KR820000111B1 - Therapeutic system for administering clonidine - Google Patents

Abstract

A therapeutic system designed to administer clonidine(I) continuously and transdermally over a prolonged period comprises a skin patch that administers I in an initial priming dose and then at a substantially const. rate. Thus, a mixt. of 5.2 wt./wt.% high-and 6.5 wt./wt.% low-mol.-wt. polyisobutene was added to a homogenized slurry of I 2.9, mineral oil 10.4, and heptane 75 wt./wt. % and mixed until I particles were suspended and polyisobutenes were dissolved. The resulting mixt. was cast onto a Medpar backing film and dried to form a I reservoir.

Description

Clonidine's Attachment Treatment

Figure is an enlarged cross-sectional view showing an embodiment of the present invention.

The present invention relates to an attachment therapy for clonidine.

There are several patents relating to bandages or skin datches for administering medications through the skin for conventional systemic circulation. For example, US Pat. No. 3742951 describes a three layer method or bandage for administering vasodilators through the skin. The bandage is composed of a drug release rate control storage layer containing a back layer vasodilator and a contact adhesive layer that allows the bandage to adhere to the skin. U.S. Patent No. 3797494 includes a back layer medicine storage layer, a microporous membrane and a contact adhesive layer for controlling the medicine rate. And similar bandages for administering systemic medications through the skin.

The skin adhesive of the present invention is specially designed for administering clonidine through the skin. In this regard, the coercive nature of the clonidine base, its derivatives and related compounds is known (see US Pat. No. 3,470,47). This patent describes that clonidine can be administered orally, parenterally (ie, subcutaneously) or intestine to treat hypertension.

U.S. Pat.No.3202660 describes an effective treatment for vasoconstrictive nerve therapy. For use in such treatments it is admixed with an inert carrier, for example suitable for topical application to mucous membranes such as the nasal cavity.

U.S. Patent No. 3190802 describes clonidine as a useful hair removal agent in shaving compositions and applies itself to facial skin in the form of shaving lotion soaps or creams.

Clonidine is also useful for the treatment of migraine headaches, as described in US Pat. No. 3,668,661 and described in E. Edelhauser. V. Nemetz. Klin Mbl. Augenheil Kunde 160 (1972) 180 and R. Jahnke, HW Thumm Klin. It is useful for the treatment of glaucoma, as described in Mbl.Augenbeilk 161 (1972) 73).

Many factors relate to the feasibility of administering certain medications through the skin to provide for treatment under a given condition. Among many requirements, the medicament itself should not inflict damage (for example, adversely affecting the skin structure causing irritation, allergies or moles) even during prolonged skin contact. Also, medications should not be unintentionally immobilized by the skin. It must also pass a relatively small area of skin at a rate effective for treatment. Clonidine is surprisingly suitable for this need.

One aspect of the invention is characterized in that the drug is clonidine and the rate is sufficient to drive α-adrenergic stimulation, which can be optionally carried out by a priming dose of clonidine. It is a treatment method by the skin adhesive type that can administer the medicine through the skin continuously at a controlled rate for a long time through the predetermined area of the skin. Preferred embodiments of this approach include clonidine dispersed in a backing layer that is not permeable to clonidine but forms a top of this form (structure), a mixture of organic nonpolar inert liquids and polyisophthenes, and gelled mixtures. A storage layer containing a sufficient amount of clonidine for a long time at that rate, and a permeable and optionally basic coating capacity for the microporous membrane layer and clonidine released from the storage layer at that rate after the adhesive adheres to the skin in proximity to the storage layer. It is characterized by including the contact bonding layer containing the.

Another aspect of the present invention is the (i) appropriate amount of benzeneamines, inert liquids, polyisobutenes and liquids that are nonsolvents of polyisobutenes, and the particle size of clonidine in the mixture in the range of 5-20 microns. It apply | coats uniformly in conditions inside. And (ii) forming a storage layer from the mixture, saturating with the microporous membrane layer inert liquid, and integrally forming the backing layer, the storage layer microporous membrane layer and the contact adhesive. This is the preparation of the preferred embodiment of the above manner. In the present invention, the term "effective surface area" means the surface area of the pressure-sensitive adhesive in which the clonidine is administered to the skin through and in contact with the skin. The meaning is also used for the description of the fixed rate of the dosage criteria and the rate of release from the storage layer of clonidine. The term substantial refers to the rate at which it can vary by ± 30%. Such changes are inherent to the recipe or exhibit temperature fluctuations, low adhesion of the adhesive to the skin. Meaning is also used with respect to the amount of clonidine that may optionally be present in the contact adhesive. By substantial is meant at least 50% to at least 75%. As used herein, the term long term usually means 0.5 to 14 days. As used herein, the term clonidine generally refers to one or two or more of 2, 6-dichloro-N-2-imidizolidine niylidene benzeneamine or other structural and functionally related benzeneamines described in U.S. Patent No. 3454701. Indicates. U.S. Patent No. 3470471 is incorporated herein because of the disclosure of such structurally and functionally related benzeneamines. The term "clonidine" refers to 2, 6-dichloro-N-2-amidizoridinilidene benzeneamine. The structural formula of the compound is as follows.

