CH624848A5 - Therapeutic system for the administration of transdermally absorbable medicaments - Google Patents

Description

The invention relates to a therapeutic system in the form of a plaster-like overlay, which transdermally delivers drugs, especially skopolamine base, initially in an initial burst of 10 to 200 jug / cm 2 of skin and thereby quickly brings the concentration of drugs in the plasma to a value in which it prevents nausea and vomiting without any unpleasant side effects and then releases it in an amount of 0.3 to 10 "g / h, so that the active substance content in the plasma is maintained. The overlay is a four-layer laminate consisting of the following layers when viewed from above: a protective back; a gel-like mineral oil-polyisobutene drug reservoir that is the source of constant dosing; a microporous membrane that controls the constant rate of release, and a gel-like mineral oil-polyisobutene drug chewing layer that serves as the source of the initial shock dose and attaches the pad to the skin.

There are some patents on bandages or pads for the administration of systemic drugs through the skin. Fig. 2 of U.S. Patent 3,797,494 shows an overlay in the form of a laminate.

Skopolamine and related compounds are known to work against nausea and vomiting. These properties have been investigated by intramuscular and oral administration of skopolamine and related compounds. 1

Skopolamic acid salts and the C4-C12 esters of skopolamine have been used topically as antiperspirants. 2

The C4-C12 scopolamine esters are reported to be more effective antiperspirants than skopolamine itself because of its higher penetration ability. These esters are described in U.S. Patent 3,767,786. They have been studied as antiperspirants by applying them in the form of solutions or creams at a dose of 2 mg on the forearm and armpit. A slight systemic response was observed. Such responses were associated with systemic responses that were obtained when the esters were administered subcutaneously, and it was estimated that only 5-10% of the esters applied to the skin were absorbed.

According to the patent cited above, mineral oil is used as a carrier for the antiperspirants which contain the esters, provided that there is also sufficient water-miscible carrier to give a medium which is absorbed by the skin.

Various surfactants have been reported to improve absorption of the scopolamine esters.

The invention relates to a therapeutic system in the form of a plaster-like pad for the administration of a drug through the undamaged skin to prevent vomiting and nausea, consisting of a laminate of a support layer which is essentially impermeable to the drug and one side of which is the top of the Pad forms; a drug reservoir layer adjacent to the other side of the pad; a microporous membrane adjacent to the underside of the drug reservoir layer and through which the drug is released from the reservoir layer after the pad has been applied to the skin; and a contact adhesive layer attached to

1 C.D. Wood and A. Graybiel, "Theory of Antimotion Sickness Drug Mechanisms". Aerosp. Med. 43: 249-52, 1972; and C.D. Wood and A. Graybiel, "A Theory of Motion Sickness Based on Pharmacological Reactions", Clin. Pharm. 11: 621-9, 1970; J.J. Brand and P. Whittingham, “Intramuscular Hyoscine in Control of Motion Sickness”. Lancet 2: 232-4. 1970.

2 F.S.K. MacMillan, H.H. Relier and F.H. Snyder, "The Antiperspirant Action of Topically Applied Anticholinergics". J. Invest. Derm. 43: 363-7, 1974.

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the microporous membrane layer is adjacent and through which the pad is attached to the skin, and optionally a peelable coating layer which is substantially impervious to the constituents of the adhesive layer and which can be peeled off before the pad is applied to the skin, which is characterized in that that the reservoir layer consists of 0.2 to 3 mg of drug, dispersed in a gel-like mixture of mineral oil with a viscosity of 10 to 100 cP at 25 ° C and polyisobutene, the curvature, porosity and thickness of the membrane, the concentration gradient of the drug over the membrane and the diffusion coefficient of the drug in the mineral oil are chosen so that the drug is released through the membrane at a substantially constant rate in an amount of 0.3 to 10 ug / h and the contact layer 10-200 fi g Contains drug per cm2 effective surface area in the same gel mixture.

