KR20010099647A - A New Composition - Google Patents

Abstract

The present invention is (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R, 3R)- A composition comprising the first component (a) as a tartrate monohydrate and paroxetine in the form of a free base, or a second component (b) as a pharmaceutically acceptable salt and / or solvate thereof, the preparation thereof, containing the composition Pharmaceutical formulations, uses and methods of treating affective disorders such as emotional disorders and anxiety disorders using the compositions, as well as kits containing the compositions.

Description

A new composition

Currently, antidepressants are generally thought to take 2 to 4 weeks to reach sufficient clinical effect. Conversely, side effects occur immediately. In other words, the slow onset of antidepressant action leads to the onset period in which the patient experiences side effects rather than the therapeutic effects of the drug. It is a heavy burden on the treating physician to persuade the patient to continue treatment during this period. In addition, in suicide patients, since the onset of action is gradual, spontaneous regeneration may occur again without experiencing a complete reversal of symptoms, thereby leaving a window of suicide risk and requiring frequent hospitalization. Antidepressants with fast onset of action are not only advantageous due to faster symptom reduction but also more satisfactory to patients and physicians and reduce the need and duration of hospitalization. Treatment of other affective disorders such as anxiety and OCD has been shown to take the same long period of time to reach sufficient clinical effect.

Prior art

WO 96/33710 discloses a compound (R) -5-carbamoyl-8-fluoro-3-N, N-dicyclo that has a high affinity for the 5-HT receptor and antagonizes the 5-HT _1A mediated response. It is disclosed that butylamino-3,4-dihydro-2H-1-benzopyrans induce a rapid improvement in depressed patients treated with serotonin reuptake inhibitors.

Summary of the Invention

The present invention relates to specific 5-HT _1A antagonist (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carbox A novel composition comprising the first component (a), which is a mid hydrogen (2R, 3R) -tartrate monohydrate, and paroxetine in the form of a free base, or the second component (b), as a pharmaceutically acceptable salt and / or solvate thereof. It is about. The compositions achieve faster onset of action and as a result provide more effective treatment of patients suffering from affective disorders, especially depression.

Acute administration of selective 5-HT reuptake inhibitors (SSRIs) in 5-HT neurons, via a negative feedback response that is believed to be mediated by geodetic 5-HT axons that release 5-HT in the chondrocyte It has been found in animal studies that reduces the transmission of electrical shock. Selective antagonists counteract the reduction in delivery induced by the 5-HT reuptake inhibitors by inhibiting the cytoplasmic 5-HT _1A autoreceptor in the chondrocyte. This suggests that selective blockade of cell dendritic autoreceptors, i.e. 5-HT _1A antagonists, may have clinical potential to improve the effectiveness of 5-HT reuptake inhibitors (SSRIs) and treatment of affective disorders, e.g. It provides new evidence for rapidly initiating effects on antidepressant action.

Compound (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R, 3R) disclosed herein Tartrate monohydrate (NAD 299) has been described as selective 5-HT _1A receptor antagonist in J. Pharmacolog. Exp. Ther., 283, 216-225 (1997).

(R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R, 3R) -tartrate monohydrate Not only has a high affinity for a specific subgroup of 5-HT _1A receptors in the CNS and acts as an antagonist for the 5-HT _1A receptors, but also shows advantageous bioavailability after oral administration.

Paroxetine is a commercially available 5-HT reuptake inhibitor (SSRI). Pharmaceutically acceptable salts of paroxetine may be hydrochloride, hydrobromide, maleate, tartrate, acetate, oxalate, fumarate, and the like, and are also included in the compositions of the present invention. Solvate forms such as hydrates and hemihydrates of salts are also included.

The composition according to the invention is present in one pharmaceutical formulation comprising component (a) and component (b), or two different pharmaceutical formulations, one for component (a) and one for component (b) May be present as. The pharmaceutical formulation may be in the form of tablets or capsules, powders, mixtures, solutions, or other suitable pharmaceutical formulations such as patch and nasal formulation.

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

The invention also relates to (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R, 3R) -A method for improving the onset of therapeutic action by simultaneous administration of a composition comprising tartrate monohydrate and paroxetine.

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

Pharmaceutical Formulations

According to the invention, the compounds in the compositions are usually administered orally, rectally, transdermally, nasal or by injection in the form of pharmaceutical formulations comprising the active ingredient in a pharmaceutically acceptable dosage form. The dosage form may be a solid, semisolid or liquid formulation. Typically, the active substance comprises from 0.1 to 99% by weight of the formulation, more particularly from 0.5 to 20% by weight of the formulation for injection and from 0.2 to 50% by weight of the formulation suitable for oral administration.

Pharmaceutical formulations comprise the active ingredients optionally together with adjuvants, excipients such as diluents and / or inert carriers.

In order to prepare pharmaceutical formulations of the compositions of the invention in the form of dosage units for oral application, selected compounds may be prepared as solid excipients, for example, starches such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch or amylopectin. Binders such as cellulose derivatives, gelatin or polyvinylpyrrolidone, disintegrants such as sodium starch glycolate, crosslinked PVP and croscarmellose sodium; It can be mixed with lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin and the like, and anti-sticking agents 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 polymers known to those skilled in the art, for example HPMC, HC or other cellulose derivatives or PVP, wherein the polymers are water or readily volatile organic solvents. Or in a mixture of organic solvents. Alternatively, tablets may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, titanium dioxide and the like. In order to easily distinguish tablets containing different active substances or different amounts of active compounds, dyes may be added to such coatings.

For the formulation of soft gelatin capsules, the active substance may be mixed, for example with vegetable oil or polyethylene glycol. Hard gelatin capsules include the aforementioned excipients, for example, lactose, saccharose, sorbitol, mannitol, starch (eg potato starch, corn starch or amylopectin), cellulose derivatives, plasticizers, polyethene glycols, waxes, Lipids or gelatin may also be used to contain granules of the active substance. In addition, liquids or semisolids of the drug can be filled into hard gelatin capsules.

Dosage units for rectal application may be in the form of suppositories comprising the active substance in a mixture with a neutral fat base or in the form of suppositories, or of a gelatin rectal capsule comprising the active substance in a mixture with vegetable or paraffin wax. Can be manufactured in the form Liquid formulations for oral application contain in the form of solutions, syrups or suspensions, for example from about 0.2% to about 20% by weight of the active substance described above and the remainder is a mixture of sugar and ethanol, water, glycerol and propylene glycol. Solution. Optionally, such liquid formulations may contain carboxymethyl-cellulose as colorants, flavors, saccharines and thickeners or excipients known to those skilled in the art.

Solutions for parenteral application by injection can be prepared in an aqueous solution containing a water-soluble pharmaceutically acceptable salt of the active substance, preferably at a concentration of about 0.5% to about 10% by weight. Such solutions may also contain stabilizers and / or buffers and may be conveniently provided in a variety of dosage unit ampoules.

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

Medical and Pharmaceutical Uses

In a further aspect, the invention provides (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen ( 2R, 3R) -Tartrate monohydrate provides a composition comprising a first component (a) and a second component (b), paroxetine, and a use in the treatment of 5-hydroxytryptamine mediated disorders such as affective disorders do. Examples of affective disorders include emotional disorders (depression, major depression episodes, mood alterations, seasonal affective disorders, bipolar disorder depression), anxiety disorders (obsessive compulsive disorder, panic disorder with or without agoraphobia, social phobia, specific phobias) , Disorders in the CNS, such as generalized anxiety disorder, post-traumatic stress disorder), personality disorders (shock control disorders, hair deprivation) and sleep disorders. Eating disorders (obesity, anorexia, gluttony), premenstrual syndrome, sexual disorders, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraines, memory disorders Dementia), pathological attack, schizophrenia, endocrine disorders (e.g., hyperprolactinemia), seizures, dyskinesia, Parkinson's disease, thermoregulation disorders, pain and other disorders in the CNS, such as hypertension, as described herein. It can also be treated with. Examples of other hydroxytryptamine mediated disorders are urinary incontinence, vasospasm and tumor growth control (eg, lung carcinoma), which may be treated with the combinations described herein.

Pharmacology

(R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxase of paroxetine-induced dorsal baling firing inhibition Antagonism by Mid Hydrogen (2R, 3R) -Tartrate Monohydrate (NAD 299)

Materials and methods

Grown male Sprague Dawley mice [B & K Universal, Sweden] were used to accommodate under controlled climatic conditions. Animals were prepared for electrophysiological recording according to standard procedures. Briefly, mice were deeply anesthetized with chloral hydrate and fixed in stereotactic framework. The extracellular recording electrode was lowered into the dorsal tendon using the stereotactic coordinates as an index, and the target neurons were identified by firing characteristics in the serotonin neurons in the nucleus. Animals were anesthetized throughout the experiment and the drug was administered intravenously via a tail vein catheter. Paroxetine (0.1 mg / kg intravenously) was administered 3 minutes prior to NAD 299 (50 nmol / kg intravenously).

result

NAD 299 was found to be able to antagonize firing inhibition in serotonergic dorsal neural cells of rats induced by paroxetine (see figure). The figure shows the median ± semi-internal quartile range based on recordings from five animals per group. Statistical evaluations of differences between treatment and control groups using the Mann-Whitney μ-test are also shown in the figure. In addition, paroxetine-induced inhibition was statistically significantly antagonized by NAD 299 treatment (p <0.05).

Discussion and conclusion

Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, are generally considered to have antidepressant efficacy due to their ability to enhance the synaptic effectiveness of serotonin in the forebrain target region of serotonergic projection from the mesothelial chondrocyte. However, the affected 5-hydroxytryptamine (5-HT) transporter protein is present in both the somatic dendritic and terminal bands, and initially the enhanced efficacy of serotonin in the somatic dendritic region is not only neuroactive but also inhibitory 5 Will inhibit whole brain synthesis and release of 5-HT through the activity of -HT _1A autoreceptors. The receptors are desensitized over time, resulting in a progressive increase in whole brain serotonin release, as shown in animal studies, and the time course in this phenomenon will clinically explain the delayed onset of antidepressant action.

There is a hypothesis that anti-inhibition of the self-inhibitory effect of SSRI by blocking the inhibitory 5-HT _1A autoreceptor should result in faster onset of action, and generally also increases the efficacy of such reagents.

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

The invention is illustrated by the following non-limiting examples.

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

Suitable pharmaceutical compositions comprising the first component (a) and the second component (b) in a single dosage form comprise the following compositions:

Furtherance Mg / tablet Active pharmaceutical ingredient (a) 5 Active pharmaceutical ingredient (b) 20 Microcrystalline cellulose 100 Corn starch 40 Povidone 4 water 50 Sodium starch glycolate 8 Magnesium stearate One

Claims (22)

(R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R, 3R) -tartrate monohydrate A composition comprising the first component (a) and paroxetine in the form of a free base, or a second component (b) as a pharmaceutically acceptable salt and / or solvate thereof. Use of a composition according to claim 1 for the manufacture of a medicament for the treatment of 5-HT mediated disorders. Use according to claim 2 for the manufacture of a medicament for the treatment of affective disorders. Use according to claim 3 for the manufacture of a medicament for the treatment of emotional disorders. 5. Use according to claim 4 for the manufacture of a medicament for the treatment of depression. Use according to claim 2 for the manufacture of a medicament in the prevention or treatment of urinary incontinence. A method of treating a 5-HT mediated disorder by administering a composition as defined in claim 1 to a patient suffering from a 5-HT mediated disorder. 8. The method of claim 7, for the treatment of affective disorders. 8. The method of claim 7, for the treatment of emotional disorders. The method of claim 9, for the treatment of depression. 8. The method of claim 7, for preventing or treating urinary incontinence. A method for improving the onset of a therapeutic action by simultaneous administration of a composition as defined in claim 1. Pharmaceutical formulations wherein the active ingredient is present in the composition as defined in claim 1, optionally in adjunct, excipient and / or inert carrier. The pharmaceutical formulation of claim 13, wherein the first component (a) is administered simultaneously with the second component (b). The pharmaceutical formulation according to claim 13 or 14, for use in the treatment of 5-HT mediated disorders. The pharmaceutical formulation according to claim 13 or 14 for use in the treatment of an affective disorder. The pharmaceutical formulation according to claim 13 or 14 for use in the treatment of emotional disorders. The pharmaceutical formulation according to claim 13 or 14 for use in the treatment of depression. The pharmaceutical formulation according to claim 13 or 14 for use in the treatment of urinary incontinence. A method of making a composition according to claim 1, wherein the first component (a) is incorporated into the same pharmaceutical formulation as the second component (b). A method of making a composition according to claim 1, wherein the first component (a) is one pharmaceutical formulation, which is combined with the second component (b) of a different pharmaceutical formulation. (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R, 3R) -tartrate monohydrate A kit containing the dosage unit of the first component (a) and paroxetine in the form of a free base, or a dosage unit of the second component (b) as a pharmaceutically acceptable salt and / or solvate thereof, optionally with instructions for use.