CA1059909A - Therapeutic system for administering scopolamine transdermally - Google Patents

Abstract

Abstract of the Disclosure A therapeutic system in the form of a bandage that administers scopolamine base transdermally in an initial pulse of 10 to 200 mcg/cm2 of skin that quickly brings the concentration of scopolamine in the plasma to a level at which emesis and nausea are inhibited without intolerable side effects, followed by a substantially constant dosage in the range of 0.3 to 10 mcg/hr that holds said level. The bandage is a four-layer laminate of, from the top: a protective backing; a gelled, mineral oil-polyisobutene-scopolamine reservoir lamina that is the source of the constant dosage; a microporous membrane that controls the constant dosage rate; and a gelled, mineral oil-polyisobutene-scopolamine adhesive layer that is the source of the pulse dose and the means by which the bandage is attached to the skin.

Description

lOS9~09 There are soveral patents that relato to bandages for administering systcmic drugs transdermally. In thi~ regard, United States Patent No.
3,797,4~4 is believod to be the most relevant to the prese~t invention.
Figure 2 of that patent shows a bandage that includes the basic elements of the invontion bandage. Indeed, tho invontion bantage is considered to be a patentable ombodiment of the bandage depicted in said Figure 2. Both bandages are la~inates that inclute a backing, a drug reserYoir, a microporous membrane ant a contact adhcsive layer. Howovor, scopolamino is present in the inven-tion bantage in specific proportions in the contact adhesive layer as well as in the reservoir. Also, tho matrix of the reservoir layer of the invention bandage is a gel.
The antiemetic and antinausoant properties of scopolamine and re-latod compounds aro known. Those propertios have been investigated by admi-nisterlng scopolamine ant related compounds intra~uscularly ant orally.
tC~. Woot and A. Graybiel, '~hoory of Antimotion Sickness Drug Mechanisms", Aerosp. Met. 43: 249-52, 1972; ant C.D. Wood ant A. Graybiol, "A Theory of Motion Sicknos~ Based on Pharmacological Roactions", Clin. Pharm. 11: 621-9, 1970; J.J. Brand and P. Whittingham, "Intramuscular Hyoscino in Control of Motion Sicknoss", Lancet 2: 232-4, 1970.) Scopolamine acid salts and the C4-C12 esters of scopolamine have beon applied topically as antiperspirants. tF.S.K. MacMillan, H.H. Reller ant P.H. Snyter, "Tho Antiperspirant Action of Topically Applied Anticholinergics", J. Invest. Der~,43: 363-7, 1964,) The C4-C12 scopolamine esters are roported to be morc offective antlperspirants than scopolamino itself because they penetrate bettor. These osters arc the subject of United Statcs Patent No.
3,767,786. They were tested as antiperspirants by applying them as solutions or creams to the forearm and axilla at a dose of 2 mg. Minor systemic respon-sos were obser~ed. Such respor.ses wera correlated with systomic responses obtained by administoring ~he esters subcutaneously and it was estimatet there-from that only 5~ to 10~ of the dermally applied esters was absorbed.

