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
  • A61K31/13—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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• This invention relates to a method for improving the glucose tolerance of humans having Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus (NIDDM) .
• NIDDM Non-Insulin Dependent Diabetes Mellitus
• NIDDM Non-Insulin Dependent Diabetes Mellitus
• R- j _ and R 2 are independently H or methyl is administered in conjunction with a pharmaceutically acceptable diluent or carrier.
• a preferred compound of formula I is N,N-dimethyl- 1- [1- (4-chlorophenyl)cyclobutyl]-3-methylbutylamine or a salt thereof, for example the hydrochloride salt.
• a particularly preferred form of this compound is N,N- 10 dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methyl ⁇ butylamine hydrochloride monohydrate (sibutramine hydro ⁇ chloride) which is described in European Patent Number 230742.
• enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; via formation of diastereoisomeric derivatives which may be
• enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
• the compound of formula I may be administered in any of the known pharmaceutical dosage forms.
• the amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 50 mg preferably 1 to 30 mg per day given in one or more doses.
• Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions.
• the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
• Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
• the tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate.
• the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
• Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
• capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner.
• the contents of the capsule may be formulated using known methods so as to give sustained release of the active compound.
• the tablets and capsules may conveniently each contain 1 to 50 mg of the active compound.
• dosage forms for oral administration include, for example; aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy- methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
• the active compound may be formulated into granules with or without additional excipients.
• the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion.
• the granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
• the therapeutically active compounds of formula I may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
• Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
• Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
• Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
• a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol .
• the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base.
• the amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
• the therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity. Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
• the therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body.
• Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused.
• the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.
• the amount of active compound present in an internal source should be such tha,t a therapeutically effective amount of the compound is delivered over a long period of time.
• the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
• the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
• the term "Impaired Glucose Tolerance” includes humans suffering from Diabetes Mellitus of the insulin or non-insulin dependent type.
• glucose tolerance includes glucose disposal in muscle tissue, and hepatic glucose output. A deviation from normal glucose tolerance is indicative of Impaired Glucose Tolerance, or with more severe deviation, of Non-Insulin Dependent Diabetes Mellitus. Glucose tolerance can be quantified by reference to the "area under the curve" relative to baseline in a glucose concentration against time course graph, by reference to the maximum glucose concentration (Cmax) in a glucose concentration against time course graph, or by reference to the fasting blood glucose concentration. A significant increase in any of these from their normal values is indicative of a reduction in glucose tolerance. Humans having Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus show significant increases in these factors and so have reduced glucose tolerance. In the management of Impaired Glucose Tolerance and Non-Insulin Dependent Diabetes Mellitus it is desirable to maintain as .near to normal glucose tolerance as possible.
• sibutramine hydrochloride to increase (improve) the glucose tolerance of humans having Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus (NIDDM) is illustrated as follows.

Landscapes

• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Diabetes (AREA)
• Emergency Medicine (AREA)
• Epidemiology (AREA)
• Obesity (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Hematology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Endocrinology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Saccharide Compounds (AREA)
• Polyesters Or Polycarbonates (AREA)
• Lubricants (AREA)
• Solid-Sorbent Or Filter-Aiding Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Materials For Medical Uses (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)

Priority Applications (8)

Applications Claiming Priority (2)

Publications (1)

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Family Applications (1)

Country Status (17)

Cited By (24)

Families Citing this family (16)

Citations (1)

Family Cites Families (5)

• 1994
  • 1994-02-03 US US08/190,924 patent/US5459164A/en not_active Expired - Lifetime
• 1995
  • 1995-02-01 IL IL11251595A patent/IL112515A/xx active IP Right Grant
  • 1995-02-01 PH PH49876A patent/PH31220A/en unknown
  • 1995-02-02 ZA ZA95814A patent/ZA95814B/xx unknown
  • 1995-02-03 AU AU17362/95A patent/AU694761B2/en not_active Ceased
  • 1995-02-03 JP JP7520676A patent/JPH10503166A/ja active Pending
  • 1995-02-03 DK DK95909382T patent/DK0814788T3/da active
  • 1995-02-03 CA CA002182620A patent/CA2182620C/en not_active Expired - Fee Related
  • 1995-02-03 EP EP95909382A patent/EP0814788B1/en not_active Expired - Lifetime
  • 1995-02-03 PT PT95909382T patent/PT814788E/pt unknown
  • 1995-02-03 ES ES95909382T patent/ES2166817T3/es not_active Expired - Lifetime
  • 1995-02-03 CN CN95192226A patent/CN1070698C/zh not_active Expired - Fee Related
  • 1995-02-03 KR KR1019960704203A patent/KR100339874B1/ko not_active Expired - Fee Related
  • 1995-02-03 AT AT95909382T patent/ATE205390T1/de not_active IP Right Cessation
  • 1995-02-03 WO PCT/US1995/001190 patent/WO1995020949A1/en not_active Ceased
  • 1995-02-03 DE DE69522716T patent/DE69522716T2/de not_active Expired - Lifetime
  • 1995-03-02 TW TW084101992A patent/TW314466B/zh not_active IP Right Cessation
• 1997
  • 1997-03-04 US US08/696,984 patent/US5942549A/en not_active Expired - Lifetime

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