AU748804B2 - Paroxetine controlled release compositions - Google Patents

Description

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AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: SmithKline Beecham p.l.c.

ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: Paroxetine controlled release compositions The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPER\MKR\GENERAL\66591-96.DIV 14/2/0 P.\OPER\MKR\SPECI\16414-00-OB5.doc-26/03/02 -1A- PAROXETINE CONTROLLED RELEASE COMPOSITIONS This application is a divisional of Australian patent application No. 66591/96, the entire contents of which are incorporated herein by reference.

The present invention relates to a novel formulation containing paroxetine or a pharmaceutically acceptable salt thereof, and to its use in the treatment and/or prophylaxis of certain disorders.

US Patent No. 4,007,196 describes inter alia a compound which is commonly known as paroxetine. This compound is a Selective Serotonin Reuptake Inhibitor (SSRI) and is currently marketed world-wide for the treatment and/or prophylaxis of depression.

The current formulation which is the only marketed formulation of paroxetine S. hydrochloride is a swallow tablet.

It has now been surprisingly found that controlled release and delayed release formulations containing paroxetine give rise to an unexpected reduction in the side effects associated with swallow tablets.

S 15 Accordingly, the present invention provides a controlled and delayed release swallow formulation containing a selective serotonin reuptake inhibit (SSRI).

A further aspect of the invention provides a controlled release or delayed release formulation wherein the SSRI is paroxetine or a pharmaceutically acceptable salt thereof.

Examples of SSRIs other than paroxetine include fluoxetine (US Patent No. 4,314,081), 20 fluvoxamine (US Patent No. 4,085,225), and sertraline (US Patent No. 4,536,518).

By controlled release is meant any formulation technique wherein release of the S:active substance from the dosage form is modified to occur at a slower rate than that from an immediate release product, such as conventional swallow tablet or capsule.

By delayed release is meant any formulation technique wherein release of the active substance from the dosage form is modified to occur at a later time than that from a conventional immediate release product. The subsequent release of active substance from a delayed release formulation may also be controlled as defined above.

Examples of controlled release formulations which are suitable for incorporating paroxetine and other SSRIs are described in: Sustained Release Medications, Chemical Technology Review No. 177. Ed. J.C.

Johnson. Noyes Data Corporation 1980.

AL/xD Controlled Drug Delivery, Fundamentals and Applications, 2nd Edition. Eds. J.R.

P:\OPER\MKR\SPEC1\66591-96.D1V 14/2/00 -2- Robinson, V.H.L. Lee, Mercel Dekkes Inc. New York 1987.

Examples of delayed release formulations which are suitable for incorporating paroxetine and other SSRIs are described in: Remington's Pharmaceutical Sciences 16th Edition, Mack Publishing Company 1980, Ed. A. Osol.

Such controlled release formulations are preferably formulated in a manner such that release of active substance such as paroxetine is effected predominantly during the passage through the stomach and the small intestine, and delayed release formulations are preferably formulated such that release of active substance such as paroxetine is avoided in the stomach and is effected predominantly during passage through the small intestine.

Said formulations are preferably formulated such that the release of the active substance is predominantly 1 /2 to 3 hours post ingestion.

The small intestine is suitably the duodenum, the ileum or the jejunem.

Patients who benefit most from the formulations of the present invention are those who are known to suffer from nausea upon oral administration using swallow tablets.

Preferred formulations are ultimately enteric coated tablets or caplets, wax or polymer coated tablets or caplets or time-release matrices, or combinations thereof.

Particularly preferred formulations are described in US Patent No. 5,102,666.

Thus, a particular aspect of the invention provides a polymeric controlled release composition comprising an active agent selected from the group consisting of SSRI's and a reaction complex formed by the interaction of a calcium polycarbophil component which is a water-swellable, but water insoluble, fibrous cross-linked carboxy-functional polymer, said polymer containing a plurality of repeating units of which at least about 80% contain at least one carboxyl functionality, and about 0.05 to about 1.5% cross-linking agent substantially free from polyalkenyl polyether, said percentages being based upon the weights of unpolymerized repeating unit and cross-linking agent, respectively, with water. The SSRI may be paroxetine. The amount of calcium polycarbophil present is from about 0.1 to about 99% by weight, for example about 10%. The amount of active agent present is from about 0.0001 to about 65% by weight, for example between about 5 and 20%. The amount of water present is from about 5 to about 200% by weight, for example between about 5 and The interaction is carried out at a pH of between about 3 and about 10, for example about 6 to 7. The calcium polycarbophil is originally present in the form of a calcium salt P:\OPER\MKR\SPECI\66591-96.DIV 14/2/00 -3containing from about 5 to about 25 calcium.

Further particularly preferred formulations are described in US Patent No. 5,422,123.