lOS9909 The abo~e ~entionet patont suggests using ~inoral oil as a vehicle for antiperspîrant co positions containing the osters, provited there is suf-ficiont water iscible vohiclo also present to provide a modium for absorption by the skin Various surfactants are reportod as absorption onhancers for the scopola ine esters The invontion provides a therapeutic system in the for~ of a bantage for ad inistering scopola ino base through unbroken skin to inhibit e esis and nausea comprising a la inate of a backing la ina that is substantially imper-eable to scopola ino base, ono face of which for~s the top of the bandage, a scopola ine base roservoir lamina adjacent the opposite face of the backing laoina, a icroporous e brane la ina adjacent and below the scopolamino reser-voir la ina through which scopolamine base is released from the roservoir la-ina aftor the bandage is affixod to the skin, a contact adhesive la ina adja-cont and below the microporous me brane lamina by which the bandage is affixed to the skin, and optionally a strippable coating la ina that is substantially i por~oablo to the co pononts of tho contact adhesive la ina and is adapted to bo strippod off tho bandage bofore the bandage is affixed to the skin charac-terizod by tho reservoir la ina being co prised of about 0 2 to about 3 g scopolamine base disporsed in a gellot mixturo of aineral oil of about 10 to about 100 cp at 25 C and polyisobutono; the tortuosity, porosity and thickness of tho e brane lad na, the concontration gradiont of scopola~ino base across tho embrano, and the diffusion coefficient of scopolamine base in the ineral oil are such that scopola ine baso is released through the membrane la ina at a substantially constant rate in the range of about 0 3 to about 10 cg por ~ 9 L ~ hour; and the contact la ina being comprised of about 10 to about 200 ~y~ scopo-la ine base per cm2 effective surface area dispensed in sait gelled ixture The invention also provites a process for Daking the above doscribed therapeutic system characterized by casting the scopola ine base roservoir la ina onto the backing lamina; casting the con~act adhesive la ina onto the strippable coating la ina; interposing the microporous e brane lamina betwoen the two castings; and laminating the two castings and interposed microporous membrane lamina together.
As used herein the term"effective surface area" means the surface area of the bandage that contacts the skin and through which scopolamine is administeret to the skin. As used herein in connection with describing the constant rate portion of the administration and the rate at which scopolmaine is released from said reservoir layer, the term "substantially" indicates that the rate may vary _20%. Such variation may be inherent in the manufac-turing procedure, or be caused by temperature fluctuation, poor affixation of the bandage to the skin, and the like.
The therapeutic system administers scopolamine transdermally to effectively inhibit nausea and emesis without eliciting intolerable parasym-patholytic side effects. It does this by delivering scopolamine base to the plasma in a controlled manner according to a precise dosage program consisting of an initial pulse administration followed by administration at a substan-tially constant rate until a desired total quantity of scopolamine has been administered.
Emesis and nausea may be induced by pregnancy, vestibular disturban-ces (e.g., those caused by motion), radiation treatment,drug treatment or treatment with anesthetics. Such illness may be inhibited by the method of this invention.
The purpose of the pulse portion ~f the dosage program is to shorten the time it takes for the scopolamine concentration in the plasma to reach the level required for preventive therapy. It partially does this by "saturating"
the skin with scopolamine. In this respect the skin initially acts as a "sink" rather than as a "conduit", with most of the scopolamine being bound within the skin and not passing through to circulation. However, once the skin is "saturated", that is the binding sites are occupied, it permits addi-tional scopolamine to pass through circulation. Thus the amount of scopola-mine administered in the pulse is a function of the area of skin being treated.

A pulse of 10 to 2G0 mcg scopolamine per cm of skin being treated will usual-ly allow the therapeutic level in the plasma to be reached within about 3 hr.
AccordinglyJ an adequate time margin of safety is provided if administration is begun at least about 3 hr before illness is expected. In most instances the pulse will be in the range of lO0 to 175 mcg scopolamine per cm2 of skin being treated. The concentration of scopolamine in the plasma can be related to the concentration of free scopolamine in the urine if the glomerular filt-ration rate of the subject is known, and it is convenient to express the quan-tity of scopola~ine in the plasma in terms of a urinary excretion rate. An average urinary excretion rate of about 0.3 mcg free scopolamine per hr was found to generally correspond to a therapeutic plasma level. However, it was also found that this rate is subject to about a ~5-fold biological variation.
Therefore, ~he rate ranges between about 0.05 and about 1.5 mcg per hr depen-ding on the individual.
The purpose of the substantially constant rate administration por-tion of the dosage program is to supplement, if necessary, the pulse administ-ration in delivering e ugh scopolamine to reach the~ above mentionet therapeu-tic level and to hold that level for as long as is necessary. It follows that the constant rate atministration portion will proceed for as long as therapy is required. In this regard a total (including the pulse) of 0.1 to 2.5 mg sco-polamine administered in accordance with the above described dosage program will provide a therapeutic effect for about 3 hours to 7 days. It also fol-lows that the level of constant rate administration may vary depending on the body weight (plasma volume) of the patient. In this regard in most instances the rate will be in the range of 3 to 4 mcg per hr for adults and 1 to 2 mcg per hr for children.
The skin location at which the therapeutic system is applied is im-portant because the histology, thickness and vascularization of skin varies from individual ts individual as well as from body site to b~dy site on a given individual, and such variance affects the efficacy with which scopolamine may ~ 059909 be delivered to the plasma Applicants have found that the effect of this variance may be substantially eliminatet in either of two ways The first way is to apply the system to a skin site, namely the mastoidal area, where scopola ine permeation does not vary significantly from individual to indivi-dual and thus the quantity of scopolamine delivered to the plasma or the rate at which such delivery is made is not significantly different between indivi-duals The second way is to eliminate the stratum cornoum as a quantity-affecting or rate-affecting element by treating the skin at the administration site with a skin per~eation enhancing agont Such treatment will allow the system to be appliet to body sites, such as the arms, legs or torso, other than the mastoital area Depending on the particular agent involved, the treataent aay occur prior to or simultaneously with the ad~inistration of scopolamine base fro the system Likewise, the quantity of agent needed will depend on the particular agent used In any event, the agent plays the dual role of increasing the per~eability of the stratum corneua to scopolanine and decreasing the tendency of the stratum corneum to bind scopolamine Ex-a ples of known agents which may be used are dodecyl pyrrolitone, dimethyl lauramide and di ethyl sulfoxide All three of these agents ay be used in pre-treat ent applications The pyrrolidone and lauraaide aar be applied to the atministration site at about 4 to 8 ag/cm2 for approxiaately an hour and then washed off They ay be incorporatet into the system and ad inistered si ultaneously with the scopol oine at approxi ately the same dosago as the scopola ine The suIfoxite is preferably used only as a pre-treatment at doses in the range of 5 to 100 mg/cm2 for approximately one hour, and then washet off The trawing is an enlarget, schematic, cross-sectional view of the preferred embotiment of the bandage of the invention The trawing depicts a bandage, generally designated 10, that when applied to skin administers sco-plamine base according to the prescribed tosage program Bandage 10 is a five-layer laainate The top layer 11 is a backing that is substantially imperme-able to scopolamine base. Its face 12 forms the top surface of the bandage.
Backing 11 serves as a protective covering, keeps the volatile components of the bandage from escaping, and fulfills a support function. Preferably, backing layer 11 is itself a laminate of films of polymer and metal foil such as aluminu~ foil. Polymers that may be used in tho layer are high and low density polyethylcne, polypropylene, polyvinylchlorite and polyethylene torephthalate.
Below and adjacent to layer 11 is a scopolamine reservoir layer 13.
