MXPA00000416A - Novel composition - Google Patents

Abstract

A pharmaceutical composition comprising anSSRI in quick-release form and a&bgr;-blocker in sustained-release form.

Claims (1)

1. PCT WORLD INTHLLECTUAL PROPERTY ORGANIZATION International Bureau INTERNA? ONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERA? ON TREATY (PCT) (51) International Patent Classification or: (11) International Publication Number: WO 99/02142 A61K 31/00 A2 (43) International Publication Date: 21 January 1999 (21.01.99) (21) International Application Number: PCT / EP98 / 04971 (81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, Fl, GB, GE, (22) International Filing Date: 7 July 1998 (07.07.98) GH, GM, GW, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, YES, SK, (30) Priority Data: SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW, 9714675. 7 1 1 July 1997 (11.07.97) GB ARIPO patent (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, UK, TJ, TM), European patent (AT, BE, CH, CY, DE, DK, ES, Fl, FR, (71) Applicant (for all designated States except US): SMITHKLINE GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BEECHAM P.L.C. [GB / GB]; New Horizons Court, Brent-BJ, CF, CG, Cl, CM, GA, GN, ML, MR, NE, SN, TD, TG). ford, Middlesex TW8 9EP (GB). (72) Inventors; and Published (75) Inventors Applicants (for US only): CUMMINGS, Paul, John Without international search report and to be republished [GB / GB]; SmithKline Beecham Pharmaceuticals, New upon receipt of that report. Frontiers Science Park South, Third Avenue, Harlow, Essex CM19 5AW (GB). TULLOCH, Ian, Frcderic [GB / GB]; SmithKline Beecham Pharmaceuticals, New Frontiers Science Park South, Third Avenue, Harlow, Essex CM19 5AW (GB). (74) Agent: WEST, Vivien; SmithKline Beecham, Corporate Intellectual Property, Two New Horizons Court, Brentford, Middlesex TW8 9EP (GB). (54) TiUe: NOVEL COMPOSITION (57) Abstract A pharmaceutical composition comprising an SSRI in a rapid-release form and a 7-blocker in a sustained-release form. INNOVATIVE SEROTONIN REABSORPTION INHIBITORS DESCRIPTIVE MEMORY This invention relates to novel formulations of selective serotonin reuptake inhibitors (SSRI). In particular, the present invention provides formulations that enhance the therapeutic activity of an SSRI, and especially, that improve the onset of the therapeutic effect. Artigas et al. (Arch. Gen Psychiatry, Vol. 51, pp 248-251, Mar. 1994) have reported that the administration of pindolol (2.5 mg, three times a day) during treatment with SSRI paroxetine (20 mg once a day) relieves depression in patients who previously showed no benefit of treatment with paroxetine. Subsequently, in EP-A-0714663 it has been proposed that the effect of the SSRI citaloprolam, fluvoxamine and paroxetine can be enhanced by co-administration in certain combinations with pindolol, pentbutolol, propranol and tertatolol among others, and other known compounds that are antagonists of serotonin receptor IA, but excluding the paroxetine-pindonol combination. A problem with any co-administration regime is to ensure patient compliance, particularly in a regime such as that proposed by Artigas, which consists of taking medication three times. 8É_aft3- £ fe during the day (assuming that the dose of paroxetine and the first dose of pindolol are taken simultaneously). The present invention aims to overcome the problems related to the co-administration of SSRIs and enhancer compounds. In its broadest aspect, the present invention provides an SSRI composition comprising an SSRI in the form of a rapid release and a β-blocker in sustained release form. The composition is conveniently in the form of a tablet or capsule. Typical SSRIs used in this invention are paroxetine, fluvoxamine, citalopram and sertraline. Preferably the SSRIs are paroxetine. The β-blocker co-administered is preferably pindolol. The preferred combination of SSRI and β-blocker is paroxetine and pindolol. Preferably the tablet or capsule contains 20 mg of paroxetine in an immediate release 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 the equivalent of a daily dose 3 times a day continuously over a period of 12-16 hours. Likewise, the dose can be released in three separate partial dispositions. When the SSRI is combined with a β-blocker in a sustained release formulation, then the composition of the invention is preferably presented as a double layer tablet in which one layer contains an SSRI in a conventional fast release formulation and the other layer contains a β-blocker in a sustained release formulation. Sustained release can be provided by formulating the β-blocker with any conventional sustained-release excipient or mixture of excipients that do not interact with the β-blocker or the SSRI. Suitably, the sustained release properties are provided by incorporating the β-blocker in an excipient that swells in the gastric juice, typically forming a gel that dissolves and / or wears while the tablet passes through the intestines of the patient. patient, 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 a primary excipient with materials that dissolve or disintegrate at a rate different from that of the primary excipient, to form micropores in a primary excipient swollen or gelled. Suitable primary excipients may be