CN118078730A - Soluble microneedle patch for enhancing hydrophobic drug loading by amino acid coordination assembly and preparation and application thereof - Google Patents
Soluble microneedle patch for enhancing hydrophobic drug loading by amino acid coordination assembly and preparation and application thereof Download PDFInfo
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- CN118078730A CN118078730A CN202410224085.5A CN202410224085A CN118078730A CN 118078730 A CN118078730 A CN 118078730A CN 202410224085 A CN202410224085 A CN 202410224085A CN 118078730 A CN118078730 A CN 118078730A
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- Prior art keywords
- hydrophobic drug
- histidine
- zinc ion
- complex
- microneedle patch
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Links
- 230000002209 hydrophobic effect Effects 0.000 title claims abstract description 103
- 239000003814 drug Substances 0.000 title claims abstract description 64
- 229940079593 drug Drugs 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000011068 loading method Methods 0.000 title abstract description 8
- 150000001413 amino acids Chemical class 0.000 title abstract description 6
- 230000002708 enhancing effect Effects 0.000 title abstract description 4
- 239000011701 zinc Substances 0.000 claims abstract description 67
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 65
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims abstract description 63
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229940109262 curcumin Drugs 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 235000012754 curcumin Nutrition 0.000 claims abstract description 31
- 239000004148 curcumin Substances 0.000 claims abstract description 31
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims abstract description 31
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 claims abstract description 23
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 claims abstract description 23
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229960001285 quercetin Drugs 0.000 claims abstract description 23
- 235000005875 quercetin Nutrition 0.000 claims abstract description 23
- 201000004384 Alopecia Diseases 0.000 claims abstract description 22
- 239000011159 matrix material Substances 0.000 claims abstract description 16
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 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 group 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 34
- 229920002674 hyaluronan Polymers 0.000 claims description 34
- 229960003160 hyaluronic acid Drugs 0.000 claims description 34
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 22
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 22
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 22
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 235000011187 glycerol Nutrition 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 201000002996 androgenic alopecia Diseases 0.000 claims description 8
- 150000003751 zinc Chemical class 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 231100000360 alopecia Toxicity 0.000 abstract description 11
- 241000699670 Mus sp. Species 0.000 abstract description 8
- 229940088597 hormone Drugs 0.000 abstract description 8
- 239000005556 hormone Substances 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 238000013271 transdermal drug delivery Methods 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 39
- 239000007864 aqueous solution Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- OHDRQQURAXLVGJ-HLVWOLMTSA-N azane;(2e)-3-ethyl-2-[(e)-(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound [NH4+].[NH4+].S/1C2=CC(S([O-])(=O)=O)=CC=C2N(CC)C\1=N/N=C1/SC2=CC(S([O-])(=O)=O)=CC=C2N1CC OHDRQQURAXLVGJ-HLVWOLMTSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical group [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 12
- 210000003491 skin Anatomy 0.000 description 9
- 210000003780 hair follicle Anatomy 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 206010068168 androgenetic alopecia Diseases 0.000 description 6
- 235000005074 zinc chloride Nutrition 0.000 description 6
- 239000011592 zinc chloride Substances 0.000 description 6
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 5
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 210000004209 hair Anatomy 0.000 description 5
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 5
- 229960000907 methylthioninium chloride Drugs 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 230000002292 Radical scavenging effect Effects 0.000 description 4
- 230000003779 hair growth Effects 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 3
- 229960003473 androstanolone Drugs 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 239000012466 permeate Substances 0.000 description 3
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
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- 238000006243 chemical reaction Methods 0.000 description 2
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- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 210000004207 dermis Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 208000024963 hair loss Diseases 0.000 description 2
- 230000003676 hair loss Effects 0.000 description 2
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 2
- -1 hydroxyl radicals Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 210000000434 stratum corneum Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 208000024556 Mendelian disease Diseases 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000001548 androgenic effect Effects 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
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- 230000002951 depilatory effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- QKUSRAKPUWQSJS-UHFFFAOYSA-N diazanium 3-ethyl-2H-1,3-benzothiazole-6-sulfonate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)C1=CC=C2N(CC)CSC2=C1.[O-]S(=O)(=O)C1=CC=C2N(CC)CSC2=C1 QKUSRAKPUWQSJS-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910001448 ferrous ion Inorganic materials 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000007760 free radical scavenging Effects 0.000 description 1
- 230000003803 hair density Effects 0.000 description 1
- 230000003660 hair regeneration Effects 0.000 description 1
- 230000003659 hair regrowth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000007425 progressive decline Effects 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Preparation (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Chemistry (AREA)
Abstract
The invention provides a soluble microneedle patch for enhancing hydrophobic drug loading by amino acid coordination assembly and preparation and application thereof, and relates to the technical field of transdermal drug delivery. The hydrophobic drug-zinc ion-histidine complex provided by the invention is formed by assembling a hydrophobic drug, zinc ions and Fmoc-histidine in a coordination manner, wherein the hydrophobic drug is curcumin or quercetin. The hydrophobic drug-zinc ion-histidine complex provided by the invention effectively improves the water solubility of the drug and can enhance the load of the hydrophobic drug. The invention provides a soluble microneedle patch, which comprises a back lining and a plurality of needle bodies combined on the surface of the back lining, wherein each needle body comprises a needle body matrix and the hydrophobic drug-zinc ion-histidine complex dispersed in the needle body matrix. The hydrophobic drug-zinc ion-histidine complex provided by the invention combines the advantage of transdermal drug delivery of a microneedle, is beneficial to further play a role of the complex, and shows excellent effect in treating male hormone alopecia of mice.