Thus, a further particular aspect of the invention provides a system for the controlled release of an active substance which is an SSRI, comprising a deposit-core comprising an effective amount of the active substance and having defined geometric form, and a support-platform applied to said deposit core, wherein said deposit-core contains at least the active substance, and at least one member selected from the group consisting of a polymeric material which swells on contact with water or aqueous liquids and a gellable polymeric material wherein the ratio of the said swellable polymeric material to said gellable polymeric material is in the range 1:9 to 9:1, and a single polymeric material having both swelling and gelling properties, and wherein the support-platform is an elastic support, applied to said deposit-core so that it partially covers the surface of the deposit-core, and follows changes due to hydration of the deposit-core and is slowly soluble and/or slowly gellable in aqueous fluids. The support-platform may comprise polymers such as hydroxypropylmethylcellulose, plasticisers such as a glyceride, binders such as polyvinylpyrrolidone, hydrophilic agents such as lactose and silica, and/or hydrophobic agents such as magnesium stearate and glycerides. The polymer(s) typically make up 30 to 90% by weight of the support-platform, for example about 35 to 40%. Plasticizer may make up at least 2% by weight of the support-platform, for example about 15 to 20%. Binder(s), hydrophilic agent(s) and hydrophobic agent(s) typically total up to about 50% by weight of the support-platform, for example about 40 to 50%. The SSRI may be paroxetine.

Paroxetine used in the present invention is suitably in the form of the free base or a pharmaceutically acceptable salt thereof. Preferably, paroxetine is suitably in the form of the hydrochloride hemihydrate.

Paroxetine hydrochloride hemihydrate may be prepared according to the procedures generally outlined in US Patent 4,721,723.

Paroxetine in the form of a controlled release or delayed release formulation can be used to treat and prevent the following disorders: Alcoholism Anxiety Depression Obsessive Compulsive Disorder Panic Disorder Chronic Pain Obesity Senile Dementia Migraine Bulimia Anorexia Social Phobia Pre-Menstrual Syndrome (PMS) Adolescent Depression Trichotillomania Dysthymia Substance Abuse These disorders are herein after referred to as "the disorders".

The present invention provides a method of treating and/or preventing the disorders by administering an effective and/or a prophylactic amount of a controlled release or delayed release formulation containing paroxetine or a 20 pharmaceutically acceptable salt thereof, to a sufferer in need thereof.

The present invention further provides the use of a controlled release or delayed release formulation containing paroxetine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament, for treating and/or preventing the disorders.

The present invention also provides a pharmaceutical composition for use in the treatment and/or prevention of the disorders which comprises a controlled release or delayed release formulation containing paroxetine or a pharmaceutically acceptable salt thereof.

The following examples illustrate the present invention.

Example 1 (Hydrophilic Matrix) Intragranular w/w Paroxetine Hydrochloride 11.45 Methocel E5 1.25 Lactose 12.3 Extragranular Methocel K100LV 30.0 Lactose 44.0 Magnesium Stearate TOTAL 100.0 Example 2 (Hydrophilic Matrix) Intragranular Paroxetine Hydrochloride 11.45 Methocel E5 1.25 Lactose 12.3 Extragranular Methocel Kl00LV 27.5 Methocel K4M Lactose 39.0 15 Magnesium Stearate TOTAL 100.0 Example 3 (pH Sensitive Coat on Immediate Release Core) 20 Tablet Core %w/w Paroxetine Hydrochloride 11.45 Lactose 64.05 Microcrystalline Cellulose 20.0 Sodium Starch Glycollate Magnesium Stearate :i TOTAL 100.0 Tablet Coating (apply approximately 6-10% of tablet core weight) %w/w Hydroxypropylmethylcellulose Phthalate 90.0 Triacetin 10.0 Example 4 (pH Sensitive Coat on Immediate Release Core) Tablet Core as in Example 3 Tablet Coating (apply approximately 6-10% of tablet core weight) %w/w Cellulose Acetate Phthalate 90.0 Diethyl Phthalate 10.0 ExampIl (Controlled Release Coating on Immediate Release Core) Tablet Core as in Example 3

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Tablet Coating (apply approximately 5-12% of tablet core weight) %w/ Eudragit RS 100 86.0 Dibutyl Phthalate 10.0 Talc FD&C Yellow No. 6 0.01 Eani~ief6 (pH Sensitive Coat on Controlled Release Core.) Tablet Core as in Example 3 Tablet Coating as in Example 3 Example 7 (Encapsulated Controlled Release Coated Beads) Pellet Non Pareil Seed Paroxetine Hydrochloride Gelatin Lactose Talc Coating Glycerylmonostearate Glyceryldistearate White Wax %wlw (approx) 8 2 %w/w 36.6 53.4 10.0 EzAmplc8 (Controlled release bilayer tablet) Active Layer Component Paroxetine Hydrochloride Methocel K4M Lactose monohydrate Polyvinylpyrrolidone Magnesium stearate Syloid 244 mg/tablet 22.89* 15.00 62.0 3.0 1.0 1.0 Function Active Hydrogel polymer Hydrophilic agent Binder Hydrophobic agent Hydrophilic agent *fee S.0 Support platform Component Compritol 888 Lactose monohydrate Polyvinylpyrrolidone Magnesium stearate Methocel E5 Iron oxide Total tablet weight mg/tablet Function 15.04 29.32 4.0 1.52 29.32 0.08 Plasticizer Hydrophilic agent Binder Hydrophobic agent Hydrogel polymer Colourant *0 S *9

S.

