DE2604718A1 - THERAPEUTIC DEVICE FOR ADMINISTERING SKOPOLAMINBASE - Google Patents

Description

ALZA Corporation
950 Page Mill Road, Palo Alto, California 94 304, USA

concerning
Therapeutic device for the administration of scopolamine base

The invention relates to a therapeutic device In the form of a plaster-like pad, the medicament, especially scopolaininbase, transdermally initially in an initial burst amount releases from 10 to 200 yug / cm skin and thereby the concentration of scopolamine in the plasma rapidly brings it to a level at which it prevents nausea and vomiting without unpleasant side effects and then in an amount of 0.3 to 10 / ug / h, so that the active ingredient content is maintained in the plasma. The edition is a four-layer laminate that, when viewed from above, consists of the consists of the following layers: a protective back; a gel-like iliner oil-polyisobutene-scopolamine reservoir, which is the source for constant dosing; a microporous membrane that ensures the constant delivery rate controls and a gel-like mineral oil-polyisobutene-scopolamine-lilebeschicht, which serves as the source for the initial shock dose, as well as from '■ means,. with which the edition is attached to the chew.

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ORIGINAL INSPECTED

· Τ_ · · ■ r. λ. j- -c · - ^ j /Or..Conditions, JiS give "c some patents on bandages / for administration

systemic drugs through the skin. FIG. 2 of US Pat. No. 3,797,494 shows an overlay in the form of a laminate.

it is known that scopolarain and related compounds are effective against nausea and vomiting. These properties were examined by intramuscular and oral administration

Λ) application of scopolamine and related compounds. '

Skopolamic acid salts and the C ₁ - C ₁ .-, - esters of Skopol-

2) amines were applied topically as antiperspirants. '

_{The C 1} -C 2 scopolamine esters are reported to be more effective antiperspirants than scopolamine itself because of their higher permeability. These esters are described in U.S. Patent 3,767,786. They have been studied as antiperspirants by applying them to the forearm and armpit in the form of solutions or creams at a dose of 2 mg. Little systemic response was observed. Such reactions were related to 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.

'' CD, Wood and A, Graybiel, "Theory of Antimotion Sickness

Drug Mechanisms ", Aerosp, Med, 43: 249-52, 1972; and CD, Wood, and A, Graybiel, "A Theory of Motion Sickness Based Oil Pharmacological Reactions," din * 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, SK MaeMillan, HH, Heller, and FH Snyder, "The Antiperspirant Action of Topically Applied Antioholinergics," j. Invest, Derm. 43; 363-7, 1974,

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

Various surfactants are indicated to improve the absorption of the scopolamine esters.

The invention relates to a therapeutic system in Form of a plaster-like pad for the administration of scopolamine base through the uninjured skin to prevent vomiting and To prevent nausea, consisting of a laminate consisting of a support layer, which is essentially responsible for the scopolamine base is impermeable and one side of which forms the top of the pad, a scopolamine base eeservoir layer, which is adjacent to the other side of the pad; a microporous Membrane attached to the bottom of the scopolamine reservoir layer and through which the scopolamine base is released from the reservoir layer after the application has been applied to the skin and a contact adhesive layer which is adjacent to the microporous membrane layer and by which the overlay is attached to the skin and optionally a peelable cover layer consisting essentially of is impermeable to the constituents of the adhesive layer and which can be peeled off before the application is applied to the skin, which is characterized in that the reservoir layer consists of about 0.2 to about 0.3 mg of scopolamine base dispersed in a gel-like mixture of mineral oil with a viscosity of about 10 to about 100 cP at 25 ° C and polyisobutene, where the curvature, porosity and thickness of the membrane, the concentration gradient the scopolamine base across the membrane and the diffusion coefficient of the scopolamine base in the mineral oil be chosen so that the scopolamine base through the membrane is released at a substantially constant rate in an amount of from about 0.3 to about 10 µg / hr and

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the contact layer of about 10 - about 200 ^ Bg of scopolamine base per cm of effective surface in the gel-like mixture.

The invention also relates to a method for the production of the therapeutic system described above, which thereby is characterized in that the okopolaminbase reservoir layer pours onto the support layer, pours the contact adhesive layer onto the removable protective layer, the microporous Brings membrane between the two poured-on layers and the two layers with the one in between laminated microporous membrane.

As used herein, the term "effective surface area" means the surface area, the pad, which is in contact with the skin and which is administered to the skin by the scopolamine. In the context of the constant rate of administration and the rate at which scopolamine is released from the reservoir layer, the term "im v / es borrowed" means that the rate can vary by + 20%. Such a 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 chew, and the like.