Layer 13 contains about 1 to about 6 mg scopolamine base, the undissolved portion of which is tepicted as troplets 14. The scopolamine base contsined in layer 13 is teli~ered to the plasma during the constant administration por-tion of the dosage program. Droplets 14 are dispersed homogeneously in a gellet mixture of mineral oil of about 10 to about 100 cp at 25C and a blend of polyisobutene. The oil will usually constituto 35~ to 65% by weight of tho mixture ant the polyisobutene will correspondingly usually constitute 35 to 6S% by weight of the mixture. The polyisobutene blend co prises a low lecular weight polyisobutene (35,000-50,000 viscosity average molecular weight) and a high molecular weight polyisobutene (1,000,000-1,500,000 visco-sity average molecular weight). Preferret mixtures co prise 35S to 65% mine-ral oil, lOS to 40% low molecular weight polyisobutene, and 20% to 40% high lecular weight polyisobutene. These oil-polyisobutene mixtures are excel-lent adhesives ant help to holt the bandage together. If they were not good adhesives, other means, such as heat soaling, would have to be used to keep the bandage together.
The mineral oil in layer 13 functions as a carrier for the scopola-mine base. Scopolamine base has limited solubility in the mineral oil (approxi-mately 2 mg/ml) and the relative amounts of each in layer 13 are such that the mineral oil is saturated with the base for essentially the entire dispensing lifetime of the bandage.
The next lamina in the bandage is a microporous m~mbrane 15 whose ~059909 pores are filled with the above described mineral oil. Membrane 15 is the element of the bandage that controls the rate at which the base is released from layer 13. The flux of scopolamine through membrane 15 and the area of membrane 15 must be such that scopolamine is released from reservoir layer 13 to the skin at a substantially constant rate in the range of 0.3 to 10 mcg/hr after the bandage has been put in use. The flux follows Ficks' law. It is a function of the tortuosity, porosity and thickness of the membrane, the oon-centration gradient of scopolamine base across the membrane and the diffusion coefficient of scopolamine base in the mineral oil. The concentration gradi-ent depends on the scopolamine concentrations in the mineral oil at the oppo-site sides of the membrane. The diffusion coefficient depends on the mineral oil viscosity and decreases with increasing viscosity. The three properties of the membrane are, of course, constant for any given membrane. Membranes that have porosities from about 0.1 to 0.85, tortuosities from 1 to 10, and thicknesses from 10 3 to 10 2 cm may be used. The membrane may be formed from polymers such as polypropylene, polycarbonates, polyvinylchloride, cellulose acetate, cellulose nitrate, and polyacrylonitrile.
Below and adjacent membrane 15 is a contact adhesiYe lamina 16.
Lamina 16 contains 10 to 200 mcg scopolamine base per cm effective surface area. The undissolved portion of the scopolamine is depicted as droplets 17.
The scoplamine base in lamina 16 is the pulse dosage of the invention method.
The scoplamine is dispersed in the same mineral oil-polyisobutene mixture that is used in layer 13. Lamina 16 is the means by which the bandage is attached to the skin. In this regard the mineral oil-polyisobutene mixture adheres less strongly to skin than it does to the other laminas of the bandage; therefore, the bandage tends to remain intact when it is pulled off the skin.
Prior to use, the bandage also includes a strippable, protective coating 18 that covers lamina 16. Just prior to use, coating 18 is peeled away from lamina 16 and discarded. It may be made from scopolamine-mineral oil im-105991~9 pormeable materials such as tho poly ers from which backing 11 may be made, with the provision that these atorials are mate strippablo, such as by sili-conizing Bandago 10 may be applied to either mastoidal rogion and it will administer scopola~ine according to the described dosago program without re-quiring any prior or si ultaneous treat ent of the rogion with a skin per-moation enhancing agent As indicatet abovo, if the b~ndage is applied to a body site other than a astoidal aroa, the site should bo treated with one or re of the describod skin per~eation enhancing agents If si~ultaneous treatment is dosired, the agent ay be incorporated into bandage 10 In that instance, layers 13 and 16 will contain effectivo quantities of such agents Tho sizo of the bandage is not critical The bandage will usually be si~ed to ad inister scopola ine to an area of skin in the range of 0 5 to 4 cm2 Corrolativoly, tho effective surfaco area of the bandage will also usually be in the range of 0 5 to 4 cm2 Tho following oxamples illustrato the in~ontion Thoy are not in-tendot to li it tho scopc of the invention in any way Unless indicated otherwise, parts are by weight Exa ple 1 A solution of 29 2 parts high molecular weight polyisobutene tsold undor the designation Vistanex MML-100, 1,200,000 viscosity average olecular weight), 36 5 parts low olecular weight polyisobutene (sold under the desig^
nation Vistanex LM-MS, 35,000 ~iscosity average locular weight), 58 4 parts mineral oil (10 cp ~ 25C), 15 7 parts scopolamine base and 860 2 parts chlo-roform is solvent cast onto an approxi ately 65 icron thickbackingfila of alu inizet polyethylone teraphthalate (sold under the designation MEDPAR) to for~ a scopolamine base reservoir layer approxiaately 50 microns thick A
contact adhesive layer-strippable coating co bination is similarly prepared by solvent casting onto a 200 micron thick siliconizod, alu~inized, polyethy-leno backod polyethylene terephthalate film a solution of 31 8 parts of said ~de ll1aM~