Clonidine is administered through the skin for systemic circulation because the treatment mode of the present invention achieves α-adrenaline agonist stimulation without the unbearable side effects such as excessive thirst, drowsiness and sedation. It may do this by randomly starting the base application dose or by releasing clonidine at a substantially constant α-adrenaline acting stimulation rate with respect to the fluid. α-adrenergic agonist is central digger (or) peripheral. Such stimulation is central to provide prophylaxis and treatment of hypertension, migraine or glaucoma or to provide treatment of vasoconstriction or migraine.

The treatment regimens of the present invention need to shorten the time to obtain the concentration of clonidine in the blood to reach the level required to induce α-adrenergic agonist stimulation, or administer a base coat dose if desired. The basic application dose is obtained by saturating the skin with clonidine at the site of administration. In this regard, the skin acts as a sink rather than a conduit without the circulation of most of the initially administered clonidine fixed to the skin. However, once the skin is saturated and the fixation site is occupied, surplus clonidine is absorbed into the capillaries even through the dermis and enters the systemic circulation. Thus, when basal dosing is administered, the amount of clonidine is a function of the area treated. Basis dose of clonidine 10-300mcg per cm 2 treated skin reaches 12-36 hours at the level of treatment in commercial blood. In most cases the basal application dose ranges from 150-250 mcg of clonidine per cm 2 treated skin. Separately, the base coat dose is expressed as the average rate of departure per point of effective area area in the first 2 hours of administration. Expressed in this way, the basic application dose is in the range of 75-125 mcg / hour / cm 2.

If treatment must be provided beyond the life of one adhesive, the adhesive must be kept on the skin for subsequent treatment. In this respect, a continuous pressure-sensitive adhesive which releases a base coating dose equal to or less than the first base coating dose or no base coating dose at all. In any case, the basic application dose of such continuous adhesives, for example, must be able to maintain blood clonidine concentration in the blood without substantial fluctuations in the level of treatment. Therefore, the basic coating dose released by such continuous adhesive is, for example, about 10 to 300 mcg / cm 2 of skin treated. The concentration of clonidine in the blood causing α-adrenergic agonist depends on the human being treated and can be seen between 0.1 and 15 mg / ml, usually between 0.2 and 3 ng / ml. The purpose of administering clonidine through the skin at a substantially constant rate, for example, is to provide a baseline dosage with sufficient clonidine to reach such a blood concentration and maintain the concentration for as long as necessary.

Constant rate administration continues while treatment is required. A substantially constant rate in the range of about 0.1 to about 100 mcg / hour, usually 0.2 to about 20 mcg / hour, will maintain the concentration of clonidine in the blood at this level.

Histology, thickness, and angiogenesis of the skin vary between individuals and between body parts of the subject, so the difference in location affects the effect of clonidine on the release of blood through the skin. It is important. This difference is actually eliminated by either method. The first method is to apply the method of the present invention to skin regions, ie, the dendritic regions, in which the amount of clonidine released in the blood or the rate of release thereof does not actually differ between individuals because the infiltration of clonidine is actually different between individuals. The second method is to remove the stratum corneum as a dose-influence or rate-influencing factor by treating the skin with a skin penetration enhancer at the site of administration. This treatment may be applied to parts of the body other than the synchronous area, for example limbs or torso. Depending on the particular enhancer that may be included and the treatment is done concurrently prior to the administration of clonidine in the manner of the invention. The amount of enhancer required in this way is determined by the enhancer used. In any case, the enhancer is dual in tendency to increase the permeability of the stratum corneum to clonidine and to decrease the stratum corneum binding or immobilizing clonidine. Examples of known enhancers used are dodecylpyrrolidendimethyldimethylulamide and dimethylsulfoside.

All of these three enhancers are used for pretreatment applications. Pyridone and lauryl are applied to the administration site at about 4 to 8 mg / cm 2 for about 1 hour and then washed off.

The accompanying drawings are enlarged cross sectional views of preferred embodiments of the treatment regimen of the present invention. This shows the treatment regimen in the form of a skin tackifier, generally represented by 10, when applied to the skin and the initial baseline dose followed by a constant rate of clonidine. Adhesive 10 is a laminate of five layers. Top layer 11 is actually an impermeable backcoat layer for clonidine. The back layer 11 acts as a protective coating and keeps the protective layer from being volatile. It also serves as a supporter. Preferably, the back layer 11 is a laminate of a film of its own polymer and a metal film such as an aluminum film. Polymers used in the layers are high density polyethylene, polypropylene, polyvinylchloride and polyethylene terephthalad.

