CN1230123A - 含碱性药物的酸加成盐的药物组合物 - Google Patents

含碱性药物的酸加成盐的药物组合物 Download PDF

Info

Publication number
CN1230123A
CN1230123A CN97197767A CN97197767A CN1230123A CN 1230123 A CN1230123 A CN 1230123A CN 97197767 A CN97197767 A CN 97197767A CN 97197767 A CN97197767 A CN 97197767A CN 1230123 A CN1230123 A CN 1230123A
Authority
CN
China
Prior art keywords
albuterol
acid
sumatriptan
medicine
caprate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN97197767A
Other languages
English (en)
Inventor
L·J·彭克勒
L·A·德科克
D·V·怀特塔克
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Farmarc Nederland BV
Original Assignee
Farmarc Nederland BV
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Farmarc Nederland BV filed Critical Farmarc Nederland BV
Publication of CN1230123A publication Critical patent/CN1230123A/zh
Pending legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/40—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
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further 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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/126—Acids containing more than four carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/843—Digestive system
    • Y10S530/847—Bile

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Nanotechnology (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • General Engineering & Computer Science (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medical Informatics (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明提供一种药物组合物,它包含碱性药物和脂肪酸或胆酸的酸加成盐。由此形成的酸加成盐增加碱性药物的经粘膜和透皮渗透性。本发明也公开这些酸加成盐、包含所述盐的包含配合物和所述盐的应用。

