CN109481423A - Diclofenac salt transdermal patch and preparation method thereof - Google Patents
Diclofenac salt transdermal patch and preparation method thereof Download PDFInfo
- Publication number
- CN109481423A CN109481423A CN201811389124.8A CN201811389124A CN109481423A CN 109481423 A CN109481423 A CN 109481423A CN 201811389124 A CN201811389124 A CN 201811389124A CN 109481423 A CN109481423 A CN 109481423A
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- CN
- China
- Prior art keywords
- diclofenac salt
- transdermal patch
- diclofenac
- patch
- sensitive adhesive
- 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.)
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- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical class OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 31
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims abstract description 28
- 230000001681 protective effect Effects 0.000 claims abstract description 19
- 239000011159 matrix material Substances 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 8
- -1 Diclofenac N- (2- ethoxy) pyrrolidines Chemical class 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 235000019441 ethanol Nutrition 0.000 claims description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical group CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 229960001259 diclofenac Drugs 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000011248 coating agent Substances 0.000 claims description 8
- 238000000576 coating method Methods 0.000 claims description 8
- 238000012545 processing Methods 0.000 claims description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 7
- 239000004743 Polypropylene Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229920001155 polypropylene Polymers 0.000 claims description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000004698 Polyethylene Substances 0.000 claims description 6
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims description 6
- 229920001577 copolymer Polymers 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229920000058 polyacrylate Polymers 0.000 claims description 6
- 229920000573 polyethylene Polymers 0.000 claims description 6
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 6
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 6
- 239000004310 lactic acid Substances 0.000 claims description 5
- 235000014655 lactic acid Nutrition 0.000 claims description 5
- 238000010422 painting Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 4
- 239000004327 boric acid Substances 0.000 claims description 4
- 229920002635 polyurethane Polymers 0.000 claims description 4
- 239000004814 polyurethane Substances 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 238000009832 plasma treatment Methods 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims 2
- ZZUUMCMLIPRDPI-UHFFFAOYSA-N 2-hydroxypropanoic acid;sodium Chemical compound [Na].CC(O)C(O)=O ZZUUMCMLIPRDPI-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 125000005396 acrylic acid ester group Chemical group 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 12
- 238000012360 testing method Methods 0.000 abstract description 10
- 239000012466 permeate Substances 0.000 abstract 1
- 230000001186 cumulative effect Effects 0.000 description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000003760 magnetic stirring Methods 0.000 description 6
- 210000003491 skin Anatomy 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 4
- 229960001193 diclofenac sodium Drugs 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 231100000435 percutaneous penetration Toxicity 0.000 description 4
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 239000004411 aluminium Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VXUVGSRJTGCPBO-UHFFFAOYSA-N 1-ethoxypyrrolidine Chemical class CCON1CCCC1 VXUVGSRJTGCPBO-UHFFFAOYSA-N 0.000 description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical group C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 229920002367 Polyisobutene Polymers 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 239000001540 sodium lactate Substances 0.000 description 2
- 229940005581 sodium lactate Drugs 0.000 description 2
- 235000011088 sodium lactate Nutrition 0.000 description 2
- 210000000434 stratum corneum Anatomy 0.000 description 2
- KUCOHFSKRZZVRO-UHFFFAOYSA-N terephthalaldehyde Chemical compound O=CC1=CC=C(C=O)C=C1 KUCOHFSKRZZVRO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000001294 Nociceptive Pain Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000026137 Soft tissue injury Diseases 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 208000004760 Tenosynovitis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- LCJHLOJKAAQLQW-UHFFFAOYSA-N acetic acid;ethane Chemical compound CC.CC(O)=O LCJHLOJKAAQLQW-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 238000005491 wire drawing Methods 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
- A61K9/70—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a diclofenac salt transdermal patch and a preparation method thereof. The invention firstly discloses a diclofenac salt transdermal patch, which sequentially comprises a backing film, a drug storage and a protective film from top to bottom; wherein, the raw materials of the drug reservoir comprise diclofenac salt, a pressure-sensitive adhesive matrix and a solubilizer. The invention further discloses a preparation method of the diclofenac salt transdermal patch. The diclofenac salt transdermal patch of the invention screens the solubilizer and the addition amount thereof through an orthogonal test to increase the solubility of the diclofenac salt in the pressure-sensitive adhesive matrix, promote the drug to permeate the skin, effectively improve the transdermal permeation amount of the patch per unit area and the stability of the patch, and improve the bioavailability of the diclofenac salt.
