DE2604718C2 - Therapeutic device for administering scopolamine base and method for its preparation - Google Patents

Description

Scopolamine and related compounds are known to have anti-nausea and vomiting effects. Vomiting and nausea may be caused by pregnancy, vestibular disorders (e.g. those caused by exercise, seasickness), radiation treatment, drug treatment or treatment with anesthetics. These properties of scopolamine have been investigated by intramuscular and oral administration of scopolamine and related compounds (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).

Scopolamine acid salts and the C ₄ -C ₁₂ esters of scopolamine have been applied topically as antiperspirants (FSK MacMillan, HH Reller and FH Snyder, "The Antiperspirant Action of Topically Applied Antichollinergics", J. Invest. Derm. 43: 363-7, 1974).

The C ₄ -C ₁₂ scopolamine esters are reported to be more effective antiperspirants than scopolamine itself because they have a higher penetrating ability. These esters are described in US Patent 3,767,786. They were tested as antiperspirants by applying them in the form of solutions or creams at a dose of 2 mg to the forearm and axilla. Little systemic reaction was observed. Such reactions were associated with systemic reactions 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 above-cited patent, mineral oil is used as a carrier for the antiperspirants containing the esters, provided that sufficient water-miscible carrier is also present to provide a medium which is absorbed by the skin. Various surfactants are disclosed to enhance the absorption of the scopolamine esters. There are also some patents on bandages or patches for administering systemic drugs through the skin. Thus, in U.S. Pat. No. 3,797,494, in Figure 2 and the corresponding explanation in columns 7-8, a drug delivery patch is described which consists of a protective backing, a reservoir layer containing the active ingredient, a microporous membrane which controls the rate of release of the active ingredient, and a pressure-sensitive adhesive layer.

The object of the invention is to develop a therapeutic device in the form of a pad or a patch, with the help of which scopolamine can be administered to the organism via the skin over a longer period of time at a uniform rate.

This object is achieved by the device specified in the main claim. Advantageous embodiments of this device are specified in the subclaims. The invention also relates to the method characterized in claim 8.

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

The reason for the initial burst administration is to shorten the time required to bring the scopolamine concentration in the blood up to the level required for preventive treatment. This partially "saturates" the skin with scopolamine. In this case the skin initially acts as a "sponge" rather than a "conduit" with most of the scopolamine being bound in the skin rather than passing through it and into the circulation. However, once the skin is "saturated," that is, the binding sites are occupied, it becomes possible for further scopolamine to enter the circulatory system. Thus, the amount of scopolamine administered in the first burst is a function of the area of skin being treated. A burst of 10-200 µg scopolamine per ^cm2 of treated skin will generally result in the therapeutic amount in the plasma being reached within about 3 hours. Consequently, an adequate safety margin is achieved if administration is started at least three hours before the onset of symptoms. In most cases, the dose is in the range of 100-175 µg scopolamine per cm ² of treated skin. The concentration of scopolamine in the plasma can be related to the concentration of free scopolamine in the urine if the glomerular filtration rate of the subjects concerned is known, and it is convenient to then express the amount of scopolamine in the plasma in terms of the urinary excretion rate. It has been shown that a mean urinary excretion rate of about 0.3 µg free scopolamine per hour generally corresponds to a therapeutic plasma level. However, it has also been shown that this rate is subject to approximately ±5-fold biological variation. Therefore, the rate is in the range of 0.05 to 1.5 µg/h depending on the individual.

The reason for the subsequent, essentially constant delivery rate in the dosing program is to support the drug pulse, where necessary, by administering sufficient scopolamine to achieve the therapeutic level in plasma specified above and to maintain this level for as long as possible. It follows that the administration at a constant rate should continue as long as the therapy requires. In this context, a total amount (including the pulse) of 0.1-2.5 mg scopolamine administered according to the dosing program specified above will produce a therapeutic effect for 3 hours up to 7 days. It also follows that the constant administration rate may vary depending on the body weight (plasma volume) of the patient. In this respect, the rate is in most cases in the range of 3-4 µg/h for adults and 1-2 µg/h for children.

