Therapeutic system for administering clonidine transdermally and process for making same

There are several patents that relate to bandages or skin patches for administering drugs transdermally to the systemic circulation. For instance, U.S. 3,742,951 describes a 3-layer system or bandage for administering vasodilators transdermally. The bandage comprises a backing layer, a drug release rate controlling reservoir layer that contains the vasodilator, and a contact adhesive layer by which the bandage is attached to the skin. U.S. 3,797,494 describes a similar bandage for administering systemic drugs transdermally comprising a backing layer, a drug reservoir layer, a microporous membrane that controls the drug release rate, and a contact adhesive layer.

The skin patch of the present invention is designed specifically to administer clonidine transdermally. In this regard, the hypotensive properties of clonidine base, derivatives thereof, and related compounds are known. See U.S. Patent No. 3,454,701. The patent states that clonidine may be formulated ^,for oral, parenteral (i.e. hypodermic’injection), or rectal administration to treat hypertension.

U.S. Patent No. 3,202,660 indicates clonidine is useful for vasoconstrictor therapy. For use in such therapy it is mixed with inert carriers to adapt it for topical application to mucous membranes such as the nasal cavity.

U.S. Patent No. 3,190,802 says that clonidine is also useful as a pilomotor agent in shaving compositions. As such it is applied to facial skin in the form of a shaving lotion, soap, or cream.

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Clonidine is also useful for treating migraine as described in U.S. patent No. 3,666,861 and for treating glaucoma as des-

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cribed in the literature references E. Edelhauser, V. Nemetz, Klin. Mbl. Augenheilkunde 160 (1972) 188 and R. Jahnke, H.W. Thumm, Klin. Mbl. Augenheilk. 161 (1972) 73.

Many factors bear on the practicability of administering a particular drug transdermally to provide therapy for a given condition. Among other requirements, the drug must not damage the skin over prolonged contact therewith (e.g. affect the skin structure adversely, or cause irritation, allergy, or sensitization). It must not be unduly immobilized by the skin. And, it must be capable of permeating through a relatively small area of skin at a therapeutically effective rate. Clonidine unexpectedly meets these requirements.

One aspect of the invention is a therapeutic system in the form of a skin patch for administering a drug continuously and transdermally at a controlled rate through a predetermined area of skin for a prolonged time period characterized in that the drug is clonidine and the rate is sufficient to effect alphaadrenergic stimulation and is optionally preceded.by a priming dose of clonidine. A preferred embodiment of the system is further characterized in that it includes a backing layer that is impermeable to clonidine and forms the top of the system, a reservoir layer that contains an amount of clonidine sufficient to provide clonidine at said rate for said period dispersed in a gelled mixture of an organic, apolar, nonvolatile inert liquid and a blend of polyisobutenes, a microporous membrane layer adjacent the reservoir and through which clonidine is released from the reservoir at said rate after the system is affixed to the skin, and a contact adhesive layer that is׳ permeable to clonidine and optionally contains said priming dose.

Another aspect of the invention is a process for making the above described preferred embodiment of the system characterized by forming the reservoir layer by (i) mixing homoϋ geneously said amont of benzeneamine, said inert liquid, said polyisobutenes and a liquid that is a nonsolvent for the benzeneamine but a solvent for the polyisobutenes under conditions that cause the particle size of the clonidine in the mixture to be in the range of about 5 to about 20 microns and (ii) casting the reservoir layer from the mixture; saturating the microporous membrane layer with said inert liquid, and laminating the backing layer, reservoir layer, microporous membrane layer, and the contact adhesive layer together.

. As used herein the term effective surface area means the surface area of the patch that contacts the skin and through which clonidine is administered to the skin. As used herein in connection with describing the constant rate of the dosage regimen and the rate at which clonidine is released from said reservoir layer, the term substantially indicates that the rate may vary + 30¾. Such variation may be inherent in the manufacturing procedure, or be caused by temperature fluctuation, poor affixation of the patch to the skin, and the like. . As used herein in connection with describing the amount of clonidine optionally present in the contact adhesive layer, the term substantial means at least about 50% and preferably at least about 75%. As used herein the term prolonged time period will usually mean a period from 0.5 to 14 days. As used herein the term clonidine denotes generally one or more of 2,6-dichloro-N-2-imidazolidinylidene benzeneamine, or benzeneamines structurally and functionally related thereto that are described in U.S. 3,454,701. U.S. 3,454,701 is incorporated herein by reference for its disclosure of such structurally and functionally related benzeneamines. With respect to the preferred embodiments of the invention the term clonidine denotes 2,6-dichloro-N-2-imidazolidinylidene benzeneamine. That compound is represented by the structural formula: /

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Thetherapeutic system administers clonidine transdermally to the systemic circulation to effect alpha-adrenergic stimulation without eliciting intolerable side effects such as excessive dry mouth, drowsiness, and sedation. It does this by delivering clonidine to the blood at a substantially constant alpha-adrenergic stimulating rate, optionally preceded by an initial priming dose. The alpha-adrenergic stimulation may be central and/or peripheral. Such stimulation is effective for providing prevention and/or curative therapy for hypertension, migraine, or glaucoma, or for vasoconstrictor or menopausal therapy. For providing therapy for hypertension or migraine the stimulation is primarily central.

The therapeutic system administers a priming dose in instances in which it is necessary or desirable to shorten the time it takes for the clonidine concentration in the blood to reach the level required to produce alpha-adrenergic stimulation. The priming dose partially does this by saturating the skin at the administration site with clonidine. In this respect the skin initially acts as a sink rather than as a conduit, with most of the clonidine initially administered being immobilized. within the skin and not passing through to circulation. However, once the skin is saturated, that is the immobilization sites are occupied, additional clonidine passes through the dermis to be picked up by the capillaries and on into systemic circulation. Thus the amount of clonidine administered in the priming dose is a function of the area of skin being treated.

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A priming dose of 10 to 300 mcg clonidine per cm of skin being treated will usually allow the therapeutic level in the blood to be reached within 12 to 36 hours. In most instances the priming dose will be. in the range of 150 to 250 mcg clonidine per cm of skin being treated. Alternatively the priming dose may be expressed in terms of the average release rate per unit of effective surface area over the first two hours of administration. Expressed in this manner in most instances the 2 priming dose will be in the range of 75 to 125 mcg/hr/cm .

If therapy is to be provided past the lifetime of a single patch, successive patches may be applied to the skin to continue therapy. In this regard it may be desirable for such successive patches to deliver a priming dose of equal or less magnitude as the priming dose of the first patch, or perhaps no priming dose, at all. In any event the priming dose, if any, in such successive patches should be such as to maintain the concentration of clonidine in the blood at a therapeutic level without substantial fluctuation above or below that level. Accordingly the priming dose, if any, delivered by such successive patches will be on 2 the order of 10 to 300 mcg/cm of skin being treated.

The concentration of clonidine in the blood that effects alpha-adrenergic stimulation is estimated to vary between 0.1 and 15 ng/ml, usually between 0.2 and 3 ng/ml, depending upon the person being treated. The purpose of administering clonidine transdermally at a substantially constant rate is to supplement the priming dose, if any, in delivering enough clonidine to reach such a blood concentration and to maintain such a concentration for as long as is necessary. It follows that the constant rate administration will proceed for as long as therapy is required. Substantially constant rates in the range of about 0.1 to about 100 mcg/hr, usually about 0.2 to about 70 mcg/hr will maintain the concentration of clonidine in the blood at a the above levels.

The skin location at which the therapeutic system is applied is important because the histology, thickness and vascularization of skin varies from individual to individual as well as from body site to body site on a given individual, and such variance affects the efficacy with which clonidine may be delivered transdermally to the blood. This variance may be substantially eliminated in either of two ways. The first way is to apply the system to a skin site, namely the mastoidal area, where clonidine permeation appears not to vary significantly from individual to individual and thus the quantity of clonidine delivered to the blood or the rate at which such delivery is made is not significantly different between individuals. The second way is to eliminate the stratum corneum as a quantityaffecting or rate-affecting element by treating the skin at the administration site with a skin permeation enhancing agent. Such treatment will allow the system to be applied to body sites, such as the arms, legs or torso, other than the mastoidal area. Depending on the particular agent involved, the treatment may occur prior to or simultaneously with the administration of clonidine from the system. Likewise, the quantity of agent needed will depend on the particular agent used. In any event, the agent plays the dual role of increasing the permeability of the stratum corneum to clonidine and decreasing thetendency of the stratum corneum to bind or immobilize clonidine. Examples of known agents which may be used are dodecyl pyrrolidone, dimethyl lauramide and dimethyl sulfoxide. All three of these agents may be used in pre-treatment applications. The pyrrolidone and lauramide may be applied to the administration site at about

ר to 8 mg/cm for approximately an hour and then washed off.

The attached drawing is an enlarged, schematic, crosssectional view of the preferred embodiment of the therapeutic system. It depicts a therapeutic system in the form of a skin patch, generally designated 10, that when applied to skin administers clonidine in an initial priming dose and then at a substantially constant rate. Patch 10 is a five-layer laminate. The top layer 11 is a backing that is substantially impermeable to clonidine. Its face 12 forms the top surface of the patch. Backing 11 serves as a protective covering, keeps the volatile components of the patch from escaping, and fulfills a support function. Preferably, backing layer 11 is itself a laminate of films of polymer and metal foil such as aluminum foil. Polymers that may be used in the layer are high and low density polyethylene, polypropylene, polyvinylchloride and polyethylene terephthalate.

