CA2342341A1 - A new composition - Google Patents
A new composition Download PDFInfo
- Publication number
- CA2342341A1 CA2342341A1 CA002342341A CA2342341A CA2342341A1 CA 2342341 A1 CA2342341 A1 CA 2342341A1 CA 002342341 A CA002342341 A CA 002342341A CA 2342341 A CA2342341 A CA 2342341A CA 2342341 A1 CA2342341 A1 CA 2342341A1
- Authority
- CA
- Canada
- Prior art keywords
- treatment
- component
- pharmaceutical formulation
- composition
- disorders
- 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.)
- Abandoned
Links
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
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a composition comprising a first component (a) which is (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and a second component (b) which is paroxetine in the form of its free base, or a pharmaceutically acceptable salt and/or solvate thereof, the preparation thereof, pharmaceutical formulations containing said composition, use of and a method of treatment of affective disorders such as mood disorders and anxiety disorders with said composition as well as a kit containing said composition.
Description
A NEW COMPOSTTION
Field of the Invention s The present invention relates to a composition which comprises a first component (a) which is (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide hydrogen (2R,3R)-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, io 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.
~s Background of the Invention Today, it is generally considered that 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 ~o effects, but riot 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. An antidepressant with fast onset zs of action would not only be beneficial due to the faster symptom reduction, but would also be more acceptable to patients and physicians and reduce the need for and duration of hospitalization. The same long period to reach full clinical effect has been shown in the treatment of other affective disorders such as anxiety and OCD.
Field of the Invention s The present invention relates to a composition which comprises a first component (a) which is (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide hydrogen (2R,3R)-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, io 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.
~s Background of the Invention Today, it is generally considered that 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 ~o effects, but riot 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. An antidepressant with fast onset zs of action would not only be beneficial due to the faster symptom reduction, but would also be more acceptable to patients and physicians and reduce the need for and duration of hospitalization. The same long period to reach full clinical effect has been shown in the treatment of other affective disorders such as anxiety and OCD.
Prior art In WO 96/33710 is disclosed that the compound (R)-5-carbamoyl-8-fluoro-3-N,N
dicyclobutylamino-3,4-dihydro-2H 1-benzopyran which has high affinity to 5-HT
receptors and antagonizes 5-HT,,~ mediated responses induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors.
Summary of the Invention io The present invention is directed to a new composition comprising of a first component (a) which is the specific 5-HTlpantagonist (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-~-carboxamide hydrogen (2R,3R)-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 ~s onset of action and consequently, provides a more efficacious treatment of the patients suffering form affective disorders, particularly depression.
It has been shown in animal studies that acute administration of selective 5-HT reuptake inhibitors (SSRIs) decreases the electrical impulse propagation in 5-HT
neurones via a Zo negative feedback reaction probably mediated by collateral 5-HT axons releasing S-HT in raphe nuclei. By inhibiting the somatodendritic 5-HT,A autoreceptors in the raphe nuclei the selective antagonists counteract the decrease in propagetion caused by 5-HT reuptake inhibitors. This indicates that a selective blockade of somatodendritic autoreceptor i.e. 5-HTtA antagonist may have a clinical potential to improve the efficacy of 5-HT
reuptake Zs inhibitors (SSRIs) and offer a new rationale for rapid onset of effect in the treatment of affective disorders, for instance the antidepressant actions.
The compound (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1=benzopyran-carboxanude hydrogen (2R,3R)-tartrate monohydrate (NAD 299) disclosed herein is described in J. Pharmacol. Exp. Ther., 283, 216-225, (1997) as a selective 5-HT~p receptor antagonist.
(R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate possesses a high affinity to the specific subgroup of 5-HT,A receptor in the CNS and acts as an antagonist on that 5-HT,A receptor, and also shows favourable bioavailability after oral administration.
Paroxetine is a 5-HT reuptake inhibitor (SSRn which is commercially available.
~o 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.
The composition according to the present invention may exist in one pharmaceutical ~s 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.
The 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.
Zs 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 (2R,3R)-tartrate monohydrate and paroxetine.
dicyclobutylamino-3,4-dihydro-2H 1-benzopyran which has high affinity to 5-HT
receptors and antagonizes 5-HT,,~ mediated responses induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors.
Summary of the Invention io The present invention is directed to a new composition comprising of a first component (a) which is the specific 5-HTlpantagonist (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-~-carboxamide hydrogen (2R,3R)-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 ~s onset of action and consequently, provides a more efficacious treatment of the patients suffering form affective disorders, particularly depression.
It has been shown in animal studies that acute administration of selective 5-HT reuptake inhibitors (SSRIs) decreases the electrical impulse propagation in 5-HT
neurones via a Zo negative feedback reaction probably mediated by collateral 5-HT axons releasing S-HT in raphe nuclei. By inhibiting the somatodendritic 5-HT,A autoreceptors in the raphe nuclei the selective antagonists counteract the decrease in propagetion caused by 5-HT reuptake inhibitors. This indicates that a selective blockade of somatodendritic autoreceptor i.e. 5-HTtA antagonist may have a clinical potential to improve the efficacy of 5-HT
reuptake Zs inhibitors (SSRIs) and offer a new rationale for rapid onset of effect in the treatment of affective disorders, for instance the antidepressant actions.
The compound (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1=benzopyran-carboxanude hydrogen (2R,3R)-tartrate monohydrate (NAD 299) disclosed herein is described in J. Pharmacol. Exp. Ther., 283, 216-225, (1997) as a selective 5-HT~p receptor antagonist.
(R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate possesses a high affinity to the specific subgroup of 5-HT,A receptor in the CNS and acts as an antagonist on that 5-HT,A receptor, and also shows favourable bioavailability after oral administration.
Paroxetine is a 5-HT reuptake inhibitor (SSRn which is commercially available.
~o 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.
The composition according to the present invention may exist in one pharmaceutical ~s 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.
The 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.
Zs 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 (2R,3R)-tartrate monohydrate and paroxetine.
A further embodiment of the present invention is a kit containing a dosage unit of (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide hydrogen {2R,3R)-tartrate monohydrate and a dosage unit of a paroxetine, optionally with instructions for use.
Pharmaceutical formulations According to the present invention the compounds in the composition will normally be administered orally, rectally, transdermally, nasally or by injection, in the form of ~o pharmaceutical formulations comprising the active ingredients in a pharmaceutically acceptable dosage form . The dosage form may be a solid, semisolid or liquid formulation.
Usually 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 is administration.
The pharmaceutical formulation comprises the active ingredients, optionally in association with adjuvants, excipients e.g. diluents, and/or inert carriers.
zo To produce pharmaceutical formulations of the composition of the invention in the form of dosage units for oral application, 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-zs 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. If coated tablets are required, the cores, prepared as described above, may be coated with a polymer known to the man skilled in the art e.g. HPMC, HC or other cellulose derivatives or PVP, wherein the 3o polymer is dissolved in water or a readily volatile organic solvent or mixture of organic solvents. Alternatively, 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.
For the formulation of soft gelatin capsules, 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), io 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 ~s base, or gelatine rectal capsules comprising the active substances in admixture with veget able oil or paraffin oil. Liquid formulations for oral application may be in the form of solutions, syrups or suspensions, for examplc'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. Optionally such liquid 2o formuiationSmay 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 2s 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 (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide hydrogen (2R,3R)-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.
Mcdical and Pharmaceutical Use io In a further aspect the present invention provides the use of the composition comprising a first component (a) which is (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and a second component (b) which is paroxetine, in the treatment of 5-hydroxytryptanune mediated ~s disorders, such as affective disorders. Examples of affective disorders are disorders in the CNS 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 io (disorders of impulse control, trichotellomania) and sleep disorders. Other disorders in the CNS such as eating disorders (obesity, anorexia, bulimia), premenstzual 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 a disorders (e g hyperprolactinaemia), stroke, dyskinesia, Parkinson's disease, thermoregulatory disordcrs, pain and hypertension may also be treated with the combination described herein. Examples of other 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:
Pharmacolotv Antagonism by (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-S-carboxamide hydrogen (2R,3R)-tartrate monohydrate (NAD 299) of the paroxetine induced suppression of dorsal raphe firing.
