Process for the manufacture of a therapeutic system in the form of a skin plaster for a continuous trasdermal application of clonidine

Start of patent period: 1980 II 15

Longest possible duration:

© Issued on: 1981 06 25 © inventor:

© Dependency: '© Pamphlets considered to delineate the state of the art:

DE-CS 2604718

- 2 - No.362884

There are several patents relating to bandages or dermal patches for the transdermal administration of drugs into the bloodstream. For example, U.S. Patent No. 3,742,951 describes a three-layer system or bandage for transdermal application of vasodilators. The bandage consists of a backing layer, a drug delivery rate controlling stock layer containing the vasodilator, and a contact adhesive layer securing the bandage to the skin. U.S. Patent No. 3,797,494 describes a similar bandage for the transdermal administration of systemic agents consisting of a backing layer, a drug reservoir layer, a drug delivery rate controlling microporous membrane, and a contact adhesive layer.

Application of scopolamine known.

The dermal patch of the invention is intended for transdermal administration of clonidine. The hypotensive properties of the clonidine base, its derivatives and known compounds are known in this context, for example from US Pat. No. 3,454,701. This patent discloses that clonidine can be formulated for oral, parenteral (eg as injection solution), or rectal administration for the treatment of hypertension.

U.S. Patent No. 3,202,660 teaches that clonidine is useful for mucosal swelling. For this purpose, it is mixed with inert carriers which allow topical application to mucous membranes, such as the nasal cavity.

U.S. Patent No. 3,190,802 discloses that clonidine can be used as a pilomotor agent in shaving compositions. In this form, it is applied to the facial skin as aftershave, soap or cream.

Clonidine is also useful for the treatment of migraine, as described, for example, in US Pat. No. 3,666,861, and for the treatment of glaucoma, as in references E. Edelhauser, V. Nemetz, Klin. Mbl. Augenheilkunde 160 (1972) 188 and R. Jahnke, HW Thumm, Klin. Mbl.

Augenheilk. 161 (1972) 73.

The feasibility of transdermal application of a given drug to achieve therapy under certain conditions depends on many factors. In addition to other conditions, the active ingredient may not damage the skin during prolonged contact, ie, do not adversely affect the skin structure or cause irritation, allergy or sensitization. It must not be too heavily immobilized by the skin and must have the ability to pass through a relatively small area of ​​skin at a therapeutically effective rate.

Clonidine unexpectedly fulfills these requirements.

In addition, it could not be foreseen from the prior art because of the different chemical constitution and the resulting different physical and pharmacological properties of the active ingredients that clonidine is suitable for transdermal application in the same way.

The invention relates to the use of a skin plaster, which consists of a drug-impermeable polymer film backing layer, adjacent thereto an active substance storage layer, adjacent to a microporous membrane of polymer film and an optionally active ingredient containing contact adhesive layer consisting of mineral oil and high and 40 low molecular weight polyisobutenes and a peelable Protective coating of an active ingredient inert, liquid-impermeable

Polymer film consists, for the continuous and transdermal application of clonidine.

The term "clonidine" denotes 2,6-dichloro-N-2-imidazolidinylidenbenzamine of the structural formula

<img file="AT362884B_D0001.tif" />

or structurally or functionally related benzamines, as described in US Pat. No. 3,454,701

- 3 no. 362884 are described. For the disclosure of such structurally and functionally related benzamines, reference is made to US Pat. No. 3,454,701.

The therapeutic system transports clonidine transdermally to the bloodstream, causing alpha-adrenergic stimulation without intolerable side effects such as excessive dry mouth,

To cause drowsiness or sedation. This is accomplished by delivering clonidine to the blood in a substantially constant rate which provides alpha-adrenergic stimulation, which may be preceded, if desired, by an initial basal dose. Alpha-adrenergic stimulation may be central and / or peripheral. The stimulation causes a preventive and / or curative treatment of hypertension, migraine or glaucoma, or of

Mucosal swelling or menopausal symptoms. For the treatment of hypertension or migraine, the stimulation is primarily central.

The therapeutic system applies a base dose in cases where it is necessary or desirable to shorten the time required to bring the clonidine concentrations in the blood to the level required to induce alpha-adrenergic stimulation.