Description

含碱性药物的酸加成盐的药物组合物
本发明背景
本发明涉及透皮或粘膜释放的药物组合物，它包含作为活性组分的碱性药物和脂肪酸或胆汁酸的酸加成盐，并涉及一些新的碱性药物和脂肪酸或胆汁酸的酸加成盐。
口服给药途径是已知的最优选的给药途径。然而，口服给药后药物进入胃肠道，由于胃肠降解和/或肝代谢，很多治疗剂在进入系统前遭受大的消除，结果导致不稳定或较差的生物利用度。口服途径的另一个不利之处是药物吞咽困难，特别对于老年人或小儿科病人，或者存在恶心和呕吐现象的病人来说更是如此。
通过口腔、鼻、眼、直肠或阴道粘膜或者通过皮肤释放药物提供了一种避免口服途径缺陷的方法，使得药物直接到达系统循环。需要产生快速治疗作用时，通过粘膜途径释放药物是一种有用的非肠道释放药物的方法。透皮途径对于持续释放活性组分来说是有利的。
在本领域中有一些已知的将药物释放到口腔和鼻腔粘膜的方法(参见Chien，Y W ed.Novel Drug Delivery Systems，第二版，MarcelDekker 1992，183-188页，244-249)。这些方法包括给予口腔的颊的和舌下的片剂或锭剂、粘性贴剂、凝胶剂、溶液或喷雾剂(粉末、液体或气雾)和给予鼻腔的溶液或喷雾剂(粉末、液体或气雾)。栓剂和阴道栓是公知的直肠和阴道释放药物的盖仑剂型，而灭菌溶液、悬浮剂和油膏是类似的公知的眼释放药物的剂型(The PharmaceuticalCodex第12版，The Pharmaceutical Press；Remington’sPharmaceutical Sciences第18版，Mack Publishing Company)。透皮释放药物已被广泛描述(Osborne，D W和Amann，A.Topical DrugDelivery Formulations.Marcel Dekker Inc.)。
目前，通过粘膜和皮肤给予的药物相对较少，这是由于存在与药物难以转运穿过粘膜或皮肤膜相关的问题。给予的药物会根据药物分子的亲脂/亲水平衡值在生物膜的脂相和水相之间分配。根据pH分配理论，可离子化的物质通过生物膜渗透取决于未离子化物质的浓度。根据其pKa，碱性药物通常随粘膜表面的pH改变其离子化的程度，结果导致差的穿过膜的渗透作用。
可通过下列方法增加经生物膜吸收的药物：(i)增加药物溶解性，(ii)调节pH使其有利于形成药物的非离子化形式，(iii)加入生物粘合剂以改善释放系统与膜之间的接触和(iv)混合所谓的渗透增强剂。
有许多已知的影响药物穿过生物膜的渗透性的渗透增强剂(近期论述参见Walker，R B和Smith，E W Advanced Drug DeliveryReviews 1996，18，295-301)。
已经研究了中等链脂肪酸(C6，C8，C10和C12)的钠盐增强亲水药物穿过肠粘膜吸收的机制(Lindmark，T等，J.Pharmacol.Exp.Ther.1995，275(2)，958-964)。
Hoffmann-La Roche在美国专利5318781中要求保护通过使用癸酸或辛酸的盐(如钠盐)和阴离子表面活性剂增强抗生素的口腔吸收作用。
Sekisui化学有限公司在JP05185371中要求保护使用月桂酸二乙醇胺盐的含有吸收促进剂的透皮制剂。
已经报道了胆酸、辛酸或癸酸的钠盐作为鼻腔药物吸收促进剂的作用(Yamamoto，A等Int.J.Pharm.1993，93(1-3)，91-99)。
报道了使用癸酸钠、月桂酸钠和由油酸钠和牛磺胆酸钠组成的混合胶束来增加头孢美唑和菊粉的结肠吸收作用(Tomita，M.等，Pharm.Res.1988，5(6)，341-346)。
已经报道了辛酸钠、癸酸钠和月桂酸钠对菊粉大鼠鼻腔吸收的促进作用(Mishima，M等，J.Pharmacobio-Dyn 1987，10(11)，624-631)。
在Sekisui化学有限公司(日本)和Dainippon药物有限公司的WO9524197中教导了经皮可吸收的硬膏剂，该硬膏剂由支持层和在其一个侧面上形成的压敏胶层组成，所述压敏胶层含有压敏胶、药物和经皮吸收促进剂。
在Theratech Inc.的EP321870中描述了使用活性剂的游离碱和酸加成盐的组合物来增强皮肤的渗透性。制备局部使用的含有能够以游离碱和酸加成盐形式存在的渗透性活性药物的组合物。所使用的酸包括盐酸、酒石酸、硫酸、氢溴酸、甲磺酸和马来酸。
研究了普萘洛尔的脂肪酸盐作为另一种聚合物制剂用于持续释放口服制剂的可能性并以狗进行了评价。观察了在给予普萘洛尔月桂酸盐后在生物利用度上的增加(Auhgst，B J；Hussain，M A，Pharm.Res，1992，9(11)，1507-9)。
T Ogiso和M Shintani在J.Pharm.Sci(1990)，79(12)，1065-1071中的文章中，检测了一系列脂肪酸(包括月桂酸和肉豆蔻酸)对普萘洛尔经皮吸收作用的影响。结果表明通过与脂肪酸形成配合物而使显著比例的普萘洛尔渗透过角质层，该配合物将分离角质层和活表皮间界面中的各个成分，于是普萘洛尔分配进入富含水的组织。
T Ogiso等在Chem.Pharm.Bull.(1991)，39(10)，2657-2661中的文章中报道了具有各种摩尔配比的月桂酸的普萘洛尔的栓剂被给予大鼠直肠。以1∶1摩尔比含月桂酸的Witespol和macrogol栓剂中普萘洛尔的吸收作用远大于单独给予普萘洛尔的。该结果支持一部分普萘洛尔(与月桂酸形成1∶1配合物)会比单独的普萘洛尔更容易渗透通过直肠粘膜的概念。
P G Green等在Pharm.Res.(1989)，6(7)，628-632中的文章中公开了阳离子药物的亲脂性可通过与脂肪酸的羧酸根阴离子形成离子对来增加。在油酸和月桂酸存在下(提供合适的pH梯度)促进阳离子穿过异-Pr肉豆蔻酸盐膜转运。
用己二酸和硬脂酸制备的缓慢溶解的沙丁胺醇盐被作为气雾剂释放到肺中后延长药物作用时间的可能方式进行了研究(Jashnani，R等，J.Pharm.Sci.1993，82(6)，613-16)。
由上述现有技术证明，通过在含有活性剂的药物组合物中以一定浓度混合游离形式的或常常钠盐形式的脂肪酸或胆酸来增强活性剂透过皮肤、肠、口腔、鼻腔或直肠粘膜，活性剂以游离酸或游离碱的形式或以简单的可药用盐的形式存在。人们很少注意到，处理活性剂方法本身产生增强渗透通过膜屏障的作用。
由于环糊精及其衍生物具有与各种各样的化合物形成包含配合物的能力，发现其广泛用作增溶剂和稳定剂(参见，J Szejtli，Cyclodextrin Technology，Kluwer Academic Press和J Szejtli&K-H Fromming，Cyclodextrins in Pharmacy，Kluwer AcademicPress)。环糊精已被用于主要通过增加溶解性来增强药物肠部的吸收。目前，已表明环糊精对药物经皮渗透有正面和负面的影响(参见，Loftsson，T等，International Journal of Pharmaceutics 1995，115，255-258，Vollmer，U等，International Journal ofPharmaceutics 1993，99，51-58，Legendre，J Y等，EuropeanJournal of Pharmaceutical Sciences 1995，3，311-322和Vollmer，U等Journal of Pharmacy and Pharmacology 1994，46，19-22)。环糊精可改善药物的鼻腔吸收性(参见，Merkus，F.W等，Pharmaceutical Research 1991，8，588-592和Shao，Z等，Pharmaceutical Research 1992，9，1157-1163)并增强经舌下给予药物/环糊精配合物的吸收性(Behrouz，S等，Journal of ClinicalEndocrinology and Metabolism 1995，80，3567-3575)。环糊精也保护鼻腔粘膜免受渗透增强剂伤害(参见，Jabbal-Gill，I等，European Journal of Pharmaceutical Sciences 1994，1(5)，229-236)。
环糊精是含有6，7或8吡喃葡萄糖单位的水溶性笼形环状低聚糖。笼的内部或“腔”是疏水性的而外部是亲水性的。腔的大小随葡萄糖单位数量的增加而增加。已经制备了一些具有改善了溶解性的环糊精衍生物如烷基、羟基烷基和磺基烷基醚(参见，J Szejtli & K-HFromming，Cyclodxtrins in Pharmacy，Kluwer Academic Press和Stella，V J等，Pharmaceutical Research 1995，12(9)S205)。
本发明概述
本发明的第一方面是提供一种配制成经皮或经粘膜释放的药物组合物，它含有作为活性组分的式I化合物和一种或多种经皮或经粘膜释放用赋形剂：
                          B+RCOO-
其中B+为碱性药物的阳离子，且RCOO-为(a)不饱和或饱和的C8-C18单羧基脂肪酸或(b)胆酸的阴离子。
本发明第二方面是提供一种式I化合物和一种或多种经皮或经粘膜释放的赋形剂：
                          B+RCOO-
其中B+为碱性药物的阳离子，且RCOO-为(a)不饱和或饱和的C8-C18单羧基脂肪酸或(b)胆酸的阴离子，条件是所述化合物不是普萘洛尔月桂酸酯或沙丁胺醇硬脂酸酯。
本发明的第三方面是提供式I化合物和一种或多种经皮或经粘膜释放的赋形剂在制备经皮或经粘膜释放的药物中的用途：
                     B+RCOO-
其中B+为碱性药物的阳离子，且RCOO-为(a)不饱和或饱和的C8-C18单羧基脂肪酸或(b)胆酸阴离子。
具体实施方案的描述
本发明的第一方面是提供一种配制成经皮或优选经粘膜释放的药物组合物，它含有作为活性组分的式I化合物和一种或多种经皮或经粘膜释放用赋形剂：
                           B+RCOO-
其中B+为碱性药物的阳离子，且RCOO-为(a)不饱和或饱和的C8-C18单羧基脂肪酸或(b)胆酸阴离子。
“碱性药物”意指含有一个或多个可质子化官能基的药物。在下表中描述了合适的药物。标有*的药物为优选的。
    种类     实例
止痛药(阿片类)(opioids)及其衍生物     可待因吗啡苯甲基吗啡右丙氧芬美沙酮喷他佐辛舒芬太尼阿芬太尼芬太尼度冷丁布托啡诺丁丙诺啡海洛因二氢可待因
    dypyrone羟考酮地匹哌酮阿法罗定左啡诺右吗拉胺氢吗啡酮纳希啡羟吗啡酮氢可酮(烯丙吗啡-拮抗剂)(纳洛酮-拮抗剂)
  抗菌剂喹诺酮 诺氟沙星环丙沙星洛米沙星balofloxacin氧氟沙星帕氟沙星多氟啶酸temafloxacincinafloxacin培氟沙星tosufloxacin依诺沙星氨氟沙星氟罗沙星
  氨基糖甙类   链霉素阿米卡星庆大霉素妥布霉素
    新霉素交沙霉素大观霉素卡那霉素新霉素B巴龙霉素sissomycin紫霉素
    糖肽类     万古霉素
    Lincosamides     克林霉素林可霉素
青霉素类、头孢菌素类及其相关的β-内酰胺类     头孢吡肟头孢甲肟头孢替安头孢氨苄巴氨西林仑氨西林匹氨西林酞氨西林
    大环内酯类     红霉素竹桃霉素
    四环素类     四环素米诺霉素罗利环素美他环素甲氯环素
    抗分枝杆菌剂     异烟肼乙胺嘧啶乙胺丁醇
    抗病毒剂     阿昔洛韦噻喹努佛
    indinavir更昔洛韦全刚烷胺吗啉胍金刚乙胺泛西洛维扎西他宾cidofovirvalacyclovirlamivudinenevirapine
    抗原生动物剂     甲硝唑特硝唑喷他咪阿的平卢咪唑双氯苄氨胍依米丁二氢依米丁卤夫酮乙啡啶美拉胂醇
    防腐剂     氨丫啶
    抗真菌剂     酮康唑伊曲康唑咪康唑
    益康唑克霉唑两性霉素B布康唑氯米达唑氯康唑地马唑芬替康唑制霉菌素氯康唑益康唑咪康唑噻康唑
    抗抑郁药(所有的种类)     氯米帕明洛非帕明苯乙肼反苯环丙胺二苯噻庚英去甲丙咪嗪(nortryptaline)阿米替林氧化丙咪嗪米安舍林马普替林地昔帕明氯哌三唑酮氟西汀曲半帕明西酞普兰多塞平三氟戊肟胺
    氯苯咪嗪诺米芬辛帕罗西汀
    抗糖尿病药     格列吡嗪甲福明苯乙氟明
    抗惊厥药     卡马西平乙琥胺苯妥英扑米酮甲琥胺
抗胆碱能药(抗毒蕈碱药)(所有的类)     阿托品苯扎托品东莨菪碱后马托品莨菪碱奥芬那君哌仑西平丙环定替仑西平丙胺太林双环维林比哌立登苯海索奥昔布宁异丙托胺(ipratropium)派喷酯美喷酯环喷托酯
