CN102349914B - 包含3,4-丙炔基全氢化嘌呤的药物组合物及其在阻滞神经元传递方面的应用 - Google Patents
包含3,4-丙炔基全氢化嘌呤的药物组合物及其在阻滞神经元传递方面的应用 Download PDFInfo
- Publication number
- CN102349914B CN102349914B CN201110208308.1A CN201110208308A CN102349914B CN 102349914 B CN102349914 B CN 102349914B CN 201110208308 A CN201110208308 A CN 201110208308A CN 102349914 B CN102349914 B CN 102349914B
- Authority
- CN
- China
- Prior art keywords
- present
- pharmaceutical composition
- gonyautoxin
- muscle
- propinoperhydropurines
- 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.)
- Expired - Fee Related
Links
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 26
- 230000005540 biological transmission Effects 0.000 title abstract description 9
- 230000001537 neural effect Effects 0.000 title abstract description 7
- 230000000903 blocking effect Effects 0.000 title abstract description 5
- 239000000203 mixture Substances 0.000 claims description 29
- ARSXTTJGWGCRRR-UHFFFAOYSA-N saxitoxin GTX2 Natural products NC(=O)OCC1NC(=N)N2CC(OS(O)(=O)=O)C(O)(O)C22NC(=N)NC12 ARSXTTJGWGCRRR-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 11
- 230000037303 wrinkles Effects 0.000 claims description 11
- ARSXTTJGWGCRRR-XXKOCQOQSA-N Gonyautoxin 2 Chemical compound NC(=O)OC[C@@H]1N=C(N)N2C[C@@H](OS(O)(=O)=O)C(O)(O)[C@@]22N=C(N)N[C@@H]12 ARSXTTJGWGCRRR-XXKOCQOQSA-N 0.000 claims description 9
- ARSXTTJGWGCRRR-LJRZAWCWSA-N [(3as,4r,9s,10as)-2,6-diamino-10,10-dihydroxy-9-sulfooxy-3a,4,8,9-tetrahydro-1h-pyrrolo[1,2-c]purin-4-yl]methyl carbamate Chemical compound [H+].NC(=O)OC[C@@H]1N=C(N)N2C[C@H](OS([O-])(=O)=O)C(O)(O)[C@@]22N=C(N)N[C@@H]12 ARSXTTJGWGCRRR-LJRZAWCWSA-N 0.000 claims description 8
- 230000001815 facial effect Effects 0.000 claims description 7
- 238000002676 facial rejuvenation Methods 0.000 claims description 7
- 239000006071 cream Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims 2
- 210000003205 muscle Anatomy 0.000 description 13
- 230000000694 effects Effects 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 108010057266 Type A Botulinum Toxins Proteins 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 208000007101 Muscle Cramp Diseases 0.000 description 7
- 208000005392 Spasm Diseases 0.000 description 7
- 210000002569 neuron Anatomy 0.000 description 7
- 206010002153 Anal fissure Diseases 0.000 description 4
- 208000016583 Anus disease Diseases 0.000 description 4
- 206010003629 Atonic urinary bladder Diseases 0.000 description 4
- 208000014094 Dystonic disease Diseases 0.000 description 4
- 208000009531 Fissure in Ano Diseases 0.000 description 4
- 208000008454 Hyperhidrosis Diseases 0.000 description 4
- 201000002904 focal dystonia Diseases 0.000 description 4
- 230000037315 hyperhidrosis Effects 0.000 description 4
