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

The present invention relates to a process for the preparation of a therapeutic system for transdermal administration of clonidine. Clonidine, like its derivatives and compounds,⁵it has hypo-tensile properties (Patent, US, no. 3454701) and can be formulated for the treatment of hypertension, oral, parenteral (injectable) or rectal. I in the Patent, US, no. 3202660 indicates that clonidiiine may be used to deflate the mucous membranes, for which purpose, clonidine is mixed with inert carrier substances, which allows its topical application to the mucosa, for example in the nasal inter-nasal cavity.

According to the US Patent, no. 3190802 clonidine can be used in shaving means 20, as a pilomotric agent, applied on the obratz in the form of aqueous solution, soap or shaving cream.

As it results from the US Patent, no. 3666861, clonidine is also suitable for treating migraine, as well as transdermal pen75336 and clonidine for the treatment of glaucoma, the latter being applied, described by E. Edelhauser, V. Remetz in Klin. MBI. Augenheiikunde 160, 1972, 188 and by R.

Jahnke and HW Thumm, Klin. MBL. Augenheilkunde, 161, 1972/73.

It is known the possibility of administering some drugs, through strips, bandages or patches, with which the active substances are introduced into the transducer.¹shore in the bloodstream. Such discs are known to contain hormonal preparations that function as hormonal endocrine microgrids, which are applied epitegumentarily and fixed by means of a bandage (Patent, RSR, no. 54007); or strips provided with .sticks to detect or treat certain diseases (Patent, France, No. 1151111). ·.

It is known a three-layer system or a bandage for the administration of vasodilators, consisting of a support layer, a storage layer, which regulates the yield rate. of the active substance, containing the vasodilator and an adhesive layer that

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7533 © which the bandage attaches to the skin. A similar known bandage, which serves for transdermal administration of systemic active substances, consists of a support layer, a storage layer of the active substance, a microporous membrane that regulates the rate of yield of the active substance, and an adhesive layer. contact.

Clonidine (2,6-dichloro - Ν-2-imidazolydinylidene-benzamine) of the formula:

<td rowspan="3">H cn, I _{/ N}- o &lt; | ^XN - Cl | H</td><td>-CHK</td>

<td> 1</td>

<td>c «j₂</td>

as its derivatives and compounds, it has hypotensive properties (Patent, US, no. 3454701) and can be formulated to treat high blood pressure, oral, parenteral (injectable) or rectal.

The possibility of transdermal administration of a drug to obtain the therapeutic effect under certain conditions depends on many factors. inter alia, on longer contact, the active substance should not harm the skin (ie the skin structure is not adversely affected and does not cause irritation, allergy or sensitization). Also, the active substance should not be too immobilized by the skin, it must be able to penetrate princes, a relatively small derailleur surface, with a therapeutically effective speed.

The present invention extends the range of possibilities of clonedin administration. carrying out a process for the preparation of a pharmaceutical form by means of which clonidine; i2,6-dichloro-N-2-imidazolidinylidene benzamine continuously diffuses into the blood, transdermally, the process consisting of homogenization of an amount of 1 ... 6 mg gasoline with a geltfiat mixture consisting of 35 ... 45¼ by weight mineral oil, with a viscosity of 10,. i00 cP 1 at 25 ° C and from

65¾ by weight poltizobutene and from this mixture, by pouring, the storage layer for benzamide is obtained, which is applied to one of the faces of a microporous membrane, with a permeability of 0.1 to 0.85 with a curvature of 1 ... 10 cm and with a thickness of 10 "³ to IO^-2 cm, obtained from polypropylene, polyfefrafrafluoroethylene, polycarbonates, polyvinyl chloride, cellulose acetate, cellulose nitrate or polyacrylonitrile, on the other side of the membrane4 a contact adhesive layer consisting of a mixture of 0.9% is applied consisting of 0.9% weight of benzamine, 75% heptane, hexane or cyclohexane, 11.7% by weight polyisobutene which is poured onto a polyethylene film with polyethylene backing and covered with a contact adhesive layer with a removable coating, these layers are packed together with a backing layer and the material thus obtained is stamped or sealed. cut dermal patches into the desired shape and size.