    抗蠕虫药     阿苯达唑甲苯达唑
    氟苯达唑芬苯达唑噻嘧啶伊维菌素
    抗痛风药     别嘌醇秋水仙碱
    抗组胺药和酚噻嗪(所有的种类)     氯苯那明茶苯海明羟嗪苯海拉明溴马秦阿司咪唑氯雷他定乙酰丙嗪硫利达嗪溴苯那敏卡比沙明氯环利嗪氯吡拉敏对氯苯丁胺氯普噻吨右氯苯那敏安他唑啉阿扎他定革苄酞嗪氯马斯汀
    克立咪唑cyroheptadine二苯拉林多西拉敏氟桂利嗪
    美喹他嗪美克洛嗪美吡拉敏非尼拉敏特非那定曲普利啶阿利马嗪依巴斯汀桂利嗪
    抗偏头痛药     麦角胺双氢麦角胺美西麦角舒马曲坦*naritriptan*almotriptanzolmitriptan*rizatriptan*eletriptan氟美烯酮苯噻啶
    镇咳药和粘液溶解药     右美沙芬福尔可定乙酰半胱氨酸那可丁
    抗肿瘤药和免疫抑制剂     硫唑嘌呤甲基尿嘧啶氟尿嘧啶长春新碱长春碱美法仑环磷酰胺
    氨鲁米特巯嘌呤他莫昔芬苯丁酸氮芥柔红霉素氮芥阿霉素
    抗疟药     奎宁氯喹乙胺嘧啶阿莫地喹哌喹氯胍甲氟喹伯氨喹卤泛群
抗焦虑药、镇静药、安眠药、精神抑制药苯并二氮卓类     溴西泮硝西泮地西泮奥沙西泮氯硝西泮chlorazepate劳拉西泮咪达唑仑三唑仑氟硝西泮
    butyrophenones     氟哌利多氟哌啶醇
    巴比妥盐     阿洛巴比妥阿普比妥苯巴比妥
    异戊巴比妥巴比妥丁巴比妥
    其它     佐匹克隆羟嗪丁螺环酮坦度吡酮
    支气管扩张药(其它)     茶碱
    心血管药a)β-阻滞药     醋丁洛尔阿普洛尔阿替洛尔拉倍洛尔美托洛尔纳多洛尔噻吗洛尔propanolol吲哚洛尔妥拉洛尔索他洛尔氧烯洛尔布尼洛尔卡拉洛尔茚诺洛尔
    b)抗心律失常药/强心药     丙吡胺美西律妥卡尼安博律定普鲁卡因胺奎尼丁多巴酚丁胺
    c)钙通道阻滞剂(所有的类)     维拉帕米地尔硫卓
    氨氯地平非洛地平尼卡地平加洛帕米普尼拉明
    c)抗高血压药/血管扩张药     二氮嗪胍乙啶可乐定肼屈嗪双肼屈嗪米诺地尔哌唑嗪酚苄明利血平酚妥拉明哌克昔林吲达帕胺异喹胍巴美生倍他尼定多巴酚丁胺吲哚拉明
    d)ACE抑制剂     卡托普利*依那普利*赖诺普利雷米普利*咪哒普利
    CNS刺激剂/减食欲药     哌醋甲酯芬氟拉明苯丙胺甲苯丙胺
    贝美格咖啡因右苯丙胺chlorphetamine芬坎法明普罗林坦
    利尿剂     呋塞米乙酰唑胺阿米洛利氨苯喋啶(triampterene)苄氟噻嗪氯噻嗪氯噻酮环噻嗪氢氟噻嗪氢氯噻嗪氢氟噻嗪
    胃肠道治疗剂a)、动力增强剂、调节剂和止吐药 多潘立酮甲氧氯普胺*西沙必利丙氯拉嗪哌仑西平西尼必利噻克利嗪*氯丙嗪甲哌氯丙嗪异丙嗪
    c)、酸分泌调节剂     西咪替丁雷尼替丁法莫替丁奥美拉唑
    尼扎替丁
    d)、止泻药     洛哌丁胺*地芬诺酯*
    e)、催吐剂     阿朴吗啡
    肌松剂     氯唑沙宗rocuronium琥珀胆碱维库胺(vecuronium)阿曲库胺法扎胺(fazadinium)多沙胺米伐克龙泮库胺筒简毒箭哌库胺十烃胺替托尼定piridinol琥乙胺
    胆碱能药     乙酰胆碱苄吡胺依酚胺毒扁豆碱新斯的明吡斯的明
   β-肾上腺素能激动剂     肾上腺素麻黄碱伪麻黄碱阿米福林羟甲唑林噻洛唑林特布他林*
    沙丁胺醇*沙美特罗*苯丙醇胺环喷他明苯福林异丙肾上腺素非诺特罗*扎莫特罗
    其它CNS活性剂     多巴胺左旋多巴
    内分泌药     溴隐亭丙硫氧嘧啶
    局麻药     利多卡因*普鲁卡因*丁卡因布比卡因*布他卡因奥布卡因甲哌卡因可卡因丙胺卡因阿米卡因氯普鲁卡因辛可卡因依替卡因丙氧卡因tropacocaine
    其它药散瞳药 环喷托酯
    Antiglaucoma     醋甲唑胺dorzolamide乙酰唑胺
    鸦片样肽     dynorphins*enkephalins
    肽     缩宫素加压素
优选的药物包括sumatriptan、沙丁胺醇(也称作舒喘灵)、可待因和洛哌丁胺。
不饱和或饱和的C8-C18单羧基脂肪酸可以是任何由食品衍生的脂肪和油制备的单羧酸，所述的食品由食品和药品管理局批准(CFR21172.860)。实例包括：
C8     辛酸CH3(CH2)6COOH
C10    癸酸CH3(CH2)8COOH
C12    月桂酸CH3(CH2)10COOH
C14    肉豆蔻酸CH3(CH2)12COOH
C16    棕榈酸CH3(CH2)14COOH
C18    硬脂酸CH3(CH2)16COOH
        油酸CH3(CH2)7CH：CH(CH2)7COOH
胆酸包括所有由胆汁衍生的单元羧酸，包括：甘氨胆酸，甘氨脱氧胆酸，胆酸，脱氧胆酸，牛磺胆酸和牛黄脱氧胆酸。
上述优选的碱性药物所使用的优选的阴离子为癸酸根、月桂酸根和甘氨脱氧胆酸根阴离子。
按照本发明，在碱性药物阳离子和脂肪酸或胆酸阴离子之间形成固体、分离形式的酸加成盐。
已知，脂肪酸和胆酸用作渗透增强剂，即改变作为屏障的膜功能的化合物或增加所需药物跨屏障的流量。这些酸加成盐的形成促进了碱性药物的透粘膜或透皮渗透。
术语“粘膜”是指位于口腔、鼻腔、直肠、阴道和眼腔的上皮膜。
术语“皮肤”意指任何皮肤表面。
本发明的药用活性剂或药物的脂肪酸和胆酸加成盐的特征在于较低的水溶性。该盐可通过任何常规的方法来制备如将药物的游离碱溶解在合适的溶剂如预先脱水的低级醇(优选甲醇或乙醇)中而获得半饱和溶液，搅拌下，向其中加入1摩尔当量的脂肪酸或胆酸。可将所得溶液在40-60℃温度下加热1-几小时。通过在真空下旋转蒸发除去溶剂并在真空中升高温度下干燥到恒重。另外，将脂肪酸或胆酸的钠盐在升高的温度下溶于水中。药物的商购盐(如盐酸盐、硫酸盐、琥珀酸盐、磷酸盐等)的溶液在升高的温度和搅拌下被缓慢加入。所得溶液被冷却到室温，过滤收集加成的盐沉淀物、用冷水洗涤并在真空下干燥。
通过与环糊精复合可增加药物的脂肪酸或胆酸加成盐的水溶性。环糊精可以是α、β或γ环糊精或其衍生物。环糊精包含复合物可基于成分之间的液态、固态或半固态的反应来制备(J Szeitli，cyclodextrin Technology，Kluwer Academic Press)。该包含复合物可通过常规方法来制备，如在少量水存在下捏合1∶1摩尔/摩尔量的盐和环糊精而产生均匀的糊状物。将混合物剧烈捏合0.25-4小时，然后在升高的温度和真空下干燥。所得产物的特征在于，相对于游离的未复合的酸加成盐来说，增加了25℃温度下的药物的水溶性。
本发明优选的药物组合物是，含有以能快速溶解的环糊精包含复合物存在的治疗剂量的脂肪酸或胆酸加成盐形式的碱性药物的舌下片。舌下给药的优选化合物包括需要快速产生治疗反应的或常规释放受限制的治疗类药物(止痛药、抗偏头痛药、止吐药、抗焦虑药、止泻药、抗心律失常剂、抗高血压药、抗绞痛药、抗气喘药、激素、基于肽的药物)。组合物可另外含有渗透增强剂如laurocapram或十二烷基硫酸钠。可加入合适量的常规赋形剂如粘合剂(微晶纤维素)、崩解剂(羧甲基纤维素钠)、缓冲剂(氨丁三醇、碳酸氢钠、碳酸钠)、芳香剂、润滑剂(硬脂酸镁、硬酯基富马酸钠)和organopletic修饰剂(木糖醇)。除芳香剂和润滑剂外的赋形剂与复合物一起制粒并干燥。干燥的颗粒与润滑剂和芳香剂一起过筛并混合。在20-50N下，将混合物压制成舌下片。
部分或完全以环糊精包含复合物存在的酸加成盐可与常规药物赋形剂一起按本领域已知的方法配制成单向释放的持续释放颊片或贴剂。优选的持续释放颊片或贴剂的赋形剂是粘合聚合物如交联的聚丙烯酸(carbomers，polycarbophils)。
酸加成盐或酸加成盐的水溶性环糊精复合物可按本领域已知的方法配制成面颊或舌下给药的滴剂、喷雾剂或胶剂。优选的赋形剂包括粘度调节剂(羟丙基甲基纤维素、carbomers、polycarbophils、壳聚糖、瓜尔胶、藻酸盐)、芳香剂、缓冲剂(氨丁三醇、碳酸氢钠、碳酸钠)、防腐剂(溴硝丙二醇、氯苄烷铵、EDTA、葡萄糖酸洗必太)和抗氧剂(N-乙酰-半胱氨酸、亚硫酸钠、sodium metabisulfite)。
酸加成盐或酸加成盐的水溶性环糊精包含复合物可按常规方法配制成吸入或鼻腔给药的粉剂。优选的赋形剂包括粘合聚合物以增加保留时间(carbomers、polycarbophils、壳聚糖)。
该盐的水溶性环糊精包含复合物可按本领域合适的方法配制成水性鼻腔喷雾剂。优选的赋形剂包括粘合聚合物以增加保留时间(carbomers、polycarbophils、壳聚糖)、粘度调节剂(烷基纤维素、羟基烷基纤维素、羟丙基甲基纤维素、carbomers、polycarbophils、壳聚糖、瓜尔胶、藻酸盐)、缓冲剂(氨丁三醇、碳酸氢钠、碳酸钠)、防腐剂(溴硝丙二醇、氯苄烷铵、EDTA、葡萄糖酸洗必太)和抗氧剂(N-乙酰-半胱氨酸、亚硫酸钠、sodium metabisulfite)。
酸加成盐或酸加成盐的水溶性环糊精包含复合物可按常规方法配制成直肠给药的栓剂。
酸加成盐或酸加成盐的水溶性环糊精包含复合物可按常规方法配制成阴道给药的阴道栓。
该酸加成盐可按常规方法配制成经眼给药的眼药膏。
酸加成盐或酸加成盐的水溶性环糊精包含复合物可按常规方法配制成经眼给药的滴眼剂。
在The Pharmaceutical Codex 12th Edition，The PharmaceuticalPress；Remington’s Phamaceutical Science 18th Edition，MackPublishing Company中可以找到配制和制备舌下、面颊、鼻腔、直肠、阴道和眼用药物组合物的一般原则。已经广泛地评论了透皮药物组合物[Osborne，D.W and Amann，A.topical Drug Delivery Formulation，Marcel Dekker Inc.]。
本发明包括能够与脂肪酸或胆酸形成酸加成盐的药物活性剂的广泛的用途。本发明组合物可用于将药物活性剂输送到下列靶区域：(1)口的舌下表面或底部，(2)口腔，(3)牙床，(4)鼻腔，(5)直肠或结肠，(6)阴道，(7)眼腔或眼盲管和(8)皮肤。
优选的药物形式是舌下给药片，鼻腔喷雾剂，颊片，栓剂(直肠和阴道)，透皮用贴剂和表面用凝胶剂。
现在提供本发明实施例。
实施例1
在搅拌下，将Sumatriptan碱(2.29g；7.75mmol)溶解在煮沸的乙酸乙酯(300mL)中。将癸酸(1.33g；7.75mmol)溶解在乙酸乙酯(10ml)中并一次加入Sumatriptan碱溶液中。将该热溶液再搅拌10分钟并冷却至室温。通过旋转蒸发将溶剂蒸发掉，得到淡黄色油状物。加入正己烷(50ml)，形成白色沉淀，将其真空过滤。将该沉淀用正己烷洗涤并在室温下干燥得到Sumatriptan碱癸酸盐，为淡黄色固体(2.79g；77.4％).通过DSC和FT-IR确定Sumatriptan碱癸酸盐的特性。DSC得到一个从94.6℃开始的单一、尖锐的吸热峰。该FT-IR明显不同于Sumatriptan碱的FT-IR。
实施例2
在磁搅拌下，将沙丁胺醇碱(13.91g；58.13mmol)溶解在乙醇(600ml；96％)中，得到淡黄色液体。在剧烈搅拌下加入癸酸(10.01g，58.11mmol)并持续搅拌直至固体物质溶解。通过旋转蒸发除掉溶剂得到淡黄色粘性半固体。将其溶解在热乙酸乙酯(300ml)中，然后在5℃下贮存36小时，得到细白色固体沉淀。通过真空过滤除掉母液，并将沉淀用冷的乙酸乙酯洗涤。通过将该沉淀在35℃和0巴大气压下贮存6小时除去任何残留的溶剂。得到沙丁胺醇癸酸盐为白色固体(18.93g；79.13mmol)。含湿量K.F.0.32％；熔点99.4℃(在DCS差示热分析图中吸热开始的温度)。沙丁胺醇碱在沙丁胺醇癸酸盐中的理论百分数为58.14％。通过实验得到的沙丁胺醇碱在沙丁胺醇癸酸盐中的百分数为56.42％。该饱和水溶液的PH为7.24。水溶解度为4.76mg/ml。
实施例3
将沙丁胺醇碱(4.00g；16.72mmol)溶解在乙醇(200ml；99.7-100％)中，向其中加入月桂酸(3.681g；18.39mmol；相对沙丁胺醇碱过量10％摩尔)并溶解。淡黄色溶液形成。通过旋转蒸发除掉乙醇，得到粘性淡黄色残渣。通过在水浴(60℃)上缓慢加热，将该残渣溶解在乙酸乙酯(10ml)中。将该溶液在冰箱中放置过夜。白色沉淀形成，将其通过真空过滤分离并用10ml冷的乙酸乙酯洗涤。将该沉淀进一步在40℃的真空烘箱中干燥16小时。得到沙丁胺醇月桂酸盐的白色粉末(6.6461g；86.5％产率)。熔点104℃(在DSC差示热分析图中吸热开始的温度)。在理论上，沙丁胺醇月桂酸盐含54.43％m/m沙丁胺醇碱。