- RPQXVSUAYFXFJA-HGRQIUPRSA-N saxitoxin Chemical compound NC(=O)OC[C@@H]1N=C(N)N2CCC(O)(O)[C@@]22N=C(N)N[C@@H]12 RPQXVSUAYFXFJA-HGRQIUPRSA-N 0.000 description 4
- RPQXVSUAYFXFJA-UHFFFAOYSA-N saxitoxin hydrate Natural products NC(=O)OCC1N=C(N)N2CCC(O)(O)C22NC(N)=NC12 RPQXVSUAYFXFJA-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 210000005070 sphincter Anatomy 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 206010033799 Paralysis Diseases 0.000 description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 3
- 229960004373 acetylcholine Drugs 0.000 description 3
- 230000003796 beauty Effects 0.000 description 3
- 206010005159 blepharospasm Diseases 0.000 description 3
- 230000000744 blepharospasm Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- -1 heterocycle guanidine compound Chemical class 0.000 description 3
- 230000004118 muscle contraction Effects 0.000 description 3
- 230000003387 muscular Effects 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- 230000003518 presynaptic effect Effects 0.000 description 3
- 230000029663 wound healing Effects 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 241000192700 Cyanobacteria Species 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- CETRDCWBMBILAL-XXKOCQOQSA-N Gonyautoxin 1 Chemical compound N=C1N(O)[C@@H](COC(=O)N)[C@@H]2NC(N)=N[C@@]22C(O)(O)[C@H](OS(O)(=O)=O)CN21 CETRDCWBMBILAL-XXKOCQOQSA-N 0.000 description 2
- JKKCSFJSULZNDN-HGRQIUPRSA-N Gonyautoxin 5 Chemical compound OS(=O)(=O)NC(=O)OC[C@@H]1N=C(N)N2CCC(O)(O)[C@@]22N=C(N)N[C@H]21 JKKCSFJSULZNDN-HGRQIUPRSA-N 0.000 description 2
- 206010018852 Haematoma Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- CETRDCWBMBILAL-LJRZAWCWSA-N [(3aS,4R,9S,10aS)-2-amino-5,10,10-trihydroxy-6-imino-9-sulfooxy-3a,4,8,9-tetrahydro-1H-pyrrolo[1,2-c]purin-4-yl]methyl carbamate Chemical compound NC(=O)OC[C@H]1[C@@H]2N=C(N)N[C@]22N(C[C@H](OS(O)(=O)=O)C2(O)O)C(=N)N1O CETRDCWBMBILAL-LJRZAWCWSA-N 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- VRRIYZJUSNMZMP-PJPYAQQDSA-N decarbamoylsaxitoxin Chemical compound OC[C@@H]1N=C(N)N2CCC(O)(O)[C@]32NC(N)=N[C@H]31 VRRIYZJUSNMZMP-PJPYAQQDSA-N 0.000 description 2
- VRRIYZJUSNMZMP-UHFFFAOYSA-N decarbamoylsaxitoxin hydrate Natural products OCC1NC(=N)N2CCC(O)(O)C22NC(=N)NC12 VRRIYZJUSNMZMP-UHFFFAOYSA-N 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- JKKCSFJSULZNDN-UHFFFAOYSA-N gonyautoxin 5 Natural products N=C1NC(COC(=O)NS(O)(=O)=O)C2NC(=N)NC22C(O)(O)CCN21 JKKCSFJSULZNDN-UHFFFAOYSA-N 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 210000003105 phrenic nerve Anatomy 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- 241000199914 Dinophyceae Species 0.000 description 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 description 1
- 241000237852 Mollusca Species 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 1