Materials and methods Adult male Sprague Dawley rats (B&K Universal, Sollentuna, Sweden) were used and were housed under controlled climate conditions. The animals were prepared for to electrophysiological recordings according to standard procedures. Briefly, the rats were deeply anaesthetized with chloral hydrate and mounted in a stereotaxic frame.
Extracellular recording electrodes were lowered into the dorsal raphe, guided by stereotaxic co-ordinates, and target neurones were identified by the firing characteristics of serotonin neurones in this nuceius. The animals were kept anaesthetized throughout the experiments and drugs ~s were administered intravenously through a tail vein catheter. Paroxetine (0.1 mg kg 1 i.v.}
was administered 3 min before NAD 299 (50 nmol kg I i.v.) Results It was also found that NAD 299 could antagonize the suppression of firing in zo serotoniner~c dorsal raphe neurones in rats induced by paroxetine (Figure).
The figure shows medians ~semi-interquartile range based on recordings from 5 animals per group.
Statistical evaluation for differences between treatment groups and controls, performed by means of the Mann-Whitney It-test, is also shown in the figure. In addition, the paroxetine-induced suppression was statistically significantly antagonised by NAD 299 treatment zs (p<0.05).
Discussion and conclusions It is generally considered that selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, owe their antidepressant efficacy to their ability to enhance the synaptic so availability of serotonin in forebrain target areas of serotoninergic projections from the midbrain raphe nuclei. However, 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 S-HT through activation of inhibitory 5-autoreceptors. As 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.
There exists the hypothesis that disinhibition of the self inhibitory effects of SSRIs by io blockade of inhibitory 5-HT~p autoreceptors should produce a faster onset of action, and also generally increase the efficacy of these agents.
The data show that (R)-3-~V.~V dicyclobutylaznino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate (NAD 299) effectively antagonizes is the inhibition of firing in serotoninergic neurones produced by acute administration of paroxetine in the rat.
The following non-limiting Example serves to illustrate the present invention.
Example s A suitable pharmaceutical composition comprising a first component (a) and a second component (b) in a single dosage form include the following:
Composition mg/tablet Active drug component (a) $
Active drug component {b) 20 Microcrystalline cellulose 100 Corn starch 40 Povidone 4 Water 50 Sodium starch glycolate 8 Magnesium stearate 1
Pharmaceutical formulations According to the present invention the compounds in the composition will normally be administered orally, rectally, transdermally, nasally or by injection, in the form of ~o pharmaceutical formulations comprising the active ingredients in a pharmaceutically acceptable dosage form . The dosage form may be a solid, semisolid or liquid formulation.
Usually 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 is administration.
The pharmaceutical formulation comprises the active ingredients, optionally in association with adjuvants, excipients e.g. diluents, and/or inert carriers.
zo To produce pharmaceutical formulations of the composition of the invention in the form of dosage units for oral application, 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-zs 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. If coated tablets are required, the cores, prepared as described above, may be coated with a polymer known to the man skilled in the art e.g. HPMC, HC or other cellulose derivatives or PVP, wherein the 3o polymer is dissolved in water or a readily volatile organic solvent or mixture of organic solvents. Alternatively, 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.
For the formulation of soft gelatin capsules, 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), io 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 ~s base, or gelatine rectal capsules comprising the active substances in admixture with veget able oil or paraffin oil. Liquid formulations for oral application may be in the form of solutions, syrups or suspensions, for examplc'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. Optionally such liquid 2o formuiationSmay 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 2s 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 (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide hydrogen (2R,3R)-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.