Description
Technical Field
The invention relates to the technical field of transdermal drug delivery, in particular to a soluble microneedle patch for enhancing hydrophobic drug loading by amino acid coordination assembly, and preparation and application thereof.
Background
Androgenetic alopecia (AGA), also known as seborrheic alopecia, is a hereditary disease that is manifested by progressive decrease in hair density due to disorder of microenvironment around hair follicles caused by oxidative stress and insufficient vascularization, but is the most common type of alopecia in clinic in men and women. Hair is an important component of the appearance of a person, and although hair loss does not cause serious harm to the physical health of the patient, it can bring psychological burden to the person, affecting the personal appearance, mental health and quality of life of the patient. The prior AGA treatment methods are limited, mainly comprise drug injection, operation, minoxidil application, finasteride oral administration and the like, but the operation has strong pain, and professional is required to operate, the drug application mode has poor compliance, the actual utilization rate is low, and the long-term drug administration has the first pass effect of the liver and has certain defects.
Curcumin (Cur) and quercetin (Que) are natural compounds and have good anti-inflammatory, antioxidant, anti-aging and free radical scavenging properties, but curcumin and quercetin have poor water solubility and stability, are fast in metabolism, have low in-vivo utilization rate and are limited in practical application. Although topical application of curcumin, quercetin has potential benefits for skin diseases, due to its strong hydrophobicity, it has poor permeability to skin, requiring higher dosage for achieving a certain therapeutic effect.
Disclosure of Invention
In view of the above, the present invention aims to provide a soluble microneedle patch with enhanced hydrophobic drug loading by amino acid coordination assembly, and preparation and application thereof. The hydrophobic drug-zinc ion-histidine complex provided by the invention can effectively improve the water solubility of curcumin and quercetin, enhance the load of curcumin and quercetin, effectively permeate the curcumin and quercetin into hair follicle areas, and promote hair growth.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a hydrophobic drug-zinc ion-histidine complex, which is formed by assembling a hydrophobic drug, zinc ions and Fmoc-histidine in a coordination manner, wherein the hydrophobic drug is curcumin or quercetin.
Preferably, the mass ratio of the hydrophobic drug, the zinc ion and the Fmoc-histidine is 1:0.067 (1-8).
The invention provides a preparation method of the hydrophobic drug-zinc ion-histidine complex, which comprises the following steps:
Mixing the hydrophobic drug, zinc salt, fmoc-histidine and alcohol-water solvent, and carrying out coordination assembly to obtain the hydrophobic drug-zinc ion-histidine complex.
Preferably, when the hydrophobic drug is curcumin, the pH value of the mixed solution obtained by mixing is 6-9; when the hydrophobic drug is quercetin, the pH value of the mixed solution obtained by mixing is 7-9.
Preferably, the temperature of the coordination assembly is room temperature and the time is 2-3 h.
The invention provides a soluble microneedle patch, which comprises a back lining and a plurality of needle bodies combined on the surface of the back lining, wherein each needle body comprises a needle body matrix and hydrophobic drug-zinc ion-histidine complexes dispersed in the needle body matrix; the needle matrix is hyaluronic acid, and the hydrophobic drug-zinc ion-histidine complex is the hydrophobic drug-zinc ion-histidine complex prepared by the technical scheme or the preparation method.
Preferably, the ingredients of the backing include polyvinylpyrrolidone and glycerin, the mass of the glycerin being 15-30% of the mass of polyvinylpyrrolidone.
Preferably, the molecular weight of the hyaluronic acid is 5kD or 400-800 kD, and the mass ratio of the hydrophobic drug-zinc ion-histidine complex to the hyaluronic acid in the needle body is (1-40): 800.
The invention provides a preparation method of the soluble microneedle patch, which comprises the following steps:
mixing the hydrophobic drug-zinc ion-histidine complex with hyaluronic acid and water, placing the obtained mixed solution into a microneedle mould, drying, and assembling the obtained needle body with a back lining to obtain the soluble microneedle patch.