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000002316 cosmetic surgery Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002638 denervation Effects 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000001097 facial muscle Anatomy 0.000 description 1
- 210000001061 forehead Anatomy 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 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
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurosurgery (AREA)
- Ophthalmology & Optometry (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Cosmetics (AREA)
Abstract
本发明涉及包含3，4-丙炔基全氢化嘌呤的药物组合物及其在阻滞神经元传递方面的应用。
Description
本申请是2004年5月14日提交的题目为“包含3，4-丙炔基全氢化嘌呤的药物组合物及其在阻滞神经元传递方面的应用”的中国专利申请02822642.9(对应国际申请PCT/US02/36412)的分案申请。
关于联邦赞助研究或开发的声明
不适用。
关于缩微胶片附件的参考
不适用。
技术领域
本发明涉及包含杂环胍类化合物的药物组合物及其在阻滞神经元传递方面的应用。更具体地，本发明涉及三环3，4-丙炔基全氢化嘌呤及其在阻滞神经元传递方面的应用。
发明背景
社会大众认为在人的颈部和脸部出现皱纹不利于美感。这些痕迹反映了脸的老化，增加了人们对年龄的主观意识。从文明社会开始，人们已经使用天然的或合成的化合物，并开发了减缓这一问题的方法(即整形外科学)。例如，整形外科医生和化妆品中心正在试验肉毒杆菌毒素A，将其用作药物制剂，以通过去除脸部皱纹来使脸部年轻化。肉毒杆菌毒素A是一种以下列方式起作用的神经毒素：通过化学去神经支配、或通过阻滞神经肌肉片中神经递质乙酰胆碱的突触前释放，从而干扰了神经肌肉传递，使肌肉麻痹，并在长达4个月的时间里防止其收缩。在人脸部局部施用时，其效果是在使用该毒素后的7-10天内出现脸部年轻化，持续期为约4个月。肉毒杆菌毒素A已被用来治疗和肌肉痉挛、局灶性张力障碍、括约肌松弛(弛缓不能和肛裂)、多汗和膀胱松弛等有关的疾病。
尽管肉毒杆菌毒素A可作为有效的脸部年轻剂，但是它是一种本质上不稳定的酶。这种不稳定性使其应用和处理复杂，且效果不尽人意。事实上，它在使用前需要冷冻，并且必须在打开容器后4小时内使用。因为它是一种酶，所以肉毒杆菌毒素A不但会产生阻止其连续注射使用的抗体，而且也会导致变态反应。此外，其疗效被延迟7-10天，这是想要得到直接疗效的病人所不希望的。因此，需要一种稳定、作用快速且不是酶的脸部年轻剂。
发明概述
根据本发明的目的，提供了新的组合物和方法。在本发明的一个方面，提供了用于干扰神经元传递的包括有效量的至少一种三环3，4-丙炔基全氢化嘌呤的药物组合物。
在本发明的第二方面，提供了包括有效量的本发明组合物和面霜的脸部年轻用制剂。
在本发明的第三方面，提供了干扰神经元传递的方法，该方法包括使神经元和有效量的本发明药物组合物接触。
在本发明的第四方面，提供了干扰肌肉收缩的方法，该方法包括使肌肉和有效量的本发明组合物接触。
附图详述
图1是显示治疗人脸的施用图案的图。
发明详述
根据本发明，已经发现包括杂环胍类化合物的组合物，更具体地，三环3，4-丙炔基全氢化嘌呤可以用于很多美容或临床应用，无需任何外科手术，也没有副作用、变态反应、免疫排斥或血肿。本发明的组合物可以用来治疗以下疾病，所述疾病包括但不限于：睑痉挛、斜视、局灶性张力障碍、括约肌松弛(弛缓不能和肛裂)、多汗、膀胱松弛、与肌肉痉挛有关的疼痛治疗、肌肉痉挛、改善的伤口愈合和脸部皱纹。根据本发明，肌肉松弛是即时的，通常在少于5分钟内产生效果。
本发明的组合物包括有效量的至少一种由下式表示的三环3，4-丙炔基全氢化嘌呤：
其中R1和R5独立地为H或OH；R2和R3独立地为H或OSO3；R4独立地为COONH2、OH、H、COONSO3或COOCH3；和药理学上可接受的载体。这些三环3，4-丙炔基全氢化嘌呤可以从腰鞭毛虫、蓝细菌(cyanobacterias)中提纯，也可以在高度污染的软体动物中积累，它们在局部注射时也是暂时性肌肉松弛剂。可以使用任何药理学上可接受的载体，所述载体包括但不限于水。本发明的化合物通常在乙酸或0.09％氯化钠的溶液中稀释。
如本文所使用的，“有效量”是指该量足以通过阻滞神经肌肉片中神经递质乙酰胆碱的突触前释放来干扰神经元传递，从而干扰传递、使肌肉麻痹以防止其收缩，或使收缩的肌肉松弛。例如，本发明组合物的有效量按每毫升溶液中40单位三环3，4-丙炔基全氢化嘌呤计可以为100至800微升的量。活性单位就是为阻止小鼠的小腿二头肌发生 肌肉收缩，作用时间为1.5至2.0小时，所需要的本发明组合物的量。本发明的化合物通常用10mM(毫摩尔)、PH为4的乙酸溶液稀释。在本发明的一个具体实施方案中，本发明组合物按每毫升10mM，pH4的乙酸溶液计包括40单位。
在本发明的一个实施方案中，参照下表1，本发明的药物组合物包括蛤蚌毒素。在本发明的第二实施方案中，本发明的药物组合物包括Gonyautoxin 2。在本发明的第三实施方案中，本发明的药物组合物包括Gonyautoxin 3。在本发明的第四实施方案中，本发明的药物组合物包括Gonyautoxin 4。在本发明的第五实施方案中，本发明的药物组合物包括Gonyautoxin 5。在本发明的第六实施方案中，本发明的药物组合物包括新蛤蚌毒素(neoSaxtoxin)。在本发明的第七实施方案中，本发明的药物组合物包括Gonyautoxin 1。在本发明的第八实施方案中，本发明的药物组合物包括脱氨甲酰基蛤蚌毒素。
表1-三环3，4-丙炔基全氢化嘌呤
