CN1331592A - Liposomic niflumic acid-new transdermal anti-inflammatory medicine - Google Patents
Liposomic niflumic acid-new transdermal anti-inflammatory medicine Download PDFInfo
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- CN1331592A CN1331592A CN99814948A CN99814948A CN1331592A CN 1331592 A CN1331592 A CN 1331592A CN 99814948 A CN99814948 A CN 99814948A CN 99814948 A CN99814948 A CN 99814948A CN 1331592 A CN1331592 A CN 1331592A
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- Prior art keywords
- liposome
- niflumic acid
- sealing
- skin
- ear
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 41
- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 4
- 239000002502 liposome Substances 0.000 claims abstract description 68
- 229960000916 niflumic acid Drugs 0.000 claims abstract description 31
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 claims abstract description 30
- 150000002632 lipids Chemical class 0.000 claims abstract description 30
- 150000002148 esters Chemical class 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 239000006071 cream Substances 0.000 claims abstract description 4
- 239000000725 suspension Substances 0.000 claims abstract 5
- 238000011160 research Methods 0.000 claims description 16
- 238000007789 sealing Methods 0.000 claims description 16
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 239000002552 dosage form Substances 0.000 claims description 10
- 238000002474 experimental method Methods 0.000 claims description 9
- 238000005516 engineering process Methods 0.000 claims description 8
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 6
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 6
- 238000009738 saturating Methods 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 235000010469 Glycine max Nutrition 0.000 claims description 4
- 244000068988 Glycine max Species 0.000 claims description 4
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 claims description 3
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 229940106189 ceramide Drugs 0.000 claims description 3
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 claims description 3
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 claims description 3
- 241000699670 Mus sp. Species 0.000 claims description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 8
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 claims 4
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 claims 4
- 210000002200 mouth mucosa Anatomy 0.000 claims 4
- 238000004090 dissolution Methods 0.000 claims 3
- 210000000214 mouth Anatomy 0.000 claims 3
- 239000003889 eye drop Substances 0.000 claims 2
- 210000004195 gingiva Anatomy 0.000 claims 2
- 239000002674 ointment Substances 0.000 claims 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims 2
- 201000004624 Dermatitis Diseases 0.000 claims 1
- 229940035676 analgesics Drugs 0.000 claims 1
- 239000000730 antalgic agent Substances 0.000 claims 1
- 238000007598 dipping method Methods 0.000 claims 1
- 239000006196 drop Substances 0.000 claims 1
- 239000000839 emulsion Substances 0.000 claims 1
- 239000003885 eye ointment Substances 0.000 claims 1
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- 239000008183 oral pharmaceutical preparation Substances 0.000 claims 1
- 201000008482 osteoarthritis Diseases 0.000 claims 1
- 239000002884 skin cream Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 230000000699 topical effect Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 17
- 238000005538 encapsulation Methods 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract 2
- 150000001875 compounds Chemical class 0.000 abstract 1
- 239000013020 final formulation Substances 0.000 abstract 1
- 230000003637 steroidlike Effects 0.000 abstract 1
- 210000003491 skin Anatomy 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 11
- 239000000232 Lipid Bilayer Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 238000005227 gel permeation chromatography Methods 0.000 description 4
- 230000036571 hydration Effects 0.000 description 4
- 238000006703 hydration reaction Methods 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000386 microscopy Methods 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000002356 single layer Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 2
- UPMBDJWMINKVIJ-UHFFFAOYSA-N 2-amino-3-hydroxy-2-methylpropane-1-sulfonic acid Chemical compound OCC(N)(C)CS(O)(=O)=O UPMBDJWMINKVIJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 2
- 101001105486 Homo sapiens Proteasome subunit alpha type-7 Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 102100021201 Proteasome subunit alpha type-7 Human genes 0.000 description 2
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- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- -1 niflumic acid ester Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 1
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
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- 230000008901 benefit Effects 0.000 description 1
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- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
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- 229940088679 drug related substance Drugs 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 229960003913 econazole Drugs 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000003010 ionic group Chemical group 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229940040064 ubiquinol Drugs 0.000 description 1
- QNTNKSLOFHEFPK-UPTCCGCDSA-N ubiquinol-10 Chemical compound COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC QNTNKSLOFHEFPK-UPTCCGCDSA-N 0.000 description 1
- 229940035936 ubiquinone Drugs 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 239000006200 vaporizer Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
- A61K9/1278—Post-loading, e.g. by ion or pH gradient
-
- 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
- A61K31/465—Nicotine; Derivatives thereof
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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]
Abstract
The present invention relates to the encapsulation of the drug Niflumic acid in liposomes with the purpose to create a new transdermal non-steroidal anti-inflammatory formulation. The Niflumic acid as well as its ester derivates, have been encapsulated into liposomes with different lipid formulations in order to achieve the increased effectiveness of the active compound. The liposome suspension, with or without the encapsulated drug has been formulated as a cream and a stability study of the final formulation has followed.