0**0

S

184.89mg *Equivalent to 20mg paroxetine as free base.

The powder blend for each layer was wet granulated in a high shear mixer/granulator and dried in a fluid bed drier. The bilayer tablets were compressed on a Manesty triple layer press.

EUMn~k-9 (Enteric coated calcium polycarbophil formulation) Core Component Paroxetine Hydrochloride Calcium polycarbophil Lactose' anhydrous Polyvinylpyrrolidone Magnesium stearate Water** mg/tablet Function 22.89* Active 20.00 Matrix 146.11 Hydrophilic agent/diluent 10.0 Binder 1 .0 Hydrophobic agent/lubricant 0.024 Granulating liquid Enteric coat Component Eudragit Talc Triethyl citrate Water** mg/tablet 22.19 1.53 1.00 24.6 Function Polymer Lubricant Plasticizer Diluent Film coat Opadry pink Water** 10.5 94.5 Film coat Diluent Polish coat Opadry clear Water** 0.750 29.3 Diluent *Equivalent to 20mg paroxetine as free base.

"*Removed during processing.

The-core constituents were wet granulated in a high shear mixer/granulator, and dried in a fluid bed drier. The magnesium stearate was then added and the mixture processed in a low shear mixer. The Mix was then compressed on a B type rotary tablet press. Coating was carried out using an Accela cota.

Example 10 (Controlled release bilayer tablet) Active Layer Component Paroxetine Hydrochloride Methocel K4M Lactose monohydrate Polyvinylpyrrolidone Magnesium stearate Syloid 244 mg/tablet 22.89* 20.00 60.0 5.0 1.0 1.0 Function Active Hydrogel polymer Hydrophilic, agent Binder Hydrophobic agent Hydrophilic agent 0 Support platform Component mg/tablet Function Compritol 888 Lactose monohydrate Polyvinylpyrrolidone Magnesium stearate Methocel E5 Syloid 244 Iron oxide 14.72 30.60 2.80 0.80 30.60 0.40 0.08 Plasticizer Hydrophilic agent Binder Hydrophobic agent Hydrogel' polymer Hydrophilic agent Colourant Total tablet weight 189.89mg *Equivalent to 20mg paroxetine as free base.

The process was as described in Example 8.

Exaill I (Controlled release bilayer tablet) Active Layer Component Paroxetine Hydrochloride Methocel K4M Lactose monohydrate Polyvinylpyrrolidone Magnesium stearate, Syloid 244 mg/tablet 22. 89* 15.00 63.31 2.0 1.0 0.40 Function Active Hydrogel polymer Hydrophilic agent Binder Hydrophobic agent Hydrophilic agent Support platform as in Example Total tablet weight 184.60mg

I

I..

*Equivalent to 20mg paroxetine as free base.

The process was as described in Example 8.

Example 12 (Enteric coated controlled release bilayer tablet) Active Layer Component Paroxetine Hydrochloride Methocel K4M Lactose monohydrate Polyvinylpyrrolidone Magnesium stearate Syloid 244 mg/tablet 28.61* 18.75 79.14 2.50 1.25 0.50 Function Active Hydrogel polymer Hydrophilic agent Binder Hydrophobic agent Hydrophilic agent Support platform Component Corupritol 888 Lactose monohydrate Polyvinylpyrrolidone Magnesium stearate Methocel E5 Syloid 244 Iron oxide mg/tablet Function 15.04 30.50 4.00 0.80 29.32 0.32 0.02 Plasticizer Hydrophilic agent Binder Hydrophobic agent Hydrogel polymer Hydrophilic agent Colourant Enteric coating .555

S

Component Eudragit Talc Triethyl. citrate Water** Total tablet weight mg/tablet 13.27 3.31 1.33 36.25 Function Polymer Lubricant Plasticizer Diluent 228.66mg0 *Equivalent to 25mg paroxetine as free base.

"*Removed during processing.

The process was as described in Example 9.

Example 13 GI tolerance study The design of the study is outlined below Subjects: Design: Treatment: Dosage: Number of subjects: Normal healthy volunteers Parallel group, placebo controlled, double blind Placebo, Immediate release paroxetine, (c)Example 8 formulation, Example 8 formulation with enteric coating.

