Method of making the therapeutic system for the transdermal serving of the clonidine

A method for producing a therapeutic system in the form of a skin patch for continuous transdermal delivery of a clonidine at a predetermined rate over a predetermined skin area for a prolonged period of time, the system comprising a clonidine impervious protective layer, clonidine containing storage layers. containing mineral oil and polyisobutene and optionally clonidine; and. % of the protective layer formed by the polymer film by mixing 1 to 1 wt. % clonidine, 5 to 20 wt. % mineral oil, 5 to 20 wt. % Polyisobutene and 50 to 80 wt. The mixture is poured and dried, the microporous membrane is saturated with mineral oil and the protective layer, the storage layer and the microporous membrane are placed on top of each other, and contact adhesive is poured onto the membrane. layer and allowed to dry, and finally a protective coating is applied.

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The present invention provides a method for the manufacture of a therapeutic system for transdermal administration of clonidine at an initial base dose of 10 to 300 micrograms / cm 2² skin. This baseline dose brings the blood clonidine concentration to a level sufficient to induce α-adrenergic stimulation without undesirable side effects, followed by continuous administration of a dose of 0.1 to 100 micrograms per hour continuously to maintain the value. The system produced by the method of the invention consists of 5 layers, which will be listed above: a protective layer, a storage gel layer consisting of mineral oil, polyisobutylene and clonidine containing clonidine for continuous continuous administration, a microporous membrane that controls a constant rate of administration, a contact layer comprising a sealant containing mineral oil, polyisobutane and clonidine in an amount, which '' serves as the base 'dose and contains the composition by which the entire system is fixed to the skin, the last layer' being a removable protective 'coating.

A number of patents are known which relate to bandages or patches for transdermal delivery of the active ingredients to the bloodstream. U.S. Pat. No. 3,742,951 describes, for example, a three-layer system in the form of a bandage for transdermal administration of vasodilators. The bandage consists of a protective layer, a reservoir which controls the release of the active substance, contains a vasodilator and, moreover, an adhesive layer by which the bandage is fastened to the skin. U.S. Pat. 3 No. 797,494 discloses a similar bandage for transdermal delivery of systemic active agents. This bandage consists of a protective layer, an active substance storage layer, a microporous membrane that controls the rate of 'drug delivery' and a contact adhesive layer ......

The therapeutic system produced by the method of the invention is particularly intended for transdermal administration of clonidine. The hypotensive properties of clonidine , its derivatives and other compounds are known, for example, from U.S. Pat. No. 3,454,701 . This patent discloses that clonidine should be administered orally, parenterally, for example, as injectable solutions or rectally to treat increased blood pressure.

U.S. Patent No. 3,202,660 discloses that clonidine can be used to eliminate mucosal edema. For this purpose, clonidine is mixed with inert carriers which can be used for topical administration, for example in the nose.

U.S. Pat. No. 3,190,802 discloses that clonidine may be used as a pilomotor in shaving preparations. For example, shaving water, soaps or creams are applied to the face skin.

Clonidine is also useful in the treatment of migraine, as shown, for example, in U.S. Patent 3,666,861 and in the treatment of glaucoma, as described in E. Edelhauser, V.

Nemetz, Wedge. Mbl. Augenheilkunde 160 (1972) 188 and R. Jahnke, HW Thumm, Klin.

Mbl. Au-genheilk. 161 (1972) 73.

Depending on a number of factors, transdermal administration of a drug to achieve a therapeutic effect under certain conditions must be respected. For example, the active substance must not cause skin damage, irritation, allergy or sensitization during prolonged contact, and must not be too immobilized by the skin. and must be able to pass through a relatively small area of ​​skin to achieve a therapeutic dose. Unexpectedly, clonidine meets all of these conditions.