Description
In the period of in the past several and since people for drug molecule in liposome wrapper technology nourish very big interest, make this technology that very big progress arranged.
Various molecule is successfully sealed, and directly the result is that toxicity lowers, pharmacokinetic property makes moderate progress and makes medicine increase the selectivity and the specificity of tissue and target organ.
In the international literature catalogue, a large amount of lists of references about the liposome medicament dosage form are arranged.Wherein many still are in the clinical research stage, and also some has been registered and begun and has sold on market.
In the other medicines of liposome dosage form, we must should be mentioned that find pleasure in (Minoxidil) in econazole, amphotericin B, minot ground and some are in the anticancer and antiviral drugs in clinical research stage.
About the purposes of the saturating preparation of skin, the subject matter of medicine by cutaneous metastatic is that the permeability of ingredient is undesirable, or since medicine to transfer to the speed of blood and lymph too fast so that reduce in the time bar internal therapy concentration of needs.The liposome dosage form not only has gratifying permeability but also has can control the effect that active component discharges.These character make the liposome dosage form be used for skin ideally and treat thoroughly.
It is a principal object of the present invention to prepare liposome and anti-inflammatory substance niflumic acid and esters thereof are encapsulated among them.Niflumic acid is a kind of well verified active component, and it has been used to the saturating preparation of various skins.
Target of the present invention is the new liposome dosage form with top standard of development and has the antiinflammatory dosage form of advanced drugs kinetic property.This medicine can be applied to similar situation in arthritis and wound and the rheumatism.
Sixty-four dollar question to be solved by this invention is to select these lipids to carry out the preparation of liposome, and they will satisfy following standard:
Biocompatibility with human skin
Be made into liposome with required physicochemical properties (number of structure, form, diameter, lipid bilayer, crystallization and with time, temperature and concentration dependent stability).
Liposome seals and keeps the ability of the required physicochemical property of medicine to medicine.
Need in satisfying the lipid of above-mentioned standard, those select according to the result of study of pharmacokinetics.
The lipid molecule that preparation is estimated is some natural molecules, for example: HSPC (hydrogenated soybean lipid), EPC is (from the mixture of the saturated and unsaturated lipid of egg, and some synthetic lipids, for example: DSPC, DMPC and DPPC, they are saturated phosphatidylcholine esters.The methodology of technology, the physicochemical property of liposome, liposomal encapsulated drug system and the pharmacokinetic study of preparation liposome hereinafter will be provided.
Scientific method (complete and analyze description)
I. lipid and raw material supply, the preparation of niflumic acid ester
Be prepared for preparing lipid or some natural materials of liposome, for example: HSPC (hydrogenated soybean lipid), EPC or some synthetic lipid, for example: phospholipid DSPC, DMPC and DPPC.The aliphatic chain of synthetic lipid is stearic acid or myristic acid or Palmic acid, and they are different aspect the parameter of the fusing point of the number of carbon atom, chain length, aliphatic chain and decision liposome physicochemical property.