The invention also relates to a method for producing the therapeutic system described above, which is characterized in that the medicament reservoir layer is poured onto the support layer, the contact adhesive layer is poured onto the removable protective layer, the microporous membrane is brought between the two cast layers and the two layers are laminated with the microporous membrane in between.

The term "effective surface area" as used herein means the surface area of the pad that is in contact with the skin and through which the drug is administered to the skin. In connection with the constant rate of administration and the rate at which the drug is released from the reservoir layer, the term "essentially" means that the rate can vary by ± 20%. Such variation may be related to the manufacturing process, or may be caused by a change in temperature, inadequate attachment of the pad to the skin, and the like.

The invention is described using skopolamine as an example of a medicament.

The therapeutic system releases the skopolamine through the skin to the body and effectively prevents vomiting and nausea without causing unacceptable parasympathological side effects. This is done by delivering the skopolamine base to the plasma in a controlled manner according to a precise dosing program consisting of an initial burst administration and then administration at substantially the same constant rate until the desired total amount of skopolamine is administered.

Vomiting and nausea can be caused by pregnancy, vestibular disorders (e.g. those caused by exercise, seasickness), radiation treatment, drug treatment or treatment with anesthetics. Such symptoms can be prevented by using the condition according to the invention.

The reason for the initial intermittent administration is to shorten the time required to bring the skopolamine concentration in the blood to the level required for the preventive treatment. As a result, the skin is partially “saturated” with Skopomain. In this case, the skin initially acts as a “sponge” rather than as a “conduit”, with the majority of the scopolamine being bound in the skin and not penetrating through it and being fed into the circulation. However, if the skin is "saturated", i.e. that the binding positions are occupied, it becomes possible that further skopolamine enters the circulatory system. Thus, the amount of scopolamine administered in the first burst is a function of the area of skin treated. A

A burst of 10-200 µg of skopolamine per cm2 of treated skin generally results in the therapeutic amount in the plasma being reached within about 3 hours. A corresponding safety margin in time is therefore achieved if administration is started at least three hours before the symptoms are expected. In most cases, the shock is in the range of 100-175 / xg skopolamine per cm2 of treated skin. The concentration of skopolamine in the plasma can be associated with the concentration of free skopolamine in the urine if the glomerular filtration rate of the subject is known, and it is convenient to then measure the amount of skopolamine in the plasma in terms of urinary excretion rate specify. It is found that an average urinary excretion rate of approximately 0.3 jug of free skopolamine per hour generally corresponds to a therapeutic level in the plasma. However, it has also been shown that this speed is subject to an approximately ± 5-fold biological variation. Therefore, the rate is in the range of about 0.05 to about 1.5 wg / h depending on the individual.

The reason for the subsequent, essentially constant, delivery rate in the dosing program is, if necessary, to support the drug surge by administering sufficient skopolamine to achieve the therapeutic amount indicated in the plasma and to maintain this level as long as possible. It follows that administration at a constant rate should continue as long as therapy requires. In this connection, a total amount (including the push) of 0.1-2.5 mg of skopolamine administered according to the dose regimen given above gives a therapeutic effect for approximately 3 hours to 7 days. It also follows that the constant rate of administration can vary depending on the patient's body weight (plasma volume). In this regard, the speed in most cases is in the range of 3-4 pg / h for adults and 1-2 / ig / h for children.

The location of the skin to which the therapeutic system is applied is important because the histology, thickness, and vascularity of the skin vary from individual to individual, as well as from body location to body location in a particular individual, and such variation affects the effectiveness with which the skopolamine is released into the plasma. It has been shown that the influence of this variation can be eliminated in two ways. One possibility is to apply the system in a place, namely the mastoidal area, where the penetration of the scopolamine does not vary greatly from one individual to another and thus the amount of skopolamine released into the plasma or the rate at which it is released, not very different in individual individuals. The second possibility is to switch off the corneal layer as a quantity-determining or speed-determining layer by treating the skin at the point of administration with an agent which facilitates skin penetration. Such treatment allows the system to be applied to areas of the body other than the mastoid area, such as the arms. Jieine or the hull. Depending on the type of agent used, the treatment can be carried out before or simultaneously with the administration of skopolamine base from the system. Similarly, the amount of agent needed depends on the particular agent used. In any case, the agent has a double role in reducing the permeability of the corneal layer to bind scopolamine. Examples of known agents that can be used for this purpose are dodecylpyrrolidone, dimethyllaurylamide

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and dimethyl sulfoxide. These three agents can be used for pretreatment. The pyrrolidone and laurylamide can be applied to the administration site in amounts of 4-8 mg / cm2 for approximately one hour and then washed off. They can also be added to the system and administered simultaneously with the skopolamine in approximately the same dose as skopolamine. The sulfoxide is preferably used only for pretreatment, in doses in the range of 5-100 mg / cm2 for about an hour, and then washed off.

The drawing shows an enlarged schematic cross section of a preferred embodiment of the overlay according to the invention. The drawing shows an overlay (generally designated 10) which, when applied to the skin, releases scopolamine base in accordance with the specified dosage program. The pad 10 is a five-layer laminate. The top layer 11 is the backing or top layer which is substantially impermeable to the scopolamine base. The side 12 of this layer 11 forms the surface of the overlay. The cover layer 11 serves as a protective layer and prevents volatile compounds from escaping from the support and has a supporting function. The cover layer 11 itself is preferably a laminate of polymer foils and a metal foil such as an aluminum foil. Polymers that can be used for this layer are high and low density polyethylene, polypropylene, polyvinyl chloride and polyethylene terephthalate.

Adjacent to this layer 11 is a Skopola min reservoir layer 13. The layer 13 contains 0.2 to 3 mg of Skopolamine base, the undissolved part of which is shown as a droplet 14. The skopolamine base contained in layer 13 is released to the plasma during the constant administration of the dosing program. The droplets 14 are homogeneously dispersed in the gel-like mixture of mineral oil with a viscosity of 10 to 100 cP at 25 ° C. and a polyisobutene. The oil usually makes up 35 to 65% by weight of the mixture and the polyisobutene corresponds to 35 to 65% by weight. The polyisobutene mixture generally comprises a low molecular weight polyisobutene (average molecular weight determined by viscosity measurement 35,000 to 50,000) and a high molecular weight polyisobutene (average molecular weight by viscosity measurement 1,000,000 to 1,500,000). Preferred mixtures contain 35 to 65% by weight of mineral oil, 10 to 40% by weight of low molecular weight polyisobutene and 20 to 40% of high molecular weight polyisobutene. These oil-poly-isobutene mixtures are excellent adhesives and are used to hold the overlay together. If they were not a good adhesive, other tools, such as heat sealing, would have to be used to hold the pad together.

The mineral oil in layer 13 serves as a carrier for the skopolamine base. Skopolamine base has limited solubility in the mineral oil (approximately 2 mg / ml) and the relative amounts in layer 13 are selected so that the mineral oil is substantially saturated with the base throughout the life and delivery time of the pad.

The next layer in the overlay is a microporous membrane 15, the pores of which are normally filled with the mineral oil described above. Membrane 15 is the part of the pad that controls the rate at which the base is released from layer 13. The flow of skopolamine through the membrane 15 and the area of the membrane 15 must be selected so that the skopolamine is released from the reservoir layer 14 to the skin at a substantially constant rate in the range from 0.3 to 10 / <g / h after the overlay has been applied to the application area. The flow follows Ficks's law. It is a function of the bend, porosity and thickness of the membrane, the concentration gradient of the skopolamine base across the membrane and the diffusion coefficient of skopolamine base in the mineral oil. The concentration gradient depends on the scopolamine concentrations 5 in the mineral oil on the opposite sides of the membrane. The diffusion coefficient depends on the viscosity of the mineral oil and decreases with increasing viscosity. The three properties of the membrane are of course constant for any given membrane. Membranes with porosities from 0.1 10 to 0.85, bends from 1 to 10 and thicknesses from 10 "3 to 10" 2 cm can be used. The membrane can be made of polymers such as polypropylene, polycarbonates, polyvinyl chloride, cellulose acetate, cellulose nitrate and polyacrylonitrile.

