CN113952319A - Skeleton type transdermal patch containing buprenorphine and preparation method thereof - Google Patents
Skeleton type transdermal patch containing buprenorphine and preparation method thereof Download PDFInfo
- Publication number
- CN113952319A CN113952319A CN202111440262.6A CN202111440262A CN113952319A CN 113952319 A CN113952319 A CN 113952319A CN 202111440262 A CN202111440262 A CN 202111440262A CN 113952319 A CN113952319 A CN 113952319A
- Authority
- CN
- China
- Prior art keywords
- buprenorphine
- transdermal patch
- layer
- drug
- patch
- 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
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 title claims abstract description 60
- 229960001736 buprenorphine Drugs 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 36
- 229940079593 drug Drugs 0.000 claims abstract description 23
- 239000003961 penetration enhancing agent Substances 0.000 claims abstract description 10
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 239000010410 layer Substances 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000011241 protective layer Substances 0.000 claims description 18
- -1 polybutylene Polymers 0.000 claims description 14
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims description 7
- 239000000853 adhesive Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- JOOXCMJARBKPKM-UHFFFAOYSA-N 4-oxopentanoic acid Chemical compound CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 6
- 239000011159 matrix material Substances 0.000 claims description 6
- 229960002622 triacetin Drugs 0.000 claims description 6
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 claims description 5
- 239000004698 Polyethylene Substances 0.000 claims description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052782 aluminium Inorganic materials 0.000 claims description 5
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 5
- 239000011248 coating agent Substances 0.000 claims description 5
- 238000000576 coating method Methods 0.000 claims description 5
- 238000013329 compounding Methods 0.000 claims description 5
- 238000005520 cutting process Methods 0.000 claims description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 5
- 229920000573 polyethylene Polymers 0.000 claims description 5
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 5
- 239000004800 polyvinyl chloride Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 235000010384 tocopherol Nutrition 0.000 claims description 5
- 229960001295 tocopherol Drugs 0.000 claims description 5
- 229930003799 tocopherol Natural products 0.000 claims description 5
- 239000011732 tocopherol Substances 0.000 claims description 5
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 5
- 239000004925 Acrylic resin Substances 0.000 claims description 4
- 239000004743 Polypropylene Substances 0.000 claims description 4
- 230000001070 adhesive effect Effects 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 239000011888 foil Substances 0.000 claims description 4
- 239000001087 glyceryl triacetate Substances 0.000 claims description 4
- 229920001155 polypropylene Polymers 0.000 claims description 4
- 229920001296 polysiloxane Polymers 0.000 claims description 4
- ASJCVVGLGXVRGQ-UHFFFAOYSA-N 1-butyl-2-methoxybenzene Chemical compound CCCCC1=CC=CC=C1OC ASJCVVGLGXVRGQ-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 3
- 239000004793 Polystyrene Substances 0.000 claims description 3
- 229940040102 levulinic acid Drugs 0.000 claims description 3
- 239000004745 nonwoven fabric Substances 0.000 claims description 3
- 229920001748 polybutylene Polymers 0.000 claims description 3
- 229920006267 polyester film Polymers 0.000 claims description 3
- 229920002223 polystyrene Polymers 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229920002367 Polyisobutene Polymers 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000012188 paraffin wax Substances 0.000 claims description 2
- 229920000728 polyester Polymers 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 229960004063 propylene glycol Drugs 0.000 claims description 2
- 229920002545 silicone oil Polymers 0.000 claims description 2
- 229920005992 thermoplastic resin Polymers 0.000 claims description 2
- 210000003491 skin Anatomy 0.000 abstract description 16
- 239000008280 blood Substances 0.000 abstract description 10
- 210000004369 blood Anatomy 0.000 abstract description 10
- 230000000202 analgesic effect Effects 0.000 abstract description 9
- 238000011282 treatment Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 6
- 206010040880 Skin irritation Diseases 0.000 abstract description 5
- 231100000475 skin irritation Toxicity 0.000 abstract description 5
- 230000036556 skin irritation Effects 0.000 abstract description 5
- 230000035515 penetration Effects 0.000 abstract description 4
- 230000004888 barrier function Effects 0.000 abstract description 3
- 230000035699 permeability Effects 0.000 abstract description 3
- 206010067484 Adverse reaction Diseases 0.000 abstract description 2
- 230000006838 adverse reaction Effects 0.000 abstract description 2
- 239000003640 drug residue Substances 0.000 abstract description 2
