hours at 37 ℃, and taking out the microneedles to obtain the microneedles with different hyaluronic acid concentrations.
Example 4:
The soluble microneedle array patch prepared according to example 1 was not sufficiently stiff, and the entire microneedle array patch was brittle and difficult to penetrate directly into the skin surface during use, and we selected to add a suitable adhesive to the microneedles to solve this problem.
Pvc k-90 is a binder that is widely used in pharmaceutical formulations and is commonly used in solid formulations. The powder can also be directly added into other powder in dry state for mixing, then added with water, alcohol or water-alcohol solution and the like for granulating, and in oral or parenteral administration, the pvp k-90 can also be used as a solubilizer for accelerating the dissolution of insoluble drugs from a solid preparation. In addition, a solution of pvp k-90 can also be used as a coating material.
The prescription adjusted according to example 1 is as follows:
The preparation method adopted by the prescription comprises the following steps: adding a proper amount of deionized water into a beaker, adding 10mg of deoxycholic acid solid dispersion powder, 30mg of chitosan, 5mg of hyaluronic acid and 1.5mgpvp k-90 into a small bottle, and dissolving with 1.5mL of deionized water; adding a stirrer, stirring on an instrument for 3.5 hours, and then carrying out ultrasonic treatment and standing for 2 hours; putting the dissolved substance into a mould, and centrifuging for 4 times at 3000rpm for 15 minutes each time; taking out the die, and adding the dissolved matters again until small bulges are formed; oven drying at 37deg.C for about 24 hr, and taking out the microneedle.
Example 5:
In order to further increase the hardness of the soluble microneedle array patch prepared according to example 1, the concentration of pvp k-90 was selected to be increased by avoiding breakage of the needle tip during use, which may not successfully puncture the skin mucosa barrier and exert the drug effect.
The solution of the pvp k-90 with a series of gradient concentrations is prepared and added into a microneedle mould, and the concentrations of the pvp k-90 are 0mg, 2mg/mL, 3.3mg/mL, 4.67mg/mL, 6mg/mL and 7.33mg/mL in sequence, and at the moment, the addition amount of each of the gradient concentrations corresponding to the pvp k-90 is 0mg, 3mg, 5mg, 7mg, 9mg and 11mg. And drying under the same condition to obtain a series of blank microneedles with gradient concentration of pvp k-90. By applying the same amount of force, we found that, over a range, the hardness of the microneedle increased with increasing pvp k-90 concentration. In addition, the viscosity of the mixed solution is too high, the fluidity is poor, and the molding is difficult. The optimum concentration of pvp k-90 was found to be 6mg/mL.
The prescription adjusted according to example 1 is as follows:
The preparation method adopted by the prescription comprises the following steps: adding a proper amount of deionized water into a beaker, adding deoxycholic acid solid dispersion powder, 30mg of chitosan, 5mg of hyaluronic acid and pvp k-90 with gradient mass into a small bottle, and dissolving with 1.5mL of deionized water; adding a stirrer, stirring on an instrument for 3.5 hours, and then carrying out ultrasonic treatment and standing for 2 hours; putting the dissolved substance into a mould, and centrifuging for 4 times at 3000rpm for 15 minutes each time; taking out the die, and adding the dissolved matters again until small bulges are formed; oven-drying at 37deg.C for 24 hr, and taking out the micropins.
Example 6:
The soluble microneedle array patch prepared according to example 5 was tested for mechanical strength and drug loading capacity.
To demonstrate the uniform distribution of deoxycholic acid solid dispersion powder on the needle tip, we performed fluorescent tracing of deoxycholic acid solid dispersion powder using FITC fluorescent staining and observations under confocal microscope. It can be seen that deoxycholic acid is evenly distributed on each tip of the microneedle array.
The mechanical strength of the soluble microneedle patch was evaluated using a extensometer. The bottom of the microneedle patch is firmly fixed to a metal plate, while the tip of the microneedle patch is pressed vertically by a stainless steel cylindrical probe with a head. The force values were recorded continuously until the displacement reached 460 μm. Compressive strength was calculated from the slope of the stress-strain curve. The results are shown in FIG. 2, and the tips of the microneedles have good mechanical strength by analysis.
Example 7:
The soluble microneedle array patch prepared according to example 5, although deoxycholic acid solid dispersion powder had good mechanical strength in the microneedle patch, a series of tests were required to verify its transdermal function. By calculating the drug carrying capacity of the soluble microneedle patch, a simulation image of the drug diffusion through the skin and a 3D simulation result of transdermal drug delivery were simulated by using computer COMSOL 6.0 software, as shown in FIG. 3. The insertion depth of the dissolvable microneedle patch was set at 407 μm. Assuming that the initial concentration of deoxycholic acid solid dispersion powder per injection is 1.43×10 -4mol/m3, the ratio of the drug dose per injection to the volume is calculated. Simulation results indicate that diffusion of the drug from a single needle tip results in a rapid increase in the amount of drug released into the skin. Furthermore, three-dimensional simulations of transdermal drug delivery using a single needle tip indicate that a larger insertion volume results in more drug release into the skin. These findings highlight the ability of the soluble microneedle patch to ensure the amount and rate of transdermal delivery of deoxycholic acid solid dispersion powder.
Claims (10)
1. A soluble microneedle patch containing deoxycholic acid, which is characterized by comprising a microneedle substrate and a soluble microneedle body, wherein the soluble microneedle body is made of a biocompatible material, and the soluble microneedle body contains deoxycholic acid solid dispersion powder; the biocompatible material is one or more of chitosan, hyaluronic acid or pvc k-90.
