KR20010021644A - Novel Comosition - Google Patents

Abstract

A pharmaceutical composition comprising SSRIs in the form of rapid release and β-blockers in the form of sustained release.

Description

Novel Comosition

The present invention relates to novel formulations of selective serotonin re-uptake inhibitors (SSRIs). In particular, the present invention provides agents which increase the therapeutic activity of SSRIs, and in particular, enhance the manifestation of the therapeutic effect.

Artigas et al. (Arch. Gen Psychiatry, Vol. 51, pp248-251, Mar. 1994) used pindolol (2.5 mg, 3 times a day) during treatment with SSRI paroxetine (20 mg, once a day). Co-administration has been reported to alleviate depression in patients who have not previously had an effect from treatment with paroxetine.

Subsequently, the effects of SSRI citaloprolam, fluvoxamine and paroxetine are combined with other compounds known as pindolol, phenbutolol, propranol and tertatolol and serotonin IA receptor antagonists, with the exception of the combination of paroxetine-pindolol, in particular It has been proposed in EP-A-0714663 which can be increased by co-administration in certain combinations of.

The problem with the co-administration method, especially the method proposed by Articas, which involves taking the drug three times in a day (assuming paroxetine and the first pindolol dose are taken simultaneously), makes the patient adhere to medication. will be.

It is an object of the present invention to overcome the problems associated with simultaneous administration of SSRIs and potentiating compounds.

In a broad aspect, the present invention provides an SSRI composition comprising SSRIs in the form of rapid release and β-blockers in the form of sustained release. The composition is conveniently in the form of a tablet or capsule.

Typical SSRIs used in the present invention are paroxetine, fluvoxamine, citalopram and sertraline. Preferably the SSRI is paroxetine. The co-administered β-blocker is preferably pindolol.

Preferred combinations of SRRI and β-blockers are paroxetine and pindolol. Preferably the tablet or capsule contains 20 mg of immediate release paroxetine and 7.5 mg of sustained release pindolol.

Typically, sustained release of β-blockers are provided by releasing three equivalent daily doses in succession over 12-16 hours. Alternatively, the dose may be released in three spaced intervals.

When SSRIs are combined with β-blockers in a continuous release formulation, the compositions of the present invention preferably comprise one layer containing the SSRI of a conventional rapid release formulation and the other layer containing a β-blocker, a sustained release formulation. It is provided as a tablet.

Sustained release can be provided by formulating a β-blocker with a conventional sustained release release excipient or blend of excipients that does not interact with the β-blocker or SRRI.

Suitably, the sustained release release swells in gastric fluid, typically forming a gel that dissolves and / or erodes as the tablet passes through the patient's digestive tract, and incorporates a β-blocker in an excipient that releases the active ingredient. Is provided. The release rate can be controlled in a conventional manner by varying the molecular weight of the excipient and / or co-formulating the major excipients with materials that form micropores in the swollen or gelled major excipients by dissolving or degrading at a different rate than the major excipients. Can be.

Suitable main excipients are, for example, methyl cellulose sold under the trade names Methocel K4M and E5, for example polyacrylic acid sold under the trade name Carbopol 974P, for example polyacrylic acid esters sold under the trade names Eudragit L30D and RS30D, xan gum And swellable binders such as starch.

The release distribution of the main excipients is lactose, in particular lactose monohydrate, for example microcrystalline cellulose sold under the trademark Avicel pH102, for example dicalcium phosphate sold under the trade name Encompress, for example under the name Povidone 30 It can be modified by incorporating polyvinyl pyrrolidone, for example fillers and disintegrants such as hydrogenated vegetable oil sold under the trade name Lubritab.

Conventional tableting excipients may be included to aid in tablet manufacture with magnesium stearate, for example a die lubricant such as glyceryl behenate sold under the name Compritol 888.

Alternatively, the composition may be in the form of a capsule comprising coated pellets of β-blockers, which are dispersed in a powder formulation of SSRI and contained in capsules of different dissolution times, all contained in a soluble capsule. Mixture.

Suitably, the coating of pellets of β-blockers is a substance resistant to gastric juice but soluble in, for example, the digestive tract. Dissolution time can be varied by varying the coating thickness. Preferably the coated pellets are mixed to provide substantially continuous release of pindolol, but the pellet is coated in three coatings so that the pindolol is released in three trenches over a predetermined dosing period, such as 12-14 hours, if necessary. It may be a mixture having a thickness. Powdered formulations of SSRIs can be prepared by mixing SSRIs with conventional excipients. Dissolvable capsules containing a combination of active ingredients can typically be made from gelatin.

Typical sustained release release formulations of the hydrophilic matrix type and enteric coating type described above that can be used in the present invention are disclosed in standard textbooks for that matter.

We believe that sustained release β-blocker formulations are suitable for clinical use when the dissolution time in acid / buffer has a release distribution measured in vitro with T _50% 1.73 h, T _90% 8.45 h and T _100% 14 h. It was finally found to obtain the release distribution.