The preparation of liposome not only can be undertaken by different phospholipids incorporate, can also be undertaken by phospholipid is combined with the cholesterol of varying level.Cholesterol can be regulated the stability of liposome, and this discharges for controlled delivery of pharmaceutical agents is essential.Can also be with having following composition and the compositions similar to skin prepares liposome: ceramide, cholesterol, sulphuric acid cholesterol and fatty acid.Target of the present invention is the product that preparation has bigger possibility biocompatibility.
II. the preparation of liposome and physicochemical property
Preparation method:
A) hydration by lipid molecule prepares the lipid film.Carry out hydration after in rotary evaporation in vacuo instrument (dodging the formula vaporizer), removing organic solvent (chloroform).For the pH regulator of lipid internal milieu, the selection of hydrating agents is very important.TES (N-three [methylol] methyl 2-aminoethyl sulfonic acid), MES (2-[N-morpholino]-ethyl sulfonic acid), HEPES (N-[2-ethoxy] piperazine-N-2-ethyl sulfonic acid) and ammonium sulfate can be used, the mensuration of pH, osmotic pressure and ionic strength need be carried out them.The hydration of lipid causes them self to form multilamellar liposome.
B) formation of monolayer and few layer liposome.Use for skin is saturating, few layer liposome has bigger advantage (because volume is less thereby permeability is better) than multilamellar liposome.The method for preparing liposome is included under-70 ℃ multilamellar liposome is freezing, heats under the temperature that is higher than aliphatic chain (suitable-anti-) fusing point immediately then.This process repeats 10 times, final widow's layer liposome that form, and its big or small homogeneity for next step provides convenience.
C) adopt extrusion system, obtain the liposomal samples of homogeneous (with regard to diameter) size with many carbon of special diameter filter membrane.
D) isolate the buffer that is not encapsulated in the liposome by gel chromatography.
In order to implement this research, need preparation MLV (multilamellar carrier), SUV (little monolayer) and LUV (big monolayer) liposome, and estimate sealing, one side is the hydration part that the hydrophilic segment of niflumic acid enters unilamellar liposome, is that esters parent ester product packaging is in the lipid bilayer of multilamellar liposome on the other hand.
Physicochemical property
The physical and chemical parameter of the liposome that must estimate in this stage has:
Number-the form of diameter-diameter homogeneity-bilayer, thermodynamic stability (relevant with the lipid sample concentration), interactional existence in the sample, the probability that is separated with temperature.
The physics and chemistry technology that adopts is had big resolution capability, be appointed as quantitatively and light-thermal technology qualitatively.
1. quasi-elastic light scattering can be studied the full distribution of liposome diameter.
Possible Study of Interaction in the sample.The research of the agglomeration that liposome is possible.The evaluation (Bi-reftactiveness) that mode of appearance is learned.
2. microscopy.Analyze with image processing and bondedly to contrast microscopy and reef knot closes contrast microscopy (Nomarski-DIC),
This technology is representative greater than the liposome of 0.5 μ m to particle diameter.
3. atomic force microscopy (AFM): can the liposome of representative diameter between 10nm-2 μ m.Also can represent lipid bilayer.
4. differential scanning calorimetry is learned (DSC): the thermokinetics research of liposome stability.Phase and the evaluation and the feature that change mutually in the lipid bilayer.The indirect purity experiment of liposome.
III. drug molecule is sealed, the Study on Physico-chemical of medicine lipid system
To adopt different types of liposome to carry out sealing of drug molecule.
