SK3262001A3 - A new composition - Google Patents

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

The present invention relates to a composition comprising the first component (a) which is (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen- (2R) monohydrate (3R) -tartrate and the second component (b) which is paroxetine or a pharmaceutically acceptable salt thereof and / or a solvate thereof. The present invention also relates to a method of preparing a composition of the invention, pharmaceutical compositions comprising said composition, and the use of said composition either by co-administration or separate administration as an improvement in the treatment of emotional disorders such as depression, anxiety, obsessive-compulsive disease and the like.

BACKGROUND OF THE INVENTION

It is generally considered that it takes 2 to 4 weeks to achieve complete clinical effect with antidepressants. In contrast, side effects occur immediately. Thus, the slow onset of action of antidepressants leads to a vulnerable period for patients in which they experience side effects but not therapeutic effects of drugs. Often, it is a great burden for the attending physician to persuade the patient to continue treatment during this period. In addition, in the suidid patients, since the onset of action is gradual, initiative can be re-established without experiencing a complete change in symptoms, leaving room for the risk of suicide attempts and frequent hospitalization. Antidepressants with a rapid onset of action would be useful not only because of the faster alleviation of symptoms, but would also be more acceptable to patients and attending physicians and would reduce the need and duration of hospitalization. Likewise, a long period of time to achieve full clinical effect has been demonstrated in the treatment of other emotional disorders such as anxiety and obsessive-compulsive disease.

WO 96/33710 discloses that compound (R) -5-carbamoyl-8-fluoro-3-N, N-dicyclobutylamino-3,4-dihydro-2H-1-benzopyran having high affinity for 5-HT receptors and antagonize the responses mediated by 5-HT _1A, leads to a rapid improvement of depressed patients treated with serotonin reuptake inhibitors.

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SUMMARY OF THE INVENTION

The present invention is directed to a novel composition consisting of the first component (a), which is a specific 5-HT _1A antagonist, (R) -3-N monohydrate, N-cyclobutylamino-8-fluoro-3,4-dihydro-2H-1- benzopyran-5-carboxamide hydrogen (2R, 3R) -tartrate, and the second component (b), which is paroxetine, in the form of the free base, or a pharmaceutically acceptable salt thereof, and / or a solvate thereof. Said composition achieves a faster onset of action and consequently provides a more effective treatment for patients suffering from emotional disorders, in particular depression.

In animal studies, acute administration of selective 5-HT reuptake inhibitors (SSRIs) has been shown to reduce the propagation of electrical impulses in 5-HT neurons through a negative feedback reaction likely to be mediated by collateral 5-HT axons releasing 5-HT in the rapea nuclei. By inhibiting somatodendritic 5-HT 1A autoreceptors in the rapha nuclei, selective antagonists counteract the reduction of the spread caused by reabsorption inhibitors

5-HT. This suggests that selective blockade of somatodendritic autoreceptors, i.e., 5-HT _1A antagonists, may exhibit clinical potential to improve the efficacy of 5-HT reuptake inhibitors (SSRIs) and provide a new basis for the rapid onset of treatment effects of emotional disorders such as antidepressant effects.

The (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R, 3R) -tartrate (NAD 299) monohydrate compound mentioned herein , is described in J. Pharmacol. Exp. Ther., 283. 216-225 (1997) as a selective 5-HT _1A receptor antagonist.

(R) -3-N, N-Dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen- (2R, 3R) -tartrate monohydrate is characterized by high affinity for a specific receptor subgroup 5 -HT _1A in the central nervous system and acts as an antagonist to this 5-HT _1A receptor, and also exhibits excellent bioavailability after oral administration.

Paroxetine is a 5-HT _1A reabsorption inhibitor (SSR) which is commercially available. Pharmaceutically available salts of paroxetine such as hydrochloride, hydrobromide. maleate, tartrate, acetate and others are also included in the compositions

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according to the invention. Also included are solvated forms such as hydrate and hemihydrate salts.

The composition of the present invention may exist in one pharmaceutical composition consisting of component (a) and component (b), or in two different pharmaceutical compositions, one for component (a) and one for component (b). The pharmaceutical preparation may be in the form of tablets or capsules, powders, mixtures, solutions or other suitable pharmaceutical forms of the preparation, such as patches and nasal preparations.

The composition of the present invention can be prepared by incorporating component (a) into the same pharmaceutical composition as component (b), for example by mixing in a conventional manner.

The present invention also includes a method of improving the onset of therapeutic effect by co-administering a composition comprising (R) -3-N, N-cyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R, 3R) - tartrate and paroxetine.

Another embodiment of the present invention is a kit comprising a (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen- (2R, 3R) -tartrate monohydrate dosage unit and a dosage unit of paroxetine, optionally with instructions for use.

Pharmaceutical preparations

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 pharmaceutical preparations containing the active ingredients in a pharmaceutically acceptable dosage form. The dosage form may be a solid, semi-solid or liquid preparation. Typically, the active ingredient will comprise 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 .

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The pharmaceutical composition contains the active ingredients, optionally together with excipients, excipients, for example diluents and / or inert carriers.

For preparing pharmaceutical compositions of the composition of the present invention in the form of dosage units for oral administration, selected compounds may be admixed with a solid excipient such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, binder, such as gelatin or polyvinylpyrrolidone, disintegrants such as sodium starch glycolate, cross-linked PVP and cross-linked sodium caramelosan 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 wheel and then compressed into tablets. If coated tablets are desired, the cores prepared as described above may be coated with a polymer known to those skilled in the art, such as HPMC, HC or other cellulose or PVP derivatives, wherein the polymer dissolves in water or in a readily a volatile organic solvent or a mixture of organic solvents. Alternatively, the tablets may be coated with a concentrated sugar solution which may contain gum arabic, gelatin, talc, titanium dioxide and the like. Dyestuffs can be added to these coatings, for example to make it easier to distinguish between tablets containing different active substances or different amounts of active compounds.

For soft gelatine capsule preparations, the active compounds can be mixed, for example, with vegetable oil or polyethylene glycol. The hard gelatin capsules may contain granules of the active ingredients using any of the above-mentioned tablet excipients such as lactose, sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives, plasticizers, polyethylene glycol, waxes, lipids or gelatin. Solid or semi-solid forms of drugs may also be filled into hard gelatin capsules.

Dosage units for rectal administration may be solutions or suspensions, or may be presented in the form of suppositories containing the active ingredients in admixture with a neutral fatty base, or gelatin rectal capsules containing the active ingredients in admixture with vegetable oil or paraffin oil.

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Liquid preparations for oral administration 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 ingredients described herein, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring, flavoring, saccharin and carboxymethylcellulose as thickeners, or other excipients known to those skilled in the art.

Solutions for parenteral use by injection may be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active ingredients, preferably at 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 preferably be provided in a variety of unit dose vials.

Suitable daily dosages of the active compounds in the composition of the present invention in the therapeutic treatment of humans are about 0.01 to 100 mg / kg body weight for oral administration and 0.001 to 100 mg / kg body weight for parenteral administration. Daily doses of (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen- (2R, 3R) -tartrate monohydrate may vary considerably. from daily doses of the active ingredient paroxetine, but the doses may also be the same for both active ingredients.

Medical and pharmaceutical use

The present invention further relates to the use of a composition comprising the first component (a), which is (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen- (2R) monohydrate (3R) -tartrate and the second component (b), which is paroxetine, in the treatment of 5-hydroxytryptamine-mediated diseases, such as emotional disorders. Examples of emotional disorders are central nervous system disorders such as mood disorders (depression, major bouts of depression, dysthymia, seasonal emotional disorders, depressive phases of bipolar disorders), anxiety (obsessive-compulsive disorders, panic attacks with / without agoraphobia, social phobia, social phobia) phobias, generalized anxiety attacks, post-traumatic stress), personality disorders (pulse control disorders, trichotheomania), and sleep disorders. Other central nervous system disorders such as eating disorders

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4 44 444 44 4 (obesity, anorexia, bulimia), premenstrual syndrome, sexual disorders, alcoholism, tobacco dependence, autism, lack of attention, hyperactivity, migraine, memory disorders (age-related memory impairment, presenile and senile dementia, such as Alzheimer's disease), pathological aggression, schizophrenia, endocrine disorders (e.g. hyperprolactinaemia), stroke, dyskinesia, Parkinson's disease, thermoregulation disorders, pain and hypertension can also be treated using the combination described herein. Examples of other hydroxytryptamine-mediated diseases are urinary incontinence, vasospasm and controlled tumor growth (e.g., lung cancer) and could also be treated using the combination described herein:

pharmacology

(R) -3-N, N-Dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen- (2R, 3R) -tartrate (NAD 299) monohydrate antagonist for suppressing dorsal nerve impulse transmission raphe induced by paroxetine.

Material and methods

Adult Sprague Dawiey rats (B & K Universal, Sollentuna, Sweden) were used and these were kept under regulated air conditioning conditions. Animals were prepared for electrophysiological recording in accordance with standard procedures. Briefly, rats were deeply anesthetized using chloral hydrate and fixed in a stereotaxic frame. Extracellular recording electrodes were triggered into the dorsal raphe, guided through stereotaxic coordinates, and target neurons were identified by transmitting the nerve pulse characteristics of serotonin neurons in this nucleus. Animals were anesthetized during the experiments and drugs were administered intravenously through the tail vein catheter. Paroxetine (0.1 mg.kg ^-1 , intravenous) was administered 3 minutes before NAD 299 (50 nmol.kg ^-1 , intravenous).

The results

It has been found that NAD 299 could antagonize suppression of nerve impulse transmission in dorsal raphe serotonergic neurons in rats induced by paroxetine (Figure). The figure shows the mean ± semi-quartile range based on records from 5 animals per group. Statistical ···············

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The evaluation for differences between treatment groups and controls, performed using the Mann-Whitney μ-test, is also shown in the figure. In addition, paroxetine-induced suppression was statistically significantly antagonized by treatment with NAD 299 (p <0.05).

Discussion and conclusions

In general, selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, are believed to be due to their antidepressant efficacy in their ability to increase the synaptic availability of serotonin in target regions of the forebrain of serotonergic projections from the middle brain raphe nuclei. However, the affected protein transporter, 5-hydroxytryptamine (5-HT) is present in both somatodendritic and terminal regions, and initially the increased availability of serotonin in previous regions will inhibit neuronal activity as well as the synthesis and release of 5-HT in the forebrain due to activation of inhibitory 5-HT _1A autoreceptors. As these receptors desensitize over time, there is a gradual increase in serotonin release in the forebrain, as shown in animal studies, and the time course for this phenomenon is likely to explain the delayed onset of antidepressant effects in clinical practice.

There is a hypothesis that disinhibiting the inhibitory effects of SSRIs alone by blocking inhibitory 5-HT _1A autoreceptors could provide a faster onset of action and also generally increase the efficacy of these agents.

Data show that (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen- (2R, 3R) -tartrate (NAD 299) monohydrate efficiently in rats antagonizes the inhibition of neurotransmission in serotonergic neurons caused by the acute administration of paroxetine.

The following non-limiting examples serve to illustrate the present invention.

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DETAILED DESCRIPTION OF THE INVENTION

A suitable pharmaceutical composition comprising the first component (a) and the second component (b) in a single dosage form comprises the following components:

Composition of mg / tablet

Drug active ingredient (s)

Active ingredient (b) of the drug 20

100 ALIGN! 10092002, 04:21:31 Microcrystalline cellulose

Corn starch

Povidone 4

Water 50

Sodium starch glycolate 8

Magnesium stearate

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Claims (22)

A composition comprising the first component (a), which is (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate hydrogen- (2R, 3R) -tartrate and the second component (b) which is paroxetine in the form of the free base, or a pharmaceutically acceptable salt thereof, and / or a solvate thereof. Use of a composition according to claim 1 for the manufacture of a medicament for the treatment of 5-HT mediated diseases. Use according to claim 2 for the manufacture of a medicament for the treatment of emotional disorders. Use according to claim 3 for the manufacture of a medicament for the treatment of mood disorders. Use according to claim 4 for the manufacture of a medicament for the treatment of depression. Use according to claim 2 in the manufacture of a medicament for the prevention or treatment of urinary incontinence. 7. A method of treating a 5-HT mediated disease by administering a composition as defined in claim 1 to a patient suffering from such disease. The method of claim 7, for the treatment of emotional disorders. The method of claim 7, for treating mood disorders. The method of claim 9, for treating depression. The method of claim 7, for preventing or treating urinary incontinence. A method for improving the onset of a therapeutic effect by co-administering the composition defined in claim 1. Pharmaceutical preparation, characterized in that the active ingredients are the ingredients of the composition defined in claim 1, optionally together with excipients, excipients and / or inert carriers. ·· ···· · · · ··· -10 · ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The pharmaceutical composition of claim 13, wherein the first component (a) is co-administered with the second component (b). A pharmaceutical composition according to any one of claims 13 to 14 for use in the treatment of 5-HT mediated diseases. A pharmaceutical composition according to any one of claims 13 to 14 for use in the treatment of emotional disorders. A pharmaceutical composition according to any one of claims 13 to 14 for use in the treatment of mood disorders. A pharmaceutical composition according to any one of claims 13 to 14 for use in the treatment of depression. A pharmaceutical composition according to any one of claims 13 to 14 for use in the treatment of urinary incontinence. A method of preparing a composition according to claim 1, wherein the first component (a) is incorporated into the same pharmaceutical composition as the second component (b). A method of preparing a composition according to claim 1, wherein the first component (a) is in one pharmaceutical formulation and is associated with the second component (b) in a different pharmaceutical formulation. Kit comprising a dosage unit of the first component (a), which is (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5 monohydrate - (2R, 3R) -tartrate carboxamide and a dosage unit of the second component (b), which is paroxetine, in the form of the free base or a pharmaceutically acceptable salt thereof and / or a solvate thereof, optionally with instructions for use. Z Z / • e · t · a · a Fig. 1 • · • a »· l / Z U-Zvi J • and a: i: • and aaa