The invention provides the application of the hydrophobic drug-zinc ion-histidine complex or the soluble microneedle patch in the preparation of drugs or medical instruments for treating androgenetic alopecia.
The invention provides a hydrophobic drug-zinc ion-histidine complex, which is formed by assembling a hydrophobic drug, zinc ions and Fmoc-histidine in a coordination manner, wherein the hydrophobic drug is curcumin or quercetin. According to the invention, zinc ions and histidine with Fmoc groups are combined with the hydrophobic drug curcumin or quercetin, the histidine with Fmoc groups can coordinate with zinc, meanwhile, pi-pi interaction between aromatic rings of the Fmoc groups enables the structure to be more stable, and the water solubility of the material is effectively improved, so that the hydrophobic drug load can be enhanced, the material can effectively permeate into hair follicle areas, and the anti-oxidation capability of curcumin and quercetin and the angiogenesis promotion capability of zinc ions are utilized, so that hair follicle microenvironment is improved, male hormone alopecia is effectively relieved, and hair growth is promoted. In addition, the hydrophobic drug-zinc ion-histidine complex provided by the invention can be uniformly dispersed at the needle tip of the microneedle, and released to the deep skin after dissolution to play a role.
The preparation method of the hydrophobic drug-zinc ion-histidine complex provided by the technical scheme is simple in process and can be carried out at normal temperature, so that the damage of high-temperature preparation conditions to the structure of the hydrophobic drug is avoided, and meanwhile, the good oxidation resistance of the hydrophobic drug is maintained.
The invention provides a soluble microneedle patch, which comprises a back lining and a plurality of needle bodies combined on the surface of the back lining, wherein each needle body comprises a needle body matrix and hydrophobic drug-zinc ion-histidine complexes dispersed in the needle body matrix; the needle matrix is hyaluronic acid, and the hydrophobic drug-zinc ion-histidine complex is the hydrophobic drug-zinc ion-histidine complex prepared by the technical scheme or the preparation method. In the invention, the hydrophobic drug-zinc ion-histidine complex has good dispersibility and stability in aqueous solution, can be uniformly dispersed at the needle tip of a microneedle, enhances the load of the hydrophobic drug, has excellent oxidation resistance and good biocompatibility, can be released to deep skin after dissolution to play a role, and can promote angiogenesis and regulate oxidative stress so as to treat male hormone alopecia; the needle matrix adopts hyaluronic acid with good biocompatibility and oxidation resistance, so that the microneedle has enough mechanical strength, can penetrate the skin and can deeply deliver medicines. Therefore, the soluble microneedle patch provided by the invention can effectively regulate the hair follicle microenvironment of patients suffering from male hormone alopecia, promote hair regeneration, and improve the current situations that the absorption efficiency of the hydrophobic drugs curcumin and quercetin is low and the effects are difficult to play in the anti-alopecia treatment process.
The invention provides the application of the hydrophobic drug-zinc ion-histidine complex or the soluble microneedle patch in the preparation of drugs or medical instruments for treating androgenetic alopecia. The results of the examples show that the hydrophobic drug-zinc ion-histidine complex provided by the invention combines the advantages of transdermal drug delivery by a microneedle, is beneficial to the further function of the complex, and shows excellent effects in treating male hormone alopecia of mice.
Drawings
FIG. 1 is a schematic flow chart of the process for preparing a soluble microneedle patch according to the present invention;
FIG. 2 is an ultraviolet absorbance spectrum of curcumin (Cur) and curcumin-zinc ion-histidine Complex (CZF) in example 1;
FIG. 3 is a graph showing the effect of the water solubility test of curcumin (Cur) and curcumin-zinc ion-histidine Complex (CZF) in example 1;
FIG. 4 is a graph showing the effect of water solubility test of quercetin (Que) and quercetin-zinc ion-histidine complex (QZF) in example 2;
FIG. 5 is a physical diagram of a Blank microneedle (Blank-MNs), a loaded CZF microneedle (CZF-MNs), and a loaded QZF microneedle (QZF-MNs) prepared in example 3;
FIG. 6 is an ultraviolet absorbance spectrum of CZF in vitro ABTS + radical scavenging prepared in example 1;
FIG. 7 is an ultraviolet absorbance spectrum of CZF in vitro hydroxyl radical scavenging prepared in example 1;
FIG. 8 is a comparison photograph of the model group and CZF-MNs group promoting hair regrowth in male hormone hair loss model mice.
Detailed Description
The invention provides a hydrophobic drug-zinc ion-histidine complex, which is formed by assembling a hydrophobic drug, zinc ions and Fmoc-histidine in a coordination manner, wherein the hydrophobic drug is curcumin or quercetin.