- 238000011068 loading method Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 231100000435 percutaneous penetration Toxicity 0.000 abstract description 2
- 210000000434 stratum corneum Anatomy 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 23
- 208000002193 Pain Diseases 0.000 description 18
- 230000036407 pain Effects 0.000 description 16
- 241001465754 Metazoa Species 0.000 description 11
- 239000000047 product Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 206010015150 Erythema Diseases 0.000 description 6
- 206010030113 Oedema Diseases 0.000 description 6
- 206010070834 Sensitisation Diseases 0.000 description 6
- 231100000321 erythema Toxicity 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 230000008313 sensitization Effects 0.000 description 6
- 239000012790 adhesive layer Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- 102000003840 Opioid Receptors Human genes 0.000 description 4
- 108090000137 Opioid Receptors Proteins 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 210000004209 hair Anatomy 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000006190 sub-lingual tablet Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HHKVOYUYPYZFHJ-SOFGYWHQSA-N (e)-3-(3,4-dihydroxyphenyl)-1-phenylprop-2-en-1-one Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)C1=CC=CC=C1 HHKVOYUYPYZFHJ-SOFGYWHQSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 208000030961 allergic reaction Diseases 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 229940090044 injection Drugs 0.000 description 2
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 229930003945 thebaine Natural products 0.000 description 2
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 description 2
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 1
- 241001539473 Euphoria Species 0.000 description 1
- 206010015535 Euphoric mood Diseases 0.000 description 1
- 229910001374 Invar Inorganic materials 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010039509 Scab Diseases 0.000 description 1
- 206010040849 Skin fissures Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229940111217 buprenorphine injection Drugs 0.000 description 1
- 229940044374 butrans Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N methyl phenyl ether Natural products COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229940121367 non-opioid analgesics Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003402 opiate agonist Substances 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 230000007084 physiological dysfunction Effects 0.000 description 1
- 229920001083 polybutene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000010181 skin prick test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Images
Classifications
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
-
- 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
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Abstract
The invention discloses a buprenorphine transdermal patch and a preparation method thereof. The buprenorphine transdermal patch can continuously release and keep the blood concentration stable in an effective treatment concentration, avoid the fluctuation of the peak valley of the blood concentration, reduce the adverse reaction and enhance the analgesic effect. But the penetration of buprenorphine into the skin is poor due to the barrier effect of the skin, and the physicochemical properties of buprenorphine. In order to solve the permeability problem, a penetration enhancer is usually added to reduce the resistance of the percutaneous penetration of the stratum corneum, but the patch has a complex structure and high production cost; or the area of administration may be enlarged to increase the degree of penetration, but at the same time increase the incidence of skin irritation. The buprenorphine transdermal patch currently on the market has a complex structure and low availability of active ingredients. The buprenorphine transdermal patch disclosed by the invention is simple in structure, lower in drug loading rate, less in drug residue, capable of being continuously applied for 3-7 days, and good in safety, and has a continuous and stable transdermal effect.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly designs a skeleton type transdermal patch containing buprenorphine and a preparation method thereof.
Background
Pain is a very common symptom, a precursor signal for many diseases, and a common cause of hospitalization of patients. Pain is a warning signal that encourages the body to avoid or remove the factors that cause the pain, and pain that is either strong or persistent in its protective effect can cause physiological dysfunction or even shock. In both developed and developing countries, people in excess of 1/5 are afflicted with pain, half of which reach moderate or severe levels that severely affect the quality of life of the patient. Pain relief is a fundamental benefit to patients { international pain research Institute (IASP) european pain research council (EIFC) and World Health Organization (WHO) take a japanese invar conference }, and there is increasing interest in the treatment and relief of blast pain.
