TRANSDERMAL FORMULATION COMPRISING ROPINIROLE

Abstract: Transdermal formulations comprising ropinirole for use in treating Parkinson's Disease.

Description: TRANSDERMAL FORMULATION COMPRISING ROPINIROLE The present invention relates to a transdermal formulation comprising 4-(2-di-n- proylaminoethyl)-2(3H)-indolone and for the use thereof in treating Parkinson's Disease. 4-(2-di-n-proylaminoethyl)-2(3H)-indolone (hereinafter referred to by its approved name Ropinirole) is the compound of formula (I): This compound was first disclosed in EP 0 113 964- A 1 (SmithKline Beckman Corp) as a peripheral, pre-synaptic U2-agonist, suitable for use in treating angina and hypertension. Subsequently, it was also shown to have central effects, as a post- synaptic U2-agonist in the brain (EP 0 299 602-A2, Smith Kline & French Laboratories). Furthermore, tolerance was developed to the peripheral effects. These central effects have led to the compound (as the hydrochloride salt) being developed for use in treating Parkinson's Disease, by oral administration of a tablet formulation. EP 0 299 602- A2 further discloses that other forms of administration may be considered for ropinirole and salts thereof, including parenteral, rectal and transdermal. A typical transdermal formulation is said to comprise a conventional aqueous or non-aqueous vehicle, for example, a cream, ointment lotion or paste in the form of a medicated plaster, patch or membrane. There is however no further guidance on suitable transdermal formulations or expected dosage for such formulations. A transdermal formulation offers the advantage of a more convenient mode of administration of the drug substance, thereby potentially enhancing patient compliance. In addition, drug substance is released in a more controlled fashion, over a prolonged period, offering potential therapeutic advantges. It has now been found that improved transdermal formulations able to provide a therapeutically useful amount of the drug may be prepared by using the free base form of the compound, in comparison to the hydrochloride salt preferred for tablet formulation. Accordingly, the present invention provides for a transdermal formulation comprising ropinirole (free base). Such formulations offer not only a more convenient method of administration but also possible therapeutic benefits and improved side effect profile. Suitable transdermal formulations are well known in the art (see for instance Percutaneous Absorption and Transdermal Therapy, K A Walters, March 1986; Pharmaceutical Dosage Forms and Drug Delivery Systems, (5th Ed.), H C. Ansel and N G. Popovich, Chapter 9, Lea and Febiger (1990), pages 307 to 320 and Sustained and Controlled Release Drug Delivery Systems, ed J R Robinson, Marcel Dekker Inc., New York (1978), pages 579 et seq.). Two main types of transdermal delivery devices are currentiy marketed and these are classified as matrix and membrane systems (Physicochemical Principles of Pharmacy, A.T. Florence and D. Attwood, 2nd Edition, Macmillan, 1993, page 331). In matrix systems, the drug is dispersed in a release controlling matrix which consists either of a gel or an adhesive film. Membrane systems generally consist of a drug reservoir, a rate-controlling membrane and an adhesive layer. In both cases the active is dissolved or suspended in a vehicle which then forms an integral part of the delivery device. The drug substance may be dissolved or suspended in a liquid or a gel. Suitable vehicles include both aqueous and non-aqueous vehicles, for instance saline and saline/propylene glycol (1:1). A penetration enhancer may also be added, if appropriate. Suitably, the transdermal formulation is provided in the form of a medicated plaster, patch or membrane, preferably a patch. Suitably the patch is between 10 and 50cm 2 , preferably between 20 and 40 cm 2 . The patch will be provided with a pharmaceutically accetable adhesive layer so that it can retained on the skin of the user. Preferably the adhesive effect of the layer will be reversible such that the patch will remain in place for the lifetime of the patch but still be easy for the Parkinson's Disease patient to apply and remove. In a further aspect, ropinirole free base may be generated in situ in the transdermal formulation, from a suitable ropinirole salt such as ropinirole hydrochloride, suitably immediately prior to use. Suitably this may be achieved by including in the formulation a base which would be brought into contact with the ropinirole salt to effect formation of the free base. The salt and base are kept apart, to avoid premature reaction, for instance in a two compartment reservoir having a rupturable barrier between the two compartments. Suitably, a preliminary evaluation of transdermal candidates is performed prior to incorporation in such a device. The most effective method is to determine drug penetration from suspensions or solutions using a human skin in vitro model, such as the Franz cell (Dematological Formulations: Percutaneous Absoφtion, B W Barry, Marcel Dekker (1983), page 245). Preferably, the delivery profile will provide a steady rate delivery. Alternatively, a compartmentalised rate controlled device may used. A suitable target skin flux will be in the range 5 to 25, preferably 10 to 15 μg/cm 2 hr. Suitably, the amount of ropinirole administered through a transdermal formulauon according to the