Description
Technical field
The present invention relates to pharmaceutical technology fields.More particularly, to a kind of diclofenac salt transdermal patch and its preparation side
Method.
Background technique
Diclofenac and its salt are a kind of important anthranilic acid non-steroidal antipyretic-antalgic anti-inflammatory agents, and pharmacology is made
With the synthesis for predominantly inhibiting prostaglandin in body.Prostaglandin has the bioactivity of height, participates in organism fever, pain
Bitterly, a variety of pathologic processes such as inflammation.Diclofenac by conjunction with Cycloxygenase cover enzyme activated centre, to block the enzyme
Conversion of arachidonic acid is converted into the metabolic process of prostaglandin, and analgesia while has both anti-inflammatory effect, maincenter Small side effects, poison
Property it is low, be preferable analgesic, can be good at release arthralgia, improve its activity.Clinic is mainly used for treating class wind
Wet arthritis, osteoarthritis, ankylosing spondylitis；Various soft tissue pain and swellings, including lumbago, scapulohumeral periarthritis, synovitis, tendon and
Tenosynovitis, neck push away disease；Soft tissue injury, including dampen, it beats and flutters wound, strain, lacerated wound, strain etc..To toothache, dysmenorrhea and cancer
Disease, postoperative pain also have good therapeutic effect.
Diclofenac and its common preparation of salt include that preparation has tablet, capsule, gelling agent, cream, patch etc.,
In, transdermal patch is not influenced with no liver first-pass effect by gastric emptying rate etc., and bioavilability is high, easy to use, no pain
Bitterly, can cancel or interrupt at any time treatment, dosage is accurate, and absorption area is fixed, blood concentration stablize the advantages that.But it is right
For diclofenac salt, Determination of oil-water partition coefficient (LogP) is lower, dissolution of the diclofenac salt in water or liposoluble constituent
Degree is all lower, to the problem of drug crystallization is precipitated in patch easily occur.
Accordingly, it is desirable to provide a kind of new diclofenac salt transdermal patch, at least one in solving the above problems.
Summary of the invention
It is an object of the present invention to provide the good Diclofenacs of a kind of drugloading rate height, drug substance stable, percutaneous permeation
Salt transdermal patch.
It is another object of the present invention to provide a kind of preparation methods of above-mentioned diclofenac salt transdermal patch.
In order to achieve the above objectives, the present invention adopts the following technical solutions:
The present invention provides a kind of diclofenac salt transdermal patches, from top to bottom successively include backing film, drug-reservoir and
Protective film；Wherein, the raw material of the drug-reservoir includes diclofenac salt, pressure sensitive adhesive matrix and solubilizer.
Further, the solubilizer include but is not limited to lactic acid, it is sodium lactate, boric acid, one or more of mixed in tartaric acid
Close object.
Further, the diclofenac salt includes but is not limited to C14H10Cl2NNaO2, DICLOFENAC DIETHYLAMINE, Diclofenac N-
One or more mixture in (2- ethoxy) pyrrolidines.
Further, the pressure sensitive adhesive matrix is pressure-sensitive acrylate, including acrylic polymer and solvent, institute
The content for stating acrylic polymer is the 20%-50% of pressure-sensitive acrylate gross mass；Preferably, the solvent packet
Include but be not limited to ethyl acetate, heptane, hexane, methanol, ethyl alcohol, isopropanol, 2,4- pentanedione, toluene, it is a kind of in dimethylbenzene or
Several mixtures.
Further, the molar ratio of the diclofenac salt and solubilizer is 1: 0.05-1: 5, preferably 1: 0.2-1: 2.
Further, the content of the diclofenac salt is the 0.5%-20%, preferably 1%- of drug-reservoir gross mass
10%.