WHO, for the pharmacological treatment of pain, gives recommendations for "step" medication: the pain-relieving drugs with different intensities should be selected according to the pain degree of the patient. Mild pain: non-steroidal anti-inflammatory drugs (NSAIDs) may be selected. Moderate pain: the opioid can be selected, and the non-steroidal anti-inflammatory drugs can be used together. (iii) severe pain: the strong opioid can be selected, and non-steroidal anti-inflammatory drugs can be used together.
Buprenorphine is a potent opioid drug for the treatment of severe pain, an analgesic with both opioid receptor agonistic and antagonistic activities, and a highly lipophilic drug. Buprenorphine has affinity for the mu, delta and kappa binding sites of all three opioid receptor subtypes. Buprenorphine, when modulated by opioid μ receptors, can exhibit opioid agonist activity at relatively low doses, producing effective analgesia; the analgesic effect of the buprenorphine with equal dose is about 25-50 times of that of morphine, but the analgesic effect of the buprenorphine with equal dose can reach 75-100 times of that of morphine. Buprenorphine has a high affinity for opioid receptors and a slow rate of dissociation, which determines its long-lasting analgesic properties. Opioid receptor antagonism occurs at high doses of buprenorphine.
Buprenorphine was synthesized by the british pharmacologist in the 60's 20 th century using thebaine (thebaine) as the starting material, and buprenorphine buccal tablets were marketed in switzerland by Indiviorplc in 1985, after which buprenorphine injections and sublingual tablets were widely used in clinic. Buprenorphine transdermal patches (3-day patches) developed by Grunnhal corporation on 24.7.2001 using the drug dispersion technology of Lohmann Therapie-Systeme, Inc. were marketed in Germany for the treatment of moderate to severe cancer pain and severe pain that were not responsive to non-opioid analgesia. MundiphiharmaA/S, 7 months 2003, introduced a 7-day patch for the treatment of chronic pain that was not controlled by non-opioid analgesics. Buprenorphine was approved in 1988 as an analgesic for clinical use, and its injection and sublingual tablet were marketed in 1991 and 1998, respectively. The buprenorphine transdermal patch which is originally ground in 7 months in 2013 is listed in China in 7 days, and the buprenorphine transdermal patch in 3 days is not imported in China.
Buprenorphine is administered by injection and orally, and the blood level usually rises rapidly at the initial stage of administration and then falls slowly. The peak-valley fluctuation of the blood concentration causes that the medicine can not continuously and effectively achieve the analgesic effect, the blood concentration exceeding the treatment dose is easy to cause euphoria to patients, and the analgesic effect of the blood concentration lower than the treatment dose is not good. The buprenorphine transdermal patch can continuously release and keep the blood concentration stable in an effective treatment concentration, avoids the fluctuation phenomenon of the blood concentration peak and valley caused by short-acting buprenorphine injection and sublingual tablets, reduces adverse reaction and enhances the analgesic effect. In addition, the transdermal patch improves the medication compliance of patients, is convenient to interrupt the medication at any time, can avoid the first pass effect of oral administration in the liver and the degradation of the medicament in the gastrointestinal tract, and reduces the individual difference of medication.
However, most drugs penetrate the skin barrier at a very low rate due to the barrier action of the skin. The physical and chemical properties of buprenorphine (large molecular weight, high melting point, and poor solubility in water and organic solvents) lead to poor skin penetration. In order to solve the permeability problem, a penetration enhancer is usually added to reduce the resistance of the percutaneous penetration of the stratum corneum and improve the permeability, but the patch has a complex structure and high production cost; or the transdermal degree needs to be increased by enlarging the administration area, but the skin contact area is enlarged, and the incidence rate of skin irritation is increased. Buprenorphine transdermal patches currently on the market have a relatively complex patch structure and the availability of the active ingredient is not high. If the commercial product BuTrans adopts a five-layer structure, the structure is as follows: 1) a backing layer; 2) a polyacrylate copolymer adhesive layer; 3) polyethylene glycol terephthalate foil for isolating the active layer and the adhesive layer, 4) a skeleton layer containing active ingredients, which is composed of active ingredients, penetration enhancer and polyacrylate copolymer and is in direct contact with skin when in use; 5) a protective layer that is torn off before use. The structure is more complex, the adhesive layer with larger area is covered on the framework layer containing the main component with smaller area, and the framework layer is separated by the isolating foil, so as to avoid the active component from diffusing to the adhesive layer. The product release 7 days after application was approximately 15% of the initial drug load.