实施例4
在剧烈搅拌下，将沙丁胺醇碱(1.2007g；.5.02mmol)溶解在乙醇(100ml)中。在搅拌下加入甘氨脱氧胆酸(Glycodeoxycholic acid)(2.4601g；水含量：4.25％w/w；5.25mmol～5％摩尔过量)并溶解。得到澄清、无色的溶液。通过真空旋转蒸发除掉乙醇，得到粘性黄色残渣。将乙酸乙酯(200ml)加入残渣中并将该混合物在水浴中加热同时不停地搅拌。当黄色残渣溶解时，白色沉淀形成。连续搅拌直至黄色残渣消失。将该乙酸乙酯溶液在冰浴中冷却。将沉淀通过真空过滤分离并在40℃烘箱中干燥20小时，得到沙丁胺醇甘氨脱氧胆酸盐(3.662g；水含量：4.95％w/w；％产率；97.9％)。通过从50到200℃差示扫描量热法分析得不到明显的热效应。在110℃以后缓慢地分解是显而易见的。饱和水溶液的PH为6.12。水溶解度大于8.35mg/ml。沙丁胺醇碱在沙丁胺醇甘氨脱氧胆酸盐中的理论百分数为34.74％。
实施例5
将可待因碱(4.0016g；12.60mmol)溶解在乙醇(100ml)中。在搅拌下加入癸酸(2.3902g；13.86mmol)并溶解。将乙醇真空除掉。将残渣再分散在乙酸乙酯(25ml)中，然后将其真空除掉，并在水浴(60℃)加热下，将残渣再溶解在乙酸乙酯(10ml)中。将该乙酸乙酯溶液在冰箱中放置16小时得到白色沉淀，将其通过真空过滤分离并用冷的乙酸乙酯(20ml)洗涤。该沉淀是非常容易潮解的，并且在放置中变为粘性、澄清的块状物。将该块状物再溶解在乙酸乙酯(200ml)中，将溶剂蒸发得到粘性黄色残渣。将该残渣在8℃下贮存48小时得到淡黄色固体。将该固体在25℃下真空(0巴)干燥。得到可待因癸酸盐为淡黄色固体(5.7301g；89.6％产率)。通过差示扫描量热法分析该物质以便测定熔点。然而从50到200℃的热分析表明无明显热效应。
实施例6
在搅拌下，将可待因碱(4.0002g；12.60mmol)溶解在乙醇(100ml；99.7-100％)中。将月桂酸(2.7822g；13.86mmol；相对可待因碱过量10％)溶解在乙醇/可待因溶液中。将得到的溶液搅拌5分钟。将乙醇通过旋转蒸发除掉，得到淡黄色残渣。通过在水浴(60℃)上加热，将该残渣再分散在乙酸乙酯(10ml)中。当所有的物质再溶解后，将该溶液在4℃下放置16小时。白色沉淀形成并将其通过真空过滤分离。将该沉淀在40℃真空烘箱中再干燥16小时，得到可待因月桂酸盐(2.4757g；36.50％)。通过差示扫描量热法分析该物质以便测定熔点。然而，从50到200℃的热分析表明无热效应。
实施例7
将甘氨脱氧胆酸钠(0.1211g；～0.24mmol)溶解在热的(80℃)去离子水(50ml)中。将洛哌丁胺HCl溶解在热的(80℃)去离子水(100ml)中。在80℃搅拌下，将洛哌丁胺HCl溶液滴加到甘氨脱氧胆酸钠溶液中。当加入洛哌丁胺HCl溶液后立即有白色沉淀形成。加完洛哌丁胺HCl溶液后，将得到的悬浮液在80℃下搅拌5分钟。将该悬浮液冷却至室温，然后通过滤纸(Whatman No 5)过滤。将该沉淀在40℃烘箱中再干燥16小时。得到白色粉末(0.0771g；34.36℃)。差示扫描量热法分析得到熔点，并表明从50到250℃无热效应。
实施例8
通过捏合方法，将Sumatriptan癸酸盐和羟丙基-β环糊精(HPB)复合。Sumatriptan癸酸盐(1.254g)和HPB(3.748g)混合在一起。加入水(4.5ml)并将该混合物在乳钵中用研杵研磨形成均匀的糊状物。连续研磨30分钟。然后，将该糊状物在真空烘箱(40℃；0巴)中干燥48小时。将该固体块状物粉碎，通过60目筛并重新放回烘箱(40℃；0巴)中12小时以确保该配合物干燥均匀。通过HPLC分析Sumatriptan碱的含量，并通过Karl Fischer分析含湿量得到下列结果：Sumatriptan碱为16.40％并且含湿量为3.45％。通过DSC，FT-IR和XRD确定该配合物的特性。
实施例9
通过捏合方法，将Sumatriptan癸酸盐和γ-环糊精复合。Sumatriptan癸酸盐(1.325g)和γ-环糊精(3.675g)混合在一起。加入水(6ml)并将该配合物在乳钵中用研杵研磨形成均匀的糊状物。连续研磨30分钟。然后，将该糊状物在真空烘箱(40℃；0巴)中干燥48小时。将该固体块状物粉碎，通过60目筛并重新放回烘箱(40℃；0巴)中12小时以确保该配合物干燥均匀。通过HPLC分析Sumatriptan碱的含量，并通过Karl Fischer分析含湿量得到下列结果：Sumatriptan碱为16.78％且含湿量为6.80％。通过DSC，FT-IR和XRD确定该配合物的特性。
实施例10
通过捏合方法，将沙丁胺醇癸酸盐和羟丙基-β环糊精(HPB)复合。沙丁胺醇癸酸盐(2.72g)和HPB(7.728g)混合在一起。加入水(5ml)并将该配合物在乳钵中用研杵研磨形成均匀的糊状物。连续研磨30分钟。然后，将该糊状物在真空烘箱(40℃；0巴)中干燥48小时。将该固体块状物粉碎，通过60目筛并重新放回烘箱(40℃；0巴)中12小时以确保该配合物干燥均匀。通过HPLC分析沙丁胺醇碱的含量，并通过Karl Fischer分析含湿量得到下列结果：沙丁胺醇碱为12.97％并且含湿量为5.56％。通过DSC，FT-IR和XRD确定该配合物的特性。在水溶液中的溶解度大于4.8mg/ml，并且饱和水溶液的PH为6.79。
实施例11
通过捏合方法，将沙丁胺醇癸酸盐和γ-环糊精复合。沙丁胺醇癸酸盐(2.409g)和γ-环糊精(7.591g)混合在一起。加入水(12ml)并将该配合物在乳钵中用研杵研磨形成均匀的糊状物。连续研磨30分钟。然后，将该糊状物在真空烘箱(40℃；0巴)中干燥48小时。将该固体块状物粉碎，通过60目筛并重新放回烘箱(40℃；0巴)中12小时以确保该配合物干燥均匀。通过HPLC分析沙丁胺醇碱的含量，并通过Karl Fischer分析含湿量得到下列结果：沙丁胺醇碱为12.83％并且含湿量为7.92％。通过DSC，FT-IR和XRD确定该配合物的特性。在水溶液中的溶解度大于3.2mg/ml，并且饱和水溶液的PH为7.00。
实施例12
通过捏合方法，将可待因月桂酸盐和羟丙基-β环糊精复合。可待因月桂酸盐(0.700g)和羟丙基-β-环糊精(2.045g)混合在一起。加入水(5ml)并将该配合物在乳钵中用研杵研磨形成均匀的糊状物。连续研磨30分钟。然后，将该糊状物在真空烘箱(40℃；0巴)中干燥48小时。将该固体块状物粉碎，通过60目筛并重新放回烘箱(40℃；0巴)中12小时以确保该配合物干燥均匀。通过HPLC分析可待因碱的含量，并通过Karl Fischer分析含湿量得到下列结果：可待因碱为14.49％并且含湿量为4.21％。通过DSC，FT-IR和XRD确定该配合物的特性。
实施例13
通过捏合方法，将可待因月桂酸盐和γ-环糊精复合。可待因月桂酸盐(0.700g)和γ-环糊精(1.754g)混合在一起。加入水(2.5ml)并将该配合物在乳钵中用研杵研磨形成均匀的糊状物。连续研磨30分钟。然后，将该糊状物在真空烘箱(40℃；0巴)中干燥48小时。将该固体块状物粉碎，通过60目筛并重新放回烘箱(40℃；0巴)中12小时以确保该配合物干燥均匀。通过HPLC分析可待因碱的含量，并通过Karl Fischer分析含湿量得到下列结果：可待因碱为16.08％并且含湿量为8.72％。通过DSC，FT-IR和XRD确定该配合物的特性。
实施例14
含相当4mg沙丁胺醇碱的舌下给药片的单位组分如下：
沙丁胺醇癸酸盐γ-CD配合物(实施例9)    32mg
乳糖NF                                20mg
硬脂酸镁                              1mg
将该配合物与乳糖混合。混入润滑剂并通过在10-30N下压片制备成舌下给药的片剂。
实施例15
将实施例12得到的可待因月桂酸盐-β-环糊精配合物(1.352g，相当于200mg可待因碱)溶解在用磷酸盐缓冲液缓冲至PH7.4的纯净去离子水(8m1)中。加入氯己定葡糖酸盐(0.01％)。通过加入PH7.4的磷酸盐缓冲液将体积调至10ml并且用氯化钠将最终溶液的渗透压调至300m0sm/kg。将溶液过滤并填充到计量剂量的鼻喷雾小瓶中。每0.25ml计量剂量含5mg适用于鼻腔给药的可待因碱。
实施例16
含相当20mg sumatriptan碱的栓剂的单位组分如下：
Sumatriptan癸酸盐                   32mg
聚乙二醇6000                        500mg
聚乙二醇1540                        300mg
聚乙二醇400                         200mg
将聚乙二醇加热刚好至上述熔点。将细碎的sumatriptan癸酸盐混合到该熔融物中。将均匀的液体熔融物倾入模具中。
实施例17
将实施例3得到的沙丁胺醇月桂酸盐(15mg相当于8mg沙丁胺醇碱)溶解在0.5ml丙二醇(95％)和月桂氮卓酮(laurocapram)(5％)的混合物中。将得到的溶液填充到储存器式透皮释放系统中。
几种游离碱、酸加成盐及其环糊精配合物的理化特性列于表1中。通过差示扫描量热法，用Perkin ElmerDSC 7测定熔点(峰开始温度)。通过振摇在PH7.4磷酸盐缓冲液中的过量化合物来测定25℃下的饱和溶解度。将该混合物过滤(0.22(m))并且通过HPLC来分析滤液中的药物含量。酸加成盐的溶解度低于相应的游离碱。可通过环糊精复合作用来增加酸加成盐的溶解度。分配系数可预测药物从含水室向膜移动的趋势，并因此发现，分配系数与生物效应非常相关〔Pharmaceutical Codex 12th Edition，Pharmaceutical Press p188〕。为了表明相对于相应的游离碱，酸加成盐具有改善的膜分配性，按照下列方法〔Pharmaceutical Codex 12 Edition，PharmaceuticalPress p70〕测定表观分配系数(Papp)：
Papp＝P/(1+10pka-PH)
其中P＝Co/Cw并且Co是药物在正辛醇中的浓度并且Cw是在25℃下，药物在PH7.4磷酸盐缓冲液中的浓度。通过HPLC测定药物的浓度。
与相应游离碱比，酸加成盐表观分配系数的增加表明其亲脂性增加，这与分子跨生物膜转移的速度有关。表1的结果清楚地说明，本发明的酸加成盐具有相对于相应游离碱高的表观分配系数。
表1：酸加成盐的熔点和平衡溶解度数据
    化合物     熔点(℃) 平衡溶解度(mg/ml)
Sumatriptan碱     169.0     2.342
Sumatriptan癸酸盐     94.6     3.849
沙丁胺醇碱     148.8     16.663
沙丁胺醇癸酸盐     99.4     3.820
沙丁胺醇月桂酸盐     104.0     4.245
沙丁胺醇甘氨脱氧胆酸盐     低于200不熔     12.363
可待因碱     152.7     10.574
可待因月桂酸盐     低于200不熔     5.227
Sumatriptan癸酸盐HPBCD     88.8     4.333
Sumatriptan癸酸盐GDC     86.8     3.250
沙丁胺醇癸酸盐HPBCD     91.0     4.107
沙丁胺醇癸酸盐GCD     低于200不熔     1.865
可待因月桂酸盐HPBCD     低于200不熔     4.263
可待因月桂酸盐GCD     低于200不熔     1.353
从DSC的开始值得到熔点。如果没有吸热，那么记录为“低于…不熔”，即DSC的最高温度。在25℃下，在PH7.4磷酸盐缓冲液(低离子强度)中的平衡溶解度。
表2酸加成盐的分配系数和表观分配系数
化合物     分配系数     表观分配系数
Sumatriptan碱     0.69     0.004039
Sumatriptan癸酸盐     1.54     0.009015
沙丁胺醇碱     0.42     0.005222
沙丁胺醇癸酸盐     0.54     0.006714
沙丁胺醇甘氨脱氧胆酸盐     0.61     0.007584
在25℃下，在PH7.4磷酸盐缓冲液和正辛醇中的表观分配系数。