A) niflumic acid is sealed
Because liposome interior has different pH value with the outside, can niflumic acid be encapsulated into the inside of liposome according to the method that active component shifts.Contain the such fact of ionic group owing to be in the acid internal medium Chinese medicine of liposome molecule, this molecule will be accepted proton and encapsulated.Seal under the transition temperature that will occur in liposome fat chain.Seal percentage ratio and be about 60-80%.The ratio of niflumic acid and lipid is 1: 53 (theoretical value is 1: 50).Can successfully isolate non-encapsulated niflumic acid by gel chromatography, obtain containing the liposome of niflumic acid.Can be with HPLC and UV-Vis to sealing niflumic acid analysis.
With UV/Vis niflumic acid/lipid is estimated.For sealing of niflumic acid, can adopt MLV (multilamellar carrier), SUV (little single-carrier) and LUV (big single-carrier) liposome, the intrinsic value of maximum possible.
Greater than 90%, and the ratio of niflumic acid and lipid is 1: 55 (theoretical value is 1: 50) with the liposomal encapsulated ratio of MLV.
B) niflumic acid lipophilic esters seals
Niflumic acid lipophilic esters is encapsulated in the liposomal lipid bilayer.Adopt multilamellar liposome so that (bilayer) available volume is increased.From the process of the lipid evaporation organic solvent that is used for preparing lipid film (referring to 2a), adding lipophilic molecules.Isolate non-encapsulated medicine by gel chromatography, and carry out the analysis of medicine/lipid ratio.Carry out the analysis of medicine with HPLC.
C) physicochemical property of drug-to-lipid system
Page 41,2,3,4 in provided physical and chemical parameter.Adopt isothermal titration to carry out the thermokinetics research that drug substance is sealed in addition.
In this, people are for because the change that occurs in the physicochemical property in the liposome that drug encapsulation caused has very big interest.
Similar in the technology that is adopted and stage 2.
In addition, also adopt the titration of isothermal trace calorifics to carry out the thermokinetics research that drug molecule is sealed.The microscope upgrading of being recommended will provide more detailed expression for the chemical composition that is in the surface of liposome under the research.Especially being encapsulated under the situation of lipid bilayer, active component can be made chart.
IV. pharmacokinetic study
Pharmacokinetic study is included in buffer solution (external) and the experiment of the drug release in 50% rat plasma (in the body).
In order to study stability of drug, carried out the dynamics research relevant (refrigerator temperature is 2 ℃, 25 ℃ of room temperatures), and under 37 ℃, carried out the research of drug release with the time.
For progressively the discharging and avoid possible toxicity phenomenon of testing drug, under 45 ℃ and 55 ℃, carried out high temperature research.In all cases, with respect to entrapped pharmaceutical preparation, those free pharmaceutical preparatioies will be under the control by gel chromatography, and analyze with UV-Vis.Also measured the ratio of medicine and lipid.
Analytical method is as follows:
A) releasing research in buffer
TES (N-three [methylol] methyl 2-aminoethyl sulfonic acid), MES (2-[N-morpholino]-ethyl sulfonic acid), HEPES (the N-[2-ethoxy] piperazine-N-2-ethyl sulfonic acid.
This is the indication that medicine discharges from liposome.After in the specified gap that material is encapsulated into liposome, material is analyzed with HPLC (mobile phase is alcohol-water) and UV-VIS.
B) release in vitro of medicine on skin
Obtain skin of back on one's body from hairless mouse, remove fatty tissue with blade, heated 60 seconds, (chorium) isolates epidermis from chorium.Adopt liposome solutions and in the interval of standard, collect blood serum sample, analyze with HPLC.
C) experiment in the body that absorbs the drug on the skin
Gather serum or plasma sample, centrifugal after, extract active component and HPLC and UV-Vis and measure.
Adopt this method, can determine that medicine is at skin, blood, intravital local concentration and total absorption strength.
Exploitation-the quality control of V. final pharmaceutical dosage form
The liposome medicament that presents optimal absorption can be mixed with cream, gel or washing liquid.For this purpose, need to select the prescription of product, so that the liposome product can disperse and/or be dissolved in wherein.
From prepared product, selected two prescriptions, they have satisfied some standards in the best way, for example application approach, outward appearance and viscosity.