Disclosure of Invention
The buprenorphine transdermal patch is simple in structure, lower in drug loading capacity, less in drug residue, capable of being continuously applied for 3-7 days, continuous and stable in transdermal effect and good in safety.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
a skeleton type transdermal patch containing buprenorphine comprises a medicine-containing layer, a back lining layer and a protective layer, wherein the medicine-containing layer is arranged between the back lining layer and the protective layer,
wherein the medicine-containing layer comprises 8 to 12 parts of active ingredients, 80 to 90 parts of adhesive, 0.5 to 5 parts of penetration enhancer and 0.5 to 2 parts of antioxidant by weight,
the active ingredient is buprenorphine free base or a pharmaceutically acceptable salt thereof,
the adhesive is one or more of acrylate pressure-sensitive adhesive, silicone pressure-sensitive adhesive, polyvinyl alcohol, polyacrylate resin IV, polybutylene and polyisobutylene,
the penetration enhancer is composed of one or more of levulinic acid, triacetin and propylene glycol,
the antioxidant is selected from one or more of butyl anisole, tocopherol and dibutyl hydroxy toluene;
the back lining layer is one of polyvinyl chloride, polyethylene, aluminum foil, polypropylene, polyester, polyvinyl chloride/thermoplastic resin/aluminum-coated polyester film and non-woven fabric;
the protective layer is one of polyethylene, polystyrene, polypropylene film and release paper treated by paraffin or dimethyl silicone oil release agent. The active ingredient of the transdermal patch can be buprenorphine free alkali or pharmaceutically acceptable salt thereof, the drug content of each patch is 5-20 mg calculated by buprenorphine, which is obviously lower than that of the existing buprenorphine transdermal patch, but the drug dosage in the same time is far better than that of the existing buprenorphine transdermal patch.
The invention also provides a preparation method of the transdermal patch.
A method for preparing a matrix-type transdermal patch containing buprenorphine, comprising the steps of:
1) mixing the components of the medicine-containing layer, adding solvent, stirring to obtain medicine-carrying matrix, wherein the solvent is ethyl acetate, or anhydrous alcohol or mixture thereof,
2) coating the prepared drug-loaded matrix prepared in the step 1) on a protective layer, drying at 40-60 ℃, then compounding with a back lining layer, and cutting into a proper area to obtain the drug-loaded matrix.
Advantageous effects
The dosage of the skeleton type transdermal patch containing the buprenorphine is 5-20 mg calculated by the buprenorphine, which is obviously lower than the dosage of the existing buprenorphine transdermal patch, but the dosage in the same time is far better than the dosage of the existing buprenorphine transdermal patch.
The preparation method is simple and easy to obtain, convenient to operate and suitable for large-scale industrial production and application.
Drawings
FIG. 1 shows examples (examples 1 to 3) of the present invention and commercially available products
In vitro transdermal flux comparison.
FIG. 2 shows examples of the present invention (examples 1 to 3) and commercially available products
Comparative pharmacokinetic profiles in rats.
Detailed Description
The technical solutions disclosed in the present invention are further illustrated below with reference to examples, but the present invention is not limited thereto.
Example 1
The transdermal patch described in this example consists of a backing layer, a drug-containing layer and a protective layer.
The preparation process comprises the following steps: taking the acrylate pressure-sensitive adhesive and the levulinic acid according to the prescription amount, and uniformly stirring. And adding buprenorphine and butyl anisole dissolved by ethyl acetate, uniformly mixing, adjusting the total weight by using absolute ethyl alcohol, coating on a protective layer, controlling the thickness, drying at 40-60 ℃, compounding with a back lining layer, and cutting into a proper area to obtain the compound buprenorphine/butyl anisole composite material.