The therapeutic system delivers the scopolamine to the body through the skin and effectively prevents vomiting and nausea without it becoming unacceptable parasympathological Side effects comes. This is done by releasing the scopolamine base into the plasma in a controlled manner according to a precise dosing program consisting of an initial burst administration and then thereafter

/ more constant

administration at essentially the same rate until the desired total amount of scopolamine has been administered.

retroactively

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Vomiting and nausea can be caused by pregnancy, vestibular disorders (e.g. those caused by Motion, seasickness), radiation treatment, drug treatment, or treatment with Anesthetics. Such symptoms can be caused by application the support according to the invention can be prevented.

The reason for the initial bursts is to reduce the time it takes to to the Skop ο larninkonz ent ration in the blood, on which for the Preventive treatment to bring necessary value. This partially "saturates" the skin with scopolamine. In In this case, the skin initially acts more as a "sponge" ("sink") than as a "conduit", with most of the Scopolamine is bound in the skin and does not penetrate through it and is added to the circulation. When the skin However . is "saturated", i.e. that the binding sites are occupied, it becomes possible that further scopolamine is in the circulatory system crosses. For example, the amount of scopolamine administered in the first burst is a function of the person being treated.

2nd skin area. · A shock of 10-200 / Ug scopolamine per cm treated skin generally results in the therapeutic amount in the plasma within about 3 hours is achieved. Consequently, a corresponding temporal safety range is achieved if the administration is at least three hours before the symptoms are expected, is started. In most cases the shock will be in the area

from 100 - 175 / Ug scopolamine per cm of treated skin. The concentration of scopolamine in plasma may be related to the concentration of free scopolamine in urine if the glomerular filtration rate of the individuals concerned is known and it is appropriate, then the The amount of scopolamine in the plasma is given in fourth for the rate of excretion in the urine. It turns out that one

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mean urinary excretion rate of approx O »3 / Ug free scopolamine per hour, generally one corresponds to the therapeutic content in the plasma. It has however also shown that this speed is an approximate Subject to + 5-fold biological variation. Therefore, the speed is in the range of about 0.05 bia about 1.5 / Ug / h depending on the individual.

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

The location of the skin to which the therapeutic system is applied is important, as is the histology, thickness and thickness Vascular supply to the skin from individual to individual as well vary from body part to body part in a particular individual and such variation the effectiveness, with which the scopolamine is released into the plasma, has been shown to affect the effect of this Variation can be essentially eliminated in two ways. One way is to connect the system to a

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Place namely to apply richly to the üiastoidalbe, where the Penetration of the scopolamine does not vary greatly from one individual to another and so does the amount released into the plasma The amount of scopolamine or the rate at which it is released is not great in individual individuals differs. The second option is the corneal layer to be switched off as a quantity-determining or speed-determining layer by treating the skin at the point of administration with a skin permeation agent. Such treatment allowed it is to apply the system to parts of the body other than the mastoid area, such as the arms, legs or the Hull. Depending on the type of agent used, the treatment can be carried out before or at the same time as the administration of Skopolamine base can be carried out of the system. Similarly, the amount of remedy needed depends on the particular one applied funds. In any case, the agent plays the double role, the permeability of the corneal layer for Increase scopolamine and decrease the tendency of the corneal layer to form scopolamine. Examples of well-known Agents that can be used for this purpose are dodecylpyrrolidone, DLmethylHaurylamid and dimethyl sulfoxide. These three agents can be used for pretreatment. The pyrrolidone and laurylamide can be applied to the administration site applied in amounts of about 4-8 mg / cm for about an hour and then washed off. You can also added to the system and administered concurrently with the scopolamine in approximately the same dose as scopolamine will. The sulfoxide is preferably only used for

treatment applied doses in the range of 5-100 mg / cm for about an hour, and then washed off.

The drawing represents an enlarged schematic cross section of a preferred embodiment of the invention The drawing shows an overlay (generally referred to as 10) that when applied to the skin is, scopolamine base according to the specified dosage

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program delivers. The support 10 is a five-layer Laminate. The upper layer 11 is the support or cover layer,

is essentially impermeable to the scopolamine base.

The side 12 of this layer 11 forms the surface of the Edition. The cover layer 11 serves as a protective layer and prevents volatile compounds from leaving the support escape and fulfills a support function. The cover layer 11 itself is preferably a laminate of polymer films and a metal foil such as aluminum foil. Polymers that can be used for these lights are High and low density polyethylene, polypropylene, polyvinyl chloride and polyethylene terephthalate.