present invention will be selected so that it will provide an amount of ropinirole substantially similar to that obtained following conventional oral administration of a tablet formulation, that is substantially similar to that obtained following administration of between 0.1 and lOmg of ropinirole (expressed as the free base) three times a day, assuming about 50% bioavailablity. Suitably the transdermal formulation is provided in unit dose form. Suitably, the transdermal formulation is provided in a range of dosage amounts, for instance to allow for titration of an individual patient's drug requirement. A suitable dose may be obtained by combining different strength formulations. Suitably, the unit dose form will provide sufficient drug substance for a 24 hour period (including, if appropriate 'off time'), to permit once-a-day application of the formulation. Suitably such application may be in the evening. Suitably, the transdermal formulation will be administered for a period of continuous therapy. Transdermal formulations according to the present invention will be of use in therapy, in particular treating Parkinson's Disease. Accordingly, in a further aspect, the present invention provides for the manufacture of a medicament comprising ropinirole (free base) adapted for a transdermal administration for use in treating Parkinson's Disease. The transdermal formulation may be used in patients in all stages of disease and/or as therapy after initial dose titration with a conventional tablet. The invention will now be illustrated by the following examples. Description 1 - preparation of ropinirole Ropinirole hydrochloride (190gm), water (1.35L) and ammonia (160mL,SG 0.88) were added to a flask fitted with stirrer and nitrogen bleed. This mixture was then stirred at ambient for ca 2hours and then extracted with dichloromethane (lx500mL, lx 250mL, lx 200mL). All the organic extracts were combined, washed with brine (3x50mL) and dried over with magnesium sulphate (if free water was still present). Removal of the solvent by evaporation under reduced pressue gave a light brown solid (142gm, 85% yield). NMR [5H(CDC1 3 )]: 0.9(6H,t),1.5(4H,m),2.7(3H,s)3.5(2H,s) 6.7-6.9(3H,m,Ar),8.6(2H,br,NH). Example 1 A typical patch comprising a membrane is as follows: a backing layer of aluminized plastic that is impermeable to ropinirole; drug reservoir containing ropinirole (30 to 60mg/ml) in a saline/propylene glycol (1:1) vehicle; ethylene- vinyl acetate copolymer membrane that is permeable to ropinirole; and a layer of hypoallergenic silicone adhesive; plus a protective peel strip covering the adhesive surface. patch size = 20-40cm 2 reservoir volume = 0.5- lml Example 2 A typical patch comprising a matrix is as follows: backing foil; drug reservoir comprising a ropinirole/lactose trituration homogeneously dispersed in a hydrogel composed of water, glycerin, poly vinyl alcohol and polyvinylpyrrolidone; adhesive layer; and a release liner. Example 3 - in vitro Percutaneous Penetration of Ropinirole The relative potential of ropinirole (as the free base) and a ropinirole salt for formulation into a transdermal delivery system was initially evaluated by determining drug penetration from suspensions or solutions using a human skin in vitro model. The in vitro percutaneous penetration method utilised saturated solutions of ropinirole hydrochloride and ropinirole free base. The in vitro set up consisted of modified Franz cells (Dematological Formulations: Percutaneous Absorption. B.W. Barry, Marcel Dekker, 1983, 245) with full thickness human abdominal skin and a receptor of 0.9% saline. The vehicles tested were ropinirole and its hydrochloride salt in aqueous 0.9% saline and aqueous 0.9% saline/propylene glycol (50:50). Samples were taken from the receptor at intervals and analysed for ropinirole content. From these results the concentration of ropinirole penetrating human skin with time could be determined. Results (SEM) = Standard Error of Mean [Rel to 1] = Skin penetration relative to formulation 1 PG = Propylene glycol Conclusions Penetration of the free base appears to be 20 fold better than the salt from the 0.9% saline vehicle and 40 fold better from the PG: saline vehicle. Using this test system, 10-20 μg of the free base penetrated through the skin over a 24 hour period. Thus, with a patch of 30 cm 2 , potentially 300-600 μg of drug could be delivered, to give therapeutically effective blood levels of ropinirole.

Claims: Claims 1. A transdermal formulation comprising ropinirole (free base). 2. A transdermal formulation as claimed in claim 1 which has a target skin flux of from 5 to 25 μg/cm 2 /hr. 2. A transdermal formulation as claimed in claim 1 in the form of a patch. 3. A transdermal formulation as claimed in claim 1 or 2 in the form of a unit dosage, comprising between 1 and 20 mg of ropinirole. 4. A transdermal formulation as claimed in any one of claims 1 to 3 in which ropinirole free base is generated in situ. 5. A transdermal formulation as claimed in any one of claim 1 to 4 adapted for once- a-day application. 6. The manufacture of a medicament comprising ropinirole (free base) adapted for transdermal administration for treating Parkinson's Disease.

Inventors: PATEL ANIL, PATEL, ANIL
Applicants: PATEL ANIL, SMITHKLINE BEECHAM PLC, PATEL, ANIL
Application year: 1996
Main classification: A61K31
IPC codes: A61K9, A61K31, A61P25