In the invention, the mass ratio of the hydrophobic drug, the zinc ion and the Fmoc-histidine is preferably 1:0.067 (1-8), and can be specifically 1:0.067:1, 1:0.067:2, 1:0.067:4, 1:0.067:6 and 1:0.067:8. In the present invention, when the hydrophobic drug is curcumin, the mass ratio of the hydrophobic drug, zinc ion and Fmoc-histidine is further preferably 1:0.067:2; when the hydrophobic drug is quercetin, the mass ratio of the hydrophobic drug, zinc ions and Fmoc-histidine is further preferably 1:0.067:1.
According to the invention, histidine with Fmoc group is introduced, the histidine can coordinate with zinc, and meanwhile, pi-pi interaction between aromatic rings of Fmoc group enables the structure to be more stable, so that the water solubility of the material is effectively improved, and the dispersibility of the material in physiological environment is remarkably improved. Therefore, the medicine can enhance the load of the hydrophobic medicine, effectively permeate into the hair follicle area, and effectively relieve the male hormone alopecia and promote the hair growth by utilizing the anti-inflammatory, antioxidant and angiogenesis promoting effects of the hydrophobic medicine-zinc ion-histidine complex.
The invention provides a preparation method of the hydrophobic drug-zinc ion-histidine complex, which comprises the following steps:
Mixing the hydrophobic drug, zinc salt, fmoc-histidine and alcohol-water solvent, and carrying out coordination assembly to obtain the hydrophobic drug-zinc ion-histidine complex.
In the present invention, unless otherwise specified, all the materials involved are commercially available products well known to those skilled in the art.
In the invention, the zinc salt is preferably zinc chloride, and the dosage of the hydrophobic drug, the zinc salt and the Fmoc-histidine is based on the fact that the mass ratio of the hydrophobic drug, the zinc ions and the Fmoc-histidine is 1:0.067 (1-8). In the invention, the alcohol in the alcohol-water solvent is preferably ethanol or methanol, the volume ratio of the alcohol to the water in the alcohol-water solvent is preferably 1:9-1:19, and the alcohol-water is used in an amount which is based on the condition that each component is fully dispersed or dissolved.
In the present invention, when the hydrophobic drug is curcumin, the pH of the mixed solution obtained by the mixing is preferably 6 to 9, more preferably 7; when the hydrophobic drug is quercetin, the pH of the mixed solution obtained by the mixing is preferably 7 to 9, more preferably 8.
In the present invention, the mixing method is preferably:
preparing an alcohol solution of the hydrophobic drug, an aqueous solution of zinc salt and a hydrochloric acid solution of Fmoc-histidine;
Dispersing the alcohol solution of the hydrophobic drug in water, slowly adding the aqueous solution of zinc chloride under the stirring condition, adjusting the pH value of the solution, and stirring for 1h in a dark place; and adding the hydrochloric acid solution of Fmoc-histidine into the mixture, and adjusting the pH value of the solution again.
In the present invention, the adjustment of the pH value of the solution and the readjustment of the pH value of the solution are both performed so as to adjust the pH value of the solution to satisfy the above-mentioned pH value range. In the present invention, the alcohol solution of the hydrophobic drug is preferably a methanol solution or an ethanol solution of the hydrophobic drug, and the concentration of the alcohol solution of the hydrophobic drug is preferably 5mg/mL. In the present invention, the concentration of the aqueous solution of zinc salt is preferably 1.4mg/mL, and the concentration of the hydrochloric acid solution of Fmoc-histidine is preferably 5mg/mL. In the invention, the alcohol solution of the hydrophobic drug, the water solution of the zinc salt and the hydrochloric acid solution of Fmoc-histidine are used in an amount which satisfies the mass ratio of the hydrophobic drug, zinc ions and Fmoc-histidine of 1:0.067 (1-8).
In the invention, the temperature of the coordination assembly is preferably room temperature, and the time is preferably 2-3 h; the coordination assembly is preferably carried out under light-proof and stirring conditions. Taking the hydrophobic drug as curcumin as an example, the conjugated beta-diketone structure in the curcumin structure is easy to coordinate with zinc ions, meanwhile, the imidazole group of histidine is also a good ligand of Zn ions, meanwhile, curcumin contains a plurality of benzene rings, hydrophobic-hydrophobic interactions exist between the curcumin and the curcumin, hydrophobic-hydrophilic interactions exist with hydrophobic groups on amino acid derivatives, and a complex aggregate of Zn ions, curcumin and amino acid derivatives is finally obtained through a plurality of non-covalent interactions and cooperation.
After the self-assembly is completed, the invention preferably collects the precipitate by centrifugation to obtain the hydrophobic drug-zinc ion-histidine complex.
The invention provides a soluble microneedle patch, which comprises a back lining and a plurality of needle bodies combined on the surface of the back lining, wherein each needle body comprises a needle body matrix and hydrophobic drug-zinc ion-histidine complexes dispersed in the needle body matrix; the needle matrix is hyaluronic acid, and the hydrophobic drug-zinc ion-histidine complex is the hydrophobic drug-zinc ion-histidine complex prepared by the technical scheme or the preparation method.