Thus, one preferred embodiment of the present invention is a sustained release form with SSRI and in vitro release distribution of T _50% 1.73 hours ± 20%, T _90% 8.45 hours ± 20% and T _100% 14 hours ± 20% Provided are formulations of phosphorus β-blockers.

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

Pindolol is typically used as a commercially available racemate. However, its active isomers may be used in biologically equally controlled dosages for recognized amounts of racemates.

Therapeutic uses of the compositions of the invention, in particular paroxetine hydrochloride and pindolol, include alcoholism, anxiety, depression, obsessive compulsive disease (OCD), panic disease, chronic pain, obesity, senile dementia, referred to herein as "diseases", Migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, hair growth, mood alteration and substance abuse.

Thus, the present invention also

The use of SSRIs and sustained release forms of β-blockers for the manufacture of tablets or capsules for the treatment or prevention of diseases of humans and animals, and

A method of treating or preventing a disease comprising administering a tablet or capsule comprising an SSRI and a sustained release form of β-blocker to an individual or animal in need thereof.

To provide.

In the uses and methods of the present invention, the tablet or capsule is preferably a composition of the present invention having the preferred values indicated above.

The invention is illustrated in the following examples.

<Example 1>

Bilayer tablets of paroxetine and sustained release pindolol were prepared as follows.

<Pindolol component>

The sustained release form of pindolol based on a hydrophilic matrix with a soluble filler / disintegrant that increases the porosity of the hydrated matrix once

7.5 parts by weight of pindolol base

Methyl cellulose (Methocel K4M) 35 parts by weight

Lactose Monohydrate 25 parts by weight

32 parts by weight of microcrystalline cellulose (Avicel pH102)

It was prepared by high shear wet granulation of a mixture of.

After drying and sieving, 0.5 parts by weight of glyceryl behenate (Compritol 888) was incorporated as a lubricant in tumble mixing.

<Paroxetine ingredient>

Immediate release formulations of paroxetine were prepared by mixing 20 parts by weight of paroxetine hydrochloride with 80 parts by weight of conventional excipients.

<Purification>

An amount of 100 mg of the sustained release pindolol formulation was filled into a tablet mold in a rotary tableting platen at the first filling position. After preliminarily pressing the powder formulation into the tablet mold, the platen was moved to the second filling position to allow 152 mg of paroxetine formulation to be introduced on top of the sustained release formulation. Complete compression of the two layer mixture in the tablet template was then made to prepare a tablet 252 mg containing 20 mg of paroxetine hydrochloride and 7.5 mg of sustained release release pindolol, with each active ingredient present as a separate layer of the bilayer tablet.

Claims (13)

A pharmaceutical composition comprising SSRIs in the form of rapid release and β-blockers in the form of sustained release. The pharmaceutical composition according to claim 1, wherein one layer contains SSRI, a rapid release formulation, and the other layer contains a β-blocker, a sustained release formulation. The pharmaceutical composition of claim 1 containing a mixture of SSRI, a rapid release formulation, and β-blocker, a sustained release formulation. The method of claim 1, wherein the β-blocker has an in vitro release distribution of T _50% 1.73 h ± 20%, T _90% 8.45 h ± 20% and T _100% 14 h ± 20%. The pharmaceutical composition is in a sustained release form. The pharmaceutical composition according to any one of claims 1 to 4, wherein the SSRI is paroxetine or a pharmaceutically acceptable derivative thereof. 6. The pharmaceutical composition of claim 5, wherein the paroxetine is in hydrochloride form. The pharmaceutical composition according to any one of claims 1 to 6, wherein the β-blocker is pindolol. 8. A pharmaceutical composition according to claim 7, wherein the pindolol is present in the racemate. The pharmaceutical composition of claim 8 which contains 20 mg of paroxetine hydrochloride and 7.5 mg of pindolol racemate. 8. A pharmaceutical composition according to claim 7, wherein pindolol is present as the active isomer. An effective amount or prophylactic amount of a pharmaceutical composition according to any one of claims 1 to 10 is determined by alcoholism, anxiety, depression, obsessive compulsive disease (OCD), panic disease, chronic pain, obesity, senile dementia, migraine, bulimia, appetite A method of treating said disease, comprising administering to a patient in need of treatment of underuse, social phobia, premenstrual syndrome (PMS), adolescent depression, hair growth, mood alteration, and substance abuse. Alcoholism, anxiety, depression, obsessive compulsive disease (OCD), panic disease, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, hair growth walls, mood alteration and Use of a pharmaceutical composition as defined in any of claims 1 to 10 in the manufacture of a medicament for the treatment or prophylaxis of substance abuse. Alcoholism, anxiety, depression, obsessive compulsive disease (OCD), panic disease, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent depression, hair growth walls, mood alteration and A pharmaceutical composition as defined in any one of claims 1 to 10 for use in the treatment or prevention of substance abuse.