The following is an example of embodiment of the invention in relation to the figure, which represents a cross-section through the pharmaceutical product-last patch.

A suspension of 2.9% by weight 2,6-dichloro-N-imidazolidenbenzamine, 10.4% by weight mineral oil (10 cP at 25 ° C) and 75% by weight heptane is prepared. The obtained suspension is homogenized for 10 minutes in a homogenizer with a speed of 5000 up to 10,000 rpm. The homogenized suspension is added under slow stirring 5.2% by weight of high molecular weight polyisobutylene, that is to say with an average molecular weight of 1200000, viscozimeir determined and 6.5% by weight polyisobutene, with a low molecular weight of 35000, determined by the viscozymmetric up to 35000 of benzamide are suspended and the polyisobuienes dissolve. The obtained mixture was ground over a 100 μ thick support film consisting of an aluminum foil coated with a polyethylene terephthalate layer which was allowed to air overnight and then dried for 15 min at 60 ° C. - an oven, retaining a layer of benzamide storage with a thickness of about 50 n.

Similarly, a combination consisting of. the adhesive contact layer and the coating layer, pouring a mixture of 0.9% by weight benzamime, 11.4% by weight mineral oil, 75% by weight heptane, 5.7% above-mentioned polyzobutene with high molecular weight and 7% by weight of the abovementioned polyisobutene, with low molecular weight. The mixture thus obtained is poured onto a sheet of polyethylene-terefitalized 25 μm thick, having polyethylene as a support and being covered with a layer of silicone and aluminum. The resulting combination has a thickness of about 175 p.

Then from the combination described above, consisting of the contact adhesive layer and the detachable coating layer, a layer is applied on one side of a polypropylene microporous membrane,

S

As the thickness of 25 µ-, previously saturated with the above-mentioned mineral oil, and on the opposite side of the membrane, the combination prepared above formed from the support layer and from the storage layer of benzamine. From the material thus resulting consisting of five layers, dermal patches, of the desired shape and of the desired size, usually, the rounds with a size of 1.1 cm are stamped.², which applied to the skin gives clonidine in a basic starting dose and then at a essentially constant rate. The patch consists of five layers. The top layer 1 is a support layer, in. waterproof essence for donidine, having an outer surface-2, which forms the surface of the patch. The backing layer ί serves as a coating, preventing the evaporation of the volatile components of the patch, also having the function of backing layer. This support layer 1 'is made of a polymer film and a sheet of metal,' such as aluminum foil. Poiimcrii that can be used for: this layer are :: high polyethylene, and low presifflie; polypropylene, polyvinyl chloride and polyethylene terephthalate.

Underneath: the layer I don't know adjacent to it, there is the storage layer 2 for clisnidine. Layer · 2 contains about 1 up to. at 6 mg. elonidine, the undissolved part of this ·, being in the form of particles. During the program of administration of its constant part clonidine, contained in layer 2. is given to the bloodstream. The pactics are brought into dispersion, homogeneous; in a mixture consisting of an inert, non-volatile, organic liquid, such as mine oil. with a viscosity of 10 to 100 'cP at 25 ° C and in a mixture of: polyiso · butene. The inert liquid represents the mixture; usually between 35 and 65 parts in: weight- and as a result polyisobutene also represents between 35 and 65% by weight. The mixture of polyisobutene consists of polyols obtained with low molecular weight. (average molecular weight 35000 .., 500 () 0 ,. determined from vifosymmetric) · and from a polyizo: butene, with high molecular weight (weight: molecular; average: 1000000 .... 1500000 # determined: also viscozimetricjc.

mixtures¹ favorites: contain .. 35 'to »· Yer: 65% oil: mineral, 10 · to 40%. can be bottled with low molecular weight · and 10 up to: 40% high molecular weight polyisobutene. These mixtures: oil / ppliizobutene · are. excellent adhesives and serve for cohesion: the patch. If these mixtures do not: ar. in adhesives, good, would. could use other means for cohesion of the patch, for example hot laminnrcrr.