2. The soluble microneedle patch containing deoxycholic acid according to claim 1, wherein the soluble microneedle patch is composed of a deoxycholic acid solid dispersion powder comprising the following components in weight ratio: chitosan = 1:3; the specific formula is as follows:
Deoxycholic acid solid dispersion powder 10mg;
30mg of chitosan;
deionized water 1.5mL.
3. The soluble microneedle patch containing deoxycholic acid according to claim 2, wherein the soluble microneedle patch is composed of a deoxycholic acid solid dispersion powder comprising the following components in weight ratio: chitosan: hyaluronic acid = 1:3: (0.2-2.5); the specific formula is as follows:
4. The soluble microneedle patch containing deoxycholic acid according to claim 2, wherein the soluble microneedle patch is composed of a deoxycholic acid solid dispersion powder comprising the following components in weight ratio: chitosan: hyaluronic acid = 1:3:0.5: (0.1 to 1.1); the specific formula is as follows:
5. The method for preparing a soluble microneedle patch containing deoxycholic acid according to any one of claims 1 to 4, comprising the steps of:
(1) And (3) putting deoxycholic acid into a round-bottomed flask containing an ethanol aqueous solution, carrying out ultrasonic treatment until the deoxycholic acid is completely dissolved, carrying out rotary evaporation, carrying out air drying at room temperature, and then grinding to obtain uniform powder.
(2) Dissolving deoxycholic acid solid dispersion powder and a biocompatible material obtained in the step (1) by deionized water;
(3) Stirring, and then carrying out ultrasonic treatment and standing;
(4) Filling the solution which is subjected to standing in the step (3) into a mould, and centrifuging;
(5) Adding the solution which is subjected to standing in the step (3) into a mould again until small bulges are formed;
(6) And (5) drying the product obtained in the step (5), and demoulding after drying to obtain the microneedle.
6. The preparation method according to claim 5, wherein the ratio of deoxycholic acid solid dispersion powder to biocompatible material in the step (2) is 1 (3-5.5) by mass; the pH value of the deionized water is 7.
7. The method according to claim 5, wherein the stirring time in the step (3) is 3 to 4 hours.
8. The method according to claim 5, wherein in the step (4), the centrifugation speed is 3000 to 4000rpm, the number of times of centrifugation is 4 to 6, and the time of each centrifugation is about 10 to 15 minutes.
9. The method according to claim 5, wherein in the step (6), the drying temperature is 35 to 40 ℃ and the drying time is 24 to 30 hours.
10. Use of a deoxycholic acid-containing soluble microneedle patch of claim 1 for the manufacture of a medicament for reducing facial and neck fat accumulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410584303.6A CN118490615A (en) | 2024-05-11 | 2024-05-11 | Soluble microneedle patch containing deoxycholic acid and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410584303.6A CN118490615A (en) | 2024-05-11 | 2024-05-11 | Soluble microneedle patch containing deoxycholic acid and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118490615A true CN118490615A (en) | 2024-08-16 |
Family
ID=92230643
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410584303.6A Pending CN118490615A (en) | 2024-05-11 | 2024-05-11 | Soluble microneedle patch containing deoxycholic acid and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118490615A (en) |
-
2024
- 2024-05-11 CN CN202410584303.6A patent/CN118490615A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Al-Japairai et al. | Current trends in polymer microneedle for transdermal drug delivery | |
| CN109528695B (en) | Microneedle transdermal drug delivery patch for treating rheumatoid arthritis and preparation method thereof | |
| AU2012247089B2 (en) | Microneedle assembly formulation for skin treatment | |
| US9675789B2 (en) | Embeddable micro-needle patch for transdermal drug delivery and method of manufacturing the same | |
| CN113133991B (en) | Colchicine soluble microneedle patch and preparation method thereof | |
| EP3117867B1 (en) | Micro-needle preparation administration member for intradermal placement of target substance and apparatus for rapid administration of micro-needle preparation | |
| WO2006063350A2 (en) | Compositions and methods for treating conditions of the nail unit | |
| EP2037880A2 (en) | Compositions and methods for treating conditions of the nail unit | |
| JP2023502519A (en) | Microneedle patches for immunostimulatory drug delivery | |
| JP2024500424A (en) | Insoluble transdermal microneedle patch and its preparation method and application | |
| CN110664787A (en) | Dexmedetomidine slow release microneedle array and preparation method thereof | |
| Gopan et al. | The use of cellulose, chitosan and hyaluronic acid in transdermal therapeutic management of obesity: A review | |
| CN114569583A (en) | Rapid separation type liposome composite sustained-release microneedle and preparation method thereof | |
| CN114948852B (en) | Microneedle system for brain disease diagnosis and treatment and preparation method thereof | |
| CN118490615A (en) | Soluble microneedle patch containing deoxycholic acid and preparation method and application thereof | |
| CN115737534A (en) | Composite microneedle patch based on silk fibroin and preparation method thereof | |
| Mao et al. | Fabrication of lidocaine-loaded polymer dissolving microneedles for rapid and prolonged local anesthesia | |
| WO2023092644A1 (en) | Composition having analgesic effect and application of composition, and microneedle patch and preparation method therefor | |
| Liu et al. | Recent advances and perspectives of microneedles as transdermal delivery vehicles for analgesic medications | |
| CN109925297A (en) | Transdermal delivery system and its preparation method and application containing aconitine | |
| CN116712665A (en) | Photothermal-chemotherapy combined therapeutic agent and preparation method and application thereof | |
| Sang et al. | A hyaluronic acid-based dissolving microneedle patch loaded with 5-aminolevulinic acid for improved oral leukoplakia treatment | |
| CN116350747A (en) | Zironoi peptide nano-microneedle and preparation method thereof | |
| CN118141744A (en) | Drug-loaded microneedle for treating sarcopenia and preparation method thereof | |
| CN118021705A (en) | Microneedle submucosa controlled release drug delivery system and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |