NZ239074A - Self-sticking matrix system for sustained transcutaneous release of piribedil - Google Patents

Abstract

The invention relates to a self-adhesive silicone elastomer matrix system for the sustained release of piribedil, which provides for the continuous and steady transdermal diffusion of piribedil.

Description

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AWUf :t.«..ow.M \ ,, ! t • -11 •. 1 " No.: Date: NEW ZEALAND PATENTS ACT, 1953 ■IULI9917 COMPLETE SPECIFICATION SELF-STICKING MATRIX SYSTEM FOR THE SUSTAINED TRANSCUTANEOUS RELEASE OF PIRIBEDIL We, ADIR ET COMPAGNIE, a French body corporate, of 1 Rue Carle Hebert, F-92415 Courbevoie, Cedex, France hereby declare the invention for which we pray that a patent may be granted to we, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(Followed by page la) m "la' 23 9 0 The present invention relates to a self-sticking matrix system for the sustained release of piribedil, which provides for continuous and gradual transcutaneous diffusion of the active principle.

Piribedil, the compound of formula (I): is a dopamine agonist which stimulates dopamine receptors and cerebral dopaminergic pathways, and is used in the treatment of psycho-behavioral disorders of cerebral senescence, early or late sequelae of stroke and extrapyramidal passive tremor and in the manifestations of arteritis of the lower limbs.

Piribedil was hitherto administered orally or by injection.

The transcutaneous administration of this active principle has the advantage from a pharmacokinetic standpoint of rapidly obtaining high and constant plasma levels, from a metabolic standpoint of avoiding substantial metabolism of the active principle by a hepatic first-pass effect, and lastly from a clinical standpoint of decreasing the doses administered by improving the efficacy, clinical acceptability and compliance on the part of the patient by a single, non-traumatizing application.

The possibilities of administration of a medicinal product through the skin depend on various factors. In particular, the compound must not adversely affect the skin in any way following prolonged contact and cause irritation, allergy or sensitization, and must be able to pass through a fairly small area of skin at a sufficient rate of diffusion to obtain plasma levels suited to the therapeutic requirements.

In point of fact, piribedil fulfills all these criteria.

More specifically, the subject of the present invention is a self-sticking matrix system which permits the sustained release of piribedil and its transcutaneous passage 239 07 through a specified area of skin, for a prolonged period and at a sufficient rate to cause the stimulation of dopamine receptors.

Thus, the transdermal piribedil system enables an improvement to be achieved in the psycho-behavioral disorders of cerebral senescence, especially mnestic functions, capacity for memorization, vigilance and capacity for adaptation to the surroundings. It is also useful for the treatment of stroke, extrapyramidal passive tremor, acute retinal ischemic events and cochleovestibular disorders of ischemic origin, and lastly in the manifestations of arteritis of the lower limbs.

For some years, a large number of patents have been describing systems for the transdermal administration of medicinal products to the general circulation.

In particular, there are self-sticking systems in which the active principle is dissolved directly in the adhesive.

Moreover, there are matrix systems in which the active principle is both dissolved and dispersed in the particulate state; the preparation is then made adhesive by coating with a surface adhesive or by a ring located around the matrix.

The transdermal system for sustained release of piribedil has the advantage of combining both of the above features of self-sticking and of a matrix containing dispersed piribedil in one and the same adhesive silicone elastomer base.

Silicone elastomers have the advantage, compared with other polymers, of not containing antioxidants, plasticizers or stabilizers.

In addition, this adhesive silicone elastomer system is new.

Lastly, the release of piribedil takes place continuously and constantly throughout the period of application of the system to the skin.

The transdermal device consists of an occlusive support film made of polyethylene/aluminum/polyester complex -3 239 07 coated with a self-sticking silicone elastomer matrix covered with a peelable protective film.

The matrix forms a polymer network capable of dissolving piribedil, having a self-sticking performance enabling the system to be maintained in place for a period of between 1 and 7 days.

The polymer skeleton consists of a medical grade silicone elastomer of general formula: CH3 M 0 Si CH3 ch3 0 - Si —1 n CH = CH2 — OM' in which M and M' are the groups: ch3 CH3 CH3 — Si — ch3 or CH2=CH Si CH3 The crosslinking of this polysiloxane is performed in the heated state by hydrosilylation using polysiloxane containing an SiH group in the presence of platinum as a catalyst, in a heated oven or using infrared radiation.

The self-sticking power of the matrix is imparted by the incorporation of a second silicone elastomer dissolved in a suitable organic solvent such as, for example, heptane, hexane or trichlorotrifluoroethane at a specified concentration.

This adhesive consists of a mixture in defined proportions of a low viscosity (12,000 to 15,000 mPa.s) polymer possessing terminal silanol groups Si-OH and a three-dimensional trimethylsiloxy silicate silicone resin.

In solution in a suitable solvent, the adhesive is produced by condensation between the silanol groups of the two polymers. The adhesive properties are evinced on evaporation of the solvent. pa 9 0 The self-sticking properties of the matrix may be enhanced by the joint use of an elastomer matrix exhibiting some degree of adhesiveness in itself and an adhesive silicone elastomer in a suitable organic solvent.

Absorption promoters may lastly be added to the matrix. These absorption promoters can be sodium lauryl sulfate, propylene glycol or dimethyl isosorbide.

The quantities of piribedil in the matrix vary in accordance with the doses necessary for a particular type of patient, and are between 10 and 500 mg.

The polysiloxanes used are biologically and pharmaceutically acceptable, non-allergenic, insoluble in the body and non-irritant to the tissues with which they are in contact.

The examples which follow illustrate the invention but in no way limit the latter.

EXAMPLE 1: 12 g of piribedil are gradually incorporated into 42 g of medical grade silicone elastomer (MDX4-4210) containing its crosslinking agent, with slow stirring. The mixture obtained is then homogenized by passage through a three- roll mill. 66 g of medical grade adhesive silicone elastomer (in 60% solution in hexane) are then introduced into the above mixture.

When the viscosity of the mixture has reached the appropriate value by evaporation of the hexane, the occlusive support film made of polyethylene/aluminum/polyester complex is coated with this mixture by means of an adjustable-thickness spreader.

Crosslinking is then carried out in a ventilated oven for 1 h at 80° C.

A peelable protective film of polyvinyl chloride is applied to the crosslinked adhesive system. 239 0 The self-sticking matrix is then cut up so as to obtain round transdermal devices of area equalling 20 cm2, corresponding to 40 mg of active principle per system.

EXAMPLE 2: 12 g of piribedil are incorporated into 42 g of medical grade silicone elastomer (MDX4-4210) containing its crosslinking agent, with slow stirring in the presence of 0.6 g of sodium lauryl sulfate. The matrix is obtained in the same manner as that described in Example 1.

The self-sticking matrix is then cut up so as to obtain square transdermal devices of area equalling 20 cm2, corresponding to 40 mg of active principle per system.

EXAMPLE 3: The production of the transdermal system is identical to that described in Example 1.

A peelable protective film of siliconized polyester is then applied to the crosslinked adhesive system.

The self-sticking matrix is lastly cut up so as to obtain round transdermal devices of area equalling 80 cm2, corresponding to 160 mg of active principle per system.

EXAMPLE 4: 4 g of micronized piribedil are incorporated into 10 g of heptane. The mixture is subjected to ultrasound. When the piribedil is completely dispersed, 20 g of medical grade silicone elastomer containing its crosslinking agent (MDX4-4210) are added to the mixture and the whole is homogenized. 14 g of medical grade adhesive silicone elastomer (in 74% solution in heptane) and 2 g of propylene glycol are then introduced into the above mixture. Coating is identical to that described in Example 1.

Crosslinking is carried out in a few minutes, after passage under an infrared radiation device. 23 90 After cooling of the matrix, a peelable protective film of polyester is applied to the crosslinked adhesive system.

The matrix is then cut up so as to obtain square transdermal devices having rounded corners, of area 20 cm2, corresponding to 80 mg of piribedil per system.

PHARMACOLOGICAL STUDY OF THE DEVICES OF THE INVENTION EXAMPLE 5: To determine the availability of piribedil transdermally, in vivo studies in healthy human subjects were performed.

The transcutaneous absorption of piribedil was determined by GC-MS assay of the plasma concentrations of the active principle during application of the device described in Example 3 for 72 hours.

The results of the absorption of piribedil are shown in Figure I.

The appearance of the curve in Diagram I shows that, for a given transdermal device, the plasma concentration of piribedil is constant during the 72 hours of application of the device, and is established very rapidly.

Claims (6)

' -7- ••'39074 WHAT we claim is »l«* II* -

1. A self-sticking matrix system for the sustained transcutaneous release of piribedil, which comprises an occlusive support film coated with a self-sticking matrix covered with a peelable protective film, wherein said piribedil is dispersed in said matrix.

2. The self-sticking piribedil matrix system as claimed in claim 1, wherein the matrix comprises a polymer skeleton consisting of a medical grade silicone elastomer in which piribedil, and optionally absorption promoters, are dispersed.

3. The self-sticking piribedil matrix system as claimed in claim 1, in which the matrix is made self-sticking by the incorporation of a second silicone elastomer dissolved in an organic solvent.

4. The self-sticking piribedil matrix system as claimed .in claim 1, wherein the polymer skeleton of the matrix is cross-linked by passage under an infrared radiation device.

5. The self-sticking piribedil matrix system as claimed in any one of claims 1 to 4, which is useful in the treatment of psycho-behavioral disorders of cerebral senescence, stroke, extrapyramidal passive tremor, acute retinal ischemic events, cochleovestibular disorders of ischemic origin and the manifestations of arteritis of the lower limbs.

6. A self-sticking matrix system for the sustained transcutaneous release of prirbedil substantially as herein described with reference to the examples. ■HC^Y 6z> By HiSrtl&f/ThoIr Authorteud Ojk A. J. FttSKJ SON iK Per Z\\