Mcdical and Pharmaceutical Use io In a further aspect the present invention provides the use of the composition comprising a first component (a) which is (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and a second component (b) which is paroxetine, in the treatment of 5-hydroxytryptanune mediated ~s disorders, such as affective disorders. Examples of affective disorders are disorders in the CNS 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 io (disorders of impulse control, trichotellomania) and sleep disorders. Other disorders in the CNS such as eating disorders (obesity, anorexia, bulimia), premenstzual 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 a disorders (e g hyperprolactinaemia), stroke, dyskinesia, Parkinson's disease, thermoregulatory disordcrs, pain and hypertension may also be treated with the combination described herein. Examples of other 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:
Pharmacolotv Antagonism by (R)-3-N,N dicyclobutylamino-8-fluoro-3,4-dihydro-2H 1-benzopyran-S-carboxamide hydrogen (2R,3R)-tartrate monohydrate (NAD 299) of the paroxetine induced suppression of dorsal raphe firing.
Materials and methods Adult male Sprague Dawley rats (B&K Universal, Sollentuna, Sweden) were used and were housed under controlled climate conditions. The animals were prepared for to electrophysiological recordings according to standard procedures. Briefly, the rats were deeply anaesthetized with chloral hydrate and mounted in a stereotaxic frame.
Extracellular recording electrodes were lowered into the dorsal raphe, guided by stereotaxic co-ordinates, and target neurones were identified by the firing characteristics of serotonin neurones in this nuceius. The animals were kept anaesthetized throughout the experiments and drugs ~s were administered intravenously through a tail vein catheter. Paroxetine (0.1 mg kg 1 i.v.}
was administered 3 min before NAD 299 (50 nmol kg I i.v.) Results It was also found that NAD 299 could antagonize the suppression of firing in zo serotoniner~c dorsal raphe neurones in rats induced by paroxetine (Figure).
The figure shows medians ~semi-interquartile range based on recordings from 5 animals per group.
Statistical evaluation for differences between treatment groups and controls, performed by means of the Mann-Whitney It-test, is also shown in the figure. In addition, the paroxetine-induced suppression was statistically significantly antagonised by NAD 299 treatment zs (p<0.05).
Discussion and conclusions It is generally considered that selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, owe their antidepressant efficacy to their ability to enhance the synaptic so availability of serotonin in forebrain target areas of serotoninergic projections from the midbrain raphe nuclei. However, 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 S-HT through activation of inhibitory 5-autoreceptors. As 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.
There exists the hypothesis that disinhibition of the self inhibitory effects of SSRIs by io blockade of inhibitory 5-HT~p autoreceptors should produce a faster onset of action, and also generally increase the efficacy of these agents.
The data show that (R)-3-~V.~V dicyclobutylaznino-8-fluoro-3,4-dihydro-2H 1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate (NAD 299) effectively antagonizes is the inhibition of firing in serotoninergic neurones produced by acute administration of paroxetine in the rat.
The following non-limiting Example serves to illustrate the present invention.
Example s A suitable pharmaceutical composition comprising a first component (a) and a second component (b) in a single dosage form include the following:
Composition mg/tablet Active drug component (a) $
Active drug component {b) 20 Microcrystalline cellulose 100 Corn starch 40 Povidone 4 Water 50 Sodium starch glycolate 8 Magnesium stearate 1
Claims (22)
1. A composition comprising of a first component (a) which is (R)-3-N,N
dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-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.
dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-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.
2. Use of the composition according to claim 1 for the manufacture of a medicament for the treatment of 5-HT mediated disorders.
3. The use according to claim 2 for the manufacture of a medicament for the treatment of affective disorders.
4. The use according to claim 3 for the manufacture of a medicament for the treatment of mood disorders.
5. The use according to claim 4 for the manufacture of a medicament for the treatment of depression.
6. The use according to claim 2 in the manufacture of a medicament in the prevention or in the treatment of urinary incontinence.
7. A method for the treatment of 5-HT mediated disorders by administering to a patient suffering therefrom the composition defined in claim 1.