在本发明的具体实施方案中，药物组合物包括三环3，4-丙炔基全氢化嘌呤的混合物。所述化合物被纯化，单独和/或混合在一起使用。在一个优选实施方案中，本发明的药物组合物包括Gonyautoxin 2、 Gonyautoxin 3和蛤蚌毒素的混合物。在另一个优选实施方案中，本发明的药物组合物包括Gonyautoxin 4、Gonyautoxin 1、Gonyautoxin 5、Gonyautoxin 3和Gonyautoxin 2的混合物。在还一个优选实施方案中，本发明的药物组合物包括新蛤蚌毒素和Gonyautoxin 2。在又一个优选实施方案中，本发明的药物组合物包括蛤蚌毒素、新蛤蚌毒素、脱氨甲酰基蛤蚌毒素、Gonyautoxin 3和Gonyautoxin 2的混合物。本领域技术人员应理解，三环3，4-丙炔基全氢化嘌呤的其它混合物和组合均在本发明的范围内。
在本发明的一个实施方案中，本发明的化合物和有效量的肉毒杆菌毒素A组合使用。在这个实施方案中，本发明的药物组合物包括有效量的肉毒杆菌毒素A和有效量的至少一种三环3，4-丙炔基全氢化嘌呤。该组合物可以用于任何美容或临床应用，其中本发明的化合物或肉毒杆菌毒素A用于治疗：例如睑痉挛、斜视、局灶性张力障碍、括约肌松弛(弛缓不能和肛裂)、多汗、膀胱松弛、与肌肉痉挛有关的疼痛治疗、肌肉痉挛、改善的伤口愈合和脸部皱纹去除。
本发明的这些药物组合物可以用于很多美容和临床应用，其包括但不限于，睑痉挛、斜视、局灶性张力障碍、括约肌松弛(弛缓不能和肛裂)、多汗、膀胱松弛、与肌肉痉挛有关的疼痛治疗、肌肉痉挛、改善的伤口愈合和脸部皱纹。通常，本发明的药物组合物以制剂形式局部施用。为形成制剂，将有效量的本发明药物组合物及其共辅药(coadjuvants)加入到面霜中。和肉毒杆菌毒素A不同，这些制剂在室温下是稳定的，不需要冷藏，是无菌的，不产生抗体，本质上不是肽，速效，并且可以重复注射而无任何副作用。
不受理论的约束，当这些化合物被局部施用时，通过可逆地与单独的生物分子受体(即，在所有神经元和可兴奋细胞中存在的电压门控钠通道)相结合以阻滞神经冲动的传播或神经元传递，由此这些化合物发挥抗痉挛效果。通过与这一通道结合，没有钠进入神经元细胞； 不发生去极化，因此神经冲动的传播被阻止。这一作用机制阻滞了神经肌肉片中神经递质乙酰胆碱的突触前释放，从而干扰了神经肌肉传递，麻痹肌肉以防止其收缩，或使由于病理问题产生的收缩肌肉松弛。这种机制对美容目的具有部分效果，因为它不让某些脸部肌肉收缩，所有这些肌肉与皱纹形成有关且会导致皱纹形成，因此产生了广受欢迎的脸部年轻化效果。
本发明的药物组合物在将被麻痹的或防止其收缩的肌肉周围局部施用。在肌肉周围的不同部位，尤其是在神经分布最多的区域周围，施用量应该不超过一毫升。活性单位就是为阻止小鼠的小腿二头肌肌肉收缩，作用时间为1.5至2.0小时，所需要的本发明组合物的剂量。当维持浓度为20-40单位/毫升时，优选的剂量率为每个注射点100至800微升，这取决于肌肉的大小、灌注和解剖位置。效果立即显现，通常在注射后最多30秒时出现。最大效果可以在15分钟内看到。其有效时间取决于给药剂量、所针对的肌肉、以及所施加的体积和具体组分。这是所有临床应用和病理学的方式。注射可以使用1毫升、具有27-30规格针头的结合菌素类一次性注射器来完成。在斜视的情况下，可以在轮匝肌中注射50-100微升体积的二十至四十单位的剂量。本发明药物制剂的应用限于大于12岁的个体。对孕妇没有禁忌。
本发明的有利性质可以参照以下实施例看到，该实施例用于说明但非限制本发明。
实施例
在施用前，建立要治疗的人的照片记录，首先是她静止且放松的脸，然后皱眉产生最大的脸部收缩。然后在这个人的前额和将要注射制剂的两侧部位放置冰块。参照图1，施用时应遵循特定模式。在图1所示的每个黑点注射点旁注射一定的体积。包括Gonyautoxin 2，Gonyautoxin 3和蛤蚌毒素的(2∶1∶1体积/体积)混合物的药物组合物以40单位/毫升的剂量被应用。每次注射均使用1毫升、27-30规格 针头的结合菌素类一次性注射器。在注射后，每个注射点用二醇(bi-alcohol)或其它任何消毒剂浸湿的纱布进行消毒。完成脸部治疗所需要的总量为1.7毫升。
期望结果是很快在脸部平静时不能皱眉，也不显出皱纹。此人体验到与施用面霜膜时类似的脸部拉伸的感觉。此后，在注射部位施用冰，时间为5分钟。在施用后30分钟，病人习惯脸部拉伸的感觉。此时，此人走出，没有可辨别的皱纹、有着年轻的脸部外观，没有脸部痕迹或血肿，且完全正常。脸部在20分钟内恢复正常颜色，这取决于被注射的病人的松弛程度。整个施用程序最多花费10分钟，由针头和注射溶液产生非常轻的疼痛。只要注射器一拔出疼痛即消失。没有任何外伤和后遗症。可以在第二天检查病人，以后每十五天检查一次。在该剂量下，疗效持续一个月。在第一个月后，可以在需要时进行重复治疗。
根据上文，可以看出实现了本发明的所有目的和特征，也得到了其它有利结果。本文所包含的本发明的实施例和描述只是说明性的，而不是限制意义上的。
Claims (5)
1.组合物在制备用于减少皱纹的药物中的应用，所述组合物包括Gonyautoxin2和Gonyautoxin3的混合物。
2.一种减少皱纹的方法，其包括局部施用组合物和面霜的步骤，所述组合物包括Gonyautoxin2和Gonyautoxin3的混合物。
3.一种脸部年轻化的方法，其包括局部施用组合物和面霜的步骤，所述组合物包括Gonyautoxin2和Gonyautoxin3的混合物。
4.如权利要求2或3所述的方法，其中每次以50-100微升所述组合物施用。
5.如权利要求2或3所述的方法，其中每次以100-800微升所述组合物施用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CL2764/2001 | 2001-11-15 | ||
| CL27642001 | 2001-11-15 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028226429A Division CN1585642A (zh) | 2001-11-15 | 2002-11-14 | 包含3,4－丙炔基全氢化嘌呤的药物组合物及其在阻滞神经元传递方面的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102349914A CN102349914A (zh) | 2012-02-15 |
| CN102349914B true CN102349914B (zh) | 2015-01-28 |
Family
ID=4574581
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110208308.1A Expired - Fee Related CN102349914B (zh) | 2001-11-15 | 2002-11-14 | 包含3,4-丙炔基全氢化嘌呤的药物组合物及其在阻滞神经元传递方面的应用 |