The rate of administration and the rate at which scopolamine is released from the reservoir layer may vary by ±20%. Such variation may be related to the manufacturing process or it may be caused by a change in temperature, inadequate attachment of the pad to the skin, and the like.

The site 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 and from site to site within a given individual, and such variation affects the effectiveness with which scopolamine is delivered to the plasma. It has been shown that the effect of this variation can be eliminated in two main ways. One is to apply the system to a site, namely the mastoid region, where penetration of scopolamine does not vary greatly from one individual to another and so the amount of scopolamine delivered to the plasma or the rate at which it is delivered does not differ greatly from individual to individual. The second is to eliminate the stratum corneum as a rate-limiting or rate-limiting layer by treating the skin at the site of administration with an agent which facilitates skin penetration. Such treatment allows the system to be applied to sites other than the mastoid region, such as the arms, legs, or trunk. Depending on the type of agent used, the treatment may be administered prior to or concurrently with the administration of scopolamine base from the system. Similarly, the amount of agent required will depend on the particular agent used. In either case, the agent plays the dual role of increasing the permeability of the corneal layer to scopolamine and decreasing the tendency of the corneal layer to bind scopolamine. Examples of known agents that may be used for this purpose are dodecylpyrrolidone, dimethyllaurylamide, and dimethylsulfoxide. These three agents may be used for pretreatment. The pyrrolidone and laurylamide may be applied to the site of administration in amounts of 4-8 mg/ ^cm2 for approximately one hour and then washed off. They may also be added to the system and administered concurrently with the scopolamine in approximately the same dose as scopolamine. The sulfoxide is preferably used only for pretreatment, in doses in the range of 5-100 mg/cm2 for approximately one hour, and then washed off.

The drawing is an enlarged schematic cross-section of a preferred embodiment of the dressing of the invention. The drawing shows a dressing (generally designated 10 ) which, when applied to the skin, releases scopolamine base according to the specified dosing schedule. The dressing 10 is a five-layer laminate. The upper layer 11 is the support or cover layer which is substantially impermeable to the scopolamine base. The side 12 of this layer 11 forms the surface of the dressing. The cover layer 11 serves as a protective layer and prevents volatile compounds from escaping from the dressing and provides a support function. Preferably, the cover layer 11 is itself a laminate of polymer films and a metal foil such as aluminum foil. Polymers which can be used for this layer are high and low density polyethylene, polypropylene, polyvinyl chloride and polyethylene terephthalate.

Below and adjacent to this layer 11 is a scopolamine reservoir layer 13. The layer 13 contains about 1 to about 6 mg of scopolamine base, the undissolved portion of which is shown as droplets 14. The scopolamine base contained in the layer 13 is released into 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 mPas at 25°C and a polyisobutene. The oil usually makes up 35 to 65% by weight of the mixture and the polyisobutene correspondingly 35 to 65% by weight. The polyisobutene blend comprises a low molecular weight polyisobutene (average molecular weight as determined by viscosity measurement 35,000 to 50,000) and a high molecular weight polyisobutene (average molecular weight as determined by viscosity measurement 1,000,000 to 1,500,000). Preferred blends contain 35 to 65% by weight mineral oil, 10 to 40% by weight low molecular weight polyisobutene and 20 to 40% high molecular weight polyisobutene. These oil-polyisobutene blends are excellent adhesives and serve to hold the overlay together. If they were not good adhesives, other means such as heat sealing would have to be used to hold the overlay together.

The mineral oil in layer 13 serves as a carrier for the scopolamine base. Scopolamine base has limited solubility in the mineral oil (approximately 2 mg/ml) and the relative amounts in layer 13 are chosen so that the mineral oil is substantially saturated with the base throughout the lifetime and delivery time of the overlay.