Example 2
The transdermal patch described in this example consists of a backing layer, a drug-containing layer, and a protective layer.
| Components | Function of | Dosage (mg) in single-dose | |
| Buprenorphine | API | ||
| 12 | |||
| Polyacrylate resin IV | Adhesive agent | 83 | |
| | Antioxidant agent | 1 | |
| Glycerol triacetate | Penetration enhancer | 4 | |
| Ethyl acetate | Solvent(s) | Proper amount of | |
| Anhydrous ethanol | Solvent(s) | Proper amount of | |
| Polyvinyl chloride/aluminum-coated polyester film | Backing layer | Proper amount of | |
| Siliconized polyethylene films | Protective layer | Proper amount of |
The preparation process comprises the following steps: taking the polyacrylate resin IV with the prescription amount, uniformly mixing with ethyl acetate, adding triacetin and uniformly stirring. And adding buprenorphine and dibutyl hydroxy toluene dissolved in ethyl acetate, uniformly mixing, adjusting the total weight by using absolute ethyl alcohol, coating on a protective layer, controlling the thickness, drying at 40-60 ℃, compounding with a back lining layer, and cutting into a proper area to obtain the compound buprenorphine/dibutyl hydroxy toluene/butyl hydroxy benzene/methyl pyrrolidone/methyl ether/ethyl ether/methyl ether/ethyl ether/methyl ether/ethyl ether/methyl ether/ethyl ether.
Example 3
The transdermal patch described in this example consists of a backing layer, a drug-containing layer, an adhesive layer, and a protective layer.
| Components | Function of | Dosage (mg) in single-dose patch | |
| Buprenorphine | API | 8 | |
| | Adhesive agent | 60 | |
| Silicone pressure sensitive adhesive | Adhesive agent | 28 | |
| | Antioxidant agent | 1 | |
| Glycerol | Penetration enhancer | 1 | |
| Propylene glycol | Penetration enhancer | 2 | |
| Anhydrous ethanol | Solvent(s) | Proper amount of | |
| Ethyl acetate | Solvent(s) | Proper amount of | |
| Non-woven fabric | Backing layer | Proper amount of | |
| Polystyrene film | Protective layer | Proper amount of |
The preparation process comprises the following steps: taking the polybutene and the silicone pressure-sensitive adhesive according to the prescription amount, uniformly mixing with ethyl acetate, adding the triacetin and the propylene glycol, and uniformly stirring. And adding buprenorphine and tocopherol dissolved in ethyl acetate, uniformly mixing, adjusting the total weight by using absolute ethyl alcohol, coating on a protective layer, controlling the thickness, drying at 40-60 ℃, compounding with a back lining layer, and cutting into a proper area to obtain the compound buprenorphine/tocopherol composite material.
Test 1: in vitro transdermal test
For examples 1 to 3 of the present invention and commercially available products
(batch No. 70239C209, expiration date to 2021.1) in vitro transdermal test comparisons were made by the following method:
in vitro transdermal tests were performed using female hairless mouse skin. Before the test, the mice were sacrificed, the back skin was taken after the hairs were shaved off, the sample was cut into a suitable area by the static diffusion cell method, the protective layer was removed, and the sample was attached to the skin of the mice and fixed in the diffusion cell. A magnetic stirrer is arranged in the receiving pool, a receiving medium is a Solenson buffer solution with the pH value of 5.20, the temperature of the system is set to be 32 +/-0.5 ℃, and the full-automatic transdermal diffusion system is started. Sampling at 0, 3h, 6h, 12h, 24h, 36h, 48h, 72h, 96h, 120h,144h and 168h, performing liquid phase analysis, recording the accumulated release amount, and drawing a curve of the accumulated transdermal amount and the time.
The result of the in vitro skin penetration test is obviousIt is indicated that this product is a commercially available product
The transdermal release degree of the drug is consistent, and the examples 1 and 2 have better transdermal effect.