This is partially achieved with the base dose by "saturating" the skin with clonidine at the site of application. The skin acts initially as a "collecting vessel" and probably not so much as a "conduit", with the bulk of the initially applied clonidine being immobilized in the skin rather than penetrating the bloodstream. However, if the skin is then "saturated" so that the immobilization sites are occupied, further clonidine penetrates the dermis and is taken up by the capillaries and further into the bloodstream. Thus, the amount of clonidine applied in the base dose is a function of the area of ​​the treated skin. A basic dose of 10 to 300 pg of clonidine per cm² Treated skin is usually sufficient to reach the therapeutic blood level within 12 to 36 hours. In most cases, the basal dose will range from 150 to 250 pg clonidine per cm² It is also possible to express the basal dose in terms of the average delivery rate per unit area applied during the first two hours of application.

Expressed in this way, the base dose is in the range of 75 to 125 pg / h.cm²,

If therapy is to be continued beyond the lifetime of a single patch, 30 additional plasters must be applied to the skin to continue therapy. It may therefore be desirable that such subsequent patches deliver a base dose of equal or lesser strength than the first patch, or contain no base dose at all.

If a base dose is ever used in such patches, care should be taken to keep the concentration of clonidine in the blood at a therapeutic level without substantial deviations from this value. Therefore, if a base dose is ever used in these subsequent patches, it should be in the range of 10 to 300 pg / cm² treated

Skin lie.

It is believed that a concentration of clonidine in the blood causing alpha-adrenergic stimulation varies between 0.1 and 15 ng / ml, normally between 0.3 and 3 ng / ml, depending on the subject being treated. The purpose of transdermal application of clonidine at a substantially constant rate is to supplement a possible basal dose by delivering enough clonidine to achieve such concentration in the blood and maintain it as long as possible. It follows that the application must be continued at constant speed as long as the therapy requires. A substantially constant velocity in the range of about 0.1 to about 100 pg / h, generally from about 0.2 to 70 pg / h,

The skin site to which the therapeutic system is applied is important because the tissue structure, thickness and blood flow of the skin varies from individual to individual, as well as from body to body of the individual, and this difference affects the effectiveness of clonidine in the blood can be supplied transdermally.

In two ways, this difference can essentially be eliminated. The first way is to attach the system to a skin site, namely the area of ​​the nipple where the

- 4 No. 362884

Clonidine permeation does not vary greatly from individual to individual, and therefore, where the amount of clonidine delivered to the blood or the rate at which it is delivered does not differ significantly among individuals. The second way is to remove the horny layer, as it is an amount or rate influencing element by treating the skin at the point of application with a skin permeation enhancer; pied treatment allows the system to be located at other body sites than in the area the nipple, namely on the arms, legs or on the trunk. Depending on the agent used, treatment may be performed before or simultaneously with the application of clonidine from the system. Likewise, the amount of agent depends on the agent used.

In any case, the agent fulfills the dual task of increasing the penetration of clonidine through the horny layer and to reduce the tendency of the horny layer to bind or fix clonidine. Examples of known agents which can be used are: dodecylpyrrolidone, dimethyllauramide and dimethylsulfoxide. All three agents can be used for pretreatment. Pyrrolidone and lauramide may be administered at the site to be treated at 4 to 8 mg / cm^a worn for about 1 h and then washed off.

The drawing is an enlarged schematic cross-sectional drawing of the preferred embodiment of the therapeutic system. It illustrates a therapeutic system in the form of a dermal patch, generally designated -10-, when applied to the skin, clonidine in an initial basal dose and then applied at a substantially constant speed. Patch -10- consists of 5 layers. The upper layer -11- is a support layer substantially impermeable to glonidine, and its outer surface forms the surface of the patch. Backing -11- serves as a protective blanket, prevents the volatile components of the plaster from escaping and performs a supporting function. Preferably, the support layer -11- is a layer of film and foil foil, like aluminum foil. Polymers which can be used in the layer are high and low pressure polyethylene, polypropylene, polyvinyl chloride and polyethylene terephthalate.

Below and adjacent to layer -11- is the clonidine storage layer -13-. Layer -13- contains about 1 to 6 mg of clonidine, the undissolved portion of which is shown as particle -14-. The clonidine containing layer 13 is delivered to the blood during the constant application portion of the dosing regimen. The particles are dispersed homogeneously in a gelled mixture of an organic, non-polar, non-volatile, inert liquid, such as in mineral oil at about 10 to about 100 cP and 25 ° C, and a mixture of polyisbutenes. It is common that the inert liquid forms 35 to 65% by weight of the mixture and the polyisobutene accordingly also comprises 35 to 85% by weight.