Further, the backing film be one or more layers laminated film, material include polyethylene terephthalate,
Polypropylene, polyethylene, vinyl-vinyl acetate copolymer, mixture one or more in polyurethane.
Further, the backing film with a thickness of 30-300 μm.
Further, the material of the protective film is surface by plasma treatment, painting fluorine or applies the poly- to benzene two of silicon processing
Formic acid glycol ester, polyethylene, mixture one or more in polypropylene film, the preferably poly- terephthaldehyde of painting fluorine processing
Sour glycol ester.
Further, the protective film with a thickness of 20-300 μm.
Further, the area of the diclofenac salt transdermal patch is 5-100cm2。
Preferably, the content range of diclofenac salt is 0.2-2mg in diclofenac salt transdermal patch every square centimeter.
Invention further provides the preparation methods of above-mentioned diclofenac salt transdermal patch, comprising the following steps:
Diclofenac salt is added in ethyl alcohol and is mixed, solubilizer is added；
Pressure sensitive adhesive matrix is added, stirring stands after removing bubble, is coated on protective film, and it is dry, cover backing film, pressure
Tightly to get.
Further, the coating thickness is 50-1000 μm；Preferably 300-600 μm.
Further, the stirring is 60 DEG C of temperature constant magnetic stirring 30-60min.
Further, the drying is 70-90 DEG C of dry 10-20min.
Beneficial effects of the present invention are as follows:
Diclofenac salt transdermal patch of the present invention screens solubilizer and its additive amount by orthogonal test to increase double chlorine sweet smell
Solubility of the hydrochlorate in pressure sensitive adhesive matrix promotes drugs through skin, effectively improves the transdermal penetration of patch unit area
The stability of amount and patch, improves the bioavilability of diclofenac salt.
Detailed description of the invention
Specific embodiments of the present invention will be described in further detail with reference to the accompanying drawing.
Fig. 1 shows the petrographic microscope photo for the diclofenac sodium transdermal patch that tested number in test example is 1-9.
Fig. 2 shows the petrographic microscope photos of C14H10Cl2NNaO2 patch commercially available in test example.
Fig. 3 shows the absolute value of C14H10Cl2NNaO2 patch 12h cumulative release amount in test example: a: the patch that tested number is 2；
B: the patch that tested number is 3；C: the patch that tested number is 9；D: commercially available C14H10Cl2NNaO2 patch.
Fig. 4 shows the relative value of C14H10Cl2NNaO2 patch 12h cumulative release amount in test example: a: the patch that tested number is 2；
B: the patch that tested number is 3；C: the patch that tested number is 9；D: commercially available C14H10Cl2NNaO2 patch.
Specific embodiment
In order to illustrate more clearly of the present invention, the present invention is done further below with reference to preferred embodiments and drawings
It is bright.Similar component is indicated in attached drawing with identical appended drawing reference.It will be appreciated by those skilled in the art that institute is specific below
The content of description is illustrative and be not restrictive, and should not be limited the scope of the invention with this.
In a first aspect, the present invention provides a kind of diclofenac salt transdermal patches, it from top to bottom successively include backing film, medicine
Object storage cavern and protective film；Wherein, the raw material of the drug-reservoir includes diclofenac salt, pressure sensitive adhesive matrix and solubilizer.
Further, the solubilizer include but is not limited to lactic acid, it is sodium lactate, boric acid, one or more of mixed in tartaric acid
Object is closed, solubilizer can effectively increase solubility of the diclofenac salt in pressure sensitive adhesive.
Further, the diclofenac salt includes but is not limited to C14H10Cl2NNaO2, DICLOFENAC DIETHYLAMINE, Diclofenac N-
One or more mixture in (2- ethoxy) pyrrolidines.
Further, the pressure sensitive adhesive matrix is pressure-sensitive acrylate, including acrylic polymer and solvent, institute
The content for stating acrylate polymer is the 20%-50% of pressure-sensitive acrylate gross mass；Preferably, the solvent is second
Acetoacetic ester, heptane, hexane, methanol, ethyl alcohol, isopropanol, 2,4- pentanedione, toluene, mixture one or more of in dimethylbenzene.