Accordingly, the present invention provides a method of making a therapeutic system in the form of a skin patch for 'continuous transdermal administration of clonidine at a controlled rate of predetermined skin area for a prolonged period of time, the system consisting of a clonidine impermeable protective layer against containing 5 to 20 micrometers of clonidine in a gelled mixture of mineral oil and high or low molecular weight isobutene, a microporous membrane of a polymeric film, the lips of which are filled with mineral oil, an adhesive layer consisting of mineral oil and a high or low molecular weight polyisobutene and optionally clonidine and a liquid-permeable polymer film protective layer consisting of a polymer film characterized in that a storage layer is formed by homogeneously mixing 1 to 6% by weight of clonidine, 5 to 20% by weight of mineral oil, 5 up to 20% by weight of polyisobutene and 50 to 80% by weight of a hydrocarbon of 6 to 7 carbon atoms, the mixture is poured onto a layer and dried by evaporating the hydrocarbon, the microporous membrane saturated with mineral oil and the protective layer, storage layer and microporous membrane stacked , a contact adhesive layer is poured onto the membrane and allowed to dry and finally applied. protective coating.

The term &amp; quot; effective area &amp; quot; refers to the surface treatment of a patch which comes into contact with the skin and is introduced into the skin by clonidine. As regards the magnitude of the constant rate of clonidine delivery, this means that the rate may be within ± 30% of the desired rate. These variations may be caused by the manufacture of the patch, may be caused by changes in temperature or by the way the patch is deposited on the skin and the like. With respect to the amount of clonidine available in the contact layer, this means that at least 50%, preferably at least 75% of the desired amount is available. The term "longer period of time" refers to half a day to 14 days. The term "clonidine" refers to 2,6-dichloro-N-2-imidazolidinylidenebenzamine or the structurally or functionally altered the above-mentioned benzamine, as described in more detail in U.S. Patent 3,454,701. As regards the structure and function of the benzamines used, it is therefore. reference can be made in this regard to the aforementioned patent. As for a preferred embodiment of the process according to the invention, the term "clonidine" means 2,6-dichloro-N-2-imadazohrdinylidenebenzamine. Thus, it is a compound of the structural formula

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The therapeutic system produced by the method of the invention converts clonidine transdermally into the bloodstream and induces α-adrenergic stimulation without undesirable side effects such as dry mouth, bias or excessive sedative effects. These results can be achieved by the fact that clonidine is delivered to the blood at a constant rate that induces α-adrenergic stimulation, optionally after an initial baseline dose. In addition, it may be central and / or peripheral - and adrenergic - stimulation. This stimulation can prevent and / or treat elevated blood pressure, migraine, glaucoma, mucosal edema, or menopausal problems. Centralized stimulation is used to treat elevated blood pressure or migraine.

By the therapeutic system according to the invention, the basic dose is administered in those cases where it is necessary or desirable to reduce the time at which the blood clonidine concentration is brought to the desired value and thus to produce - α-adrenergic stimulation. The basic dose also achieves this effect in part by saturating the skin at the site of administration with clonidine. Thus, the skin serves as an initial reservoir and only then as a route of administration, with the major amount of clonidine administered initially being immobilized in the skin and not getting into the bloodstream. The skin is saturated so that the sites where the active substance is immobilized are already occupied - so that further clonidine passes freely through the skin - and reaches the capillaries and into the bloodstream. Thus, the basic dose of clonidine administered is a function of the skin area. Basic dose of 10-300 micrograms-clonidine per cm² the treated skin is usually sufficient to achieve the desired blood level within 12 to 36 hours.

In most cases, this basic dose is in the range of 150 to 250 micrograms of clonidines per cm 2 of treated skin. It is also possible to express the basic dose - in the form of an average rate - of the passage of -clonidine through the cutaneous unit in. - the first - two - hour administration. In this expression, the basic dose is in the range of 75. up to - 125 micrograms / hour / cm 2.

If a therapeutic effect is not required with a single patch, additional patches must be applied to the skin to continue treatment. In this case, it is desirable that the additional patches contain a lower dose than the base dose in the first patch or - need not contain any - the base dose.