In the present invention, the needle matrix is hyaluronic acid, the molecular weight of the hyaluronic acid is preferably 5kD or 400-800 kD, more preferably 5kD, and the needle formed by the hyaluronic acid with the molecular weight of 5kD has better skin penetration capability. In the present invention, the mass ratio of the hydrophobic drug-zinc ion-histidine complex to hyaluronic acid in the needle is (1-40): 800, more preferably (3-10): 800. In the invention, the hydrophobic drug-zinc ion-histidine complex has good dispersibility, can better maintain the structures of curcumin and quercetin, can be uniformly dispersed in the microneedle, and is beneficial to subcutaneous drug delivery and drug effect. In the embodiment of the invention, the needles in the soluble microneedle patch form a microneedle array of 15×15, the distance between adjacent needles is 800 μm, each needle is in the shape of a rectangular pyramid, the needle length is 900 μm, the side length of a pyramid base is 400 μm, and the loading amount of the hydrophobic drug-zinc ion-histidine complex in the soluble microneedle patch is 0.1-4 mg.
In the present invention, the components of the backing preferably include polyvinylpyrrolidone (PVP) having a molecular weight of preferably 50kD and glycerin having a mass of preferably 15 to 30% and more preferably 20 to 25% of the mass of polyvinylpyrrolidone. In the present invention, the thickness of the backing is preferably 1mm. According to the invention, polyvinylpyrrolidone is used as a main body material of the back lining, and a certain proportion of glycerin is doped to provide flexibility, so that the obtained back lining is soft and easy to attach, and is suitable for attaching curved interfaces such as scalp and skin.
Microneedles (MNs) as a transdermal delivery means can penetrate the stratum corneum of the skin without touching the dermis layer, thus being almost painless, and there are currently many modes of metallic microneedles, coated microneedles, hollow microneedles, soluble microneedles, etc. Wherein, the metal micro-needle is generally formed into micropores through the needle body, then the medicine is smeared, the steps are complicated, and the risk of breakage of the needle body exists; the coated microneedle is sprayed on the surface of the needle body to load the drug, and the drug loading rate is generally low; hollow microneedles are more complex to operate, just like a small syringe. The soluble micro-needle can release the medicine through the dissolution of the needle body, and has simple operation and high loading rate, thereby receiving wide attention of people. The needle body material of the soluble microneedle patch provided by the invention adopts hyaluronic acid with good biocompatibility and oxidation resistance, the prepared microneedle patch has enough mechanical strength, the needle body is soluble, the hydrophobic drug-zinc ion-histidine complex can be directly delivered to the deep part of the skin, the microneedle can reach the upper dermis through the epidermis layer of the skin to realize the minimally invasive and minimally painful administration mode, subcutaneous accurate administration is realized, and simultaneously, the generation of blood vessels can be stimulated through mechanical stimulation caused by the penetration of the microneedle, thereby being beneficial to remodeling the hair follicle microenvironment. When the soluble microneedle patch provided by the invention is used, the patch is simple and easy to operate, the material has good biocompatibility and oxidation resistance, and the hair can be regenerated by adjusting the microenvironment around the hair follicle to help the hair enter the growing period from the resting period.
The invention provides a preparation method of the soluble microneedle patch, which comprises the following steps:
mixing the hydrophobic drug-zinc ion-histidine complex with hyaluronic acid and water, placing the obtained mixed solution into a microneedle mould, drying, and assembling the obtained needle body with a back lining to obtain the soluble microneedle patch (MNs).
The flow of the process of preparing a dissolvable microneedle patch according to the present invention is shown in fig. 1.
The hydrophobic drug-zinc ion-histidine complex is preferably dispersed in water, and the resulting complex dispersion is mixed with hyaluronic acid. In the invention, the mass content of the hyaluronic acid in the mixed solution is preferably 10-40%, more preferably 20%, and the amount of the hydrophobic drug-zinc ion-histidine complex and the hyaluronic acid is preferably 20% so as to satisfy the condition that the mass ratio of the hydrophobic drug-zinc ion-histidine complex to the hyaluronic acid in the needle body is (1-40): 800. The present invention is not particularly limited to the microneedle mould, and a microneedle mould which satisfies the size requirements of the microneedles, which are well known to those skilled in the art, may be used. The present invention preferably allows the resulting mixture to enter the micro-wells of the microneedle mould under vacuum or centrifugation conditions and fills the tips with the mixture. In the present invention, the temperature of the drying is preferably 50 ℃, the time is preferably 5min, and the drying is preferably performed in a forced air oven.
In the present invention, the method for preparing the backing preferably comprises: mixing polyvinylpyrrolidone water solution with glycerol, placing the obtained backing mixed solution into a backing mould, and drying to obtain the backing.
