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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/20—Hypnotics; Sedatives
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a composition which comprises a first component (a) which is ( ⁇ )-3-NN-dicyclobutylamino-8-fluoro-3,4-dihydro-2H- l-benzopyran-5- carboxamide hydrogen (2_?,3i.)-tartrate monohydrate and a second component (b) which is paroxetine, or a pharmaceutically acceptable salt and/or solvate thereof.
• the present invention also relates to a process for the preparation of the inventive composition, pharmaceutical formulations containing said composition and to the use of said composition either by concomitant administration or by separate administration as an improvement of the treatment of affective disorders such as depression, anxiety, obsessive compulsive disorder (OCD), etc.
• antidepressants take 2-4 weeks to reach full clinical effect. In contrast, the side effects occur immediately. Thus, slow onset of action of antidepressants leads to a vulnerable period for patients in which they experience the side effects, but rfot the therapeutic effects of drugs. There is often a heavy burden on the treating physician to persuade the patient to continue with the treatment during this period. Furthermore, in suicidal patients, as the onset of action is gradual, initiative may be regained without the experiencing of full reversal of symptoms, leaving a window of risk for suicide and a frequent requirement for hospitalization.
• the present invention is directed to a new composition
• a new composition comprising of a first component (a) which is the specific 5-HT ⁇ antagonist ( ⁇ -3-NN-d_cyclobutylamino-8-fluoro-3,4- dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2_?,3i?)-tartrate monohydrate and a second component (b) which is paroxetine, in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof.
• Said composition attains a faster onset of action and consequently, provides a more efficacious treatment of the patients . suffering form affective disorders, particularly depression.
• Paroxetine is a 5-HT reuptake inhibitor (SSRI) which is commercially available.
• Pharmaceutically acceptable salts of paroxetine such as the hydrochloride, hydrobromide, maleate, tartrate, acetate etc. are also included in the inventive composition. Also solvate forms such as the hydrate and hemihydrate of the salts are included.
• composition according to the present invention may exist in one pharmaceutical formulation comprising the component (a) and component (b), or in two different pharmaceutical formulations, one for component (a) and one for component (b).
• the pharmaceutical formulation may be in the form of tablets or capsules, powders, mixtures, solutions or other suitable pharmaceutical formulation forms such as patches and nasal formulations.
• composition of the present invention can be prepared such that component (a) is incorporated into the same pharmaceutical formulation as component (b) by e.g. mixing in a conventional way.
• the present invention also includes a method of improving the onset of therapeutic action by concomitant administration of a composition comprising of (R)-3-N,N- dicyclobutylamino-8-fluoro-3,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2 ⁇ ,3_?)-tartrate monohydrate and paroxetine.
• a further embodiment of the present invention is a kit containing a dosage unit of (R)-3- NN-dicyclobutylamino-8-fluoro-3,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2_?,3i?)-tartrate monohydrate and a dosage unit of a paroxetine, optionally with instructions for use.
• the compounds in the composition will normally be administered orally, rectally, transdermally, nasally or by injection, in the form of pharmaceutical formulations comprising the active ingredients in a pharmaceutically acceptable dosage form .
• the dosage form may be a solid, semisolid or liquid formulation.
• the active substances will constitute between 0.1 and 99% by weight of the formulation, more specifically between 0.5 and 20% by weight for formulations intended for injection and between 0.2 and 50% by weight for formulations suitable for oral administration.
• the pharmaceutical formulation comprises the active ingredients, optionally in association with adjuvants, excipients e.g. diluents, and/or inert carriers.
• the selected compounds may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or poly- vinylpyrrolidone, disintegrants e.g. sodium starch glycolate, cross-linked PVP and cross- caramellose sodium and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and an antisticking agent such as talc or colloidal silicon dioxide, and then compressed into tablets.
• a solid excipient e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or poly- vinylpyrrolidone, disintegrants e.g. sodium starch
• the cores may be coated with a polymer known to the man skilled in the art e.g. HPMC, HC or other cellulose derivatives or PNP, wherein the polymer is dissolved in water or a readily volatile organic solvent or mixture of organic solvents.
• a polymer known to the man skilled in the art e.g. HPMC, HC or other cellulose derivatives or PNP, wherein the polymer is dissolved in water or a readily volatile organic solvent or mixture of organic solvents.
• the tablets can be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatin, talcum, titanium dioxide, and the like.
• Dyestuffs may be added to these coatings for instance in order to readily distinguish between tablets containing different active substances or different amounts of the active compounds.
• the active substances may be admixed with e.g. a vegetable oil or polyethylene glycol.
• Hard gelatin capsules may contain granules of the active substances using any of the above mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives, plasticizers, polyetheneglycol, waxes, lipids or gelatin. Also liquids or semisolids of the drug can be filled into hard gelatin capsules.
• Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substances in a mixture with a neutral fatty base, or gelatine rectal capsules comprising the active substances in admixture with vegetable oil or paraffin oil.
• Liquid formulations for oral application may be in the form of solutions, syrups or suspensions, for example " solutions containing from about 0.2% to about 20% by weight of the active substances herein described, the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol.
• such liquid formulations may contain colouring agents, flavouring agents, saccharin and carboxymethyl-cellulose as a thickening agent or other excipients known to a person skilled in the art.
• Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substances, preferably in a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules. Suitable daily doses of the active compounds in the composition of the invention in therapeutic treatment of humans are about 0.01-100 mg/kg bodyweight for peroral administration and 0.001-100 mg kg bodyweight for parenteral administration.
• the daily doses of the active ingredient C_ ⁇ -3-NN-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l- benzopyran-5-carboxamide hydrogen (2i?,3i?)-tartrate monohydrate may very well differ from the daily doses of the active ingredient paroxetine but the doses can also be the same for both of the active ingredients.
• the present invention provides the use of the composition comprising a first component (a) which is ' ⁇ -3-NN-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l- benzopyran-5-carboxamide hydrogen (2 ⁇ ,3i?)-tartrate monohydrate and a second component (b) which is paroxetine, in the treatment of 5-hydroxytryptamine mediated disorders, such as affective disorders.
• a which is ' ⁇ -3-NN-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l- benzopyran-5-carboxamide hydrogen (2 ⁇ ,3i?)-tartrate monohydrate
• a second component (b) which is paroxetine in the treatment of 5-hydroxytryptamine mediated disorders, such as affective disorders.
• affective disorders are disorders in the C ⁇ S such as mood disorders (depression, major depressive episodes, dysthymia, seasonal affective disorder, depressive phases of bipolar disorder), anxiety disorders (obsessive compulsive disorder, panic disorder with/without agoraphobia, social phobia, specific phobia, generalized anxiety disorder, posttraumatic stress disorder), personality disorders (disorders of impulse control, trichotellomania) and sleep disorders.
• disorders in the C ⁇ S such as eating disorders (obesity, anorexia, bulimia), premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders (age associated memory impairment, presenile and senile dementia such as Alzheimer's disease), pathological aggression, schizophrenia, endocrine disorders (e g hyperprolactinaemia), stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain and hypertension may also be treated with the combination described herein.
• hydroxytryptamine mediated disorders are urinary incontinence, vasospasm and growth control of tumors (e g lung carcinoma) and it may be possible to treat those with the combination described herein as well.
• NAD 299 could antagonize the suppression of firing in serotoninerglc dorsal raphe neurones in rats induced by paroxetine (Figure).
• Figure shows medians +semi-interquartile range based on recordings from 5 animals per group.
• the paroxetine- induced suppression was statistically significantly antagonised by NAD 299 treatment (p ⁇ 0.05).
• SSRIs selective serotonin reuptake inhibitors
• paroxetine selective serotonin reuptake inhibitors
• SSRIs selective serotonin reuptake inhibitors
• the 5-hydroxytryptamine (5-HT) transporter protein affected is present both in somatodendritic and terminal regions, and initially the enhanced availability of serotonin in the former areas will inhibit neuronal activity as well as forebrain synthesis and release of 5-HT through activation of inhibitory 5-HTJA autoreceptors.
• these receptors desensitize with time there is a gradual increase in forebrain serotonin release, as has been shown in animals studies, and the time-course for this phenomenon probably explains the delayed onset of antidepressant actions clinically.
• a suitable pharmaceutical composition comprising a first component (a) and a second component (b) in a single dosage form include the following:

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• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Epidemiology (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Urology & Nephrology (AREA)
• Anesthesiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Pyrane Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (12)

Applications Claiming Priority (2)

Publications (1)

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ID=20412627

Family Applications (1)

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Cited By (2)

Citations (1)

• 1998
  • 1998-09-16 SE SE9803156A patent/SE9803156D0/xx unknown
• 1999
  • 1999-09-13 CZ CZ2001961A patent/CZ2001961A3/cs unknown
  • 1999-09-13 AU AU63780/99A patent/AU6378099A/en not_active Abandoned
  • 1999-09-13 PL PL99346763A patent/PL346763A1/xx unknown
  • 1999-09-13 KR KR1020017003337A patent/KR20010099647A/ko not_active Application Discontinuation
  • 1999-09-13 IL IL14151999A patent/IL141519A0/xx unknown
  • 1999-09-13 CN CN99811010A patent/CN1317964A/zh active Pending
  • 1999-09-13 TR TR2001/00779T patent/TR200100779T2/xx unknown
  • 1999-09-13 HU HU0103544A patent/HUP0103544A3/hu unknown
  • 1999-09-13 WO PCT/SE1999/001597 patent/WO2000015218A1/en not_active Application Discontinuation
  • 1999-09-13 ID IDW20010581A patent/ID28785A/id unknown
  • 1999-09-13 EE EEP200100157A patent/EE200100157A/xx unknown
  • 1999-09-13 SK SK326-2001A patent/SK3262001A3/sk unknown
  • 1999-09-13 BR BR9913748-8A patent/BR9913748A/pt not_active Application Discontinuation
  • 1999-09-13 EP EP99951319A patent/EP1128825A1/en not_active Withdrawn
  • 1999-09-13 JP JP2000569802A patent/JP2002524508A/ja active Pending
  • 1999-09-13 CA CA002342341A patent/CA2342341A1/en not_active Abandoned
  • 1999-09-15 AR ARP990104626A patent/AR021808A1/es not_active Application Discontinuation
• 2001
  • 2001-03-07 IS IS5879A patent/IS5879A/is unknown
  • 2001-03-08 ZA ZA200101946A patent/ZA200101946B/en unknown
  • 2001-03-15 NO NO20011312A patent/NO20011312L/no unknown

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