Test 2: pharmacokinetic testing
For examples 1 to 3 of the present invention and commercially available products
(batch No. 70239C209, expiration date to 2021.1) rat pharmacokinetic experiments were performed as follows:
adult healthy SD rats were randomly divided into test and control groups of 24 animals each. Before the experiment, the hairs on the back of the SD rat are removed and respectively pasted with the buprenorphine transdermal patch and a contrast commercially available patch
Transdermal patch. After the administration, blood is respectively collected by indwelling tubes for 1h, 3h, 5h, 8h, 12h, 24h, 36h, 48h, 72h, 96h, 120h,144h,168h and 192 h. Blood samples were centrifuged at 10000r/min for 5min, plasma was accurately pipetted 400. mu.l, 2mol/L NaOH solution 100. mu.l was added, and vortexed for 30 s. Adding 1.5ml of n-hexane, and carrying out vortex oscillation for 3 min; centrifuging at 3000r/min for 10min, sucking supernatant, and transferring into another centrifuge tube; adding 1.5ml n-hexane, extracting repeatedly for 1 time, and collecting supernatant and mixing with the 1 st extractive solution. Then placing in a constant temperature water bath at 40 ℃ for drying by distillation, adding mobile phase 100 mul, quickly shaking for 5s for dissolving, centrifuging at 3500r/min for 10min, sucking up and precisely measuring supernatant 40 mul, injecting sample, and measuring.
The blood concentrations of the experimental animals in the test group and the control group are shown in fig. 2, and the results show that the buprenorphine transdermal patches prepared in examples 1-3 have similar pharmacokinetic profiles to those of the commercial products.
Test 3: skin irritation test
Local unhairing treatment is carried out on the back of 6 rabbits 24 hours before the test, the same-body self-contrast method is adopted, the left side is a test area to which a buprenorphine transdermal patch (the patch prepared in the example 1-3) of the invention is applied, and the right side is a control area to which a blank control patch is applied. The patch is applied for 7 days and 14 days continuously, the application part is cleaned with warm water after removing the patch, and the patch is applied again after 1 h. Before the first administration, 1h after each cleaning and 24h, 48h and 72h after the last administration of the medicine for removing the medicine, whether the applied part has erythema and edema and the recovery condition and time of the change are observed, and the stimulation evaluation intensity of the buprenorphine transdermal patch is evaluated according to the evaluation result.
Experiments show that the product has good general conditions and weight increase in administration process and observation period. Edema was not seen in the test and control zones, mild erythema appeared in one animal on day 14 and resolved 24h after drug withdrawal, with the average scores in the test and control zones being 0 and 0.05, respectively, and no irritation was assessed according to the skin irritation intensity assessment criteria.
Therefore, the buprenorphine transdermal patch and the blank patch are continuously administrated to rabbits for 14 days in a percutaneous mode, and the skin irritation strength is nonirritant.
Test 4: skin allergy test
30 guinea pigs which are qualified for quarantine are divided into 3 groups, the groups are divided into a buprenorphine transdermal patch test group, a blank patch group and a positive control group by a random equilibrium method, 10 each group are respectively attached to a patch (buprenorphine transdermal patch test group), a blank patch (blank patch group) and 0.2mL of a 1% ethanol solution of positive sensitizer 2, 4-dinitrochlorobenzene (positive control group) prepared in the embodiment 1-3 in a hair removal area on one side of the back before administration, and sensitization is carried out for 3 times on the 0 th, 7 th and 14 th days as an induction period. Stopping the drug for 14 days after the last sensitization in the induction period, exciting the hair-removed area on the other side of the back of the animal on the 14 th day after the last sensitization, observing the skin and general reactions of each animal 1h, 24h, 48h and 72h after the excitation, grading, and evaluating the skin anaphylactic reaction degree, wherein the negative control group and the positive control group are the same as the test object group. The results of each animal were evaluated for allergic response and allergic intensity.
Tests showed that no erythema, edema or other abnormalities were observed during the dosing and observation period in the buprenorphine transdermal patch test group and the blank patch group. The animals in the positive control group are subjected to initial sensitization and then have chapped edges of the administration area, and the animals in the positive control group can observe light to moderate erythema, chapped skin, scabbing and thickening after the 2 nd sensitization and the 3 rd sensitization, and recover before excitation. And in the excitation stage, observation is carried out for 1h, 24h, 48h and 72h after the medicine is removed, mild and moderate erythema and edema appear in all animals of the positive control group after the medicine is removed for 1h, the anaphylactic reaction is relieved along with the prolonging of the observation time, the edema parts of 2 animals are peeled and shed at 48h, all the animals recover at 72h, and the positive rate is 100%. The buprenorphine transdermal patch test group and the blank patch group have no skin allergic reaction such as erythema, edema and the like, and animals in each group have no systemic allergic reaction such as asthma, unstable standing or shock and the like.