Pressure-sensitive acrylate is smaller to the stimulation of skin in the present invention, seldom causes allergic reaction, and having property
Matter is stablized, the features such as using rear noresidue.
Further, the molar ratio of the diclofenac salt and solubilizer is 1: 0.05-1: 5, preferably 1: 0.2-1: 2,
It such as can be 1: 0.05,1: 0.2,1: 1,1: 1.5,1: 2,1: 3,1: 4,1: 5 etc..When rubbing for diclofenac salt and solubilizer
That ratio can all make that Diclofenac salt crystal is precipitated in patch, the percutaneous permeation of patch is made to be deteriorated not in above range.
Further, the content of the diclofenac salt is the 0.5%-20%, preferably 1%- of drug-reservoir gross mass
10%, such as can be 0.5%, 1%, 3%, 5%, 7%, 9%, 10%, 11%, 13%, 15%, 17%, 20% etc..When
The low percutaneous permeation that can make patch of Diclofenac salt content is deteriorated, and weakens therapeutic effect；Diclofenac salt too high levels can make
Crystallization is precipitated in patch, reduces the bioavilability of diclofenac salt.
Further, the backing film be one or more layers laminated film, material include polyethylene terephthalate,
Polypropylene, polyethylene, vinyl-vinyl acetate copolymer, mixture one or more in polyurethane.
Further, the backing film with a thickness of 30-300 μm；It such as can be 30 μm, 50 μm, 100 μm, 150 μm, 200
μm, 250 μm, 300 μm etc..
Further, the material of the protective film is surface by plasma treatment, painting fluorine or applies the poly- to benzene two of silicon processing
Formic acid glycol ester, polyethylene, mixture one or more in polypropylene film, the preferably poly- terephthaldehyde of painting fluorine processing
Sour glycol ester.
Further, the protective film with a thickness of 20-300 μm；Such as can for 20 μm, 50 μm, 100 μm, 150 μm,
200 μm, 250 μm, 300 μm etc..
Further, the area of the diclofenac salt transdermal patch is 5-100cm2；It such as can be 5cm2、20cm2、
40cm2、60cm2、80cm2、100cm2Etc..
Preferably, the content range of drug is 0.2-2mg in diclofenac salt transdermal patch every square centimeter；Such as it can be with
For 0.2mg, 0.5mg, 1mg, 1.5mg, 2mg etc..
Second aspect, the present invention provides the preparation methods of above-mentioned diclofenac salt transdermal patch, comprising the following steps:
Diclofenac salt is added in ethyl alcohol and is mixed, solubilizer is added；
Pressure sensitive adhesive matrix is added, stirring stands after removing bubble, is coated on protective film, and it is dry, cover backing film, pressure
Tightly to get.
Further, the coating thickness is 50-1000 μm；Preferably 300-600 μm；It such as can be 50 μm, 100 μ
M, 300 μm, 500 μm, 600 μm, 700 μm, 900 μm, 1000 μm etc..
Further, the stirring is 60 DEG C of temperature constant magnetic stirring 30-60min.
Further, the drying is 70-90 DEG C of dry 10-20min.
Hereinafter the present invention will be further described through by specific embodiment.
In the present invention, if not refering in particular to, used raw material and equipment etc. are commercially available or commonly used in the art.
Method in following embodiments is unless otherwise instructed the conventional method of this field.
A kind of diclofenac sodium transdermal patch of embodiment 1
1, each raw material is weighed:
2, the preparation of transdermal patch
C14H10Cl2NNaO2 is added in ethyl alcohol, lactic acid is added after mixing, dissolves C14H10Cl2NNaO2, DURO-TAK is added
87-2677 medical pressure sensitive adhesive (contains acrylate and vinyl acetate copolymer 39.5%, ethyl acetate 22.4%, isopropanol
22.4%, heptane 12.7%, toluene 3%), 60 DEG C temperature constant magnetic stirring 1 hour, stand 1 hour removing bubble, be coated on protection
On film, coating thickness is 300 μm, 70 DEG C of drying 20min, covers backing film, is compressed, and cutting, aluminium plastic bag is sealed.Protective film
Material is the polyethylene terephthalate for applying fluorine processing, with a thickness of 200 μm；Backing membrane material is poly terephthalic acid second two
Alcohol ester, with a thickness of 100 μm.