selected from swellable binders such as methylcellulose, for example, those sold under the tradename Methocel K4M and E5, ethylcellulose, polyacrylic acid, for example, those sold under the tradename Carbopol 974P, polyacrylic esters, such as those sold under the trade name Eudragit L30D and RS30D, xanthan gum and starch. The release profile of the primary excipient can vary by incorporating fillers and disintegrators such as lactose, especially lactose monohydrate, microcrystalline cellulose, such as that sold under the trade name Avicel pH102, calcium sulfate, dicalcium phosphate such as that sold under the trade name Encompress, polyvinylpyrrolidone such as that sold under the trade name Povidone 30, hydrogenated vegetable oils such as those sold under the trade name Lubritab. Conventional tableting excipients may also be included to aid in the manufacture of the tablet, such as die lubricants, etc., such as magnesium stearate, glyceryl behenate such as that sold under the tradename Compritol 888. Also, the composition may be presented in the form of a capsule comprising pellets coated with a β-blocker, which is a mixture of coated pellets having different dissolution times, dispersed in a powder formulation of an SSRI, all contained within a soluble capsule. For example, suitably, coating the pellets of the β-blocker is a material that is resistant to gastric juices but, which dissolves in the intestine. The dissolution times can vary when changing the thickness of the coating. Preferably, the coated pellets are mixed to provide a substantially continuous release of pindolol, but if desired, the pellets can be a mixture of three coating thicknesses so that the pindolol is released in three partial dispersions during the desired dose period as 12-14 hours. An SSRI powder formulation can be made by mixing the SSRI with conventional excipients. Soluble capsules containing the combination of active ingredients can be conventionally made from gelatin. Typical sustained release formulations of the hydrophilic matrix type described above and type of enteric coating that can be used in this invention are described in standard textbooks on the subject. It has been found that a release profile suitable for clinical use is obtained when the sustained release β-blocker formulation has a release profile measured in vitro in acid / pH regulator that has a dissolution time T50% of 1.73 hours, a Tg0% of 8.45 hours and a T.oo% of 14 hours. Also, a preferred embodiment of the invention provides a formulation of an SSRI and a β-blocker in which the β-blocker is in a sustained release form having an in vitro release profile in which the T50% is 1, 73 hours ± 20%, T90% is 8.45 hours ± 20% and T10o% is 14 hours ± 20%. Preferably, the 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 as the commercially available racemate. However, the active isomers thereof can be used at a dose adjusted for bioequivalence at an established dose of the racemate. Therapeutic uses of compositions of this invention, especially compositions of paroxetine hydrochloride and pindolol, include treatment of alcoholism, anxiety, depression, compulsive-obsessive disorders (OCD), panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia. , anorexia, social phobia, premenstrual syndrome (PMS), depression in adolescents, trichotillomania, dysthymia and excessive use of substances; referred to herein as "the disorders". Accordingly, the present invention also provides the use of an SSRI and a sustained release form of a β-blocker for the manufacture of a tablet or capsule for the treatment or prophylaxis of disorders in humans and animals, and a method for the treatment or prophylaxis of the disorders, which comprises administering a tablet or capsule comprising an SSRI and a sustained release form of 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 a composition of this invention having preferred values indicated above. The invention is illustrated by the following example: EXAMPLE 1 The double-layer paroxetine and pindolol sustained-release tablets were manufactured as follows: Pindolol Component A sustained release form of pindolol based on a hydrophilic matrix with a soluble filler / disintegrator was prepared to increase the porosity in the matrix once hydrated by high shear wet granulation of a mixture of: After drying and screening, 0.5 parts by weight of glyceryl behenate (Compritol 888) was incorporated as a lubricant by stirring. Paroxetine Component An immediate release formulation of paroxetine was prepared by mixing 20 parts by weight of paroxetine hydrochloride and 80 parts by weight of conventional excipients. Tableting 100 mg of sustained-release pindolol formulation was loaded into the tablet molds on a rotating tabletop in a first loading station. After preliminary light pressure to place the powder formulation in the tablet mold, the stage was directed to a second loading station where 152 mg of paroxetine formulation was introduced into the top of the sustained release formulation. The double layer mixture in the tablet mold was fully pressed to prepare 252 mg of tablet with 20 mg of paroxetine hydrochloride and 7.5 mg of pindolol on a sustained release basis, each active component being in separate layers of a double tablet. cap. mk.