Therefore, the skin allergic reaction is not generated after the skin allergic and excitation of the patch to the guinea pig, which indicates that the patch of the invention is safe and nontoxic to the skin.
The above description is only a preferred embodiment of the present invention, and not intended to limit the present invention in other forms, and any person skilled in the art may apply the above modifications or changes to the equivalent embodiments with equivalent changes, without departing from the technical spirit of the present invention, and any simple modification, equivalent change and change made to the above embodiments according to the technical spirit of the present invention still belong to the protection scope of the technical spirit of the present invention.
Claims (2)
1. A skeleton type transdermal patch containing buprenorphine is characterized in that the transdermal patch consists of a medicine-containing layer, a back lining layer and a protective layer, the medicine-containing layer is positioned between the back lining layer and the protective layer,
wherein the medicine-containing layer comprises 8 to 12 parts of active ingredients, 80 to 90 parts of adhesive, 0.5 to 5 parts of penetration enhancer and 0.5 to 2 parts of antioxidant by weight,
the active ingredient is buprenorphine free base or a pharmaceutically acceptable salt thereof,
the adhesive is one or more of acrylate pressure-sensitive adhesive, silicone pressure-sensitive adhesive, polyvinyl alcohol, polyacrylate resin IV, polybutylene and polyisobutylene,
the penetration enhancer is composed of one or more of levulinic acid, triacetin and propylene glycol,
the antioxidant is selected from one or more of butyl anisole, tocopherol and dibutyl hydroxy toluene;
the back lining layer is one of polyvinyl chloride, polyethylene, aluminum foil, polypropylene, polyester, polyvinyl chloride/thermoplastic resin/aluminum-coated polyester film and non-woven fabric;
the protective layer is one of polyethylene, polystyrene, polypropylene film and release paper treated by paraffin or dimethyl silicone oil release agent.
2. A method for preparing a matrix-type transdermal patch containing buprenorphine, characterized by comprising the steps of:
1) the drug-carrying matrix is prepared by mixing the components of the drug-containing layer of claim 1, adding a solvent and uniformly stirring, wherein the solvent is ethyl acetate, or absolute ethyl alcohol or the mixture of the ethyl acetate and the absolute ethyl alcohol,
2) coating the prepared drug-loaded matrix prepared in the step 1) on a protective layer, drying at 40-60 ℃, then compounding with a back lining layer, and cutting into a proper area to obtain the drug-loaded matrix.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111440262.6A CN113952319A (en) | 2021-11-30 | 2021-11-30 | Skeleton type transdermal patch containing buprenorphine and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111440262.6A CN113952319A (en) | 2021-11-30 | 2021-11-30 | Skeleton type transdermal patch containing buprenorphine and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113952319A true CN113952319A (en) | 2022-01-21 |
Family
ID=79472482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111440262.6A Pending CN113952319A (en) | 2021-11-30 | 2021-11-30 | Skeleton type transdermal patch containing buprenorphine and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113952319A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116098878A (en) * | 2023-01-04 | 2023-05-12 | 新领医药技术(深圳)有限公司 | Stable transdermal drug delivery kit, preparation method and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100221313A1 (en) * | 2008-12-01 | 2010-09-02 | Innovative Pharmaceuticals, Llc | Transdermal reservoir patch |
| CN103893154A (en) * | 2012-12-26 | 2014-07-02 | 江苏康倍得药业有限公司 | Buprenorphine-containing transdermal delivery system |
| US20140363487A1 (en) * | 2011-12-12 | 2014-12-11 | Purdue Pharma L.P. | Transdermal delivery system comprising buprenorphine |