The next layer in the dressing is a microporous membrane 15 , the pores of which are filled with the mineral oil described above. The membrane 15 is the part of the dressing which controls the rate at which the base is released from layer 13. The flux of scopolamine through the membrane 15 and the area of the membrane 15 must be selected so that the scopolamine is released from the reservoir layer 13 to the skin at a substantially constant rate in the range of 0.3 to 10 µg/h after the dressing is applied to the area of application. The flux follows Fick's law. It is a function of the twist of the pores, the porosity and thickness of the membrane, the concentration gradient of the scopolamine base across the membrane and the diffusion coefficient of scopolamine base in the mineral oil. The concentration gradient depends on the scopolamine concentrations in the mineral oil on 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 of 0.1 to 0.85, pore twist of 1 to 10 and thickness of 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.

Below and adjacent to the membrane 15 there is an adhesive layer 16. The layer 16 contains 10 to 200 µg scopolamine base per cm ² of effective surface.

The undissolved part of the scopolamine is indicated as droplet 17. The scopolamine base of layer 16 represents the shock dosage when applying the dressing according to the invention. The scopolamine is dispersed in the same mineral oil-isobutene mixture as is used in layer 13. The dressing is attached to the skin with the help of layer 16. The mineral oil-isobutene mixture adheres less firmly to the skin than to the other layers of the dressing and therefore the dressing remains intact when it is peeled off the skin.

Prior to application, the overlay also includes a peelable protective layer 18 covering layer 16. Immediately prior to application, layer 18 is peeled away from layer 16 and discarded. It may be made of materials impermeable to scopolamine mineral oil, such as the polymers from which top layer 11 is made, provided that these substances have been made peelable , e.g. by silicone treatment.

The dressing 10 may be applied to the mastoid region and deliver scopolamine according to the dosing schedule described above without the need for prior or concurrent treatment of the area with a skin penetrability enhancing agent. As stated above, if the area of skin to which the dressing is applied is other than the mastoid region, the area of skin to which the dressing is applied should be previously treated with one or more of the skin penetrability enhancing agents described above. If concurrent treatment is desired, the agent may be incorporated into the dressing 10 , in which case layers 13 and 16 will contain effective amounts of such agents.

The size of the patch is not critical. It is generally of such a size that the scopolamine is applied to an area of skin in the range of 0.5 to 4 cm ² . Accordingly, the effective surface area of the patch is also generally in the range of 0.5 to 4 cm ² .

The invention is explained in more detail by the following non-limiting examples. Unless otherwise stated, parts are always parts by weight.

example 1

A solution of 29.2 parts of high molecular weight polyisobutene (average molecular weight determined by viscosity measurement 1 200 000), 36.5 parts of low molecular weight polyisobutene (average molecular weight determined by viscosity measurement 35 000), 58.4 parts of mineral oil (10 mPa s at 25°C), 15.7 parts of scopolamine base and 860.2 parts of chloroform is poured onto an approximately 65 µm thick covering layer of an aluminum polyethylene terephthalate laminate, forming a scopolamine base reservoir layer approximately 50 µm thick. A combination adhesive layer and peelable layer is prepared in a similar manner by pouring onto a 200 µm thick silicone-treated aluminum-polyethylene-polyethylene terephthalate film a solution of 31.8 parts of the high molecular weight polyisobutene, 39.8 parts of the low molecular weight polyisobutene, 63.6 parts of the mineral oil, 4.6 parts of the scopolamine base and 860.2 parts of chloroform. The resulting contact adhesive layer is approximately 50 µm thick.

The combination of cover layer and reservoir layer prepared as described above is then applied to one side of a 25 µm thick microporous polypropylene membrane saturated with mineral oil, and the layer of adhesive and release liner described above is applied to the other side of the membrane. One cm ² round disk-shaped pieces are punched out of the resulting 5-layer laminate. Each of these deposits releases 130 to 150 µg/cm ² scopolamine initially and then at an essentially constant rate of 3 to 3.5 µg per cm 2 · hour.