For the life-span of product is described, these two products have been carried out stability experiment, the parameter of being studied is as follows: outward appearance, pH, viscosity, solid residue, active component and anti-corrosion measure etc.Research is in different temperature (for example 4,25,37,45 ℃) and freezing-separate under the refrigerated endless form and carry out.
Also the concentration of product in microorganism of selecting has been carried out the microbiology experiment.Also carried out exciting (challenge) experiment to prove the effectiveness of corrosion protection system.
VI. the effectiveness of liposome medicament
A) pharmacokinetic study
Carry out according to the 4th section described method,, adopt the mice that does not have hair in vivo promptly at the external ecbatic that is used for.Ensuing method is described identical with the 4th section, and different is to substitute the liposome product with final products to be applied directly on the skin.The product of result of study and non-liposome dosage form is compared.
From the final products of previous stage, select one and have the dynamic (dynamical) product of optimal drug, but can also carry out the further improved research of the composition relevant with drug release.
B) pharmaceutical research
In vivo the pharmacological property of final selected product is tested.On the skin of hairless mouse, cause inflammation with ultraviolet light; test inflammation by the formation of measuring prostaglandin and free radical; because this can estimate by the reduction of natural inhibitor skin care effect, what they showed is that the antioxidant capacity of antioxidant such as vitamin E, vitamin C, ubiquinone and ubiquinol on skin descends.
Claims (17)
1. be encapsulated in the liposome with the anti-inflammatory drug niflumic acid and as all derivants of synthesizing ester, these liposomees are prepared by following lipid: EPC (egg phosphatidylcholine), DSPC (distearoyl phosphatidylcholine), DMPC (dimyristoyl phosphatidyl choline), DPPC (dipalmitoyl phosphatidyl choline), HSPC (hydrogenated soya phosphatide phatidylcholine), the compositions that their mixture, the above-mentioned lipid mixtures of mentioning and they and cholesterol and ceramide are formed.
Described in the claim 1 in inner fat layer and sealing at surface of liposome.
3. sealing described in the claim 1 is characterized in that new liposome product can be used as antiinflammatory, rheumatism and analgesic drug product and is applied topically to skin, eyes, ear and oral cavity, also can be applied to arthrosis and the similar imbalance relevant with wound.
4. be encapsulated in the liposome with radiolabeled niflumic acid and as all derivants of synthesizing ester, these liposomees are prepared by following lipid: EPC (egg phosphatidylcholine), DSPC (distearoyl phosphatidylcholine), DMPC (dimyristoyl phosphatidyl choline), DPPC (dipalmitoyl phosphatidyl choline), HSPC (hydrogenated soya phosphatide phatidylcholine), the compositions that their mixture, the above-mentioned lipid mixtures of mentioning and they and cholesterol and ceramide are formed.
5. sealing of the niflumic acid described in the claim 1,2 and 4 and all synthesizing esters thereof is characterized in that the method sealed pharmaceutically active to be transferred to liposome interior (pH gradient) by this method.
6. claim 1,2,3, liposome product described in 4 and their pharmaceutical dosage form is characterized in that can alleviating the inflammation of skin after topical therapeutic is carried out in skin, eyes, ear and oral cavity.
7. the niflumic acid described in the claim 1,2 and 3 and all synthesizing esters sealing in liposome thereof, the dissolution experiment that it is characterized in that medicine is to carry out under the condition of pH=1-10.
8. claim 1, the niflumic acid described in 2,3 and 7 and all synthesizing esters sealing in liposome thereof, the dissolution experiment that it is characterized in that medicine is to carry out under the condition of pH=4.5.
9. claim 12, the niflumic acid described in 3,7 and 8 and all synthesizing esters sealing in liposome thereof, the dissolution experiment that it is characterized in that medicine is to carry out under the condition of pH=7.1.