Underneath the back layer 11 is an adjacent clonidine storage layer 13. Layer 13 contains about 1 to about 6 mg of clonidine, the non-hazardous portion of which is indicated as particle 14. Clonidine contained in layer 13 is released into the blood between certain dose portions of the dosage program. Particles 14 are uniformly dispersed at 25 ° C. in a gelled mixture of a mixture of polyisobutenes with an organic nonpolar non-odorous inert liquid such as mineral oil of about 10 to 100 CP. Inert liquids usually comprise 35 to 65% by weight of the mixture and polyisobdenes correspondingly constitute 35-65% by weight of the mixture.

The polyisobutene mixture is made of low molecular weight polyisobdenum (35, 000-50, 000 viscosity average molecular weight) and high molecular weight polyisobdenum (1,000, 000-1, 500, 000 viscosity average molecular weight).

Preferred mixtures are 35% to 65% mineral oil, 10% to 40% low molecular weight polyisobdenum and 10% to 40% high molecular weight polyisobdenum. This makes the oil-polyisodecide mixture an excellent adhesive. So it helps to keep the adhesive together. If these are not good adhesives, other means, such as heat seals, can be considered to hold the adhesive together.

The inert liquid (mineral oil) in layer 13 functions as a carrier of clonidine. Inert liquids have a converted solubility of clonidine (eg, solubility in mineral oil is about .05 mg / ml). And each of the relative amounts in layer 13 should be one in which the inert liquid can basically saturate with clonidine for the entire dispersion life of the adhesive.

The next layer of the pressure-sensitive adhesive is microporous membrane 15 whose micropores are filled with the inert liquid. Membrane 15 is an element of the adhesive that controls the rate at which clonidine is released in layer 13. The flow of clonidine through the membrane 15 and the region of membrane 15 must be such that clonidine can release to the skin at a constant rate within the range of 0.1 to 100 mcg / hour in the reservoir layer 3 after the adhesive has been used. It is a function of the meandering, porosity and thickness of the membrane, the concentration gradient of clonidine through the membrane and the diffusion constant of clonidine in the inert liquid, which is inert liquid on the opposite side of the membrane. The diffusion constant depends on the viscosity of the inert liquid and the decrease in increasing viscosity The three properties of the membrane are of course constant for a given membrane porosity of about 0.1 to 0.85 mesotropes 1 to 10 and use a film having a thickness of 10 ^-3 to 10 ^-2. membrane polymer for example poly-propyne, poly fill to trad Oe styrene, polycarbonate net, poly Carbonyl chloride, cellulose acetate date, to form a cellulose-house acetamido, nitro mouse red and poly arc cut into cellular roll.

Underneath membrane 15 is the adjacent adhesive layer 16. Layer 16 contains 10 to 300 mcg of clonidine per cm 2 of effective area. The undissolved portion of clonidine is represented by particle 17. Clonidine in layer 16 is administered as a base coat dose. It is uniformly dispersed in an inert liquid polybdenum mixture as used for clonidine layer 13. Layer 16 thereby becomes a means that can adhere to the adhesive skin. In this respect, the inert liquid-polyisobdenum mixture is weaker against the skin than the other layers of the adhesive and therefore the adhesive tends to remain intact when peeled off the skin.

A protective layer 18 covering or peeling off the adhesive or layer 16 prior to use. Immediately before use, sheath 18 is removed from layer 16. It can be made of a clonidine-inert liquid, impermeable material such as polymer 11, for example, so that these materials can be removed by something such as siliconization.

Adhesive 10 can be made by the following method.

The composition which forms layer 13 is prepared by uniformly mixing clonidine, an inert liquid, and a liquid which is an insoluble solvent of clonidine or a solvent of polyisobutene. Low molecular hydrocarbons such as isobutane, hexane and cyclohexane are used. The mixture should be cut very finely to ensure a suitable clonidine particle size in the layer.

The size of the particles affects the dissolution rate of clonidine and the adhesive properties of the layer, among other components of the layer. Particle sizes in the range of about 5-20 microns (number of average diameters) are accommodated. Subsequently, a low shear mixing means such as a magnetic stirrer or a rotating wheel is used, and a mixture of high molecular weight and low molecular weight polyisobdenes is added until the clonidine particles are dissolved to dissolve the polyisobdenum. The relative ratios of clonidine, inert liquid and polyisobutene of this composition are as described above. The composition for forming the contact adhesive layer 16 is prepared in the same manner as the composition for layer 13 with proper control of the proportions of the components. The average diameter of clonidine particles is actually calculated by

Where d is the average number of diameters, p is the density of clonidine, and A is the surface area.

