Field of the Invention, -The present to a composition comprising a first component (a) which is (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro- (2R, 3R) -tartrate acid monohydrate 2H-1-benzopyran-5-carboxamide 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, the pharmaceutical formulations containing the composition and the use of the composition either by concomitant administration or by "separate administration as an improvement of the treatment of "affective" conditions, such as depression, anxiety, obsessive-compulsive disorder(OCD), etc.
Background of the InventionCurrently, in general, it is considered that antidepressants take 2-4 weeks to reach the full clinical effect. Pogá &J. In this case, collateral effects may occur immediately. In this way, the slow start of action of antidepressants leads to a vulnerable period for patients in whom they experience side effects, but not the therapeutic effects of the drugs. Often, there is a heavy burden on medical treatment to persuade the patient to continue with the treatment during this period. In addition, in suicidal patients, as the onset of action is gradual, the initiative could be recovered without the experimentation of the complete inversion of the symptoms, leaving a window of risk for the suicide and a frequent requirement of hospitalization. An antidepressant with rapid onset of action would not only be beneficial because of the faster symptomatic reduction, but would also be more acceptable to patients and physicians and reduce the need and duration of hospitalization. The same long period to achieve the full clinical effect has been shown in the treatment of other affective conditions, such as anxiety and OCD.
Previous artIn the WO that the compound (R) -5-carbamoyl-8-fluoro-3-N, -dicyclobutylamino-3, 4-dihydro-2H-l-benzopyran which has high affinity to the 5-HT receptors and antagonizes the responses mediated by 5-HT1A, induces rapid improvement of depressive patients treated with serotonin reuptake inhibitors.
Brief Description of the InventionThe present invention relates to a novel composition comprising a first component (a) which is the specific 5-HT1A antagonist (R) -3-N, N-dicyclobutylamino- (2R, 3R) -tartrate acid monohydrate. 8-fluoro-3, 4-dihydro-2H-l-benzopyran-5-carboxamide and a second component (b) which is paroxetine, in the form of the free base, or a pharmaceutically acceptable salt and / or solvate thereof. The composition achieves a faster onset of action and consequently, provides a more effective treatment of patients suffering from affective disorders, particularly depression.
It has been shown in animal studies that acute administration of selective selective 5-HT reuptake inhibitors (SSRIs) decreases the propagation of the electrical impulse in 5-HT neurons via a negative feedback reaction. mediated probably by l ^ @ js collateral 5-HT axons that release 5-HT in the raphe nucleus. By inhibiting the 5-HT1A autoreceptors of the dendritic soma in the raphe nucleus, selective antagonists counteract the decrease in propagation caused by the 5-HT reuptake inhibitors. This indicates that a selective blocker of the soma autoreceptor of the dendrite i.e. 5-HT1A antagonist could have a clinical potential to improve the efficiency of 5-HT reuptake inhibitors (SSRIs) and offer a new rational for the rapid onset of effect in the treatment of affective disorders, for example, antidepressant actions .
The (R) -3-N, -dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide (NAD299) acid monohydrate compound described herein is describes in J. Pharmacol. Exp. Ther., 283, 216-225, (1997) as a selective 5-HT1A receptor antagonist.tí; / - .. * ».« .. • Monohydrate of (2R, 3R) -tartrate acid of (R) -3-N, N-dicylobutyl-lamino-8-fluoro-3, 4-dihydro -2H-l-benzopyran-5-carboxamide possesses a high affinity to the specific subgroup of the 5-HT1A receptor in the CNS and acts as an antagonist on such 5-HT1A receptor, and also shows favorable bioavailability after oral administration.
Paroxetine is a 5-HT reuptake inhibitor (SSRI) that is commercially available. The pharmaceutically acceptable salts of paroxetine, such as hydrochloride, hydrobromide, maleate, tartrate, acetate, etc. they are also included in the inventive composition. Also included are solvated forms, such as the hydrate and hemihydrate of the salts.