| CNA028226429A Pending CN1585642A (zh) | 2001-11-15 | 2002-11-14 | 包含3,4－丙炔基全氢化嘌呤的药物组合物及其在阻滞神经元传递方面的应用 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028226429A Pending CN1585642A (zh) | 2001-11-15 | 2002-11-14 | 包含3,4－丙炔基全氢化嘌呤的药物组合物及其在阻滞神经元传递方面的应用 |
Country Status (18)
| Country | Link |
|---|---|
| US (5) | US20030100574A1 (zh) |
| EP (1) | EP1443932B1 (zh) |
| JP (2) | JP5331959B2 (zh) |
| KR (2) | KR20100135884A (zh) |
| CN (2) | CN102349914B (zh) |
| AU (1) | AU2002348370B8 (zh) |
| BR (1) | BR0214126A (zh) |
| CA (1) | CA2466697C (zh) |
| EA (1) | EA006739B1 (zh) |
| ES (1) | ES2401570T3 (zh) |
| HU (1) | HUP0402268A2 (zh) |
| IL (1) | IL161949A0 (zh) |
| MX (1) | MXPA04004543A (zh) |
| NO (1) | NO20042475L (zh) |
| NZ (1) | NZ533309A (zh) |
| PL (1) | PL370686A1 (zh) |
| WO (1) | WO2003047589A1 (zh) |
| ZA (1) | ZA200403765B (zh) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2401570T3 (es) * | 2001-11-15 | 2013-04-22 | Phytotox Limited | Composiciones farmacéuticas que contienen 3,4-propinoperhidropurinas y usos de las mismas para bloquear la transmisión neuronal |
| AU2005244096B2 (en) * | 2004-05-07 | 2011-03-17 | Algenis Spa | Transdermal administration of phycotoxins |
| MXPA06012962A (es) * | 2004-05-07 | 2007-06-12 | Phytotox Ltd | Metodos para el tratamiento de heridas con gonyautoxinas. |
| EP1877058A4 (en) * | 2005-05-05 | 2008-06-25 | Phytotox Ltd | USE OF PHYCOTOXINES IN VETERINARY MEDICINE APPLICATIONS |
| JP2009177044A (ja) * | 2008-01-28 | 2009-08-06 | Panasonic Corp | 電気ヒューズ回路 |
| CL2009000723A1 (es) * | 2009-03-24 | 2009-06-19 | Proteus Sa | Metodo de purificacion industrial de ficotoxinas biologicamente activas que comprende proporcionar una cantidad adecuada de una fuente de ficotoxinas como por ejemplo el cultivo de un clon de cianobacterias. |
| EP2459565B1 (en) * | 2009-05-07 | 2018-05-02 | The Board of Trustees of The Leland Stanford Junior University | Saxitoxin derivatives, methods and compositions for studying, imaging, and treating pain |
| EP2533785B1 (en) * | 2010-02-10 | 2014-04-23 | Phytotox Limited | Treatment of loss of sense of touch with saxitoxin derivatives |
| NZ710890A (en) * | 2013-03-15 | 2016-11-25 | Childrens Medical Ct Corp | Neosaxitoxin combination formulations for prolonged local anesthesia |
| GB201602576D0 (en) | 2016-02-12 | 2016-03-30 | Bergen Teknologioverforing As | Process |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6030974A (en) * | 1997-04-02 | 2000-02-29 | The Regents Of The University Of California | Method of anesthesia |
Family Cites Families (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3957966A (en) * | 1972-05-19 | 1976-05-18 | Gaf Corporation | Stabilized vitamin food coatings |