In the present invention, the mass content of polyvinylpyrrolidone in the polyvinylpyrrolidone aqueous solution is preferably 20%, and the amount of the polyvinylpyrrolidone aqueous solution and the amount of glycerin are such that the mass of glycerin is 15 to 30% of the mass of polyvinylpyrrolidone. The present invention is not particularly limited to the backing mold, and may employ a corresponding mold known to those skilled in the art. In the present invention, the temperature of the drying is preferably room temperature, and the backing mixed solution is preferably additionally added during the drying to obtain a backing of a desired thickness.
In the present invention, the backing is preferably prepared in advance, and the preparation time period can be reduced by 5 to 9 hours by preparing the backing in advance.
In the present invention, the method of assembly is preferably: and (3) coating a polyvinylpyrrolidone aqueous solution on the surface of a microneedle mould of the needle body, then attaching the back lining to the microneedle mould, and drying to obtain the soluble microneedle patch. In the invention, the mass content of polyvinylpyrrolidone in the polyvinylpyrrolidone aqueous solution is preferably 20%; the drying temperature is preferably room temperature and the drying time is preferably 3 hours. After the assembly, the bases of the respective needle bodies are formed in the same plane and are integral.
The invention provides the application of the hydrophobic drug-zinc ion-histidine complex or the soluble microneedle patch in the preparation of drugs or medical instruments for treating androgenetic alopecia. The method of application of the present invention is not particularly limited, and may be applied by methods well known to those skilled in the art. The hydrophobic drug-zinc ion-histidine complex and the soluble microneedle patch provided by the invention can enhance the load of the hydrophobic drug, promote hair growth and treat male hormone alopecia.
To further illustrate the present invention, the following describes in detail the amino acid coordinated assembly enhanced hydrophobic drug loaded soluble microneedle patches provided herein, and their preparation and use, with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Preparation of curcumin-zinc ion-histidine Complex (CZF):
An ethanol solution of curcumin (Cur) at a concentration of 5mg/mL, an aqueous solution of zinc chloride at a concentration of 1.4mg/mL, and a hydrochloric acid solution of Fmoc-histidine at a concentration of 5mg/mL were prepared in advance. 100. Mu.L of curcumin in ethanol solution was dispersed in 1650. Mu.L of water, 50. Mu.L of zinc chloride aqueous solution was slowly added with stable stirring, and the pH was adjusted to 7 and stirred for 1h in the absence of light. Then 200. Mu.L of Fmoc-histidine hydrochloride solution was added, the pH was adjusted to 7, and the mixture was stirred at room temperature under dark conditions for 2 hours. And centrifuging to collect precipitate to obtain curcumin-zinc ion-histidine Complex (CZF), and dispersing the curcumin-zinc ion-histidine complex in deionized water for later use.
The ultraviolet absorption spectra of curcumin before and after formation of the complex, namely, the ultraviolet absorption spectra of curcumin (Cur) and curcumin-zinc ion-histidine Complex (CZF), were tested and the results are shown in fig. 2. It can be seen that CZF presents a pronounced shoulder, indicating complex formation.
The water solubility of curcumin (Cur) and curcumin-zinc ion-histidine Complex (CZF) was tested by: 3mg of Cur and CZF were dispersed in 1.5mL of water and 1.5mL of 20wt% aqueous hyaluronic acid (molecular weight: 5 kD), respectively, and allowed to stand for 30 minutes, followed by photographing and observation. The test results are shown in FIG. 3, and Cur-HA, CZF, CZF-HA in FIG. 3 are shown in sequence, wherein Cur is dispersed in water, cur is dispersed in hyaluronic acid solution, CZF is dispersed in water, and CZF is dispersed in hyaluronic acid solution. As can be seen from fig. 3, the dispersibility in water after Cur forms the complex CZF is greatly improved, and the same uniform dispersibility is maintained even when dispersed in an aqueous solution of Hyaluronic Acid (HA).
Example 2
Preparation of quercetin-zinc ion-histidine complex (QZF):
A methanol solution of quercetin (Que) at a concentration of 5mg/mL, an aqueous solution of zinc chloride at a concentration of 1.4mg/mL, and a hydrochloric acid solution of Fmoc-histidine at a concentration of 5mg/mL were prepared in advance. 200. Mu.L of quercetin in methanol was dispersed in 1500. Mu.L of water, and 100. Mu.L of zinc chloride aqueous solution was slowly added with stable stirring, and the pH was adjusted to 8 and stirred for 1 hour under dark conditions. Then 200. Mu.L of Fmoc-histidine hydrochloride solution was added, the pH was adjusted to 8, and the mixture was stirred at room temperature under dark conditions for 2 hours. Centrifuging and collecting precipitate to obtain quercetin-zinc ion-histidine complex (QZF), and dispersing in deionized water for use.