10. claim 1,2,3, niflumic acid and all synthesizing esters thereof behind liposomal encapsulated described in 4,5, it is characterized in that adopting have high resolution, qualitative, quantitatively reach the physical and chemical parameter that technology such as calorimetric obtain the medicine lipid system.
11. the liposome product described in the claim 1, to it is characterized in that utilizing these products to carry out in mice, rat under 2-55 ℃ on one's body external/interior medicine dynamics research.
12. pharmaceutical dosage form is characterized in that it contains claim 1, the niflumic acid of sealing described in 2,3 and 4 and all synthesizing esters thereof.
13. be used for skin and the saturating pharmaceutical preparation of skin described in the claim 12, it contains the niflumic acid of sealing, and can be mixed with cream, gel, ointment, skin cream, skin suspension, the saturating obedient sheet of skin and dipping dressing.
14. be used for oral pharmaceutical preparation described in the claim 12, it contains the niflumic acid of sealing, and can be mixed with collutory, gingiva solution, oral mucosa suspension, oral mucosa drop, oral mucosa gel, gingiva gel, oral mucosa solution, washing liquid of oral cavity.
15. the pharmaceutical preparation that is used for eye described in the claim 12, it contains the niflumic acid of sealing, and can be mixed with the eye drop of eye cream, eye ointment, eye gel, solution of eyedrop, eye drip suspension, slow release.
16. the pharmaceutical preparation that is used for ear described in the claim 12, it contains the niflumic acid of sealing, and can be mixed with ear frost, ear gel, credulous unguentum, an ear solution, an ear suspension, an ear Emulsion with the gill tampon.
17. liposome product and the claim 12 described in the claim 1,13,14, the pharmaceutical preparation described in 15,16, it contains the niflumic acid of sealing.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GR980100469 | 1998-12-24 | ||
| GR98100469 | 1998-12-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1331592A true CN1331592A (en) | 2002-01-16 |
Family
ID=10943556
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99814948A Pending CN1331592A (en) | 1998-12-24 | 1999-12-22 | Liposomic niflumic acid-new transdermal anti-inflammatory medicine |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP1140089A1 (en) |
| JP (1) | JP2002533394A (en) |
| KR (1) | KR20010089889A (en) |
| CN (1) | CN1331592A (en) |
| AU (1) | AU1673400A (en) |
| BR (1) | BR9917006A (en) |
| CA (1) | CA2357765A1 (en) |
| CZ (1) | CZ20012240A3 (en) |
| GR (1) | GR1003359B (en) |
| HU (1) | HUP0104853A3 (en) |
| IL (1) | IL143499A0 (en) |
| IS (1) | IS5964A (en) |
| MX (1) | MXPA01006462A (en) |
| NO (1) | NO20013015D0 (en) |
| PL (1) | PL349344A1 (en) |
| SK (1) | SK7962001A3 (en) |
| WO (1) | WO2000038681A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100377704C (en) * | 2002-11-26 | 2008-04-02 | 吉里德科学公司 | Liposomal formulations |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20060015534A (en) * | 2003-04-25 | 2006-02-17 | 더 펜 스테이트 리서치 파운데이션 | Method and system for systemic delivery of growth arresting, lipid-derived bioactive compounds |
| US20050255154A1 (en) | 2004-05-11 | 2005-11-17 | Lena Pereswetoff-Morath | Method and composition for treating rhinitis |
| JP4791082B2 (en) * | 2005-05-30 | 2011-10-12 | 株式会社クラレ | Liposomes and topical skin preparations containing the same |