Adjacent below this layer 11 is a scopolamine reservoir ± layer 13. The layer 13 contains approximately 1 to approximately 6 mg of scopolamine base, the undissolved part 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 dosage program. The droplets 14 are homogeneously dispersed in the gel-like mixture of mineral oil with a viscosity of about 10 to about 100 cP at 25 ° C and a polyisobutene. The oil usually makes up from 35 to 65% by weight of the mixture and the polyisobutene correspondingly from 35 to 65 % by weight. The isobutene mixture comprises a low molecular weight isobutene (mean molecular weight determined by viscosity measurement 35,000 to 50,000) and a high molecular weight polyisobutene (mean molecular weight determined by viscosity measurement 1,000,000 to 1,500,000). Preferred mixtures contain 35 to 65 wt -.% Mineral oil, 10 to 40 wt -.% Low molecular weight polyisobutylene and 20 to 40% high molecular weight isobutene. These oil-polyisobutene mixtures are excellent adhesives and serve to hold the pad together. If they were not good adhesives, other means such as heat sealing would have to be used to hold the pad together.

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The mineral oil in layer Λ ο 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 saturated with the base for substantially the entire life and dispensing time of the pad.

The next layer in the overlay is a microporous membrane 15, the pores of which are filled with the mineral oil described above. The membrane 15 is that part of the support which controls the speed at which the base is released from the layer 13. The flow of scopolamine through the membrane 15 and the area of the membrane 15 must be selected so that the scopolamine from the reservoir layer 13 arrives at an essentially constant rate in the range from 0.3 to 1N / Ug /.h the skin is released after the pad is applied to the application area. The flow follows the i'icks' see law. It is a function of the curvature, porosity and thickness of the membrane, the concentration gradient of the scopolamine base across the membrane and the diffusion coefficient of the scopolamine base in the mineral oil. The concentration gradient depends on the concentrations of scopolamine 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 about 0.1 to 0.85, bends from 1 to 10, and thicknesses from 10 ^v to

10 cm can be applied to ground. The membrane can be made of polymers be made such as polypropylene, polycarbonates, polyvinyl chloride, cellulose acetate, cellulose nitrate and Polyacrylonitrile.

An adhesive layer 16 is located below the membrane 15, adjoining it. The layer 16 contains

ρ 10 to 200 / Ug scopolamine base per cm of effective surface.

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The undissolved part of the scopolamine is indicated as droplet 17. The scopolamine base of layer 16 provides the shock dosage when using the pad according to the invention. The scopolamine is in the same mineral oil-isobutene mixture dispersed as applied in layer 13. With the help of the layer 16, the rest on the skin attached. The mineral oil-isobutene mixture adheres less firmly to the skin than to the other layers of the pad and therefore the pad remains intact when it is peeled from the skin.

The pad also includes a peelable protective layer 18 overlaying layer 16 prior to use. Direct prior to use, layer 18 is peeled from layer 16 and discarded. It can consist of materials which are impermeable to skopolainin mineral oil, such as those polymers from which the cover layer 11 is made provided that these substances are e.g. have been made peelable by silicone treatment.

The pad 10 can either be applied to the mastoid area and gives scopolamine as described above Dose program without prior or simultaneous treatment of the area with one of the penetrability of the Skin conditioning agent is needed. As said above, the area of the skin to which the pad is applied should be if it is a site other than the mastoid area, previously with one or more of the above-described, skin permeability enhancing agents are treated. When concomitant treatment takes place should, the agent can be built into the support 10. In this case layers 13 and 16 contain effective ones Amounts of such agents.

The size of the edition is not critical. It has generally such a size that the scopolamine on one Skin area on the order of 0.5 to 4 cm is applied. The effective surface of the support lies accordingly

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generally also in the range from 0.5 to 4.

The invention is illustrated in more detail by the following non-limiting examples. Here are among parts, unless otherwise stated, always to be understood as parts by weight,

example 1

A solution of 29.2 parts of high molecular weight polyisobutene (Vistanex MML-100, mean molecular weight determined by viscosity measurement 1,200,000), 36.5 parts of low molecular weight polyisobutene (Vistanex Lh-MS, mean molecular weight determined by viscosity measurement 35,000), 58.4 parts mineral oil (10 cp at 25 ⁰ C), 15.7 parts and 860.2 parts of chloroform is Skopolaminbase / poured onto an approximately 65 m thick covering layer of a laminate Aluminiumpolyäthylenterephthalat (Medpar), wherein a Skopolaminbasen-ReservoJr layer of about 50 / by thickness arises. A combination of adhesive layer and peelable layer is produced in a similar manner by applying a solution of 31 »8 parts of the high molecular weight polyisobutene, 39, ö 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 is poured on. The resulting contact adhesive layer is approximately 50 µm thick.