The composition according to the present invention could exist in a pharmaceutical formulation comprising component (a) and component (b), or in two different pharmaceutical formulations, one for component (a) and one for component (b) . The pharmaceutical formulation could be in the form of tablets or capsules, powders, mixtures, solutions or other forms of appropriate pharmaceutical formulations, such as patches and nasal formulations.
The composition of the present invention can be prepared so that the component (a > is incorporated in the same pharmaceutical formulation as the component (b), for example, by mixing in a conventional manner.
The present invention also includes a method for improving the onset of therapeutic action by concomitant administration of a composition, comprising (R) -3-N, N-dicyclobutylamino-8 (2R, 3R) -tartrate acid monohydrate. -fluoro-3, 4-dihydro-2H-l-benzopyran-5-carboxamide 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- (2R, 3R) -tartrate acid monohydrate. 2H-l-benzopyran-5-carboxamide and a dosage unit of paroxetine, optionally with instructions for use.** * • "Í Pharmaceutical formulationsAccording to-a-, frßsente • Lín, v, &.ncAón - :, ¿losoo pu? Est sz en. or by? ... injection, ", in the form.", "pharmaceutical formulations comprising the active ingredients in a pharmaceutically acceptable dosage form. The dosage form could be a solid, semi-solid or liquid formulation. Usually, the active substances will constitute between 0.1 and 99% insolid excipient, e.g. lacfcj | Já, sucrose, sorbitol, mannitol, starches, such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder, such as gelatin or polyvinylpyrrolidone, disintegrators e.g. sodium starch glycolate, crosslinked PVP and cross sodium caramelose and a lubricant, such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and an anti-sticking agent, such as talc or colloidal silicon dioxide and then compressed into tablets. If coated tablets are required, the centers, prepared as described above, could be coated with a polymer known to the person skilled in the art, e.g. HP C, HC or other cellulose derivatives or PVP, where the polymer is dissolved in water or an organic solvent or mixture of easily volatile organic solvents. Alternatively, the tablets may be coated with a concentrated sugar solution which could contain e.g. gum arabic, gelatin, talcum, titanium dioxide and the like. Dyestuffs could be added to these coatings, for example, to easily distinguish between tablets containing different active substances or different amounts of the active compounds.
For the formulation of soft gelatin capsules, the active substances could be mixed with e.g. a vegetable oil or polyethylene glycol. The hard gelatin capsules may contain granules of the active substances, if any of the excipients mentioned above for the tablets e.g. lactose, sucrose, _sorbitol, mannitol, starches (e.g., potato starch, corn starch or amylopectin), cellulose derivatives, plasticizers, polyethylene glycol, waxes, lipids or gelatin. Also the liquids or semisolids of the drug can be filled into hard gelatin capsules.
The dosage units for rectal application can be solutions or suspensions or they can be prepared in the form of suppositories, which comprise the active substances in a mixture with a neutral fat base or rectal gelatin capsules comprising the active substances in mixture with vegetable oil or paraffin oil. Liquid formulations for oral application could 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 described herein, the sugar balance beingmixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid formulations could contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose as a thickening agent or other excipients known to one skilled in the art.
Solutions for parenteral injection applications can be prepared in an aqueous solution of a pharmaceutically acceptable salt soluble in water of the active substances, preferably in a concentration of about 0.5% to about 10% by weight. These solutions could also contain stabilizing agents and / or buffering agents and could conveniently be provided in several dosage unit vials.
Daily appropriate dosages of the active compounds in the composition of the invention, in the therapeutic treatment of humans are about 0.01-100 mg / kg of body weight for percutaneous administration and 0.001-100 mg / kg of body weight for administration parenteral Daily dosages of the active ingredient monohydrate of (2R, 3R) art or (R) -3-N, N-dicyclobutylamino t8¡ £ fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide acid could very different from the daily dosages of the active ingredient of paroxetine, but the dosages can also be the same for both of the active ingredients.