Preferred blends include 35 to 65% mineral oil, 10 to 40% low molecular weight polyisobutene and IQ to 40% high molecular weight polyisobutene. These oil-polyisobutene compounds are excellent adhesives and serve to hold the patch together. If they were not good adhesives, one could use other means to hold the patch together, such as heat sealing.

The inert liquid (mineral oil) in layer -13- acts as a carrier for the clonidine. Preferably, an inert liquid is one in which clonidine is only marginally soluble (eg its solubility in mineral oil is about 0.5 mg / ml ). The relative amounts of the two components in the layer -13- should be such that the inert liquid is saturated with clonidine, so that this is sufficient for the entire useful life of the patch substantially.

The next layer of the patch is a microporous membrane -15-, whose pores are described with the 50 obeh! inert liquid are filled. The membrane -15- is there? Element of the patch that regulates the rate at which clonidine is released from layer -13-. The flow of clonidine through the membrane -15- and the region of the membrane -15- must be controlled so that clonidine from the reservoir layer -13- to the skin in a substantially constant

- 5 No. 362884

Speed ​​is in the range of 0.1 to 100 pg / h delivered after the use of the patch . The river follows Fick's law. This is a function of the curvature, permeability and thickness of the membrane, the concentration gradient of the clonidine through the membrane and the diffusion coefficient of the clonidine in the inert liquid. The concentration gradient depends on the clonidine concentrations in the inert liquid on the opposite sides of the membrane. The diffusion coefficient depends on the viscosity of the inert liquid and decreases with increasing viscosity. Of course, the three properties of the membrane are constant for each membrane. Membranes having a permeability of about 0.1 to 0.85, curvatures of 1 to 10, and thicknesses of IO^-3 until 10^-3 cm can be used. The membrane may consist of polymers such as polypropylene, polytetrafluoroethylene, polycarbonates, polyvinyl chloride, cellulose acetate, cellulose nitrate and polyacrylonitrile.

Below and adjacent to the membrane -15- is a contact adhesive layer -16-. Layer -16- contains 10 to 300 pg of clonidine per cm 'effective surface area. The undissolved portion of clonidine is designated particle -17--. The clonidine in layer -16- is applied as a base15 dose. The clonidine is dispersed in the same, inert, liquid polyisobutene mixture used in layer-13-. Layer -16- is the agent whereby the patch is applied to the skin. In this regard, the mixture of inert liquid and polyisobutene is less adherent to the skin than it adheres to the other layers of the patch; therefore, the patch tends to stay whole when peeled off the skin.

Before use, the plaster also includes a peel-off protective cover -18- which seals the

Layer -16- covered. Shortly before use, the coating -18- is peeled off the layer -16- and discarded. It may be made of clonidine-inert, liquid-impermeable material, eg, made of polymers from which the backing layer -11- is made, it being understood that these materials are peelable, which can be achieved, for example, by siliconizing.

The patch -10- can be prepared in the following manner. The mixture for forming layer -13- is prepared by homogeneously mixing clonidine, the inert liquid, and a liquid in which clonidine is not soluble but which is a solvent for polyisobutene. Low molecular weight hydrocarbon solvents such as heptane, hexane and cyclohexane can be used. It should be mixed at high agitation speed to be sure to get the right particle size of clonidine in the layer. The particle size affects the dissolution rate of the clonidine in the other components of the layer and the adhesive properties of the layer. Particle sizes in the range of 5 to 20 pm (average diameter) are acceptable. Then the mixture of high and low molecular weight polyisobutenes is added using a low shear device such as a magnetic stirrer or a rotary wheel until the clonidine particles are suspended and the polyisobutenes are dissolved. The relative proportions of clonidine, inert liquid and polyisobutene in this mixture are given above. The mixture for making the pressure-sensitive adhesive layer -16- is prepared just like the mixture for layer -13- by suitably adjusting the proportions of the ingredients. The average diameter of the clonidine particles can be determined by measuring their specific surface, according to the empirically derived equation; such as a magnetic stirrer or a rotary wheel until the clonidine particles are suspended and the polyisobutenes are dissolved. The relative proportions of clonidine, inert liquid and polyisobutene in this mixture are given above. The mixture for making the pressure-sensitive adhesive layer -16- is prepared just like the mixture for layer -13- by suitably adjusting the proportions of the ingredients. The average diameter of the clonidine particles can be determined by measuring their specific surface, according to the empirically derived equation; such as a magnetic stirrer or a rotary wheel until the clonidine particles are suspended and the polyisobutenes are dissolved. The relative proportions of clonidine, inert liquid and polyisobutene in this mixture are given above. The mixture for making the pressure-sensitive adhesive layer -16- is prepared just like the mixture for layer -13- by suitably adjusting the proportions of the ingredients. The average diameter of the clonidine particles can be determined by measuring their specific surface, according to the empirically derived equation; The mixture for making the pressure-sensitive adhesive layer -16- is prepared just like the mixture for layer -13- by suitably adjusting the proportions of the ingredients. The average diameter of the clonidine particles can be determined by measuring their specific surface, according to the empirically derived equation; The mixture for making the pressure-sensitive adhesive layer -16- is prepared just like the mixture for layer -13- by suitably adjusting the proportions of the ingredients. The average diameter of the clonidine particles can be determined by measuring their specific surface, according to the empirically derived equation;

