OA11276A

OA11276A - Novel composition comprising an ssri and a beta-b locker.

Info

Publication number: OA11276A
Application number: OA1200000006A
Authority: OA
Inventors: Paul John Cummings; Ian Frederic Tulloch
Original assignee: Smithkline Beecham Plc
Priority date: 1997-07-11
Filing date: 2000-01-11
Publication date: 2003-07-31
Also published as: CN1262627A; BG104119A; HUP0003074A2; WO1999002142A2; KR20010021644A; NO20000107D0; AP2000001728A0; AU9340198A; WO1999002142A3; PE99699A1; HUP0003074A3; JP2002508003A; NO20000107L; PL338017A1; EP0996466A2; EA200000112A1; CA2295822A1; SK72000A3; CO4950552A1; ID24191A

Abstract

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

Description

01 1

This invention is concemed with novel formulations of sélective serotonin re-uptake inhibitors (SSRI's). In particular the présent invention providesformulations that potentiate the therapeutic activity of an SSRI, and especially thatimprove the onset of the therapeutic effect.

Artigas et al (Arch. Gen Psychiatry, Vol. 51, pp 248-251, Mar. 1994) hâvereported that administration of pindolol (2.5 mg. three times a day) duringtreatment with the SSRI paroxetine (20 mg once per day) relieved dépréssion inpatients previously showing no benefit from treatment with paroxetine.

Subsequently, it has been proposed in EP-A-0714663 that the effect of the SSRIscitaloprolam, fluvoxamine and paroxetine can be potentiated by co-administrationin certain combinations with inter alla pindolol, penbutolol, propranol andtertatolol and other compounds known to be serotonin IA receptor antagonists, butexcluding the combination paroxetine-pindolol. A problem with any co-administration régime is ensuring patient compliance,particularly in a régime such as proposed by Artigas which involves takingmédication on three occasions during the day (assuming that the paroxetine doseand the first pindolol dose are taken simultaneously).

The présent invention aims to overcome the problems associated with co-administration of SSRIs and potentiating compounds.

In its broadest aspect, the présent invention provides an SSRI compositioncomprising an SSRI in quick release form and a β-blocker in sustained releaseform. The composition is conveniently in tablet or capsule form.

Typical SSRIs used in this invention are paroxetine, fluvoxamine, citalopram andsertraline. Preferably the SSRI is paroxetine. The co-administered β-blocker ispreferably pindolol.

2 011

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

Typically the sustained release form of the β-blocker is provided to release theéquivalent of a three times daily dose continuously over a period of 12-16 hours.Alternatively, the dose may be released in three spaced tranches.

When the SSRI is combined with a β-blocker in a continuous release formulation,then the composition of the invention is preferably presented as a bi-layer tablet inwhich one layer contains an SSRI in a conventional quick release formulation andthe other layer contains a β-blocker in a sustained release formulation.

The sustained release may be provided by formulating the β-blocker with anyconventional sustained release excipient or blend of excipients that does notinteract with the β-blocker or the SSRI.

Suitably, the sustained release properties are provided by incorporating the β-blocker in an excipient which swells in gastric juice, typically forming a gel whichdissolves and/or is abraded as the tablet passes through the patient's gut, releasingthe active ingrédient. The rate of release may be controlled in a conventionalmanner by varying the molecular weight of the excipient and/or co-formulating aprimary excipient with materials that dissolve or disintegrate at a different ratethan the primary excipient, to form micropores in a swollen or gelled primaryexcipient.

Suitable primary excipients may be selected from swellable binders such asmethyl cellulose for example as sold under the trade mark Methocel K4M and E5,ethyl cellulose, polyacrylic acid for example as sold under the trade markCarbopol 974P, polyacrylic esters for example as sold under the trade markEudragit L30D and RS30D, xanthan gum, and starch.

The release profile of the primary excipient may be varied by incorporating fillersand disintegrants such as lactose especially lactose monohydrate, microcrystalline 01 cellulose for example as sold under the trade mark Avicel pH102, calciumsulphate, dicalcium phosphate for example as sold under the trade markEncompress, polyvinyl pyrrolidone for example as sold under the trade markPovidone 30, hydrogenated vegetable oils for example as sold under the trademark Lubritab.

Conventional tableting excipients may aiso be included to assist tabletmanufacture, for example as die lubricants etc., such as magnésium stéarate,glyceryl behenate for example as sold under the trade mark Compritol 888.Altematively, the composition may be a capsule présentation comprising coatedpellets of a β-blocker, which is a mixture of coated pellets having differentdissolution times, dispersed in a powder formulation of an SSRI, ail containedwithin a soluble capsule.

Suitably, the coating of the pellets of the β-blocker is a material that is résistant togastric juices but dissolves in the gut, for example. Dissolution times may bevaried by varying the coating thickness. Preferably the coated pellets are mixed soas to provide a substantially continuous release of pindolol, but if desired thepellets may be a mixture of three coating thicknesses so that pindolol is released inthree tranches over a the desired dosage period such as 12-14 hours. A powderedformulation of the SSRI be be made by blending the SSRI with conventionalexcipients. Soluble capsules to contain the combination of active ingrédients maybe conventionally made from gélatine.

Typical sustained release formulations of the above described hydrophilic matrixtype and enteric coating type that may be used in this invention are disclosed instandard textbooks on the subject.

We hâve found that a suitable release profile for clinical use is obtained when thesustained release β-blocker formulation has a release profile measured in vitro inacid/buffer which has a dissolution time TJ0„/o of 1.73 hours, a T90% of 8.45 hoursand a T,00./o of 14 hours. Û1 /.: / c

Accordingly, a preferred embodiment of the invention provides a formulation ofan SSRI and a β-blocker in which the β-blocker is in a sustained release formhaving a release profile in vitro in which the T500/o is 1.73 hours + 20%, the T90„/o is8.45 hours + 20% and the T100„/o is 14 hours + 20%.

Preferably, the SSRI is paroxetine hydrochloride, most preferably at a dosage of20 mg, and the β-blocker is pindolol, most preferably at a dosage of 7.5 mg.

The pindolol is typically used as the commercially available racemate. However,active isomers thereof may be used at a dosage adjusted for bioquivalence to astated dose of the racemate.

Therapeutic uses of compositions of this invention, especially compositions ofparoxetine hydrochloride and pindolol, include treatment of alcoholism, anxiety,dépréssion, obsessive compulsive disorder (OCD), panic disorder, chronic pain,obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrualsyndrome (PMS), adolescent dépréssion, trichotillomania, dysthymia andsubstance abuse; referred to herein as "the Disorders".

Accordingly, the présent invention also provides use of an SSRI and a sustained release form of a β-blocker for the manufacture ofa tablet or capsule for the treatment or prophylaxis of the Disorders in humans andanimais, and a method for the treatment or prophylaxis of the Disorders, which comprisesadministering a tablet or capsule comprising an SSRI and a sustained release formof a β-blocker to a person or animal in need thereof.

In the use and method of the invention, the tablet or capsule is preferably acomposition of this invention having the preferred values indicated above.

The invention is illustrated by the following Example: 01127/

Example 1

Bi-layer tablets of paroxetine and sustained release pindolol were manufactured asfollows.

Pindolol Component A sustained release form of pindolol based upon a hydrophilic matrix with asoluble filler/disintegrant to increase the porosity of the matrix once hydrated wasprepared by high shear wet granulation of a mixture of : pindolol base methylcellulose (Methocel K4M)lactose monohydrate microcrystalline cellulose (Avicel pH102) 7.5 parts by weight35 parts by weight25 parts by weight32 parts by weight

After drying and screening, 0.5 parts by weight of glyceryl behenate (Compritol888) as a lubricant were incorporated by tumble blending.

Paroxetine Component

An immédiate release formulation of paroxetine was prepared by blending 20parts per weight of paroxetine hydrochloride and 80 parts per weight ofconventional excipients.

Tableting 100 mg. amounts of the sustained release pindolol formulation were charged intotablet moulds in a rotary tableting platen at a first charging station. After apreliminary light pressing to locate the powdered formulation in the tablet mould,the platen was indexed to a second charging station where 152 mg. of theparoxetine formulation were introduced on top of the sustained releaseformulation. The two layer mixture in the tablet mould was then given a full pressto préparé 252 mg. tablets containing 20 mg. paroxetine hydrochloride and 7.5 6 01 1 z mg. pindolol in a sustained release base, each active component being in separatelayers of a bi-layer tablet.

Claims

0 r ιZ. / Claims

1. A pharmaceutical composition comprising an S SRI in quick-release form and aβ-blocker in sustained-release form.
2. A pharmaceutical composition according to claim 1 winch takes the form of abi-layer tablet in which one layer contains the S SRI in a quick-release formulationand the other layer contains the β-blocker in a sustained-release formulation.
3. A pharmaceutical composition according to claim 1 which takes the form of acapsule which contains an admixture of a quick-release formulation of the SSRIand a sustained-release formulation of the β-blocker.
4. A pharmaceutical composition according to any one of claims 1 to 3 in whichthe β-blocker is in a sustained release form having a release profile in vitro inwhich the T50% is 1.73 hours + 20%, the Tgo% is 8.45 hours + 20% and the T,oo% is14 hours+ 20%.
5. A pharmaceutical composition according to any one of claims 1 to 4 in whichthe SSRI is paroxetine or a pharmaceutically acceptable dérivative thereof.
6. A pharmaceutical composition according to claim 5 in which the paroxetine isin the form of the hydrochloride.
7. A pharmaceutical composition according to any one of claims 1 to 6 in whichthe β-blocker is pindolol.
8. A pharmaceutical composition according to claim 7 in which the pindolol isprésent as the racemate.
9. A pharmaceutical composition according to claim 8 which contains 20mg ofparoxetine hydrochloride and 7.5mg of pindolol as the racemate. C1 1
10. A pharmaceutical composition according to claim 7 in which the pindolol isprésent as an active isomer.
11. A method of treatment of alcoholism, anxiety, dépréssion, obsessive 5 compulsive disorder (OCD), panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome(PMS), adolescent dépréssion, trichotillomania, dysthymia, and substance abusewhich comprises administering an effective or prophylactic amount of apharmaceutical composition as defined in claim 1 according to any one of daims 10 1 to 10 to a sufferer in need thereof.
12. The use of a pharmaceutical composition as defined in daims 1 to 10 in themanufacture of a médicament for the treatment or prévention of alcoholism,anxiety, dépréssion, obsessive compulsive disorder (OCD), panic disorder, chronic 15 pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia,premenstrual syndrome (PMS), adolescent dépréssion, trichotillomania,dysthymia, and substance abuse.
13. A pharmaceutical composition as defined in daims 1 to 10 for use in the 20 treatment or prévention of alcoholism, anxiety, dépréssion, obsessive compulsivedisorder (OCD), panic disorder, chronic pain, obesity, senile dementia, migraine,bulimia, anorexia, social phobia, premenstrual syndrome (PMS), adolescent,dépréssion, trichotillomania, dysthymia, and substance abuse.