The inert liquid (mineral oil) in strip 2 has the function of a vehicle for c'lonfdin. As an inert liquid, preferably uh liquid hh is used, which clonidine has only limited solubility (for example, the solubility-clonidine in mineral oil is read 0.5 mg / ml). The relative amounts of the two components in layer 2 must be so chosen that the inert liquid is saturated with clonidine, so that the clonidine stored in this layer is essentially sufficient for the entire lifetime of the patch.

The next layer of the patch is a microporous membrane 3, the pores of which are clogged with the inert liquid described above. Membrane 3 is the patch element, which regulates the rate at which clonidine is transferred from layer 2. The flow of clonidine - through membrane 3 and in the area of ​​this membrane must be so regulated that clonidine di. in storage layer 2 is transferred to the skin, after its dermal application with a constant velocity of 0.1 to 100 mg / h. The flow follows Ridi's law, according to which the flux is a function of the curvature, permeability and thickness of the membrane, the concentration gradients of the first membrane clonidine and the diffusion coefficient of the clonidine in the inert liquid present in the part. The diffusion coefficient depends on the viscosity of the inert liquid and decreases with increasing its viscosity. Naturally, the three features of the membrane are for each membrane constant. It is possible to use membranes with a permeabilification of about 0.1 to 0.85, with a curvature between 1 and 10 and with IO thickness^-³to IO ² cm. The membrane can be made of polymers, such as polypropylene, polytetrafluoroethylene, polycarbonates, polyvinyl chloride, acetate. of cellulose, nitrogen of. cellulose and polyacrynitrile.

Under the membrane. 3 and adjacent to it, there is the adhesive layer of contact 4. This layer 4 contains 10 up to 300) &lt;g donidine 'per cm² active surface. The undissolved clonidine moiety is particles. Clonidine from layer 4^! it is given as a dose of e^J the base; hh this layer, the cididine is brought hh. dispersion in the same inert and liquid mixture of polybutylene, as used in. layer 2. Layer 4 is miijlo'cul 'with which the patches are applied to the skin. From this point of view; the mixture of inert liquid and polyisobutene adheres less to the skin than to other layers of the patch, which is why the patch tends to remain in the rear, when it is detached from the skin.

Prior to use, the patch also comprises a removable protective layer 5, which covers layer 4. Immediately prior to use, layer 5 is detached from layer 4 and discarded. The layer 5 can be made of an inert material with respect to clonidine and non-penetrable for liquids, for example^;n polymers, from which the support layer is prepared. provided that these materials are removable, which is not achieved for example by silicone.

The patch can be prepared as follows. The mixture for the S layer is prepared by homogeneous mixing of the clonidine with the inert liquid and with a liquid in which the clonidine is not soluble, but is a solvent for polyisobufen. Solvents of low specific weight, containing hydrocarbons, such as heptane, hexane and cyclohexane may be used. Work with high mixing speed, to be sure that the layer will obtain a suitable granulation for clonidine. The granulation influences the dissolution rate of clonidine in the other components of the layer, as well as the adhesive properties of it. Granulations between 5 and 20 μ (average diameter) are acceptable. The polyisobutene mixture is then added to the homogeneous mixture in the high and reduced molecular weight, using for this purpose a device with a low shear effect, for example a magnetic stirrer or a rotary disc, until the clonidine particles are suspended and the polyisobutins dissolve. . The relative amounts of clonidine, inert liquid and polyisobutene in this mixture are mentioned above. The mixture for obtaining the adhesive layer of contact 4 is prepared in the same way as the mixture for layer 2, adapting the relative quantities of the components accordingly. The average diameter of clonidine particles can be determined by measuring their specific surface area, according to the empirical equation:

<img file="RO75336A_D0001.tif" />

where d represents the average diameter, p represents the density of clonidine and A represents its specific surface, (S. Brunner, P. Emmeit, E. Teller, J. Am. Chem. Soc. 60, 309 (1938); S. Gregg, The Surîace Chemystry of Soîids, 2nd ed., 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, Butterwo.rd and Co. Ltd., London (1962); C.