| JP4931369B2 (en) * | 2005-05-31 | 2012-05-16 | ポーラ化成工業株式会社 | Liposomes and therapeutic compositions containing the same |
| PL1888033T3 (en) | 2005-06-09 | 2014-09-30 | Meda Ab | Method and composition for treating inflammatory disorders |
| BR112013003658B1 (en) | 2010-07-28 | 2022-02-22 | Life Technologies Corporation | Pharmaceutical composition comprising azide-modified isoprenoid fatty acid, carbohydrate and lipid, use of such components and method of inhibiting infectivity of a virus |
| US20120028335A1 (en) | 2010-07-28 | 2012-02-02 | Life Technologies Corporation | Anti-viral azide-containing compounds |
| AU2013212068B2 (en) | 2012-01-26 | 2018-02-15 | Life Technologies Corporation | Methods for increasing the infectivity of viruses |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4528193A (en) * | 1978-12-27 | 1985-07-09 | A. Natterman & Cie. Gmbh | Inflammation-preventing pharmaceutical composition of oral administration |
| EP0225162B1 (en) * | 1985-11-27 | 1992-01-22 | Ethicon, Inc. | Inhibition of post-surgical adhesion formation by the topical administration of non-steroidal anti-inflammatory drug |
| EP0249561B1 (en) * | 1986-06-12 | 1992-05-13 | The Liposome Company, Inc. | Compositions using liposome-encapsulated non-steroidal anti-inflammatory drugs |
| EP0825852B1 (en) * | 1995-04-18 | 2004-07-07 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Liposome drug-loading method and composition |
-
1998
- 1998-12-24 GR GR980100469A patent/GR1003359B/en not_active IP Right Cessation
-
1999
- 1999-12-22 SK SK796-2001A patent/SK7962001A3/en unknown
- 1999-12-22 AU AU16734/00A patent/AU1673400A/en not_active Abandoned
- 1999-12-22 MX MXPA01006462A patent/MXPA01006462A/en unknown
- 1999-12-22 IL IL14349999A patent/IL143499A0/en unknown
- 1999-12-22 PL PL99349344A patent/PL349344A1/en not_active Application Discontinuation
- 1999-12-22 CA CA002357765A patent/CA2357765A1/en not_active Abandoned
- 1999-12-22 EP EP99959605A patent/EP1140089A1/en not_active Withdrawn
- 1999-12-22 KR KR1020017008144A patent/KR20010089889A/en not_active Application Discontinuation
- 1999-12-22 JP JP2000590635A patent/JP2002533394A/en active Pending
- 1999-12-22 WO PCT/GR1999/000048 patent/WO2000038681A1/en not_active Application Discontinuation
- 1999-12-22 CZ CZ20012240A patent/CZ20012240A3/en unknown
- 1999-12-22 CN CN99814948A patent/CN1331592A/en active Pending
- 1999-12-22 BR BR9917006-0A patent/BR9917006A/en not_active Application Discontinuation
- 1999-12-22 HU HU0104853A patent/HUP0104853A3/en unknown
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2001
- 2001-06-08 IS IS5964A patent/IS5964A/en unknown
- 2001-06-18 NO NO20013015A patent/NO20013015D0/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100377704C (en) * | 2002-11-26 | 2008-04-02 | 吉里德科学公司 | Liposomal formulations |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010089889A (en) | 2001-10-12 |
| MXPA01006462A (en) | 2002-06-04 |
| HUP0104853A3 (en) | 2003-05-28 |
| HUP0104853A2 (en) | 2002-05-29 |
| NO20013015L (en) | 2001-06-18 |
| JP2002533394A (en) | 2002-10-08 |
| EP1140089A1 (en) | 2001-10-10 |
| CZ20012240A3 (en) | 2001-11-14 |
| IL143499A0 (en) | 2002-04-21 |
| NO20013015D0 (en) | 2001-06-18 |
| WO2000038681A1 (en) | 2000-07-06 |
| CA2357765A1 (en) | 2000-07-06 |
| GR1003359B (en) | 2000-04-10 |
| IS5964A (en) | 2001-06-08 |
| BR9917006A (en) | 2001-10-30 |
| AU1673400A (en) | 2000-07-31 |
| SK7962001A3 (en) | 2002-02-05 |
| PL349344A1 (en) | 2002-07-15 |
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