S. Brunauer, P. Emmit, E. Teller, The Journal-Off American Chemical Society [J. Am. Chem. Soc.] 60, 309 (1938) S. Gregg The Surface chemistry of Solids, Ragfan Rheinhard Publishers, New York State (1861) S. Gregg and K. Singh, Adsufson Surface Adsorption, Surface Area and porosity Academic Press New York State (1967): D. Onde and A. Crowell, Physical Adsorption of Gases Buttonworth Lon Lancesi (1962): JM Dalla Valla Fine Particle Measurements Macmillian New York State (1959)

The storage layer tissue is then formed on one surface of back layer 11 and dried to form layer 13. Thus, the adhesive contact layer composition is formed on one surface of the coating layer 18 which can be peeled off, and dried to form the layer 16. The storage layer-back layer combination is then laminated onto one surface of the microporous membrane layer 15 (saturated with inert liquid) and a combination combining the contact adhesive layer and the removable coating layer is deposited on the other surface of layer 15. . The resulting laminate is made into a generally large sheet which is cut from it into the desired size of a suitable shape to puncture the cut adhesive.

Adhesive 10 is applied to each mastoid and is used on any part of the body other than the mastoid where the clonidine can be administered according to the described dosing program without the need for prior or simultaneous treatment at that site by the skin permeability enhancer. If so, the area should be treated with one or more skin penetration enhancers. If simultaneous treatment is desired, the drug may be incorporated into the adhesive 10. In that case, layers 13 and 16 contain an effective amount of the agent.

Clonidine was recognized to have a topical antimicrobial effect without irritating the skin. Therefore, it is not necessary to use additional fungicides that inhibit biogrowth in the closed skin area.

The size of the pressure-sensitive adhesive is not limited. The pressure-sensitive adhesive is usually sized such that clonidine can be administered to an area of the skin within the range of 0.5 to 10 cm 2. Therefore, the effective surface area of the pressure-sensitive adhesive is usually in the range of 0.5 to 10 cm 2. The present invention will be described with reference to the following examples. It is not intended to limit the scope of the invention to any extent.

2.9% by weight 2.6 Dichloro-N-2-imidazoridinilidene benzeneamine 10.4% by weight mineral oil (10 cps 25 ° C.) and 75% by weight heptan were prepared, and the slabs were made with a polytron mixer at 5000-10000 rpm for 10 minutes. Mix. A mixture of 5.2% by weight polymer polyisobutene (named Vista Nex MML-100 Viscosity Molecular Weight 1, 200, 000) and Vistanex LM-MS Viscosity Average Molecular Weight 35, 000 are then mixed in a mixer One slab is added and mixed at low shear until the benzeneamine particles are suspended and the polyisobutenes are dissolved.

The resulting mixture was molded on a 1000 micron thick backing film of aluminized polyetchenedereptared (named MEDPAR) and dried overnight with air to form a benzeneamine storage layer about 5 microns thick. Dry for minutes.

The adhesive layer-peel coating combination is 0.9 weight% benzeneamine, 11.4 weight% mineral oil, 75 weight% heptane 5.7 weight% low molecular weight poly on a 125 micron thick siliconized aluminum-treated polystyrene backed polystyrene terephthalene film. It is prepared by molding a mixture made with isobten and the thickness of the combination is about 175 microns. The contact adhesive layer-removable coating layer combination was laminated on one surface of a 25 micron thick unsuccessful polypropylene film (sold as Celgard 2400) saturated with mineral oil and the back layer-benzeneamine storage layer The combination is laminated to the opposite surface of the membrane. In the resulting 5-layered laminate, a discoidal skin adhesive with an area of 1.1 cm 2 was punched out.

The inbitum test of this pressure-sensitive adhesive shows that the initial application amount of 60 mcg of benzeneamine (first average of 2 hours) and then basically a fixed amount of 3 mcg / hour (average of 168 hours) are released. The basic equivalent emission obtained by the in-demand test.

Claims (1)

As described above, a clonidine storage layer containing a sufficient amount of clonidine necessary for central alpha adrenergic stimulation for a long time in the vicinity of the back layer not permeating clonidine is formed and the clonidine storage layer in the opposite vicinity of the storage layer. After forming a microporous membrane layer capable of releasing clonidine at a predetermined rate from a predetermined portion of the skin from the skin and forming a pressure-sensitive adhesive layer to adhesively fix the attachment treatment to the predetermined area of the skin adjacent to the microporous membrane layer Clonidine skin adhesives, characterized in that during the control of the central alpha-adrenaline stimulation during the continuous administration of clonidine to a predetermined area of the skin.

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