β

Ora and JM Dalia Valla, Fine Partide Measurements, Macmillan, NY (1959).

Then the mixture prepared for the storage layer 2 is poured onto one of the surfaces of the support layer 1 and allowed to dry to form the layer 2. Similarly, it is poured onto one of the surfaces of the removable protective layer 5, the mixture prepared for the contact adhesive layer and allow to dry to form the layer. Then, the storage layer / the protective layer of the assembly is applied as a layer on one of the surfaces of the microporous membrane 5 (saturated with the inert liquid) and the adhesive layer of the counter / removable protective layer the assembly is applied as a layer on the other side of the membrane. The layer formation, thus obtained, is usually produced in the form of mani tapes, from which the patches are sectioned or stamped to the desired shape and size.

In connection with the application of the skin patch, the term "active surface" means the surface of the patch in contact with the skin, and by which clonidine is transferred to the skin. In the context that describes the constant dosing rate and the rate at which clonidine is dispensed, from the storage layer, the expression "essentially means that the rate may vary by + 30%. Such variations may be conditioned by the process of preparation, temperature variations, improper application of the patch on the skin and other similar causes. The expression "essentially used in relation to the amount of clonidine present optionally in the adhesive layer of contact means that this layer contains at least 50%, preferably 75% of the total amount of clonidine. The expression "a longer time Inngat usually refers to a duration of time between 0.5 and 14 days.

The therapeutic system, according to the invention, introduces clonidine into the bloodstream, tranderma, causing aifo-adrenergic stimulation here, with no intolerable side effects, such as intensive drying in the mouth, mouthfeel or tiredness, The lack of side effects is due to the fact that clonidine is introduced into blood with a essentially constant velocity, which stimulates an olfactory-adrenergic action, optionally preceded by a basic initial dose. NJia-adrenergic stimulation may be central and / or peripheral. Stimulation causes a preventive and / or curative treatment, of mucosal inflammation or of menopause disorders. For the treatment of high blood pressure or migraine, stimulation is mainly central.

Through the therapeutic system, according to the invention, a dose of baq is administered

2, in cases where it is necessary or desirable, such as the time required to bring the concentration of clonidine to the value required for, the triggering of adri-adrenergic stimulation to be shortened. This effect is obtained with the basic dose in part by that, that in the place of application the skin "saturates with clonidine: In this case the skin acts at the beginning as a "capture vessel and less as a" conduit, the main amount of clonidine initially administered being immobilized in the skin, without penetrating the bloodstream. but once the skin is "saturated, so that the immobilization sites are occupied, another amount of clonidine enters the skin, being received by the capillary and then by the bloodstream. As a result, the amount of clonidine administered in the base dose is σ as a function of the treated dermal surface. A base dose of 10 up to 300 μρ / cm² The treated skin is usually sufficient to achieve a therapeutic level of clonidine in the blood within 12 to 36 h. In most cases the base dose is between 150 and 250 tg / cm²Tartar skin, however, the basic dose can also be expressed in the form of the average yield rate per unit area, over which the first two hours of administration were performed. Expressed in this form, the base dose represents 75 to 125 µg / h / cm² clonidine.

If the therapeutic program extends beyond the time of using a single patch, in this case for further treatment, other skin patches should be applied. Sometimes it is desirable that the following patches contain the same basic dose as the first or lower patch, or do not contain a base dose at all.