The water solubility of quercetin (Que) and quercetin-zinc ion-histidine complex (QZF) was tested by: 3mg of Que and QZF mg of the solution were respectively dispersed in 1.5mL of water and 1.5mL of 20wt% aqueous solution of hyaluronic acid (molecular weight: 5 kD), and the mixture was allowed to stand for 30 minutes, and photographed and observed. The results of the test are shown in FIG. 4, and in FIG. 4, que and Que-HA, QZF, QZF-HA are shown in order, wherein Que is dispersed in water, que is dispersed in hyaluronic acid solution, QZF is dispersed in water, and QZF is dispersed in hyaluronic acid solution. As can be seen from fig. 4, the dispersibility in water after the Que forms the complex QZF is greatly improved, and the same uniform dispersibility is maintained even when dispersed in an aqueous solution of Hyaluronic Acid (HA).
Example 3
(1) Preparation of microneedle backings
Preparing 20% PVP (polyvinylpyrrolidone, molecular weight of 50 kD) aqueous solution, adding glycerol 20% of PVP mass, taking 400 μl of the mixed solution into a back lining mould, drying at room temperature, and adding back lining with thickness of about 1 mm.
(2) Preparation of Blank microneedles (Blank-MNs)
Selecting hyaluronic acid with molecular weight of 5kD, preparing an aqueous solution with mass concentration of 20%, taking 400 mu L to a microneedle mould, vacuumizing for 10min to fill the needle tip with the mixed solution, placing the mould in a blast oven at 50 ℃ for drying for 5min, smearing 50 mu L of 20% PVP aqueous solution, attaching the microneedle back lining prepared in the step (1) on the mould, and drying at room temperature for 3h to obtain the blank microneedle.
(3) Preparation of Supported CZF microneedles (CZF-MNs)
80Mg of hyaluronic acid (molecular weight 5 kD) was dispersed in 400. Mu.L of an aqueous solution of a complex containing 0.3mg CZF (prepared in example 1), and the resulting mixture was placed in a mold and evacuated for 10 minutes to fill the tip of the needle. And (3) placing the mould in a blast oven at 50 ℃ for drying for 5min, smearing 50 mu L of 20% PVP aqueous solution, attaching the back lining prepared in the step (1) on the mould, and drying at room temperature for 3h to obtain CZF-MNs.
(4) Preparation of Supported QZF microneedles (QZF-MNs)
80Mg of hyaluronic acid (molecular weight 5 kD) was dispersed in 400. Mu.L of an aqueous solution of a complex containing 0.3mg QZF (prepared in example 2), and the resulting mixture was placed in a mold and evacuated for 10 minutes to fill the tip of the needle. And (3) placing the mould in a blast oven at 50 ℃ for drying for 5min, smearing 50 mu L of 20% PVP aqueous solution, attaching the back lining prepared in the step (1) on the mould, and drying at room temperature for 3h to obtain QZF-MNs.
The Blank microneedle (Blank-MNs), the load CZF microneedle (CZF-MNs) and the load QZF microneedle (QZF-MNs) are all 15×15 microneedle arrays, the distance between adjacent needle bodies is 800 μm, each needle body is in the shape of a rectangular pyramid, the needle length is 900 μm, and the side length of a pyramid base is 400 μm.
FIG. 5 is a graphical representation of the Blank microneedle (Blank-MNs), load CZF microneedle (CZF-MNs) and load QZF microneedle (QZF-MNs) prepared in example 3. As can be seen from fig. 5, the microneedles are uniform in color and the complex is uniformly distributed in the needle.
The compressive strain force at 50% deformation of the Blank microneedles (Blank-MNs) was 0.15N, and the compressive strain force at 50% deformation of the loaded CZF microneedles (CZF-MNs) and loaded QZF microneedles (QZF-MNs) was further improved, more than the minimum force required to penetrate the stratum corneum (0.045N) reported in the past.
Test example 1
Evaluation of ABTS + radical scavenging by CZF prepared in example 1:
2, 2-Di-aza-bis (3-ethyl-benzothiazole-6-sulfonic acid) diammonium salt (ABTS) can be oxidized by potassium persulfate to form a free radical (ABTS +),ABTS+ has an absorption peak between 650 and 850 nm), the ABTS solution is mixed with potassium persulfate (wherein the final concentration of ABTS is 7mM, and the final concentration of potassium persulfate is 2.45 mM) and incubated overnight to obtain an activated free radical ABTS +, CZF is mixed with 50 mu L of ABTS + solution, wherein the final concentration of CZF is 100 mu g/mL, incubated for 0 to 30min, and the absorption change of ABTS + is detected.
The test results are shown in fig. 6. As can be seen from fig. 6, the absorption of ABTS + gradually decreased with increasing incubation time of CZF with ABTS +, indicating that CZF effectively scavenged ABTS + radicals.