Medical and Pharmaceutical UseIn a further aspect of the present invention, there is provided the use of the composition comprising a first component (a) which is (R) -3-N, N-dicyclobutylamino-8 (3R) -tartrate acid monohydrate. -fluoro-3, 4-dihydro-2H-l-benzopyran-5-carboxamide and a second component (b) which is paroxetine, in the treatment of conditions mediated by 5-hydroxytryptamine, such as affective affections. Examples of affective disorders are conditions in the CNS, such as mood disorders (depression, episodes of major depression, dysthymia, temporary affective disorder, depression phases of bipolar disorder), anxiety disorders (obsessive-compulsive disorder, panic disorder) with / without agoraphobia, social phobia, specific phobia, suffering from sleep anxiety Other illnesses in the CNS, such as hunger conditions (obesity, anorexia, bulimia), premenstrual syndrome, sexual disorders, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders, (deficiency of memory associated with age, presenile and senile dementia, such as Alzheimer's disease), pathological aggression,PharmacologyAntagonism by (R) -3-N, N-dicyclobutylamino-8-fluoro-3, 4-dihydro-2H-l-benzopyran-5-carboxy-carbamide (NAD 299) monohydrate (2R, 3R) -tartrate acid (NAD 299) Paroxetine-induced suppression of dorsal raphe excitation.
Materials and methodsAdult male Sprague Dawley rats (B &K Universal, Sollentuna, Sweden) were used and housed under controlled climatic conditions. The animals were prepared for electrophysiological recordings according to standard procedures. Briefly, the rats were deeply anesthetized with chloral hydrate and mounted in a stereotaxic frame. The extracellular recording electrodes were decreased in the dorsal raphe, were guided by stereotactic coordinates and the white neurons were identified by the excitation characteristics of the serotonin neurons in this nucleus. The animals were anesthetized through all the experiments and the drugs were administered intravenously by means of a catheter in the tail vein. Paroxetine (0.1 mg kg "1 i.v.) was administered 3 min before NAD 299 (50 nmol kg" 1 i.v.).
ResultsIt was also found that NAD 299 could antagonize suppression of excitation in serotonergic dorsal raphe neurons in rats induced by paroxetine (Figure). The figure shows the means ± semi-interquartile range based on the records of the 5 animals per group. The statistical evaluation for the differences between the treatment groups and controls, made by means of the Mann-Whitney μ test, is also shown in the figure. In addition, suppression induced by paroxetine was statistically significantly antagonized by treatment with NAD 299 (p <0.05).
Discussion and ConclusionsIn general, selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, are considered to owe their antidepressant efficacy to their ability to improve the synaptic availability of serotonin in the brain's anterior white areas.* _É * * the kl projections of the raphe of the half of the brain. l ff? However, the affected 5-hydroxytryptamine (5-HT) transporter protein is present in the dendritic and terminal soma regions, and initially the improved availability of serotonin * in the previous areas will inhibit neuronal activity, as well as the synthesis of the anterior brain and the release of 5-HT through the activation of the 5-HT1A autoreceptors inhibitors. Both these receptors are de-entitized over time, there is a gradual increase in serotonin release from the forebrain, as shown in animal studies, and the time course for this phenomenon probably explains the delayed onset of actions clinically antidepressantIt is hypothesized that the disinhibition of the self-inhibiting effects of SSRIs by the blockade of the autoreceptors of 5-HT1A inhibitors, should produce a faster onset of action and also increase, in general, the efficiency of these agents.
The results show that (R) -3-N, N-dicyclobutylamino- (2R, 3R) -tartrate acid monohydrate8 -. 8-Fluoro-3, 4-dihydro-2H-l-gi @ nzopyran-5-carboxamide (NAD 299) effectively antagonizes the inhibition of excitation in serotonergic neurons produced by the acute administration of paroxetine in the rat.
The following non-limiting example serves to illustrate the present invention.
EXAMPLE An appropriate pharmaceutical composition comprising a first component (a) and a second component (b) in a unit dosage form, includes the following:Composition mg / tablet Component of the active drug (a) 5 Component of the active drug (b) 20 Microcrystalline cellulose 100 Corn starch 40 Povidone 4 Water 50 Corn starch glycolate 8 Magnesium stearate 1~ ^ K ^ This date is stated, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.
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