When using a base dose in the following patches, care must be taken that the clonidine concentration in the blood is maintained at a therapeutic level, without a significant deviation from this baseline. So, if a base dose is used for this next patch, this dose should be between 10 and 300 mg / cm² treated skin.

It is assumed that the concentration of clonidine in blood, capable of triggering alpha-adrenergic stimulation, varies between 0.1 and 15 Rg / sral, normally between 0.3 and 3 ng / ml, depending on the person being treated. The purpose of transdermal use of clonidine at a essentially constant rate is to supplement an eventual baseline dose by yielding a sufficient amount of clonidine to achieve such a concentration in the skin and to maintain this concentration for as long as possible. . From this it follows that the use with constant speed should be continued as long as the therapy is requested. An essentially constant velocity, between about 0.1 and about 100 µg, generally between about 0.2 and 70 rg / h is usually sufficient to maintain the clonidine concentration in the blood at the therapeutic level mentioned above. .

The place on the skin, where the therapeutic system according to the invention is applied, is an important element, because the structure of the tissues, the thickness and the blood irrigation of the skin, varies from individual to individual and also varies depending on the place of application on the skin. skin of the individual, the difference influencing the effectiveness with which clonidine is introduced traiisdermal into the blood, This distinction can be removed in two ways. The first way is to apply the system on the skin, in one place, namely in the nipple area, where clonidine penetration does not seem to vary much from individual to individual and therefore the amount of clonidine given in blood or the rate at which it is not given it is essentially different from different individuals. The second way is the removal of the layer of horny substance, representing an element that influences the timing or rate of yield, by treating the place of application with an agent that stimulates the penetration of chloride through the skin. This treatment allows the system to be applied to other parts of the body in the nipple to be applied in the area of ​​the nipples, ie on the arms, legs or trunk, depending on the agent used, the treatment can be applied before or concomitantly with the use of clonidine from system. The amount of the agent also depends on the agent used. This agent performs two functions, on the one hand it increases the penetration of clonidine into the skin and on the other hand it decreases the tendency of horny substances to bind or fix clonidine.

Examples of known agents that can be used include dodecylpyrrolidone, diionethyl gold amide and dimethylsulfoxide. All these three agents can be used for pre-treatment. Pyrolidone and lauramide are applied on the site to be treated in an amount of 4 to 8 mg / cm² for about an hour, after which they are removed by washing t> upa as shown, the patch is applied to the nipple area, administering clonidine, according to progra75330

The dosage volume without the need for preliminary or concomitant treatment of the respective area with an agent that stimulates clonidine penetration through the skin. If, however, as mentioned above, the patch is applied to a different location of the body, the respective place must be treated with one or more skin penetrating agents, from the ones mentioned above. If simultaneous treatment is desired, then agent 10 may be incorporated into the patch. In this case, layers 3 and 4 may contain an effective amount of such an agent.

It should be noted that clonidine does not irritate the skin and that it exerts a microbial action. ₁₅local cid. In addition, an additional biocidal agent should not be used for the preparation of the patch to prevent the development of - some organisms in place - the patch is glued to the skin.₂₀

The size of the patch is not decisive. Generally, a patch is applied with a size that transfers clonidine from the patch on a dermal surface of 0.5 to 1.0 cm². in this context,₂₅the active patch dust will also represent 0.5 to 10 cm².

In vitro tests have shown that the patch, according to the invention, releases a basic starting dose. of 60> 'g petrol (the average value of the first³⁰two hours), followed by an essentially constant dose of 3, i * g / h (average of 168 h). In vivo tests showed yield rates essentially similar to those observed in, vi tr,³⁵

The invention has the advantage. that it provides a process for the preparation of a therapeutic system in the form of patches with the jug whose active substance continuously diffuses into the blood with a⁴⁰constant speed, maintaining focus. tion. of the active substance in the blood for a long time at the same therapeutic level '.