| US4001413A (en) * | 1973-06-12 | 1977-01-04 | Astra Pharmaceutical Products, Inc. | Pharmaceutical local anesthetic composition employing saxitoxin |
| US4029794A (en) * | 1973-06-12 | 1977-06-14 | Astra Pharmaceutical Products, Inc. | Pharmaceutical local anesthetic composition |
| US5183462A (en) * | 1990-08-21 | 1993-02-02 | Associated Synapse Biologics | Controlled administration of chemodenervating pharmaceuticals |
| GB9120306D0 (en) * | 1991-09-24 | 1991-11-06 | Graham Herbert K | Method and compositions for the treatment of cerebral palsy |
| US5562907A (en) * | 1993-05-14 | 1996-10-08 | Arnon; Stephen S. | Method to prevent side-effects and insensitivity to the therapeutic uses of toxins |
| US5437291A (en) * | 1993-08-26 | 1995-08-01 | Univ Johns Hopkins | Method for treating gastrointestinal muscle disorders and other smooth muscle dysfunction |
| AU2431995A (en) * | 1994-05-09 | 1995-11-29 | William J. Binder | Method for reduction of headache pain |
| US5504117A (en) * | 1994-05-27 | 1996-04-02 | Neptune Pharmaceutical Corporation | Pharmacologic preparation for the treatment of anal disorders |
| JP3517031B2 (ja) * | 1995-06-09 | 2004-04-05 | 日清紡績株式会社 | 生物学的活性物質の分析法 |
| JP3359193B2 (ja) * | 1995-07-21 | 2002-12-24 | キヤノン株式会社 | 露光装置及びそれを用いたデバイスの製造方法 |
| US5837265A (en) * | 1996-03-08 | 1998-11-17 | The Regents Of The University Of California | Chemically-modified clostridiatoxin with improved properties |
| US5721215A (en) * | 1996-03-20 | 1998-02-24 | Allergan | Injectable therapy for control of muscle spasms and pain related to muscle spasms |
| WO1998009523A1 (en) * | 1996-09-05 | 1998-03-12 | Massachusetts Institute Of Technology | Compositions and methods for treatment of neurological disorders and neurodegenerative diseases |
| CN1081034C (zh) * | 1997-03-07 | 2002-03-20 | 潘心富 | 一种双胍基氢化嘌呤环类化合物的戒毒药 |
| US6326020B1 (en) * | 1997-05-16 | 2001-12-04 | Children's Medical Center Corporation | Local anesthetic formulations |
| CA2505933C (en) * | 1997-07-15 | 2008-09-30 | Richard A. Schmidt | Use of botulinum toxin for treating urinary incontinence |
| US6432986B2 (en) * | 1997-07-21 | 2002-08-13 | Bruce H. Levin | Compositions, kits, and methods for inhibiting cerebral neurovascular disorders and muscular headaches |
| US6159944A (en) * | 1998-02-27 | 2000-12-12 | Synchroneuron, Llc | Method for treating painful conditions of the anal region and compositions therefor |
| BR9914891A (pt) * | 1998-10-27 | 2001-07-17 | Mayo Foundation | Processos para aperfeiçoamento de cura de ferimento |
| US6261573B1 (en) * | 1998-10-30 | 2001-07-17 | Avant Immunotherapeutics, Inc. | Immunoadjuvants |
| US6183747B1 (en) * | 1999-07-14 | 2001-02-06 | Kaijun Ren | Use of plant Momordica charactia extracts for treatment of acne acid |