The combination of Cover layer and reservoir layer are then placed on one side of one 25 µm thick microporous polypropylene membrane (Celgard 2400) saturated with mineral oil, and the one described above Layer of adhesive and peelable protective layer. . on

ρ the other side applied to the membrane. One cm tall, round, disc-shaped pieces are punched out of the resulting 5-layer laminate. Each of these conditions sets

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initially 130 to 150 μg / cm scopolamine free and then with essentially constant speed 3 Ms 3.5 / Ug per cm. 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 cP at 25 ^° C.), 12.8 parts of scopolamine base, 8.8 parts Dimethyllaurylamide and 883.2 parts of chloroform were poured onto the topcoat described in Example 1 to form a scopolamine base reservoir layer approximately 50 µm thick, and a combination of adhesive layer and peelable protective layer was similarly made by pouring a 23.5 solution 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 dimethyl laurylamide and 882.6 parts of chloroform on the silicone-treated polyethylene terephthalate film described in Example 1. The resulting The contact layer was approximately 50 µm thick.

The top layer-reservoir combination described above was then placed on one side of a 25 µm thick microporous polypropylene membrane (Celgard 2400) that was saturated with the mineral oil was applied and the adhesive-protective layer combination described above on the other side of the membrane, p

Round, disc-shaped pieces 4 cm in size were punched out of the resulting 5-layer laminate. Each edition '

is designed to initially 125 ug / cm scopolamine

releases and then with an essentially constant

speed 2 / Ug / cm, hour.

The pads of Example 2 were tested in double blind tests as follows. Seventeen people became Before being exposed to movement at sea, a pad is attached behind the ear. Placebo editions (no Scopolamine) were also applied to 18 people.

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All persons were "known to experience movement-induced nausea (seasickness). Only one of the 17 persons who had received the pad according to Example 2 experienced nausea, which required additional medication during the stay at sea In contrast, nine of those who received placebos received additional medication while at sea.

../Patent claims

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Claims (8)

Expectations 1. [Therapeutic "device in the form of a pad or plaster for administering Skopola.minbase through the intact skin to prevent vomiting and nausea, comprising a laminate of a cover layer which is essentially impermeable to the Skopolaminba.se, and one side of which forms the top of the pad, a Skopola.minbase reservoir layer, adjacent to the other side of the cover layer, a microporous membrane, adjacent to the skopolamine reservoir layer and through which the Skopola.minbase, after the Auf ^1o ~ 3 has been applied to the skin, is released from the reservoir layer, a contact adhesive layer adjacent to the microporous membrane with which the overlay is attached to the skin and optionally a peelable protective layer, which is essentially is impermeable to the components of the contact adhesive layer and which can be peeled off before the overlay is attached to the skin It is noted that the reservoir layer is about 0.2 - about 3 mg Skopola.minba.se in a gel-like mixture consisting of mineral oil with a viscosity of about. 10 to about 100 cP at 25 ⁰ C and from polyisobutene, is dispersed, the curvature, porosity and thickness of the membrane, the concentration gradient of the Skopola.minba.se across the membrane and the diffusion coefficient of the Skopolaminbase in the mineral oil are chosen so that the Skopolamine bases through the membrane at a substantially constant speed of about. 0.3 to about 10 / µg / hr is released and the contact adhesive layer about. 10 to ρ
contains about 200 / ng Skopola.minba.se per cm of effective surface dispersed in the gel-like mixture. -2- 609834/1004 - 2 - 2. Edition according to claim 1, characterized in that g e k e η η - ζ e i c.h η e. t that the mineral oil 35 - 65 wt .-? o and that Polyisobutene make up 35-65% by weight of the gel mixture. 3. Edition according to claim 1 or 2, characterized in that the polyisobutene is a mixture of one Polyisobutene with an average molecular weight determined by viscosity measurement of 35,000-50,000 and one second polyisobutene with an average molecular weight determined by viscosity measurement of 1,000,000 to 1,500,000 is. 4. Edition according to claim 3 »characterized in that the mineral oil make 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 mixture. 5. Edition according to claim 1-4, characterized in that the microporous membrane has a porosity from about 0.1-0.85, a bend of about 1-10 -3 -2 and a thickness of approximately 10-10 cm. 6. Support according to claims 1-5, characterized in that the microporous membrane made of Polyiee-TstrtWn consists. 7. Support according to claims 1-6, characterized in that the top layer made of aluminum treated polyethylene terephthalate. 8. A method for producing the support according to claim 1-7, characterized in that the the mixture forming the scopolamine base reservoir, optionally together with a volatile solvent, on the cover layer 609834/1004 pouring the mixture forming the adhesive layer onto the removable protective layer, optionally together with a solvent poured on, brings the microporous membrane between the two poured layers "and laminated with them. 6 0 9 - ./10 0