Below and adjacent to layer 11 is a clonidine reservoir layer 13. Layer 13 contains about 1 to about 6 mg of clonidine, the undissolved portion of which is depicted as particles 14. The clonidine contained in layer 13 is delivered to the blood during the constant administration portion of the dosage program. Particles 14 are dispersed homogeneously in a gelled mixture of an organic, apolar, nonvolatile inert liquid, such as mineral oil of about 10 to about 100 cp at 25°C, and a blend of polyisobutenes. The inert liquid will usually .constitute 35% to 65% by weight of the mixture and the polyisobutene will correspondingly usually constitute 35% to 65% by weight of the mixture. The polyisobutene blend comprises a low molecular weight polyisobutene (35,000-50,000 viscosity average molecular weight) and a high molecular weight polyisobutene (1,000,0001,500,000 viscosity average molecular weight). Preferred mixtures comprise 35% to 65% mineral oil, 10% to 40% low molecular weight .9 polyisobutene, and 10% to 40% high molecular weight polyisobutene. These oil-polyisobutene mixtures are excellent adhesives and help to hold the patch together. If they were not good adhesives, other means, such as heat sealing, could be considered to keep the patch together.

The inert liquid (mineral oil) in layer 13 functions as a carrier for the clonidine. It is preferable that the inert liquid be one in which clonidine has limited solubility (for instance, its solubility in mineral oil is approximately 0.5 mg/ml) and the relative amounts of each in layer 13 be such that the inert liquid is saturated with the clonidine for essentially the entire dispensing lifetime of the patch.

The next lamina in the patch is a microporous membrane 15 whose pores are filled with the above described inert liquid. Membrane 15 is the element of the patch that controls the rate at which the clonidine is released from layer 13. The flux of clonidine through membrane 15 and the area of membrane 15 must be such that clonidine is released from reservoir layer 13 to the skin at a substantially constant rate in the range of 0.1 to 100 mcg/hr after the patch has been put in use. The flux follows Fick's law. It is a function of the tortuosity, porosity and thickness of the membrane, the concentration gradient of clonidine across the membrane and the diffusion coefficient of clonidine in the inert liquid. The concentration gradient depends on the clonidine concentrations in the inert liquid at the opposite sides of the membrane. The diffusion coefficient depends on the inert liquid viscosity and decreases with increasing viscosity. The three properties of the membrane are, of course', constant for any given membrane. Membranes that have porosities from about 0.1 to 0.85, tortuosities from 1 to

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10, and thicknesses from 10 ^J to 10 cm may be used. The membrane may be formed from polymers such as polypropylene, polytetrafluorethylene, polycarbonates, polyvinylchloride, cellulose acetate, cellulose nitrate, and polyacrylonitrile.

Below and adjacent membrane 15 is a contact adhesive lamina

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16. Lamina 16 contains 10 to 300 mcg clonidine per cm effective surface area. The undissolved portion of the clonidine is depicted as particles 17. The clonidine in lamina 16 is administered as a priming dose. The clonidine is dispersed homogeneously in the same inert liquid polyisobutene mixture that is used in layer 13. Lamina 16 is the means by which the patch is attached to the skin. In this regard the inert 1iquid-polyisobutene mixture adheres less strongly to skin than it does to the other laminas of the patch; therefore, the patch tends to remain intact when it is pulled off the skin.

Prior to use, the patch also includes a strippable, protective coating 18 that covers lamina 16. Just prior to use, coating 18 is peeled away from lamina 16 and discarded. It may be made from clonidine-inert liquid impermeable materials such as the polymers from which backing 11 may be made, with the provision that these materials are made strippable, such as by siliconizing.

Patch 10 may be made in the following manner. The composition for forming layer 13 is made by mixing homogenously clonidine, the inert liquid and a liquid that is a nonsolvent for clonidine but a solvent for the polyisobutene. Low molecular weight hydrocarbon solvents such as heptane, hexane, and cyclohexane may be used. The mixing should be done at a high shear to ensure proper clonidine particle size in the layer. Particle size affects the dissolution rate of clonidine in the other components of the layer and the adhesive properties of the layer. Particle sizes in the range of about 5 to 20 microns (number average diameter) are acceptable. The mixture of high and low molecular weight polyisobutenes is then added using a low shear mixing means such as a magnetic stirrer or rotating wheel until the clonidine particles are suspended and the polyisobutenes are dissolved. The relative proportions of clonidine inert liquid, and polyisobutene in this composition are stated above. The composition for forming contact adhesive layer 16 is made in the same manner as the composition for layer 13 using an appropriate adjustment in the proportions of the ingredients. The number average diameter of the clonidine particles may be determined from measurements of' their specific surface area according to the empirically derived equation:

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A p wherein d is the number average diameter, p is the density of clonidine and A is the specific surface area. S. Brunauer, P. Emmett, E. Teller, J. Am. Chem. Soc. 60, 309 (1938); S. Gregg ״The Surface Chemistry of Solids, 2nd dd., Reinhold Publishing Corp., N.Y. (1961); S. Gregg and K. Sing, Adsorption, Surface Area and Porosity, Academic Press, N.Y. (1967); D. Yound and

A. Crowell, Physical Adsorption of Gases, Butterworth and Co. Ltd., London (1962); C. Orr and J.M. Dalia Valla, Fine Particle Measurements, Macmillian, N.Y. (1959).

The reservoir layer composition is then cast onto one face of backing layer 11 and allowed to dry to form layer

13. Similarly, the contact adhesive layer composition is cast onto one face of strippable coating layer 18 and allowed to dry to form layer 16. The reservoir layer-backing layer assembly is then laminated to one face of microporous membrane layer 15 (saturated with the inert liquid) and the contact adhesive layer-strippable coating layer assembly is laminated to the other face of membrane layer 15. The resulting laminate is usually made in large sheets from which individual patches 10 of the desired size and shape may be cut or punched.

Patch 10 may be applied to either mastoidal region and it will administer clonidine according to the described dosage program without requiring any prior or simultaneous treatment of the region with a skin permeation enhancing agent. As indicated above, if the patch is applied to a body site other than a mastoidal area, the site should be treated with one or more of the described skin permeation enhancing agents. If simultaneous treatment is desired, the agent may be incorporated into patch 10. In that instance, layers 13 and 16 will contain effective quantities of such agent.

It has also been found fortuitously that clonidine is not irritating to the skin and that it has a local microbiocidal effect. Thus no additional biocidal agent need be used to inhibit organism growth at the occluded skin site.

The size of the patch is not critical. The patch will usually be sized to administer clonidine to an area of skin in the range of 0.5 to 10 cm². Correlatively, the effective surface area of the patch will also usually be in the range of 0.5 to 10 cm².

-a The following example illustrates the invention. It is not intended to limit the scope of the invention in any way. Unless indicated otherwise, parts are by weight.

A slurry of 2.9 w/w% 2.6-dichloro-N-2-imidazolidinylidene benzeneamine, 10.4 w/w% mineral oil (10 cp @ 25°C), and 75 w/w% heptane was prepared. The slurry was homogenized for 10 minutes @ 5000-10000 rpm in a Polytron homogenizer. A mixture of 5.2 w/w% of high molecular weight polyisobutene (sold under the designation Vistanex MML-100, 1,200,000 viscosity average molecular weight) and 6.5 w/w% of low molecular weight polyisobutene (sold under the designation Vistanex LM-MS, 35,000 viscosity average molecular weight) was then added to the homogenized slurry and mixed at low shear until the benzeneamine particles were suspended and the polyisobutenes were dissolved. The resulting mixture was cast onto a 100 micron thick backing film of aluminized polyethylene terephthalate (sold under the designation MEDPAR), allowed to air dry overnight and then oven dried for 15 minutes @ 60°C to form a benzeneamine reservoir layer approximately 50 microns thick.

A contact adhesive layer-strippable coating combination was similarly prepared by casting a similarly prepared mixture of 0.9 w/w% of the benzeneamine, 11.4 w/w% of said mineral oil, 75 w/w% heptane, 5;7 w/w% of said high molecular weight polyisobutene, and 7 w/w% of said low molecular weight polyisobutene onto a 125 micron thick siliconized, aluminized, polyethylenebacked polyethylene terephthalate film. The combination was about 175 microns thick.

The above described contact adhesive layer-strippable coating layer combination is then laminated to one face of a 25

X micron thick microporous polypropylene membrane (sold under the designation Celgard 2400) saturated with said mineral oil and the above described backing layer-benzeneamine reservoir layer combination is laminated to the opposite face of the 2 membrane. Circular, disc-shaped skin patches, 1.1 cm in area, are punched from the resulting 5-layer laminate.

In vitro tests of the patches indicated they released an initial priming dose of 60 mcg of the benzeneamine (average over the first two hours) followed by an essentially, constant dosage of 3 mcg/hr (average over 168 hours). In vivo tests gave release rates essentially equivalent to those obtained in the in vitro tests.