15 Below the membrane 15 there is an adhesive layer 16 adjacent to it. Layer 16 contains 10 to 200 [.ig. Skopolamine base per cm 2 effective surface. The undissolved part of the skopolamine is indicated as droplet 17. The skopolamine base of layer 16 represents the shock absorption when using the overlay according to the invention. The skopolamine is dispersed in the same mineral oil-polyisobutene mixture as is used in layer 13. With the help of layer 16, the pad is attached to the skin. The mineral oil-polyisobutene mixture 25 adheres less firmly to the skin than to the other layers of the overlay and therefore the overlay remains intact when it is removed from the skin.

Before use, the pad generally also includes a removable protective layer 18 that covers layer 16. Immediately prior to use, layer 18 is stripped from layer 16 and discarded. It can consist of materials which are impermeable to skopolamine mineral oil, such as those polymers from which the cover layer 11 has been produced, provided that these substances, e.g. have been made strippable by silicone treatment.

The pad 10 can either be applied to the mastoid area and releases skopolamine according to the dose program described above, without prior or simultaneous treatment of the area with an agent that improves the penetrability of the skin. As stated above, the area of the skin to which the overlay is applied, if it is other than the mastoid area, should be previously treated with one or more of the 45 skin penetration enhancing agents described above. If a simultaneous treatment is to take place, the agent can be built into the pad 10. In this case, layers 13 and 16 contain effective amounts of such agents.

So the size of the edition is not critical. It is generally of such a size that the skopolamine is applied to a skin area of the order of magnitude of 0.5 to 4 cm 2. Accordingly, the effective surface of the overlay is generally also in the range from 0.5 to 55 4 cm 2.

The invention is illustrated by the following examples. Parts, unless otherwise stated, are always parts by weight.

60 Example 1

A solution of 29.2 parts of high molecular weight polyisobutene (Vistanex MML-100, average molecular weight determined by viscosity measurement 1,200,000), 36.5 parts of low molecular weight polyisobutene (Vistanex LM-MS, average molecular weight determined by viscosity measurement 65,000 35,000), 58 , 4 parts of mineral oil (10 cP at 25 ° C), 15.7 parts of skopolamine base and 860.2 parts of chloroform is applied to an approximately 65 μm thick cover layer made of an aluminum polyethylene

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poured onto the rephthalate laminate (MEDPAR), creating a sco-polamin base reservoir layer approximately 50 μm thick. A combination of adhesive layer and peelable layer is similarly made by placing a solution of 31.8 parts of the high molecular weight polyisobutene, 39.8 parts of the low molecular weight polyisobutene on a 200 mm thick silicon-treated aluminum-poly-5-ethylene-polyethylene terephthalate film , 63.6 parts of the mineral oil, 4.6 parts of the skopolamine base and 860.2 parts of chloroform is poured on. The resulting contact adhesive layer io is approximately 50 [im. thick.

The combination of top layer and reservoir layer prepared as described above is then applied to one side of a 25 [in thick microporous polypropylene membrane (Cel-gard 2400) saturated with mineral oil, and the layer of adhesive and removable protective layer described above is applied to the other side Membrane applied. A cm2 large, round, disc-shaped pieces are punched out of the resulting 5-layer laminate. Each of these pads initially releases 130 to 150 / <g / cm2 of skopolamine and then 20 to 3 to 3.5 [ig per cm • hour at an essentially constant speed.

Example 2

A solution of 22.3 parts of high molecular weight polyisobutene, as in Example 1.28 parts of low molecular weight polyisobutene, as in Example 1.44.9 parts of mineral oil (66 cP at 25 ° C.), 12.8 parts of Skopolamine base, 8. 8 parts of dimethyllaurylamide and 883.2 parts of chloroform were poured onto the top layer described in Example 1, a Skopo-30 laminbase reservoir layer having a thickness of approximately 50 μm being formed. A combination of adhesive layer and peelable protective layer was similarly prepared by pouring on a solution of 23.5 parts of high molecular weight isobutene, 29.5 parts of low molecular weight isobutene, 47.6 parts of mineral oil, 7.8 parts of scopolamine base, 9.0 parts of dimethyl laurylamide and 882.6 parts of chloroform on the silicone-treated polyethylene terephthalate film described in Example 1. The resulting contact layer was approximately 50 µm thick.