d = -

Ap where d is the average diameter in cm, p the clonidine density in g / cm³ and A denotes the specific surface area in cm '/ g.

The mixture of the stock layer is then poured onto one surface of the support layer -11- and allowed to dry to form layer -13-. Similarly, the mixture of the contact adhesive layer is poured onto one surface of the peelable protective layer -18- and allowed to dry to form layer -16. The composite stock layer / support layer is then layered on one side 50 of the microporous membrane layer -15- (saturated with the inert liquid) and

- 6 No. 362884 and the composite contact adhesive layer / peelable protective layer is coated on the other side of the membrane layer -15-. The resulting sheet is generally made in large webs from which individual patches of the desired size and shape can be cut or stamped.

The plaster -10- may be applied around the nipples and will apply clonidine according to the dosage regimen described without the need for prior or simultaneous treatment of the skin permeation enhancer area. However, as noted above, if the patch is applied to a different body site, the site should be treated with one or more of the skin-penetrating agents described. If concomitant treatment is desired, the agent may be incorporated into the plaster. In this case, layers -13 and 16-may contain an effective amount of such an agent.

Coincidentally, it has also been found that clonidine does not irritate the skin and that it exerts a local, microbiocidal effect. Thus, no additional biocidal agent need be used to prevent the growth of organisms at the adhered skin site.

The size of the patch is not crucial. The patch should generally be so large that it has clonidine on a skin area of ​​0.5 to 10 cm² applies. In this context, the effective surface of the patch also 0.5 to 10 cm² be.

The following example illustrates the invention. It is not intended to limit the scope of the invention in any way. Unless otherwise stated, these are

Parts as parts by weight.

A slurry of 2.9 weight percent 2,6-dichloro-N-2-imidazolidinylidenebenzamine, 10.4 weight percent mineral oil (10 cP at 25 ° C), and 75 weight percent heptane was prepared. In a polytron homogenizer, the slurry was homogenized for 10 minutes at 5,000 to 10,000 rpm. A mixture of 5.2% by weight of high molecular weight polyisobutene, 1,200,000 viscosity average molecular weight, and 6.5% by weight of low molecular weight polyisobutene, 35,000 viscosity average molecular weight, was then added to the homogenized slurry and mixed with slow stirring until the benzamine particles were suspended and the polyisobutenes were dissolved. The resulting mixture was poured onto a 10 μm thick support film of aluminum foil-coated polyethylene terephthalate:

A combination of the contact adhesive layer and the peelable coating was similarly prepared using a similarly prepared mixture of 0.9 wt.% Benzamine, 11.4 wt.% Mineral oil, 75 wt.% Heptane, 5.7 wt .-% of said high molecular weight polyisobutene and 7 wt .-% of said low molecular weight polyisobutene was poured onto a 125 pm thick coated with silicone and aluminum, polyethylene-protected polyethylene terephthalate film. The combination was about 175 pm thick.

Then, the above-described combination of the contact adhesive layer and the peelable coating was coated on one side of a 25 μm thick microporous polypropylene membrane saturated with said mineral oil and the combination of the support layer with the benzamine reservoir layer described above layered opposite side of the membrane. Round, disc-shaped skin patches of 1.1 cm² Size was punched out of the resulting five-layered structure.

In vitro tests with the plasters showed that they released an initial base dose of 60 pg of the benzamine (average during the first two hours) followed by a substantially constant dose of 3 pg / h (average of 168 h). In vivo tests showed delivery rates substantially similar to those obtained in the in vitro assays.