Protective film is torn when use, being pasted on skin on one side containing drug-reservoir.
Percutaneous penetration the result shows that, 24 hours cumulative release amounts of the patch can reach 31.77 μ g/cm2。
A kind of diclofenac sodium transdermal patch of embodiment 2
1, each raw material is weighed:
2, the preparation of transdermal patch
C14H10Cl2NNaO2 is added in ethyl alcohol, boric acid is added after mixing, promotes C14H10Cl2NNaO2 dissolution, DURO- is added
TAK 387-2510 medical pressure sensitive adhesive (contains acrylate polymer 40.5%, ethyl acetate 54.1%, hexane 5.4%), and 60 DEG C
Temperature constant magnetic stirring 30min stands 1 hour removing bubble, is coated on protective film, and coating thickness is 600 μm, 90 DEG C of drying
10min covers backing film, compresses, and cutting, aluminium plastic bag is sealed.Protection membrane material is the poly terephthalic acid for applying silicon processing
Glycol ester, with a thickness of 30 μm；Backing membrane material is polyurethane, with a thickness of 300 μm.
Protective film is torn when use, being pasted on skin on one side containing drug-reservoir.
Percutaneous penetration the result shows that, 24 hours cumulative release amounts of the patch can reach 16.95 μ g/cm2。
A kind of diclofenac sodium transdermal patch of embodiment 3
1, each raw material is weighed:
2, the preparation of transdermal patch
C14H10Cl2NNaO2 is added in ethyl alcohol, tartaric acid is added after mixing, promotes C14H10Cl2NNaO2 dissolution, is added
DURO-TAK 387-2510 medical pressure sensitive adhesive, 60 DEG C of temperature constant magnetic stirring 45min, is completely dissolved C14H10Cl2NNaO2, stands 1
Hour removes bubble, is coated on protective film, and coating thickness is 1000 μm, 80 DEG C of drying 15min, covers backing film, compresses, cuts
It cuts, aluminium plastic bag is sealed.Protection membrane material is polypropylene, with a thickness of 300 μm；Backing membrane material is ethane-acetic acid ethyenyl ester
Copolymer, with a thickness of 20 μm.
Protective film is torn when use, being pasted on skin on one side containing drug-reservoir.
Percutaneous penetration the result shows that, 24 hours cumulative release amounts of the patch can reach 50.43 μ g/cm2。
The screening of test example drug-reservoir formula
This test example by the test of 24 factor, 3 horizontal quadratures, screened diclofenac salt, medical pressure sensitive adhesive, solubilizer,
The molar ratio of C14H10Cl2NNaO2 and solubilizer, 5 factors of content of dispersion to the crystallinity of diclofenac salt transdermal patch, adhesion and
The influence of percutaneous permeation.
Specific test method the following steps are included:
C14H10Cl2NNaO2 is added in ethanol in proper amount, solubilizer is added after mixing, is then added medical pressure sensitive adhesive, 60 DEG C
Temperature constant magnetic stirring 1 hour, it is completely dissolved C14H10Cl2NNaO2, stands 1 hour removing bubble and obtain the pressure-sensitive sol solution of drug containing, into
Row crystallinity inspection；
Further, by drug containing pressure sensitive adhesive solution coating on protective film, coating thickness is 300 μm, 70 DEG C of drying 20min,
Backing film is covered, is compressed, cutting obtains transdermal patch.
Crystallinity inspection uses polarized light microscopic method, and obtained result is as illustrated in fig. 1 and 2, and 3,9 nodeless mesh of prescription is precipitated,
Prescription 2 has a small amount of crystallization to be precipitated.Prescription Isosorbide-5-Nitrae, 5,6,7,8 and commercially available patch have crystallization be precipitated.Meeting when thering is crystallization to be precipitated in patch
So that the percutaneous permeation of patch is deteriorated, therefore selects adhesion detection and the transdermal experiment of the progress patch of prescription 2,3,9.