8. The method according to claim 7 for the treatment of affective disorders.
9. The method according to claim 7 for the treatment of mood disorders.
10. The method according to claim 9 for the treatment of depression.
11. A method according to claim 7 for the prevention or the treatment of urinary incontinence.
12. A method of improving the onset of therapeutic action by concomitant administration of a composition defined in claim 1.
13. A pharmaceutical formulation wherein the active ingredients are those in the composition defined in claim 1, optionally in association with adjuvants, excipients and/or inert carriers.
14. A pharmaceutical formulation according to claim 13 wherein the first component (a) is concomitantly administered with the second component (b).
15. A pharmaceutical formulation according to any one of claims 13-14 for use in the treatment of 5-HT mediated disorders.
16. A pharmaceutical formulation according to any one of claims 13-14 for use in the treatment of affective disorders.
17. A pharmaceutical formulation according to any one of claims 13-14 for use in the treatment of mood disorders.
18. A pharmaceutical formulation according to any one of claims 13-14 for use in the treatment of depression.
19. A pharmaceutical formulation according to any one of claims 13-14 for use in the treatment of urinary incontinence.
20. A process for the preparation of the composition according to claim 1 whereby the first component (a) is incorporated into the same pharmaceutical formulation as the second component (b).
21. A process for the preparation of the composition according to claim 1 whereby the first component (a) is in a one pharmaceutical formulation and is combined with the second component (b) is in a different pharmaceutical formulation.
22. A kit containing a dosage unit of a first component (a) which is (R)-3-N,N
dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and a dosage unit of a second component (b) which is paroxetine, in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof, optionally with instructions for use.
dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and a dosage unit of a second component (b) which is paroxetine, in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof, optionally with instructions for use.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9803156-0 | 1998-09-16 | ||
| SE9803156A SE9803156D0 (en) | 1998-09-16 | 1998-09-16 | A new composition |
| PCT/SE1999/001597 WO2000015218A1 (en) | 1998-09-16 | 1999-09-13 | A new composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2342341A1 true CA2342341A1 (en) | 2000-03-23 |
Family
ID=20412627
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002342341A Abandoned CA2342341A1 (en) | 1998-09-16 | 1999-09-13 | A new composition |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP1128825A1 (en) |
| JP (1) | JP2002524508A (en) |
| KR (1) | KR20010099647A (en) |
| CN (1) | CN1317964A (en) |
| AR (1) | AR021808A1 (en) |
| AU (1) | AU6378099A (en) |
| BR (1) | BR9913748A (en) |
| CA (1) | CA2342341A1 (en) |
| CZ (1) | CZ2001961A3 (en) |
| EE (1) | EE200100157A (en) |
| HU (1) | HUP0103544A3 (en) |
| ID (1) | ID28785A (en) |
| IL (1) | IL141519A0 (en) |
| IS (1) | IS5879A (en) |
| NO (1) | NO20011312L (en) |
| PL (1) | PL346763A1 (en) |
| SE (1) | SE9803156D0 (en) |
| SK (1) | SK3262001A3 (en) |
| TR (1) | TR200100779T2 (en) |
| WO (1) | WO2000015218A1 (en) |
| ZA (1) | ZA200101946B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60122015T2 (en) * | 2000-10-13 | 2006-11-23 | Neurosearch A/S | TREATMENT OF AFFECTIVE DISORDERS BY COMBINED EFFECT OF A NICOTINE RECEPTOR AGONIST AND A MONOAMINERGIC SUBSTANCE |