In the event that the following patches do not contain any basic dose, care should be taken to ensure that the clonidine concentration in the blood is maintained at the desired therapeutic level without major deviations from this value. - In case - if the following patches are not used - the basic doses are not used, these patches should contain 10 to 300 microgam / cm² skin.

The concentration of clonidine in the blood for - inducing α-adrenergic stimulation - ranges from 0.1 to 15 ng / ml, typically 0.3 to 3 ng / ml, depending on the subject being treated. The purpose of transdermal administration of clonidine at a steady rate is to - supplement - a possible basic dose, - which has been administered with a sufficient amount of clonidine and to achieve - a concentration in the blood to maintain the desired level as long as possible. It follows that the - transdermal - administration at a constant - rate should be continued as long as the duration of the treatment is to last. Usually, the active ingredient should be administered at a rate of 0.1 to 100 micrograms / hour, which is sufficient to maintain the blood clonidine concentration at the above-mentioned level.

The site at which the therapeutic system produced by the method of the invention is applied is important because the tissue structure, thickness, and permeability vary between individuals, affecting the efficacy with which clonidine can be transdermally delivered to the blood.

This difference can be compensated in two ways. The first option is -. to store the system in a place that - in terms of - clonidine permeability - does not change much in the individual and thus achieves a sufficient level of clonidine in the blood. For example, the patch can be placed on the breast nipple. The second option is to remove - the angular layer, which constitutes a major obstacle to the - intersection of the active ingredient - so that the skin at the site of treatment is treated with a composition that facilitates penetration of the skin. This method makes it possible to place the system produced by the method according to the invention - in a different place - than, for example, on the breast nipple, for example on the upper or lower limbs or on the trunk. Depending on the formulation used, treatment with the formulation may be performed prior to or concurrent with the administration of clonidine. At the same time, the amount of - the composition used - depends on the type of composition. In any case, the composition fulfills the dual function of increasing the penetration of the clonidine through the cornered layer and reducing the ability of the corner layer to fix the clonidine. An example of known means

Which may be used for this purpose are dodecylpyrrolidone, dimethyl lauramide and dimethyl sulfoxide. All three compositions can be used for pretreating the skin. Pyrrolidone alauramide is applied to the skin in an amount of 4 to 8 mg / cm 2² for 1 hour, after which the skin is washed.

The invention will be explained in more detail with reference to the accompanying drawing, which shows an enlarged schematic cross-section of a preferred embodiment of a therapeutic system made by the method according to the invention. It is a skin patch 10 that clonidine is released upon application to the skin at an initial base dose and then at a constant rate. The patch 10 consists of five layers. The topsheet 11 is a protective layer that is substantially impermeable to clonidine. The outer surface 12 is the top surface of the patch. The topsheet 11 prevents the liquid components of the patch from reaching the surface and is a protective layer for the entire patch. It preferably consists of a polymer film and a metal foil, for example an aluminum foil. Polymers which can be used in this layer are polyethylene, polypropylene, polyvinyl chloride and polyethylene terephthalate.

Below and in contact with the topsheet 10 is a clonidine storage layer 13. The storage layer 13 contains 1 to 6 mg of clonidine, the insoluble portion of which is shown as particles 14. The clonidine contained in the storage layer 13 is slowly introduced into the bloodstream at a constant rate. The particles 14 are homogeneously dispersed in a gel consisting of a mixture of an organic, apolar, nonvolatile inert liquid, such as a mineral oil of 10 to 100 cp at 25 ° C in admixture with polyisobutene. The inert liquid should comprise 35-65% by weight of the composition and polyisobutene 35-65% by weight of the composition. The blend of polyisobutenes consists of low molecular weight polyisobutenes having an average molecular weight of 35,000 to 50,000 and high molecular weight polyisobutenes having an average molecular weight of 1,000,000 to 1,500,000 as determined by viscosimetry.

Preferred compositions comprise 35 to 65% mineral oil, 10 to 40% low molecular weight polyisobutenes and 10 to 40% high molecular weight polyisobutenes. These mixtures of oil and polyisobutenes are excellent tackifiers and serve to ensure that the patch produced by the method of the invention has sufficient cohesion. Otherwise, however, any other means could be used for this purpose, for example heat melting.