Claims (15)

1、一种配制成经皮或经粘膜释放的药物组合物，它含有作为活性组分的式I化合物和一种或多种经皮或经粘膜释放用的赋形剂：
                        B+RCOO-
其中B+为碱性药物的阳离子，且RCOO-为(a)不饱和或饱和的C8-C18单羧基脂肪酸或(b)胆酸的阴离子。
2、权利要求1的药物组合物，其中B+为碱性药物的阳离子，所述碱性药物选自可待因、吗啡、芬太尼、naratriptan、zolmitriptan、rizatriptan、维拉帕米、尼卡地平、卡托普利、依那普利、雷米普利、甲氧氯普胺、噻克利嗪、地芬诺酯、沙美特罗、非诺特罗、特布他林、布比卡因、利多卡因、普鲁卡因和dinorphin。
3、权利要求1的药物组合物，其中B+为碱性药物的阳离子，所述碱性药物选自sumatriptan、沙丁胺醇、可待因和洛哌丁胺。
4、权利要求1-3任一药物组合物，其中RCOO-为选自癸酸根、月桂酸根和甘氨脱氧胆酸根的阴离子。
5、权利要求1-4任一药物组合物，其中活性组分以环糊精配合物的形式使用。
6、权利要求1-3任一药物组合物，其中活性组分选自sumatriptan癸酸盐、sumatriptan月桂酸盐、sumatriptan甘氨脱氧胆酸盐、沙丁胺醇月桂酸盐、沙丁胺醇癸酸盐、沙丁胺醇甘氨脱氧胆酸盐、可待因癸酸盐、可待因月桂酸盐、洛哌丁胺甘氨脱氧胆酸盐、sumatriptan癸酸盐环糊精配合物、沙丁胺醇癸酸盐环糊精配合物和沙丁胺醇甘氨脱氧胆酸盐环糊精配合物。
7、权利要求1-6任一药物组合物，选自舌下给药片剂、鼻喷雾剂、颊片和栓剂。
8、权利要求1-6任一药物组合物，选自透皮给药的药膏和表面给药的凝胶。
9、式I化合物：
                     B+RCOO-
其中B+为碱性药物的阳离子，且RCOO-为(a)不饱和或饱和的C8-C18单羧基脂肪酸或(b)胆酸的阴离子，条件是所述化合物不是普萘洛尔月桂酸酯或沙丁胺醇硬脂酸酯。
10、权利要求9的化合物，其中B+为碱性药物的阳离子，所述碱性药物选自可待因、吗啡、芬太尼、naratriptan、zolmitriptan、rizatriptan、维拉帕米、尼卡地平、卡托普利、依那普利、雷米普利、甲氧氯普胺、噻克利嗪、地芬诺酯、沙美特罗、非诺特罗、特布他林、布比卡因、利多卡因、普鲁卡因和dinorphin。
11、权利要求9的化合物，其中B+为碱性药物的阳离子，所述碱性药物选自sumatriptan、沙丁胺醇、可待因和洛哌丁胺。
12、权利要求9-11的化合物，其中RCOO-为选自癸酸根、月桂酸根和甘氨脱氧胆酸根的阴离子。
13、权利要求9-12的化合物，它选自sumatriptan癸酸盐、sumatriptan月桂酸盐、sumatriptan甘氨脱氧胆酸盐、沙丁胺醇癸酸盐、沙丁胺醇月桂酸盐、沙丁胺醇甘氨脱氧胆酸盐、可待因癸酸盐、可待因月桂酸盐、洛哌丁胺甘氨脱氧胆酸盐。
14、一种环糊精配合物，它包含式I化合物和不饱和或饱和α，β或γ-环糊精：
                         B+RCOO-
其中B+为碱性药物的阳离子，且RCOO-为(a)不饱和或饱和的C8-C18单羧基脂肪酸或(b)胆酸的阴离子。
15、式I化合物在制备透粘膜或透皮释放的药物方面的应用，
                         B+RCOO-
其中B+为碱性药物的阳离子，且RCOO-为(a)不饱和或饱和的C8-C18单羧基脂肪酸或(b)胆酸的阴离子。
CN97197767A 1996-07-11 1997-07-11 含碱性药物的酸加成盐的药物组合物 Pending CN1230123A (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ZA96/5889 1996-07-11
ZA965889 1996-07-11