| EP1859807A4 (en) * | 2005-03-04 | 2008-04-23 | Univ Tokyo Medical & Dental | Recurrence preventive therapeutic agent for psychostimulant-induced psychosis and schizophrenia |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9501567D0 (en) * | 1995-04-27 | 1995-04-27 | Astra Ab | A new combination |
-
1998
- 1998-09-16 SE SE9803156A patent/SE9803156D0/en unknown
-
1999
- 1999-09-13 CZ CZ2001961A patent/CZ2001961A3/en unknown
- 1999-09-13 AU AU63780/99A patent/AU6378099A/en not_active Abandoned
- 1999-09-13 EE EEP200100157A patent/EE200100157A/en unknown
- 1999-09-13 TR TR2001/00779T patent/TR200100779T2/en unknown
- 1999-09-13 IL IL14151999A patent/IL141519A0/en unknown
- 1999-09-13 WO PCT/SE1999/001597 patent/WO2000015218A1/en not_active Application Discontinuation
- 1999-09-13 BR BR9913748-8A patent/BR9913748A/en not_active Application Discontinuation
- 1999-09-13 EP EP99951319A patent/EP1128825A1/en not_active Withdrawn
- 1999-09-13 HU HU0103544A patent/HUP0103544A3/en unknown
- 1999-09-13 ID IDW20010581A patent/ID28785A/en unknown
- 1999-09-13 SK SK326-2001A patent/SK3262001A3/en unknown
- 1999-09-13 CN CN99811010A patent/CN1317964A/en active Pending
- 1999-09-13 PL PL99346763A patent/PL346763A1/en unknown
- 1999-09-13 CA CA002342341A patent/CA2342341A1/en not_active Abandoned
- 1999-09-13 KR KR1020017003337A patent/KR20010099647A/en not_active Application Discontinuation
- 1999-09-13 JP JP2000569802A patent/JP2002524508A/en active Pending
- 1999-09-15 AR ARP990104626A patent/AR021808A1/en not_active Application Discontinuation
-
2001
- 2001-03-07 IS IS5879A patent/IS5879A/en unknown
- 2001-03-08 ZA ZA200101946A patent/ZA200101946B/en unknown
- 2001-03-15 NO NO20011312A patent/NO20011312L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0103544A2 (en) | 2002-05-29 |
| TR200100779T2 (en) | 2001-10-22 |
| HUP0103544A3 (en) | 2003-12-29 |
| ZA200101946B (en) | 2002-06-10 |
| NO20011312D0 (en) | 2001-03-15 |
| NO20011312L (en) | 2001-05-16 |
| PL346763A1 (en) | 2002-02-25 |
| ID28785A (en) | 2001-07-05 |
| IS5879A (en) | 2001-03-07 |
| SE9803156D0 (en) | 1998-09-16 |
| EP1128825A1 (en) | 2001-09-05 |
| CN1317964A (en) | 2001-10-17 |
| AU6378099A (en) | 2000-04-03 |
| EE200100157A (en) | 2002-08-15 |
| JP2002524508A (en) | 2002-08-06 |
| SK3262001A3 (en) | 2001-08-06 |
| CZ2001961A3 (en) | 2001-08-15 |
| BR9913748A (en) | 2001-07-10 |
| AR021808A1 (en) | 2002-08-07 |
| IL141519A0 (en) | 2002-03-10 |
| WO2000015218A1 (en) | 2000-03-23 |
| KR20010099647A (en) | 2001-11-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6169098B1 (en) | Composition and methods employing it for the treatment of 5-HT-mediated disorders | |
| CN108042808B (en) | Combination comprising brexpiprazole or salt thereof and a second drug for the treatment of central system diseases | |
| US20110136865A1 (en) | Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists | |
| US20050203130A1 (en) | Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists | |
| JP4571485B2 (en) | Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists | |
| JP2007513052A (en) | Combination of serotonin reuptake inhibitor and agomelatine. | |
| US6472423B1 (en) | Pharmaceutical composition | |
| CA2342341A1 (en) | A new composition | |
| AU6378199A (en) | A new composition | |
| CA2342233A1 (en) | A new composition | |
| CA2342223A1 (en) | A new composition | |
| JP4571645B2 (en) | Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists | |
| MXPA01002370A (en) | A new composition | |
| MXPA01002543A (en) | A new composition | |
| CA2351674A1 (en) | Use of a 5ht2a and 5ht2a/c receptor antagonist for preparing medicines for treating snoring and high resistance syndrome of upper anatomical airways | |
| AU2004269857A1 (en) | The combination of a serotonin reuptake inhibitor and Amoxapine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |