SK72000A3 - Novel composition comprising an ssri and a beta-blocker - Google Patents

Abstract

A pharmaceutical composition comprising an SSRI in quick-release form and a beta -blocker in sustained-release form.

Description

Pharmaceutical composition and its use

Technical field

The invention relates to novel pharmaceutical compositions of selective serotonin re-uptake inhibitors (SSRIs). More particularly, the invention relates to formulations which are suitable for increasing the therapeutic efficacy of SSRIs, and in particular for improving the onset of therapeutic effect.

BACKGROUND OF THE INVENTION

Artigas et al. (Ar. Gen. Psychiatry, 1994, 51, 248-251) report that administration of pindolol (2.5 mg three times a day) during treatment with SSRI paroxetine (20 mg once a day) alleviates depression in patients who have not received prior treatment with paroxetine successful.

It was then reported in EP-A-0 714 663 that the effect of SSRIs of citaloprolam, fluvoxamine and paroxetine can be increased by concomitant administration in certain combinations with inter alia pindolol, penbutolol, propranol and tertatol and other compounds known as serotonin IA antagonists, but paroxetine-pindolol combinations.

In the co-administration regimen, the problem is to ensure the patient's well-being, especially in the regimen proposed by Artigas, in which the drugs are administered three times daily (assuming the paroxetine dose and the first pindolol dose are co-administered).

The present invention aims to overcome the problem associated with the simultaneous administration of SSRIs and SSRI enhancers.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising an SSRI in a rapid release form of the active ingredient and a β-blocker in a sustained release form. The pharmaceutical composition is usually in the form of tablets or capsules.

Typical SSRIs used in this invention are paroxetine, fluvoxamine, citalopram and setralin. A preferred SSRI is paroxetine. The co-administered preferred β-blocker is pindolol.

A preferred combination of SSRI and β-blocker is paroxetine and pindolol. The tablet or capsule preferably contains 20 mg paroxetine in an immediate release form and 7.5 mg pindolol in a sustained release form.

The sustained release β-blocker form typically provides a continuous drug equivalent of a triple daily dose for 12 to 16 hours. Optionally, said dose may be released in three differentiated stages.

When the SSRI is combined with a β-blocker that is in a sustained release formulation, then a preferred composition of the invention is in the form of a bilayer tablet; one layer contains an SSRI in a conventional quick release formulation the other layer contains a β-blocker formulated for sustained release of the drug.

Prolonged release can be achieved by formulating a β-blocker with any slow release component or mixture of components or excipients that do not interact with the β-blocker or SSRI.

Suitably, the ability to slowly release the drug is achieved by incorporating the β-blocker into a component or excipient which swells in the gastric juice, typically forming a gel that dissolves and / or abrades as the tablet passes through the patient's intestines, releasing the active ingredient. The rate of release can be controlled in a conventional manner by varying the molecular weight of the excipient and / or co-formulating the primary excipient with materials that dissolve or cause disintegration of said excipient at a rate other than dissolving or disintegrating the primary excipient itself to form micropores in swollen or a gel-like primary excipient.

Suitable primary excipients may be selected from swellable binders such as methylcellulose, for example methylcellulose supplied under the tradename Methocel K4M and E5, ethylcellulose, polyacrylic acid such as sold under the trademark Carbopol 974P, polyacrylic esters such as sold under the name Eudragit L30D and RS30D, xanthan gum and starch.

The release profile of the primary excipient can be adjusted by incorporating fillers and disintegrants such as lactose, closer lactose monohydrate, microcrystalline cellulose, supplied for example under the trade name Avicel pH12, calcium sulfate, dibasic calcium phosphate, sold for example under the trade name Encompress, polyvinyl supplied, for example, under the tradename Povidone 30, hydrogenated vegetable oils, sold for example under the tradename Lubritab.

Also included in the pharmaceutical compositions of the present invention are conventional tabletting excipients for the manufacture of tablets, such as lubricants and others, for example magnesium stearate, glycerol behenate, marketed, for example, with the trade name Compritol 888.

The pharmaceutical composition may optionally be in the form of capsules containing coated β-blocker pills which are a mixture of coated pills with different dissolution times dispersed in an SSRI powder formulation; this system is all in a soluble capsule.

The β-blocker pill coating is preferably a material that is resistant to gastric juice but dissolves, for example, in the intestines. The dissolution time may vary depending on the thickness of the coating. The coated pills of different coating thicknesses are preferably mixed so as to allow a substantially continuous release of pindolol; however, if desired, it may be, for example, a mixture of pills with three differently thick coatings; then, the pindolol is released at three different time stages over the required time from administration, for example 12 to 14 hours. An SSRI powder formulation can be prepared by mixing the SSRI with conventional excipients. Soluble capsules to be combined with the active ingredients may be conventional gelatin capsules.

Typical sustained release formulations of the aforementioned hydrophilic matrix type and intestinal release formulations described in the basic textbooks of the art may be used in the present invention.

The inventors have found that a suitable release profile for clinical use can be achieved if the extended release β-blocker formulation when measuring the in vitro release profile in an acid / buffer environment has a dissolution time of T 50% 1.73 hours, T 90% 8.45 hours and Tioo% 14 hours.

A preferred embodiment of the present invention has an SSRI and a β-blocker formulation in which the β-blocker is in sustained release form and has an in vitro release profile: T ₅₀ % = 1.73 hours ± 20%, Tg ₀ % = 8, 45 hours ± 20% and T ₁₀ % = 14 hours + 20%.

The preferred SSRI is paroxetine hydrochloride, most preferably at a dose of 20 mg, and the β-blocker is pindolol, most preferably at a dose of 7.5 mg.

Pindolol is typically used in the form of a commercially available racemate. However, it is possible to use the active isomer of pindolol at a dose adjusted to the same bioequivalence with the determined dose of the racemate.

The therapeutic use of the compositions of the present invention, particularly paroxetine hydrochloride and pindolol hydrochloride compositions, includes the treatment of alcoholism, stress, depression, obsessive compulsive disorder (OCD), panic, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual. syndrome (PMS), adolescent depression, trichothilomania, dysthymia and substance dependence; hereinafter referred to as malfunctions.

The invention also encompasses the use of an SSRI and a β-blocker which is in sustained release form for the manufacture of tablets or capsules for the treatment or prophylaxis of said disorders in humans and animals, and a method of treating or prophylaxis of said disorders. A β-blocker in sustained release form to a person or animal in need thereof.

In use and in the method of the present invention, a tablet or capsule that is formulated according to the present invention with the preferred values outlined above will be preferred.

The invention is further illustrated by examples.

-5Examples of embodiments of the invention

Example 1

Bilayer tablets of paroxetine and pindolol were prepared in sustained release form.

Pindolol component

The sustained release form of pindolol, based on a hydrophilic matrix with a soluble / disintegrating filler to increase the porosity of the matrix during hydration, was prepared by high performance wet granulation of a mixture of:

pindolol base 7.5 parts by weight methylcellulose (Methocel K4M) 35 parts by weight lactose monohydrate 25 parts by weight microcrystalline cellulose (Avicel pH 12) 32 parts by weight.

After drying and sieving, 0.5 part by weight of glycerol behenate (Compritol 888) was added as a lubricant with stirring in a tumbler.

Paroxetine component

An immediate release formulation of paroxetine active ingredient was prepared by mixing 20 parts by weight of paroxetine hydrochloride with 80 parts by weight of conventional excipients and additives.

tabletting

100 mg amounts of the sustained release pindolol formulation were filled into tablet forms at the first fill position of the rotary tabletting plate. After the initial gentle compression of the powder formulation in tablet form, 152 mg of paroxetine formulation was poured onto the sustained release formulation in the second filling position. The bilayer mixture was then subjected to full compression pressure in tablet form; a 252 mg tablet was prepared containing 20 mg paroxetine hydrochloride and 7.5 mg pindolol, which is in a matrix with

- sustained release, wherein each active ingredient is in a separate layer of a bilayer tablet.

Claims (12)

PATENT CLAIMS What is claimed is: 1. A pharmaceutical composition comprising SSRI in a rapid release form of an active ingredient and a β-blocker in a sustained release form. The pharmaceutical composition of claim 1, which is in the form of a bilayer tablet, wherein one layer comprises an SSRI in a rapid release formulation and the other layer comprises a β-blocker in the sustained release formulation. The pharmaceutical composition of claim 1, which is in the form of a capsule containing a mixture of a quick release SSRI formulation and a β-blocker that is in a sustained release formulation. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that the β-blocker is in a sustained release form with an in vitro release profile in which the T ₅₀ < / ₀ is 1.73 hours ± 20%, Tgo <% is 8.45 hours ± 20%, and T 10% is 14 hours ± 20%. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the SSRI is paroxetine, or a pharmaceutically acceptable derivative thereof. Pharmaceutical composition according to claim 5, characterized in that the paroxetine is in the form of paroxetine hydrochloride. The pharmaceutical composition according to any one of claims 1 to 6, wherein the β-blocker is pindolol. Pharmaceutical composition according to claim 7, characterized in that pindolol is present as a racemate. Pharmaceutical composition according to claim 8, characterized in that it contains 20 mg of paroxetine hydrochloride and 7.5 mg of pindolol as a racemate. Pharmaceutical composition according to claim 7, characterized in that pindolol is present as the active isomer. Pharmaceutical composition according to claims 1 to 10 for use in the treatment of alcoholism, stress, depression, obsessive compulsive disorder (OCD), panic conditions, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS) ), adolescent depression, trichothilomania, dysthymia and substance dependence. Use of a pharmaceutical composition according to claims 1 to 10 for the manufacture of a medicament for the treatment or prevention of alcoholism, stress, depression, obsessive compulsive disorder (OCD), panic conditions, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, trichothilomania, dysthymia and substance dependence.