| US6265379B1 (en) * | 1999-10-13 | 2001-07-24 | Allergan Sales, Inc. | Method for treating otic disorders |
| WO2001036588A2 (en) * | 1999-11-16 | 2001-05-25 | The General Hospital Corporation | Fusion proteins that specifically inhibit protein synthesis in neuronal cells |
| US6261572B1 (en) * | 2000-01-11 | 2001-07-17 | Allergan Sales, Inc. | Method for treating a pancreatic disorder with a neurotoxin |
| US6337075B1 (en) * | 2000-01-11 | 2002-01-08 | Allergan Sales, Inc. | Methods for treating diabetes |
| US6143306A (en) * | 2000-01-11 | 2000-11-07 | Allergan Sales, Inc. | Methods for treating pancreatic disorders |
| US6464986B1 (en) * | 2000-04-14 | 2002-10-15 | Allegan Sales, Inc. | Method for treating pain by peripheral administration of a neurotoxin |
| US6299893B1 (en) * | 2000-04-17 | 2001-10-09 | Marvin Schwartz | Method to reduce hair loss and stimulate hair regrowth |
| US6306423B1 (en) * | 2000-06-02 | 2001-10-23 | Allergan Sales, Inc. | Neurotoxin implant |
| US6306403B1 (en) * | 2000-06-14 | 2001-10-23 | Allergan Sales, Inc. | Method for treating parkinson's disease with a botulinum toxin |
| CN1284536C (zh) * | 2000-09-18 | 2006-11-15 | 威克斯医药有限公司 | 河豚毒素或蛤蚌毒素及其类似物在制备用于全身镇痛的镇痛药中的应用 |
| CN1203857C (zh) * | 2000-09-18 | 2005-06-01 | 威克斯医药有限公司 | 局部麻醉与镇痛的新方法 |
| CN1240702C (zh) | 2000-09-18 | 2006-02-08 | 威克斯医药有限公司 | 高获得率提取替曲朵辛的方法 |
| US6423319B1 (en) * | 2000-10-04 | 2002-07-23 | Allergan Sales, Inc. | Methods for treating muscle injuries |
| CN1236773C (zh) * | 2000-11-22 | 2006-01-18 | 南宁枫叶药业有限公司 | 用于镇痛、麻醉或治疗药物依赖性的制剂 |
| US20020086036A1 (en) * | 2000-12-05 | 2002-07-04 | Allergan Sales, Inc. | Methods for treating hyperhidrosis |
| CN1382443A (zh) * | 2001-04-25 | 2002-12-04 | 威克斯医疗仪器有限公司 | 钠离子通道阻断剂在制备用于局部神经麻醉或镇痛的药物中的应用 |
| CN1269482C (zh) * | 2001-05-18 | 2006-08-16 | 威克斯医药有限公司 | 钠离子通道阻断剂和阿片类镇痛剂在制备用于对哺乳动物进行协同镇痛的药物中的应用 |
| ES2401570T3 (es) * | 2001-11-15 | 2013-04-22 | Phytotox Limited | Composiciones farmacéuticas que contienen 3,4-propinoperhidropurinas y usos de las mismas para bloquear la transmisión neuronal |
| CN1194693C (zh) * | 2002-01-11 | 2005-03-30 | 中国科学院海洋研究所 | 麻痹性贝毒毒素作为制备疗治疼痛病症药物的应用 |
| US20040009180A1 (en) * | 2002-07-11 | 2004-01-15 | Allergan, Inc. | Transdermal botulinum toxin compositions |
-
2002
- 2002-11-14 ES ES02782296T patent/ES2401570T3/es not_active Expired - Lifetime
- 2002-11-14 WO PCT/US2002/036412 patent/WO2003047589A1/en active Application Filing
- 2002-11-14 KR KR1020107024821A patent/KR20100135884A/ko not_active Application Discontinuation
- 2002-11-14 NZ NZ533309A patent/NZ533309A/xx not_active IP Right Cessation
- 2002-11-14 US US10/294,288 patent/US20030100574A1/en not_active Abandoned
- 2002-11-14 JP JP2003548844A patent/JP5331959B2/ja not_active Expired - Fee Related
- 2002-11-14 MX MXPA04004543A patent/MXPA04004543A/es active IP Right Grant