The top layer-reservoir combination described above was then applied to one side of a 25 µm thick microporous polypropylene membrane (Celgard 2400) saturated with the mineral oil and the adhesive-protective layer combination described above to the other side of the membrane. 4 cm2 round, disc-shaped pieces were punched out of the resulting 5-layer laminate. Each pad is designed to release 125 [ig / cm2 of skopolamine at the beginning and then at an essentially constant speed of 2 / ug / cm2 ■ hour.

The conditions of Example 2 were examined as follows in double blind tests. Seventeen people had a pad placed behind their ears before being exposed to the movement at sea. Placebo requirements (no skopolamine) were also applied to 18 people. All people were known to experience nausea (motion sickness) caused by exercise. Only one of the 17 people who received the example 2 condition experienced nausea that made additional medication necessary while at sea. In contrast, nine of those who received placebos received additional medication while at sea.

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Claims (10)

624 848 1, characterized in that the mixture forming the medicament reservoir is poured onto the cover layer, the mixture forming the adhesive layer is poured onto the removable protective layer, the microporous membrane is placed between the two poured layers and laminated therewith. 1,500,000. 1. Patch-like pad in the form of a laminate for transdermal administration of a transdermally absorbable drug, consisting of a cover layer (11) which is practically impermeable to the drug and one side of which forms the top (12) of the pad, one on the other side of the Cover layer adjoining drug reservoir layer (13), a microporous membrane (15) adjoining the drug reservoir layer, through which the drug is released from the reservoir layer, and a contact adhesive layer adjoining the microporous membrane (16 ), with which the pad is attached to the skin, characterized in that the reservoir layer (13) contains 0.2 to 3 mg of medicament in a gel-like mixture consisting of mineral oil with a viscosity of 10 to 100 cP at 25 ° C and Contains dispersed polyisobutene, the bend, porosity and thickness of the membrane (15), the concentration gradient of the drug over the membrane ran (15) and the diffusion coefficient of the drug in the mineral oil are such that the drug through the membrane (15) at a substantially constant rate of 0.3 to 10 / * g / h is released, and the contact adhesive layer (16) contains 10 to 200 jug of drug per cm 2 of active surface dispersed in the same gel mixture. 2. Pad according to claim 1, characterized in that it also comprises a removable protective layer which is practically impermeable to the components of the contact adhesive layer and can be removed before the pad is attached to the skin. 2nd PATENT CLAIMS 3. Edition according to claim 1 or 2, characterized in that the mineral oil 35 to 65 wt .-% and the polyisobutene make up 35 to 65 wt .-% of the gel mixture. 4. Edition according to claim 1 or 3, characterized in that the polyisobutene is a mixture of a polyisobutene with an average molecular weight determined by viscosity measurement of 35,000 to 50,000 and a second polyisobutene with an average molecular weight determined by viscosity measurement of 1,000,000 to 5. Edition according to claim 4, characterized in that the mineral oil 35 to 65 wt .-%, the low molecular weight polyisobutene 10 to 40 wt .-% and the high molecular weight polyisobutene make up 20 to 40 wt .-% of the gel mixture. 6. pad according to claim 3, characterized in that the microporous membrane has a porosity of 0.1 to 0.85, has a bend of 1 to 10 and a thickness of IO-3 to 10 ~ 2 cm. 7. Edition according to claim 3 or 6, characterized in that the microporous membrane consists of polypropylene. 8. Edition according to claim 3, characterized in that the cover layer consists of aluminum-treated polyethylene terephthalate. 9. A method for producing the pad according to claim 10. The method according to claim 9, characterized in that the mixture forming the drug reservoir and / or the mixture forming the adhesive layer is poured together with a volatile solvent onto the cover layer or onto the removable protective layer.