The inert liquid, for example the mineral oil in the storage layer 13, is also a carrier for clonidine. Preferably, an inert liquid is used in which the clonidine is only sparingly soluble, for example 0.5 mg / ml. The relative amounts of the two components in the storage layer 13 need to be adjusted so that the inert liquid is saturated with clonidine and thus that clonidine is available for the entire period of use of the patch produced by the method of the invention.

Another layer of the patch produced by the method of the invention is a microporous membrane 15, the pores of which are filled with the above-mentioned inert liquid. The microporous membrane 15 controls the rate at which clonidine is released from the storage layer 13. Clonidine flow through the microporous membrane 15 and the region of the membrane must be controlled such that clonidine is released from the storage layer 13 to the skin at a substantially constant rate of 0.1 to 100 micrograms / hour after application of the patch of the invention. The flow follows Fick's law. This rate is a function of the curvature of the permeability and thickness of the membrane, as well as the clonidine concentration gradient on the membrane and the diffusion coefficient of the clonidine through the inert liquid. The concentration gradient depends on the concentration of clonidine in the inert liquid on both opposite sides of the microporous membrane 15. The diffusion coefficient depends on the viscosity of the inert liquid and decreases with increasing viscosity. Of course, the properties of the membrane are constant for each membrane. Membranes having a transmittance of 0.1 to 0.85, a curvature of 1 to 10 and a thickness of 10 '³ to 10² cm are preferred for use in the inventive plaster. The membrane may be made of polymers such as polypropylene, polytetrafluoroethylene, polycarbonates, polyvinyl chloride, cellulose acetate, cellulose nitrate and polyacrylonitrile.

Below the microporous membrane 15 is a contact adhesive layer 16. The contact adhesive layer 16 contains 10 to 300 micrograms of clonidine per cm² effective surface area. The insoluble fraction of clonidine is shown as particles 17. Clonidine in the contact adhesive layer 16 is administered as a basic dose. This clonidine is dispersed in the same inert liquid mixture of polyisobutenes as used in the storage layer 13. The contact adhesive layer 16 is a means to keep the patch on the skin. In this respect, the mixture of the inert liquid and the polyisobutenes has a less strong skin effect than the other patch layer. For this reason, the patch remains whole even when removed from the skin.

Prior to use, the patch has a removable protective layer 18 that covers the contact adhesive layer 16. Just prior to use, the protective layer 18 is removed from the contact adhesive layer 16 and discarded. This layer can be made of a material which is inert to clonidine and is impermeable to liquid, for example of the polymer which forms the topsheet 11, with the¹ ensure that these materials can be removed, for example by siliconizing.

The patch 10 can be manufactured, for example, as follows. The composition for forming the storage layer 13 is produced as a homogeneous mixture of clonidine, an inert liquid and a liquid in which clonidine is insoluble but which is a solvent for polyisobutene. Low molecular weight hydrocarbons such as heptane, hexane and cyclohexane can be used. The mixture must be vigorously mixed to ensure that the clonidine particles in the layer are of the desired size. The particle size affects the dissolution rate of clonidine in the other components of the layer and the tack properties of the layer. Particles with an average size of 5 to 20 microns are acceptable. Then, the salt is added to the mixture by means of a device which mixes the mixture less vigorously, such as a magnetic stirrer or a rotary drum, and a low molecular weight polyisobutene. thereby obtaining a suspension of the clonidine particles and dissolution of the polyisobutenes. The relative proportions of clonidine, inert liquid and polyisobutenes in this mixture have been mentioned above. The composition for the production of the contact adhesive layer 16 is prepared in the same way as the composition for the storage layer 13, only the ratios of the individual components need to be adjusted. The average particle size of clonidine can be determined by measuring its specific surface area according to an empirically derived equation

<img file="CS216917B2_D0003.tif" />

where d is the average particle size, p is the clonidine density a

A means the specific surface area of ​​the particles.