| US20150306093A1 (en) * | 2012-12-12 | 2015-10-29 | Purdue Pharma L.P. | Transdermal delivery system |
| US20160008294A1 (en) * | 2013-06-04 | 2016-01-14 | Purdue Pharma L.P. | Transdermal delivery system |
| US20180256562A1 (en) * | 2015-09-14 | 2018-09-13 | Amneal Pharmaceuticals Llc | Transdermal Delivery System |
-
2021
- 2021-11-30 CN CN202111440262.6A patent/CN113952319A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100221313A1 (en) * | 2008-12-01 | 2010-09-02 | Innovative Pharmaceuticals, Llc | Transdermal reservoir patch |
| US20140363487A1 (en) * | 2011-12-12 | 2014-12-11 | Purdue Pharma L.P. | Transdermal delivery system comprising buprenorphine |
| US20150306093A1 (en) * | 2012-12-12 | 2015-10-29 | Purdue Pharma L.P. | Transdermal delivery system |
| CN103893154A (en) * | 2012-12-26 | 2014-07-02 | 江苏康倍得药业有限公司 | Buprenorphine-containing transdermal delivery system |
| US20160008294A1 (en) * | 2013-06-04 | 2016-01-14 | Purdue Pharma L.P. | Transdermal delivery system |
| US20180256562A1 (en) * | 2015-09-14 | 2018-09-13 | Amneal Pharmaceuticals Llc | Transdermal Delivery System |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116098878A (en) * | 2023-01-04 | 2023-05-12 | 新领医药技术(深圳)有限公司 | Stable transdermal drug delivery kit, preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8481560B2 (en) | Abuse deterrent transdermal formulations of opiate agonists and agonist-antagonists | |
| EP2123274B1 (en) | Medicinal composition for transdermal absorption, medicinal composition storing unit and transdermal absorption preparation using the same | |
| EP2552924B1 (en) | Transdermally deliverable opioid prodrugs, abuse-resistant compositions and methods of using opioid prodrugs | |
| US20090246265A1 (en) | Abuse deterrent transdermal formulations of opiate agonists and agonist-antagonists | |
| US7759358B2 (en) | Oral bioavailable prodrugs | |
| KR20020000811A (en) | Pharmaceutical preparation containing the active substance diamorphine and its utilization in a method for treating opiate addiction | |
| EP3043777A1 (en) | Sublingual buprenorphine spray | |
| WO2008036980A1 (en) | Transdermally deliverable buprenorphine prodrugs and abuse-resistant compositions thereof | |
| JP2003531157A (en) | Minimizing adverse experiences associated with oxybutynin treatment | |
| CN103432104B (en) | A kind of transdermal patch containing pramipexole | |
| KR920010392B1 (en) | Process for preparing pharmaceutical composition for the transdermal systemic administration | |
| KR20180042378A (en) | Non-aqueous patches containing lidocaine | |
| CN103622903A (en) | Propranolol hydrochloride lipidosome gel and preparation method thereof | |
| CN113952319A (en) | Skeleton type transdermal patch containing buprenorphine and preparation method thereof | |
| JPH04128231A (en) | Method of treating addiction to cocaine or heroin comprising percutaneously delivering buprenorphine | |
| US10874658B2 (en) | Sublingual opioid formulations containing naloxone | |
| CN111346077B (en) | Tapentadol transdermal drug delivery pharmaceutical composition, preparation method and application thereof | |
| US9566341B1 (en) | Compounds including Cox inhibitor moiety and enhanced delivery of active drugs using same | |
| CN102000044A (en) | Azasetron transdermal patch and preparation method thereof | |
| CN110585174B (en) | Transdermal sustained-release patch for resisting schizophrenia | |
| EP3054918B9 (en) | Novel formulation | |
| CN111419826B (en) | Sufentanil transdermal drug delivery pharmaceutical composition, preparation method and application thereof | |
| CN1780611B (en) | Tamper-resistant transdermal dosage form comprising an active agent component and an adverse agent component at the distal site of the active agent layer | |
| CN113318096A (en) | Transdermal therapeutic system of huperzine A and its derivatives | |
| CN100459977C (en) | Skin penetrating paste of indomethacin albuterol |
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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220121 |
|
| RJ01 | Rejection of invention patent application after publication |