Adhesion by initial adhesion force, hold viscous force and peel strength and embody, the results are shown in Table 1: 2, No. 3 prescription patches
Initial adhesion force, to hold viscous force and commercially available patch close, but carries out that wire drawing can be generated when peel test, does not meet version Chinese Pharmacopoeia in 2015
Relevant regulations.No. 9 prescription patch initial adhesion forces, hold viscous force and peel strength are appropriate, therefore selected No. 9 prescriptions are optimal prescription.
Percutaneous penetration uses improved Franz diffusing cells method, pig ear skin is fixed on diffusion cell, corium is towards receiving
Room, stratum corneum side is to supply chamber.Patch sticks on stratum corneum side, and appropriate pH=7.4 phosphate buffer is added in receiving chamber.37
DEG C water bath with thermostatic control circulation simultaneously samples for magnetic agitation 1,2,3,4,5,6,8,10,12 hour, dense with high performance liquid chromatography measurement sample
Degree, as a result sees figures 3 and 4, as can be seen from the figure: patch unit area prepared by 2,3, No. 9 drug containing pressure sensitive adhesives of prescription tires out
Product burst size relative value is without significant difference.Its unit area cumulative release amount absolute value is mainly related with the content of dispersion of patch.Patch
The content of dispersion of agent unit area is higher, and transdermal penetration amount is higher.It can be obviously increased in drug containing pressure sensitive adhesive using lactic acid as solubilizer
The content of dispersion of C14H10Cl2NNaO2, is scattered in C14H10Cl2NNaO2 in pressure sensitive adhesive with molecular forms, improves drug per unit area
The stability of transdermal penetration amount and patch.Wherein the crystallized property of the drug containing pressure sensitive adhesive of No. 9 prescriptions checks stability with higher,
And the adhesive force of patch is moderate, and has preferable percutaneous permeation.
The result of 1 drug-reservoir recipe determination of table
Note: a in table, b, c are respectively medical pressure sensitive adhesive the DURO-TAK 387-2510, DURO- for being purchased from Henkel company
TAK87-6908 (contains polyisobutene 38%, normal heptane 62%), DURO-TAK 87-2677 product.
The cumulative release amount result of 2 different component of table and the drug-reservoir formula of content
Note: the molar ratio of bulk pharmaceutical chemicals and solubilizer is fixed as 1: 1 in table；A, b, c are respectively the doctor for being purchased from Henkel company
With pressure sensitive adhesive DURO-TAK 387-2510, DURO-TAK 87-6908 (containing polyisobutene 38%, normal heptane 62%), DURO-
TAK 87-2677 product.
Investigate diclofenac salt type, solubilizer type, diclofenac salt and solubilizer molar ratio, content of dispersion etc. because
Element, as shown in Tables 1 and 2, show can to increase using solubilizer of the present invention solubility of the diclofenac salt in medical pressure sensitive adhesive,
The percutaneous permeation of drug-reservoir and percutaneous cumulative release amount.
Obviously, the above embodiment of the present invention be only to clearly illustrate example of the present invention, and not be pair
The restriction of embodiments of the present invention may be used also on the basis of the above description for those of ordinary skill in the art
To make other variations or changes in different ways, all embodiments can not be exhaustive here, it is all to belong to this hair
The obvious changes or variations that bright technical solution is extended out are still in the scope of protection of the present invention.
Claims (10)
1. a kind of diclofenac salt transdermal patch, which is characterized in that from top to bottom successively include backing film, drug-reservoir and protection
Film；Wherein, the raw material of the drug-reservoir includes diclofenac salt, pressure sensitive adhesive matrix and solubilizer.
2. diclofenac salt transdermal patch according to claim 1, which is characterized in that the solubilizer is lactic acid, lactic acid
Sodium, boric acid, mixture one or more of in tartaric acid.