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 mPa s at 25°C), 12.8 parts of scopolamine base, 8.8 parts of dimethyllaurylamide and 883.2 parts of chloroform is poured onto the top layer described in Example 1 to form a scopolamine base reservoir layer approximately 50 µm thick. A combination adhesive layer and peelable protective layer is similarly prepared by pouring a solution of 23.5 parts of the high molecular weight isobutene, 29.5 parts of the low molecular weight isobutene, 47.6 parts of the mineral oil, 7.8 parts of scopolamine base, 9.0 parts of dimethyllaurylamide and 882.6 parts of chloroform onto the silicone-treated polyethylene terephthalate film described in Example 1. The resulting contact layer is approximately 50 µm thick.

The cover layer-reservoir combination described above is then applied to one side of a 25 µm thick microporous polypropylene membrane saturated with the mineral oil, and the adhesive-protective layer combination described above is applied to the other side of the membrane. 4 cm ² round disk-shaped pieces were punched out of the resulting 5-layer laminate. Each layer is designed to initially release 125 µg/cm ² scopolamine and then release 2 µg/cm ² · hour at an essentially constant rate.

The pads of Example 2 were tested in double-blind trials as follows. Seventeen subjects had a pad placed behind the ear before being exposed to agitation at sea. Placebo pads (no scopolamine) were also applied to 18 subjects.

All subjects were known to experience motion-induced nausea (seasickness). Only one of the 17 subjects who received the Example 2 regimen experienced nausea that required additional medication while at sea. In contrast, nine of those who received placebos received additional medication while at sea.

Claims (8)

1. Therapeutic device in the form of a pad or a patch for administering scopolamine through intact skin, comprising a laminate of a cover layer which is substantially impermeable to the active ingredient and one side of which forms the top of the pad, an active ingredient reservoir layer adjacent to the other side of the cover layer, a microporous membrane adjacent to the active ingredient reservoir layer and through which the active ingredient is released from the reservoir layer after the pad has been applied to the skin, a contact adhesive layer adjacent to the microporous membrane with which the pad is attached to the skin and optionally a removable protective layer which is substantially impermeable to the components of the contact adhesive layer and which can be removed before the pad is attached to the skin, characterized in that the reservoir layer contains 0.2 to 3 mg of scopolamine base in a gel-like mixture consisting of mineral oil with a viscosity of 10 to 100 mPa s at 25°C and of polyisobutene which is dispersed, wherein the scopolamine base is released through the membrane at a substantially constant rate of 0.3 to 10 µg/h, and the contact agent layer contains 10 to 200 µg scopolamine base per cm ² of effective surface dispersed in the gelatinous mixture. 2. Coating according to claim 1, characterized in that the mineral oil makes up 35-65% by weight and the polyisobutene makes up 35-65% by weight of the gel-like mixture. 3. Coating according to claim 1 or 2, characterized in that the polyisobutene is a mixture of a polyisobutene with an average molecular weight of 35,000-50,000 determined by viscosity measurement and a second polyisobutene with an average molecular weight of 1,000,000 to 1,500,000 determined by viscosity measurement. 4. A coating according to claim 3, characterized in that the mineral oil makes up 35-65% by weight, the low molecular weight polyisobutene 10-40% by weight and the high molecular weight polyisobutene 20-40% by weight of the gel-like mixture. 5. A support according to claims 1-4, characterized in that the microporous membrane has a porosity of approximately 0.1-0.85, a curvature of the pores of approximately 1-10 and a thickness of the membrane of 10 ^-3 -10 ^-2 cm. 6. Pad according to claims 1-5, characterized in that the microporous membrane consists of polypropylene. 7. Cover according to claims 1-6, characterized in that the cover layer consists of polyethylene terephthalate treated with aluminum. 8. Process for producing the overlay according to claims 1-7, characterized in that the mixture forming the scopolamine base reservoir is poured onto the cover layer, optionally together with a volatile solvent, the mixture forming the adhesive layer is poured onto the removable protective layer, optionally together with a solvent, the microporous membrane is placed between the two poured-on layers and laminated with them.