- 2002-11-14 AU AU2002348370A patent/AU2002348370B8/en not_active Ceased
- 2002-11-14 BR BR0214126-4A patent/BR0214126A/pt active IP Right Grant
- 2002-11-14 HU HU0402268A patent/HUP0402268A2/hu unknown
- 2002-11-14 KR KR10-2004-7007435A patent/KR20040066816A/ko not_active Application Discontinuation
- 2002-11-14 CA CA2466697A patent/CA2466697C/en not_active Expired - Lifetime
- 2002-11-14 CN CN201110208308.1A patent/CN102349914B/zh not_active Expired - Fee Related
- 2002-11-14 PL PL02370686A patent/PL370686A1/xx not_active Application Discontinuation
- 2002-11-14 CN CNA028226429A patent/CN1585642A/zh active Pending
- 2002-11-14 EP EP02782296A patent/EP1443932B1/en not_active Expired - Lifetime
- 2002-11-14 IL IL16194902A patent/IL161949A0/xx unknown
- 2002-11-14 EA EA200400670A patent/EA006739B1/ru not_active IP Right Cessation
-
2004
- 2004-05-17 ZA ZA2004/03765A patent/ZA200403765B/en unknown
- 2004-06-14 NO NO20042475A patent/NO20042475L/no not_active Application Discontinuation
-
2006
- 2006-01-24 US US11/338,156 patent/US20060122200A1/en not_active Abandoned
-
2010
- 2010-10-01 JP JP2010223330A patent/JP2011068649A/ja active Pending
-
2012
- 2012-06-04 US US13/487,722 patent/US9301958B2/en not_active Expired - Fee Related
-
2013
- 2013-10-01 US US14/043,634 patent/US8889681B2/en not_active Expired - Fee Related
-
2014
- 2014-04-10 US US14/249,914 patent/US8871763B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6030974A (en) * | 1997-04-02 | 2000-02-29 | The Regents Of The University Of California | Method of anesthesia |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8889681B2 (en) | Use and application of a pharmaceutical composition containing a mixture of natural-origin heterocyclical guanidine, for cosmetology, wound healing, focal dystonia and muscular spasm-related clinical pathologies | |
| CA2607206C (en) | Transdermal administration of phycotoxins | |
| US7846483B2 (en) | Cosmetic composition for skin application suitable for relaxing expression wrinkles | |
| EP2533785A1 (en) | Treatment of loss of sense of touch with saxitoxin derivatives | |
| EP1135094B1 (en) | Method to reduce hair loss and stimulate hair regrowth | |
| EP0841895A1 (en) | Slimming cream based on plants | |
| CA2356543A1 (en) | Process and composition for improving the growth of human head hair | |
| CN100584375C (zh) | 一种疤痕治疗的新制剂 | |
| RU2286791C1 (ru) | Способ лечения рубцов | |
| RU2076709C1 (ru) | Способ лечения вибрационной болезни | |
| Andre et al. | Focal hyperhidrosis: Diagnosis, treatment, and follow-up................ Oliver Kreyden | |
| BRPI0214126B1 (pt) | Composição farmacêutica para interferir na transmissão neuronal, e, preparação para o rejuvenescimento facial |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150128 Termination date: 20201114 |