Publications (1)

Publication Number Publication Date
CN1230123A true CN1230123A (zh) 1999-09-29

Family

ID=25585787

Family Applications (1)

Application Number Title Priority Date Filing Date
CN97197767A Pending CN1230123A (zh) 1996-07-11 1997-07-11 含碱性药物的酸加成盐的药物组合物

Country Status (10)

Country Link
US (1) US6255502B1 (zh)
EP (1) EP1024833A1 (zh)
JP (2) JP2001508027A (zh)
KR (2) KR20000022239A (zh)
CN (1) CN1230123A (zh)
AU (2) AU712546B2 (zh)
BR (2) BR9710289A (zh)
CA (2) CA2259418A1 (zh)
IL (2) IL127956A0 (zh)
WO (2) WO1998002187A1 (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101005825B (zh) * 2004-08-17 2011-02-09 荷兰联合利华有限公司 含树枝状大分子的毛发护理组合物
CN101043908B (zh) * 2004-10-21 2011-11-16 皮埃尔法布尔制药公司 含有美喹他嗪、环糊精和相互作用试剂的络合物
CN102933198A (zh) * 2009-09-25 2013-02-13 雷迪博士实验室有限公司 包含曲普坦化合物的制剂
CN106220562A (zh) * 2016-07-29 2016-12-14 上海璃道医药科技有限公司 两种喹啉环类药物的新用途
CN106880598A (zh) * 2015-12-14 2017-06-23 山东新时代药业有限公司 一种依折麦布片剂