Brunauer, S. Emmett, E. Teller, J. Am. Chem. Soc. 60, 309 (1938), S. Gregg, "The Surface Chemistry of Solids", 2nd Edition, Reinhold Publishing Corp. NY (1961), S. Gregg and S. Sing "Adsorption, Surface Area and Porosity", Academic Press, NY (1967),

D. Yound and A. Crowell, “Physical Adsorption. of Gases', Butterworth and Co. Ltd., London (1962), C. Orr and JM Da-lla Valla, "Fine Particle Measurements", Macmillian, NY (1959).

The composition for the storage layer 13 is then poured onto the top layer 11 and allowed to dry to form the storage layer 13. In the same manner, the contact adhesive layer 16 'is poured onto the removable protective layer 18 and allowed to dry. On one side of the microporous membrane 15 is deposited an upper layer 11 and a storage layer 13, the microporous membrane being pre-saturated with an inert liquid. On the other side of the microporous membrane 15 a protective layer 18 and a contact adhesive layer 16 are deposited. Usually, large areas are used from which the desired patches 10 of various sizes and shapes can then be separated.

The plaster 10 can be applied to the breast nipple and administered clonidine according to the above method without the need for a prior or simultaneous application of a skin permeation enhancer to the skin area. If it is desired to apply the patch to another part of the body, the site must be pretreated with a skin permeation enhancer as described above. If simultaneous treatment is desired, such a composition may be incorporated into the patch 10, in which case the composition may comprise a storage layer 13 and a contact adhesive layer 16.

In addition, clonidine was found to be non-irritating to the skin and to have a local microbiocidal effect. Accordingly, there is no need to use the desired additional biocidal composition to suppress the growth of microorganisms on the covered portions of the skin.

The size of the patch is not critical. The patch should usually be sized so that the clonidine is in contact with 0.5-10 cm² skin. In this case, the total area of ​​the patch is also in the range of 0.3 to 10 cm 2.

The invention will be illustrated by the following example, which is not intended to limit the scope of the invention in any way. Unless otherwise stated, all parts are by weight.

Example

A mixture of 2.9% by weight of 2,6-dichloro-N-2-imidazolylmidene-benzamide is prepared,

10.4 wt% mineral oil of 10 cp at 25 ° C and 75 wt% heptane. In a homogenizer (Polytron), the web is homogenized for 10 minutes at 5000 to 10,000 rpm. To the homogenized mixture is then added a mixture of 5.2 wt% high molecular weight. polyisobutene (Vistanex MML-100, average molecular weight 1,200,000 in viscosimetric assay) and 6.5 wt% low molecular weight polyisobutene (Vistanex LM-MS with average molecular weight 35,000 in viscosimetric assay), and the resulting mixture was stirred slowly until a suspension of the benzamine particles is formed and the polyisobutene is dissolved. The resulting mixture was poured onto a protective filter consisting of an aluminum foil with a layer of polyethylene terephthalate (Medpar). total thickness of 100 microns, the two layers are allowed to air dry overnight and then dried for 15 minutes at 60 ° C to provide a benzamine-containing storage layer of approximately 50 microns thickness.

In a similar manner, a bilayer is prepared from a contact adhesive layer and a protective layer. by pouring a mixture of 0.9% by weight of benzamine, 11.4% by weight of mineral oil, 75% by weight of heptane, 5.7% by weight of said high molecular weight polyisobutene and 7% by weight of the above. low molecular weight. Polyisobutene to 125 microns thick, polyethylene terephthalate film coated with silicone and aluminum, protected and reinforced with polyethylene. The thickness of the two layers together is approximately 175 microns.

Then. apply the above-mentioned two-layer contact adhesive layer and protective layer to one side of a microporous polypropylene membrane with a thickness of 25 microns (Celgard 2400) saturated with mineral

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oil, and on the other side of the membrane a bilayer of the storage layer and the top layer is applied. Then, 1.1 cm circular patches can be cut from the resulting formation².

In vitro experiments have shown that the patch initially releases the baseline