3. diclofenac salt transdermal patch according to claim 1, which is characterized in that the diclofenac salt and solubilizer
Molar ratio be 1: 0.05-1: 5, preferably 1: 0.2-1: 2.
4. diclofenac salt transdermal patch according to claim 1, which is characterized in that the content of the diclofenac salt is
The 0.5%-20% of drug-reservoir gross mass, preferably 1%-10%.
5. diclofenac salt transdermal patch according to claim 1, which is characterized in that the diclofenac salt is that double chlorine are fragrant
Sour sodium, DICLOFENAC DIETHYLAMINE, mixture one or more in Diclofenac N- (2- ethoxy) pyrrolidines.
6. diclofenac salt transdermal patch according to claim 5, which is characterized in that the pressure sensitive adhesive matrix is acrylic acid
Esters pressure sensitive adhesive, including acrylic polymer and solvent；Preferably, the content of the acrylate copolymer is acrylic acid
The 20%-50% of esters pressure sensitive adhesive matrix gross mass；It is furthermore preferred that the solvent is ethyl acetate, heptane, hexane, methanol, second
Alcohol, isopropanol, 2,4- pentanedione, toluene, mixture one or more of in dimethylbenzene.
7. diclofenac salt transdermal patch according to claim 1, which is characterized in that the backing film is one or more layers
Laminated film, material include polyethylene terephthalate, polypropylene, polyethylene, vinyl-vinyl acetate copolymer,
One or more mixture in polyurethane；Preferably, the backing film with a thickness of 30-300 μm.
8. diclofenac salt transdermal patch according to claim 1, which is characterized in that the material of the protective film is surface
By plasma treatment, the polyethylene terephthalate that applies fluorine or apply silicon processing, polyethylene, it is a kind of in polypropylene film or
A variety of mixtures, the preferably polyethylene terephthalate of painting fluorine processing；It is furthermore preferred that the protective film with a thickness of
20-300μm。
9. a kind of preparation method of diclofenac salt transdermal patch a method as claimed in any one of claims 1-8, which is characterized in that including
Following steps:
Diclofenac salt is added in ethyl alcohol and is mixed, solubilizer is added；
Pressure sensitive adhesive matrix is added, stirring stands after removing bubble, is coated on protective film, and it is dry, backing film is covered, is compressed, i.e.,
?.
10. preparation method according to claim 9, which is characterized in that the coating thickness is 50-1000 μm；Preferably
It is 300-600 μm.
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| CN201811389124.8A CN109481423B (en) | 2018-11-20 | 2018-11-20 | Diclofenac salt transdermal patch and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811389124.8A CN109481423B (en) | 2018-11-20 | 2018-11-20 | Diclofenac salt transdermal patch and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112933062A (en) * | 2019-12-10 | 2021-06-11 | 福建医科大学 | Gelsemii gerbil transdermal patch and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4738848A (en) * | 1985-06-04 | 1988-04-19 | Nitto Electric Industrial Co., Ltd. | Anti-inflammatory analgesic adhesive preparation |
| CN1462187A (en) * | 2001-05-23 | 2003-12-17 | 株式会社脱苦海 | Analgesic/antiinflammatary patches for topical use |
| WO2005102306A1 (en) * | 2004-04-23 | 2005-11-03 | Hisamitsu Pharmaceutical Co., Inc. | Anti-inflammatory analgesic adhesive patch |
-
2018
- 2018-11-20 CN CN201811389124.8A patent/CN109481423B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4738848A (en) * | 1985-06-04 | 1988-04-19 | Nitto Electric Industrial Co., Ltd. | Anti-inflammatory analgesic adhesive preparation |
| CN1462187A (en) * | 2001-05-23 | 2003-12-17 | 株式会社脱苦海 | Analgesic/antiinflammatary patches for topical use |
| WO2005102306A1 (en) * | 2004-04-23 | 2005-11-03 | Hisamitsu Pharmaceutical Co., Inc. | Anti-inflammatory analgesic adhesive patch |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112933062A (en) * | 2019-12-10 | 2021-06-11 | 福建医科大学 | Gelsemii gerbil transdermal patch and preparation method thereof |
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