Families Citing this family (135)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9706089D0 (en) * 1997-03-24 1997-05-14 Scherer Ltd R P Pharmaceutical composition
US20040043071A1 (en) * 2002-06-21 2004-03-04 Pauletti Giovanni M. Intravaginal mucosal or transmucosal delivery of antimigraine and antinausea drugs
AU2406299A (en) * 1998-02-12 1999-08-30 Centrapharm Inc. Sublingual drug formulations having combined rapid onset of action and long lasting therapeutic effect
DE19810951B4 (de) * 1998-03-13 2005-09-29 Ciba Speciality Chemicals Holding Inc. Verwendung eines textilen Materials als transdermales Abgabesystem sowie Verfahren zu seiner Herstellung
US6362371B1 (en) * 1998-06-08 2002-03-26 Advanced Medicine, Inc. β2- adrenergic receptor agonists
GB9816556D0 (en) * 1998-07-30 1998-09-30 Pfizer Ltd Therapy
US6255334B1 (en) * 1998-10-30 2001-07-03 Pfizer Inc 5HT 1 receptor agonists and metoclopramide for the treatment of migraine
US6849263B2 (en) * 1998-12-21 2005-02-01 Generex Pharmaceutical Incorporated Pharmaceutical compositions for buccal delivery of pain relief medications
US7087215B2 (en) * 1998-12-21 2006-08-08 Generex Pharmaceuticals Incorporated Methods of administering and enhancing absorption of pharmaceutical agents
DE19901085C2 (de) * 1999-01-14 2003-12-18 Lohmann Therapie Syst Lts Transdermales therapeutisches System mit einer selbstklebenden Matrix, enthaltend organische Säure-Additionssalze von Alkaloiden des Morphin- bzw. Morphinantyps
GB9915231D0 (en) 1999-06-29 1999-09-01 Pfizer Ltd Pharmaceutical complex
GB9928578D0 (en) 1999-12-03 2000-02-02 Zeneca Ltd Pharmaceutical formulations
GB9930026D0 (en) * 1999-12-21 2000-02-09 Univ Sheffield Novel compounds of unsaturated fatty acids
US20060083691A1 (en) * 2000-05-10 2006-04-20 Wermeling Daniel P Intranasal opioid compositions, delivery devices and methods of using same
US20040115133A1 (en) * 2000-05-10 2004-06-17 Wermeling Daniel P. Intranasal opioid compositions
US6610271B2 (en) * 2000-05-10 2003-08-26 University Of Kentucky Research Foundation System and method for intranasal administration of lorazepam
AU2001286518A1 (en) * 2000-08-15 2002-02-25 University Of Kentucky Research Foundation Programmable multi-dose intranasal drug delivery device
ATE316786T1 (de) * 2000-11-22 2006-02-15 Rxkinetix Inc Behandlung von mukositis
US20040176359A1 (en) * 2001-02-20 2004-09-09 University Of Kentucky Research Foundation Intranasal Benzodiazepine compositions
NZ528377A (en) * 2001-03-27 2005-05-27 Galen Chemicals Ltd Intravaginal drug delivery devices for the administration of an antimicrobial agent
AU2002256471B2 (en) * 2001-05-03 2007-05-24 Allergan, Inc. Compositions having enhanced pharmacokinetic characteristics
US20020198209A1 (en) 2001-05-03 2002-12-26 Allergan Sales Inc. Compositions having enhanced pharmacokinetic characteristics
US7766013B2 (en) 2001-06-05 2010-08-03 Alexza Pharmaceuticals, Inc. Aerosol generating method and device
WO2002094242A1 (en) * 2001-05-24 2002-11-28 Alexza Molecular Delivery Corporation Delivery of rizatriptan or zolmitriptan through an inhalation route
JP2005503425A (ja) 2001-05-24 2005-02-03 アレックザ モレキュラー デリヴァリー コーポレイション 所定の吸入ルートによる薬剤エステルの送出
US20070122353A1 (en) 2001-05-24 2007-05-31 Hale Ron L Drug condensation aerosols and kits
DE10141650C1 (de) 2001-08-24 2002-11-28 Lohmann Therapie Syst Lts Transdermales Therapeutisches System mit Fentanyl bzw. verwandten Substanzen
US7030082B2 (en) * 2001-09-07 2006-04-18 Nobex Corporation Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith
US6770625B2 (en) * 2001-09-07 2004-08-03 Nobex Corporation Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith
CN1703197A (zh) * 2001-11-14 2005-11-30 阿尔扎有限公司 可注射的长效组合物和其使用
US20070196415A1 (en) * 2002-11-14 2007-08-23 Guohua Chen Depot compositions with multiple drug release rate controls and uses thereof
JP2005519873A (ja) * 2001-11-14 2005-07-07 アルザ・コーポレーション カテーテル注入可能なデポー組成物およびそれらの使用
WO2003063927A2 (en) * 2001-11-16 2003-08-07 Eisai Co. Ltd Compositions and methods to treat gastrointestinal disorders
DE10157475A1 (de) * 2001-11-23 2003-06-18 Hans-Hermann Gerdes Verfahren und Mittel zur Beeinflussung von interzellulärer Kommunikation und interzellulären Organellentransport
US20030158118A1 (en) * 2001-11-26 2003-08-21 Weidner Morten Sloth Combination of cimetidine and cysteine derivatives for treating cancer
WO2003068209A1 (en) * 2002-02-14 2003-08-21 Sonus Pharmaceuticals, Inc. Metformin salts of lipophilic acids
AU2003241464A1 (en) * 2002-05-17 2003-12-02 Eisai Co., Ltd. Compositions and methods using proton pump inhibitors
KR100469995B1 (ko) * 2002-05-20 2005-02-05 안국약품 주식회사 천식치료제를 함유한 매트릭스형 패취
US20040001889A1 (en) 2002-06-25 2004-01-01 Guohua Chen Short duration depot formulations
US8840928B2 (en) * 2002-07-05 2014-09-23 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US10004729B2 (en) 2002-07-05 2018-06-26 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US7399488B2 (en) * 2002-07-05 2008-07-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opiods and other drugs
US8557291B2 (en) * 2002-07-05 2013-10-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
JP4569080B2 (ja) * 2002-07-17 2010-10-27 大正製薬株式会社 点鼻剤組成物
DK1539101T3 (da) * 2002-07-31 2009-04-27 Alza Corp Injicerbare, multi-modale polymere depotsammens tninger og anvendelser deraf
ES2319400T3 (es) * 2002-07-31 2009-05-07 Durect Corporation Composiciones deposito inyectables y empleo de las mismas.
MXPA05005038A (es) * 2002-11-12 2005-07-01 Teva Pharma Composiciones farmaceuticas y formas de dosis para la entrega bucal y sublingual de tizanidina y metodos para administrar tizanidina sublingual o bucalmente.
US7524515B2 (en) * 2003-01-10 2009-04-28 Mutual Pharmaceuticals, Inc. Pharmaceutical safety dosage forms
GB0300531D0 (en) 2003-01-10 2003-02-12 West Pharm Serv Drug Res Ltd Pharmaceutical compositions
US20080213363A1 (en) * 2003-01-23 2008-09-04 Singh Nikhilesh N Methods and compositions for delivering 5-HT3 antagonists across the oral mucosa
DK1599186T3 (da) * 2003-02-24 2013-07-08 Pharmaceutical Productions Inc System til administration af transmukalt lægemiddel
US9254294B2 (en) 2003-02-24 2016-02-09 Pharmaceutical Productions Inc. Transmucosal hormone delivery system
US10172810B2 (en) 2003-02-24 2019-01-08 Pharmaceutical Productions, Inc. Transmucosal ketamine delivery composition
WO2004076403A1 (en) * 2003-02-24 2004-09-10 Transform Pharmaceuticals, Inc. Sumatriptan crystalline forms, pharmaceutical compositions and methods
US9358296B2 (en) 2003-02-24 2016-06-07 Pharmaceutical Productions Inc. Transmucosal drug delivery system
US9498454B2 (en) 2003-02-24 2016-11-22 Pharmaceutical Productions Inc. Transmucosal drug delivery system
WO2004093917A2 (en) * 2003-04-22 2004-11-04 Nastech Pharmaceutical Company Inc. Intranasal administration of triptans
US7306812B2 (en) 2003-05-09 2007-12-11 Cephalon, Inc. Dissolvable backing layer for use with a transmucosal delivery device
US7276246B2 (en) * 2003-05-09 2007-10-02 Cephalon, Inc. Dissolvable backing layer for use with a transmucosal delivery device
WO2004104490A1 (en) 2003-05-21 2004-12-02 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
WO2005033049A2 (en) * 2003-10-01 2005-04-14 Taro Pharmaceuticals U.S.A., Inc. METHOD OF PREPARING 4-AMINO-1H-IMIDAZO(4,5-c)QUINOLINES AND ACID ADDITION SALTS THEREOF
EP1677758A1 (en) * 2003-10-31 2006-07-12 ALZA Corporation Compositions and dosage forms for enhanced absorption of 3-amino-n-butyl-phosphinic acid
RS20050835A (en) * 2004-01-06 2007-08-03 Panacea Biotec Ltd., Compositions of buccal dosage forms for extended drug release and the process of preparing such compositions
GB0400804D0 (en) 2004-01-14 2004-02-18 Innoscience Technology Bv Pharmaceutical compositions
CA2554489A1 (en) * 2004-01-28 2005-08-11 The Regents Of The University Of California Novel interstitial therapy for immediate symptom relief and chronic therapy in interstitial cystitis
GB0406445D0 (en) * 2004-03-23 2004-04-28 Astrazeneca Ab Combination therapy
US20050232981A1 (en) * 2004-04-15 2005-10-20 Ben-Sasson Shmuel A Compositions capable of facilitating penetration across a biological barrier
US20070219131A1 (en) * 2004-04-15 2007-09-20 Ben-Sasson Shmuel A Compositions capable of facilitating penetration across a biological barrier
ATE521355T1 (de) 2004-05-19 2011-09-15 Los Angeles Biomed Res Inst Verwendung eines detergens zur nicht- chirurgischen entfernung von fett
US7754230B2 (en) * 2004-05-19 2010-07-13 The Regents Of The University Of California Methods and related compositions for reduction of fat
US20060127468A1 (en) * 2004-05-19 2006-06-15 Kolodney Michael S Methods and related compositions for reduction of fat and skin tightening
WO2005123043A2 (en) * 2004-06-10 2005-12-29 Duramed Pharmaceuticals, Inc. Formulations of sumatriptan for absorption across biological membranes, and methods of making and using the same
CA2569958C (en) 2004-06-12 2016-03-22 Jane C. Hirsh Abuse-deterrent drug formulations
US7244765B2 (en) * 2004-06-25 2007-07-17 Cytokine Pharmasciences, Inc Guanylhydrazone salts, compositions, processes of making and methods of using
GB0416861D0 (en) * 2004-07-29 2004-09-01 Quadrant Drug Delivery Ltd Composition
US20060051413A1 (en) * 2004-09-08 2006-03-09 Chow Sing S M Method of enhancing absorptions of transmucosal administration formulations
EP1793673A4 (en) * 2004-09-27 2009-08-12 Cargill Inc CYCLODEXTRIN INCLUSION COMPLEXES AND METHOD FOR THEIR PREPARATION
CA2867023A1 (en) * 2004-10-04 2006-04-20 Kevin H. Mayo Calixarene-based peptide conformation mimetics, methods of use, and methods of making
US20060142234A1 (en) * 2004-12-23 2006-06-29 Guohua Chen Injectable non-aqueous suspension
US20110039943A1 (en) * 2005-03-14 2011-02-17 Robert Alonso Methods for treating skin disorders with topical nitrogen mustard compositions
US7872050B2 (en) * 2005-03-14 2011-01-18 Yaupon Therapeutics Inc. Stabilized compositions of volatile alkylating agents and methods of using thereof
US8501818B2 (en) * 2005-03-14 2013-08-06 Ceptaris Therapeutics, Inc. Stabilized compositions of alkylating agents and methods of using same
JP5011776B2 (ja) * 2005-03-28 2012-08-29 大正製薬株式会社 銅化合物配合組成物
JP2008546386A (ja) * 2005-06-13 2008-12-25 カーギル インコーポレイテッド シクロデキストリン包接複合体及びその製造方法
AU2006259878A1 (en) * 2005-06-13 2006-12-28 Cargill, Incorporated Cyclodextrin inclusion complexes and methods of preparing same
US20070020186A1 (en) * 2005-07-22 2007-01-25 Alpex Pharma S.A. Solid dosage formulations of narcotic drugs having improved buccal adsorption
KR20080028480A (ko) * 2005-08-01 2008-03-31 테바 파마슈티컬 인더스트리즈 리미티드 티자니딘 조성물 및 이 조성물을 사용하는 치료 방법
US20070042041A1 (en) * 2005-08-17 2007-02-22 Board Of Trustees Of The University Of Arkansas Drug-surfactant complexes for sustained release
DK1965787T3 (da) * 2005-11-30 2013-06-03 Endo Pharmaceuticals Inc Behandling af xerostomi med en svovlindeholdende antioxidant
EP1832572A1 (en) * 2006-03-08 2007-09-12 Stirling Products Limited Process for the enantiomeric enrichment of salbutamol and salbutamol precursors
US20080044462A1 (en) * 2006-04-06 2008-02-21 Collegium Pharmaceutical, Inc. Delaware Stabilized transdermal bupropion preparations
JP2009539978A (ja) * 2006-06-13 2009-11-19 カーギル インコーポレイテッド 大粒子シクロデキストリン包接複合体及びその製造方法
AU2007275581B2 (en) 2006-07-21 2011-09-08 Biodelivery Sciences International, Inc. Transmucosal delivery devices with enhanced uptake
US20090023637A1 (en) * 2006-08-30 2009-01-22 Parsons C Lowell Methods for detecting and treating interstitial cystitis
SI2124556T1 (sl) 2006-10-09 2015-01-30 Charleston Laboratories, Inc. Farmacevtske sestave
US8969402B2 (en) * 2006-11-15 2015-03-03 Steven A. Rich Combined acetylcholinesterase inhibitor and quaternary ammonium antimuscarinic therapy to alter progression of cognitive diseases
WO2008083213A2 (en) * 2006-12-27 2008-07-10 Cargill, Incorporated Stabilisation by preparing cyclodextrin inclusion complexes
US20080275030A1 (en) * 2007-01-19 2008-11-06 Sveinbjorn Gizurarson Methods and Compositions for the Delivery of a Therapeutic Agent
WO2008112661A2 (en) 2007-03-09 2008-09-18 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
ES2575549T3 (es) * 2007-04-11 2016-06-29 John A. Mccarty Comprimido de melatonina y métodos de preparación y uso
US20080283693A1 (en) * 2007-05-15 2008-11-20 Evans Michael J F Propulsion apparatus and system
TW200904485A (en) * 2007-05-18 2009-02-01 Alcon Res Ltd Phospholipid compositions for contact lens care and preservation of pharmaceutical compositions
USRE46397E1 (en) 2007-11-07 2017-05-09 Svip5 Llc Slow release of organic salts of local anesthetics for pain relief
US8124126B2 (en) 2008-01-09 2012-02-28 Charleston Laboratories, Inc. Pharmaceutical compositions
JP2011514358A (ja) * 2008-03-14 2011-05-06 セファロン、インク． 改良された経粘膜組成物および剤形
ES2848841T3 (es) * 2008-03-27 2021-08-12 Helsinn Healthcare Sa Composiciones estabilizadas de agentes de alquilación y métodos de utilización de estas composiciones
WO2010016219A1 (ja) 2008-08-05 2010-02-11 株式会社メドレックス 塩基性薬効成分の脂肪酸塩、安息香酸塩を含有する外用剤とその製造方法
TW201010727A (en) * 2008-09-03 2010-03-16 Alcon Res Ltd Pharmaceutical composition having relatively low ionic strength
EP2334285A1 (en) * 2008-09-12 2011-06-22 Critical Pharmaceuticals Limited Improvements in the absorption of therapeutic agents across mucosal membranes or the skin
BRPI0918652B1 (pt) 2008-09-17 2021-10-19 Chiasma, Inc. Composição farmacêutica compreendendo um meio hidrofóbico e uma forma sólida que compreende polipeptídeo e sal de ácido graxo de cadeia média, processo de produção da mesma e forma de dosagem oral
US8101593B2 (en) 2009-03-03 2012-01-24 Kythera Biopharmaceuticals, Inc. Formulations of deoxycholic acid and salts thereof
EP2451274B1 (en) 2009-07-08 2017-10-04 Charleston Laboratories, Inc. Pharmaceutical compositions
US11337962B2 (en) 2009-09-25 2022-05-24 Upsher-Smith Laboratories, Llc Formulations comprising triptan compounds
AU2010299607B2 (en) 2009-09-25 2016-07-28 Tonix Medicines, Inc. Formulations comprising triptan compounds
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
ES2471076T3 (es) * 2010-06-28 2014-06-25 Ratiopharm Gmbh Compuestos de inclusión de silodoxina-ciclodextrina
CA2827643C (en) 2011-02-18 2019-05-07 Kythera Biopharmaceuticals, Inc. Treatment of submental fat
US8653058B2 (en) 2011-04-05 2014-02-18 Kythera Biopharmaceuticals, Inc. Compositions comprising deoxycholic acid and salts thereof suitable for use in treating fat deposits
US11786455B2 (en) 2011-05-10 2023-10-17 Itochu Chemical Frontier Corporation Non-aqueous patch
BR112013028802B1 (pt) 2011-05-10 2021-10-26 Itochu Chemical Frontier Corporation Curativo adesivo não-aquoso
US9925264B2 (en) 2011-05-10 2018-03-27 Itochu Chemical Frontier Corporation Non-aqueous patch
CA2834327C (en) 2011-09-19 2017-05-30 Orexo Ab New abuse-resistant pharmaceutical composition for the treatment of opioid dependence
LT2823815T (lt) 2011-09-27 2018-08-27 Itochu Chemical Frontier Corporation Nevandeninis pleistras
US9901539B2 (en) 2011-12-21 2018-02-27 Biodelivery Sciences International, Inc. Transmucosal drug delivery devices for use in chronic pain relief
JP6564369B2 (ja) 2013-12-09 2019-08-21 デュレクト コーポレイション 薬学的活性剤複合体、ポリマー複合体、ならびにこれらを伴う組成物及び方法
US10238709B2 (en) 2015-02-03 2019-03-26 Chiasma, Inc. Method of treating diseases
MA43047A (fr) 2015-06-15 2018-08-08 Qaam Pharmaceuticals Llc Sels d'acides gras de glycopyrronium et leurs procédés de production
JP2019507181A (ja) 2016-03-04 2019-03-14 チャールストン ラボラトリーズ，インコーポレイテッド 医薬組成物
WO2017222575A1 (en) 2016-06-23 2017-12-28 Collegium Pharmaceutical, Inc. Process of making more stable abuse-deterrent oral formulations
EP3704123A1 (en) * 2017-10-30 2020-09-09 Theracaine LLC Hydrophobic acid addition salts and pharmaceutical formulations thereof
BR112022013784A2 (pt) 2020-01-13 2022-10-11 Durect Corp Sistemas de distribuição de fármacos de liberação prolongada com impurezas reduzidas e métodos relacionados
KR20210150676A (ko) 2020-06-04 2021-12-13 허승찬 인터넷을 이용한 전자상거래 방법
US11141457B1 (en) 2020-12-28 2021-10-12 Amryt Endo, Inc. Oral octreotide therapy and contraceptive methods
US12109202B2 (en) 2021-01-29 2024-10-08 Qaam Pharmaceuticals, Llc Fixed dose combination of cholinesterase inhibitor and a quaternary ammonium antimuscarinic agent to treat neurodegenerative cognitive disorders
WO2024144413A1 (ru) * 2022-12-28 2024-07-04 Общество С Ограниченной Ответственностью "Ферринг Продакшн" Жидкая фармацевтическая композиция для назального введения, содержащая ризатриптан