30 mg once daily for 3 days 452 evaluable (488 randomised, 485 evaluable) The study was conducted to compare the incidence, severity and duration of nausea and vomiting, and diarrhoea (theoretically if the controlled release formulations slow down absorption of paroxetine then, as paroxetine is known to be prokinetic to the GI tract there may be an increased incidence).

Adverse experiences (AE) information was assessed each morning at the time of dosing and again 24 hours following the last dose. Investigators and subjects were given diary cards detailing how to classify severity of AEs in order to standardise as much as possible across all 6 centres.

Of the 485 evaluable subjects, 18 withdrew, 17 because of adverse events.

Subjects with nausea/vomiting on the day of withdrawal were more common on than either of and The incidence of nausea/vomiting and diarrhoea is shown in the table below: Incidence of nausea Incidence of diarrhoea (b) 59% 15% (c) 49% 21% (d) 39% 20% Placebo 13% 7% The incidence of nausea was increased for both and placebo compared to the expected rates of approximately 25% and 5% respectively for volunteers at these dosages for 3 days duration. The overall incidence of nausea was less on and 12 P:'OPER\MKRSPEC\6414-00-353 doc-1912'01 13than on The severity of nausea was also decreased as shown in the next table.

Nausea severity Placebo None 50 63 74 104 (87%) Mild 45 40(33%) 30 16(13%) Moderate 21(17%) 17(14%) 15(12%) 0 Severe 6 1 3 0 Severity of diarrhoea is reported in the table below: Severity of diarrhoea Placebo None 104 95 97 112(93%) Mild 16(13%) 16(13%) 16(13%) 8(7%) SModerate 0(0%) Severe 0(0%) In conclusion, there appears to be a trend for to reduce the incidence of nausea and the dropout rate due to adverse events in comparison to but analysis of the results was complicated by a statistically significant treatment-by-centre difference. shows a S• 10 halving in the dropout rate and a fall in incidence of nausea of 20% (a proportional fall of In addition there is a reduction in severity of nausea of those individuals who report

S

nausea on and There is an increase in incidence of diarrhoea on both of and (d) in relation to but this is confined to an increase in the number of individuals reporting moderate diarrhoea and there is no increase in those with severe diarrhoea.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Claims (9)

1. A controlled and delayed release swallow formulation containing a selective serotonin reuptake inhibitor (SSRI).

2. A formulation according to claim 1 wherein the SSRI is paroxetine or a pharmaceutically acceptable salt thereof.

3. A formulation according to either claim 1 or 2, which comprises enteric coated tablets or caplets, wax or polymer coated tablets or caplets or time-release matrices, or combinations thereof.

4. A formulation according to any one of the preceding claims, which is a polymeric controlled release composition comprising an active agent selected from the group o 15 consisting of SSRI's and a reaction complex formed by the interaction of a calcium polycarbophil component which is a water-swellable, but water insoluble, fibrous cross- linked carboxy-functional polymer, said polymer containing a plurality of repeating units of which at least about 80% contain at least one carboxyl functionality, and about 0.05 to about 1.5% cross-linking agent substantially free from polyalkenyl polyether, said 20 percentages being based upon the weights of unpolymerised repeating unit and cross- linking agent, respectively, with water.

A formulation according to any one of claims 1 to 3, which is a system for the controlled release of an active substance which is an SSRI, which formulation comprises a deposit-core and a support platform, wherein: the deposit-core is of defined geometric form, comprises an effective amount of the active substance and has in addition to the active substance, at least one member selected from the group consisting of; P:OPER\MKR\SPECI 6414-00-085.doc-26/03/02 a polymeric material which swells on contact with water or aqueous liquids and a gellable polymeric material wherein the ratio of the said swellable polymeric material to said gellable polymeric material is in the range 1:9 to 9:1, and; a single polymeric material having both swelling and gelling properties; and; the support-platform applied to said deposit-core, is an elastic support, partially covering the surface of the deposit-core to form a bilayer tablet, follows changes due to hydration of the deposit-core, and is slowly soluble and/or slowly gellable in aqueous fluids.

6. A method of treating and/or preventing the disorders by administering an effective and/or a prophylactic amount of a controlled release or delayed release formulation according to any preceding claim, to a sufferer in need thereof. 15

7. Use of a controlled release or delayed release formulation according to any one of claims 1 to 5 in the manufacture of a medicament, for treating and/or preventing the disorders. S*

8. A process for the preparation of a formulation according to any one of claims 1 to 20 5, which comprises combining the constituents thereof in the required proportions.

9. A controlled and delayed release swallow formulation of claim 1, substantially as hereinbefore described with reference to the examples. DATED this 26th day of March, 2002 SmithKline Beecham p.l.c. By DAVIES COLLISON CAVE Patent Attorneys for the Applicant