Evaluation of CZF prepared in example 1 for hydroxyl radical scavenging:
The Fenton reaction of hydrogen peroxide with ferrous ions can occur to generate hydroxyl radicals, which can degrade Methylene Blue (MB) such that its absorption at 650nm is reduced. mu.L of MB solution with a concentration of 1mg/mL was added to CZF aqueous solutions with different concentrations (0, 50, 100, 200. Mu.g/mL), and Fe 2+/H2O2(Fe2+:0.1mM;H2O2:0.5 mM was added thereto to prepare 2mL of a mixed solution. After 5min of reaction, the change in absorption of MB was measured.
The test results are shown in fig. 7. As can be seen from fig. 7, the absorption of MB gradually recovered with increasing CZF concentration, which suggests the ability of CZF to scavenge hydroxyl radicals, CZF has great potential for use in scavenging reactive oxygen species.
Test example 2
1. Establishment of androgen alopecia mouse model
C57BL/6 (7 weeks old) male mice were anesthetized with isoflurane, a 2cm×2cm area was shaved on the backs of the mice with a pet shaver, and the depilatory cream was applied uniformly for 5min and washed with warm water. Topical application of 0.2% dihydrotestosterone solution (50% ethanol aqueous solution as solvent). 1 time a day to the end of the experiment.
2. Treatment of androgenic alopecia mice
Model group: from day 1 after dehairing, a topical application of a 0.2% strength by mass dihydrotestosterone solution (50% aqueous ethanol solution) was applied. 1 time per day to 14 days.
CZF-MNs group: from day 1 after dehairing, a topical application of a 0.2% strength by mass dihydrotestosterone solution (50% aqueous ethanol solution) was applied. A piece of CZF-MNs microneedle was pressed into the skin with finger-abdominal force on the back of the mice 1 time a day for treatment.
Photographs of the backs of the mice in the model group and CZF-MNs group were taken on days 0, 7, and 14, and as shown in FIG. 8, it was seen that the backs of the mice in the CZF-MNs group developed new hair, and that the hair was bright and dense. CZF-MNs showed excellent effects in the treatment of the androgenic mouse model of alopecia.
The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that modifications and adaptations to the present invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The hydrophobic drug-zinc ion-histidine complex is characterized by being formed by assembling a hydrophobic drug, zinc ions and Fmoc-histidine in a coordination manner, wherein the hydrophobic drug is curcumin or quercetin.
2. The hydrophobic drug-zinc ion-histidine complex according to claim 1, wherein the mass ratio of hydrophobic drug, zinc ion to Fmoc-histidine is 1:0.067 (1-8).
3. A process for the preparation of a hydrophobic drug-zinc ion-histidine complex according to claim 1 or 2, characterized in that it comprises the following steps:
Mixing the hydrophobic drug, zinc salt, fmoc-histidine and alcohol-water solvent, and carrying out coordination assembly to obtain the hydrophobic drug-zinc ion-histidine complex.
4. The method according to claim 3, wherein when the hydrophobic drug is curcumin, the pH of the mixed solution obtained by the mixing is 6 to 9; when the hydrophobic drug is quercetin, the pH value of the mixed solution obtained by mixing is 7-9.
5. The method according to claim 3 or 4, wherein the temperature of the coordination assembly is room temperature for 2 to 3 hours.
6. A dissolvable microneedle patch comprising a backing and a plurality of needles bonded to a surface of the backing, the needles comprising a needle matrix and a hydrophobic drug-zinc ion-histidine complex dispersed in the needle matrix; the needle matrix is hyaluronic acid, and the hydrophobic drug-zinc ion-histidine complex is the hydrophobic drug-zinc ion-histidine complex according to claim 1 or 2 or the hydrophobic drug-zinc ion-histidine complex prepared by the preparation method according to any one of claims 3-5.
7. The dissolvable microneedle patch of claim 6, wherein the backing comprises a composition comprising polyvinylpyrrolidone and glycerin, the glycerin being 15-30% of the mass of polyvinylpyrrolidone.
8. The soluble microneedle patch of claim 6, wherein the molecular weight of the hyaluronic acid is 5kD or 400-800 kD, and the mass ratio of the hydrophobic drug-zinc ion-histidine complex to the hyaluronic acid in the needle body is (1-40): 800.
9. The method for preparing the soluble microneedle patch according to any one of claims 6 to 8, comprising the steps of:
mixing the hydrophobic drug-zinc ion-histidine complex with hyaluronic acid and water, placing the obtained mixed solution into a microneedle mould, drying, and assembling the obtained needle body with a back lining to obtain the soluble microneedle patch.
10. Use of a hydrophobic drug-zinc ion-histidine complex as claimed in claim 1 or 2 or a soluble microneedle patch as claimed in any one of claims 6 to 8 in the manufacture of a medicament or medical device for the treatment of androgenic alopecia.
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