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4722941A (en) * 1978-06-07 1988-02-02 Kali-Chemie Pharma Gmbh Readily absorbable pharmaceutical compositions of per se poorly absorbable pharmacologically active agents and preparation thereof
US5288498A (en) * 1985-05-01 1994-02-22 University Of Utah Research Foundation Compositions of oral nondissolvable matrixes for transmucosal administration of medicaments
US5288497A (en) * 1985-05-01 1994-02-22 The University Of Utah Compositions of oral dissolvable medicaments
GB9012663D0 (en) 1990-06-07 1990-08-01 Erba Carlo Spa Galenic formulations containing cyclodextrins
IT1263831B (it) * 1993-01-29 1996-09-04 Paolo Chiesi Complessi di inclusione multicomponente ad elevata solubilita' costituiti da un farmaco di tipo basico, un acido ed una ciclodestrina
US5985316A (en) * 1995-04-28 1999-11-16 Alza Corporation Composition and method of enhancing electrotransport agent delivery

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101005825B (zh) * 2004-08-17 2011-02-09 荷兰联合利华有限公司 含树枝状大分子的毛发护理组合物
CN101043908B (zh) * 2004-10-21 2011-11-16 皮埃尔法布尔制药公司 含有美喹他嗪、环糊精和相互作用试剂的络合物
CN102933198A (zh) * 2009-09-25 2013-02-13 雷迪博士实验室有限公司 包含曲普坦化合物的制剂
CN102933198B (zh) * 2009-09-25 2015-10-07 雷迪博士实验室有限公司 包含曲普坦化合物的制剂
CN106880598A (zh) * 2015-12-14 2017-06-23 山东新时代药业有限公司 一种依折麦布片剂
CN106880598B (zh) * 2015-12-14 2021-08-31 山东新时代药业有限公司 一种依折麦布片剂
CN106220562A (zh) * 2016-07-29 2016-12-14 上海璃道医药科技有限公司 两种喹啉环类药物的新用途

Also Published As

Publication number Publication date
BR9710289A (pt) 1999-08-17
CA2259418A1 (en) 1998-01-22
IL127956A0 (en) 1999-11-30
KR20000022239A (ko) 2000-04-25
KR20000023708A (ko) 2000-04-25
WO1998002186A1 (en) 1998-01-22
AU712546B2 (en) 1999-11-11
WO1998002187A1 (en) 1998-01-22
AU3455197A (en) 1998-02-09
US6255502B1 (en) 2001-07-03
JP2001508027A (ja) 2001-06-19
EP1024833A1 (en) 2000-08-09
BR9710241A (pt) 1999-08-10
AU3455297A (en) 1998-02-09
CA2257860A1 (en) 1998-01-22
IL127955A0 (en) 1999-11-30
JP2000505090A (ja) 2000-04-25

Similar Documents

Publication Publication Date Title
CN1230123A (zh) 含碱性药物的酸加成盐的药物组合物
US20240066024A1 (en) Transmucosal delivery device with enhanced uptake
KR101503074B1 (ko) 소용량 경구 경점막 투여 형태
Bhati et al. A detailed review on oral mucosal drug delivery system
EP1652518B1 (en) Pharmaceutical composition for sublingual administration
KR20050105198A (ko) 무가당 경구 경점막 고상 투여 형태 및 그의 용도
US20060002989A1 (en) Formulations of sumatriptan for absorption across biological membranes, and methods of making and using the same
TW201043280A (en) Pharmaceutical system for trans-membrane delivery
KR20150063567A (ko) 고형 제형
CN101678112A (zh) 用于递送治疗剂的方法和组合物
ZA200506833B (en) Sugar-free oral transmucosal solid dosage forms and uses thereof
TW201118084A (en) The use of an opioid receptor antagonist for the treatment or prevention of gastrointestinal tract disorders
US20170217976A1 (en) 6-(amino acid)-morphinan derivatives in combination with permeation enhancers for use as an orally, rectally, transdermally or nasally administered medicament
Menra et al. A REVIEW ON BUCCAL FILM: AN INOVATIVE DOSAGE FORM.
Lamey et al. Buccal and sublingual delivery of

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C01 Deemed withdrawal of patent application (patent law 1993)
WD01 Invention patent application deemed withdrawn after publication