high molecular weight polyisobutene, 39 8 parts of sait low molecular weight polyisobutene, 63 6 parts of said d neral oil, 4 6 parts of scopola~ine base ant 860 2 parts chloroform The rosulting contact athesive layer is approxi-~ately 50 microns thick The above toscribet backing_roservoir layor combination is then lami-natet to one face of a 25 ~icron thick microporous polypropylene membrane (sold under the tesignation Celgart 2400) saturatet with sait mineral oil ant the above described contact athesive layer-strippable coating combination is la inatet to the opposite faco of the me~brane Ono cm2 circular, tisc-shapet bantages are punch cut from the resulting S-layer laminate Each bantage is dosignet to release an initial 130-150 cg/cm2 pulse of scopola ine followet by an ossontially constant tosage of 3-3 5 mcg/c~2/hr Exa ple 2 A solution of 22 3 parts of the high molecular weight polyisobutene described in Ex~rple 1, 28 0 parts of the low olocular woight polyisobutene toscribet in Exa~plo 1, 44 9 parts mineral oil (66 cp e 25C), 12 8 parts scopola ino baso, 8 8 parts dimethyl laura ide and 883 2 parts of chlorofor~
is solvent cast onto tho backing film tescribod in Exa ple 1 to form a scopola-ine base resorvoir layor approximately 50 icrons thick A contact athesive layer-strippable coating combination is similarly preparod by solvent casting onto the siliconi~ed polyethylene terophthalate film described in Example 1 a solution of 23 5 parts of said high molecular weight polyisobutene, 29 5 parts of sait low molocular weight polyisobutene, 47 6 parts mineral oil (66 cp 0 25C), 7 8 parts scopola ine base, 9 0 parts dimethyl lauramide and 882 6 parts chloroform The resulting contact layer is approxi~ately SO ~icrons thick The abovo describet backing-reservoir layer combination is then la-minated to one face of a 25 micron thick icroporous polypropylene me brane (sold under the designation Celgard 2400) saturated with said mineral oil and the above described contact adhesive layer-strippable coating combination is - 30 laminated to the opposite face of the me~brane Four cm2 circular, disc-shaped ~ ~r~ rl~

_ 9 _ bandages are punch cut from the resulting 5-layer la~inate. ~ach bandage is designed to release an initial 125 mcg/cm2 pulse of scopolamine followed by an essentially constant dosage of 2 mcg/cm2/hr.
The bandages of Example 2 were tested on a double blind basis as follows. A bandage was applied to the skin behind the ear of 17 subjects prior to exposure to motion at sea. Placebo bandages (no scopolamine present) were similarly applied to 18 subjects. All subjects had a prior history of experiencing tion-induced nausea. Only one of the 17 subjects wearing the bandages of 8xa~ple 2 beca~e ill to the extent that additional antinauseant medication has to be administered while at sea. In contrast, 9 of the sub-jects wearing the placebo bandages had to receive additional antinauseant metication while at sea.

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Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A therapeutic system in the form of a bandage for administering scopolamine base through unbroken skin to inhibit emesis and nausea com-prising a laminate of a backing lamina that is substantially impermeable to scopolamine base, one face of which forms the top of the bandage, a scopolamine base reservoir lamina adjacent the opposite face of the backing lamina, a microporous membrane lamina adjacent and below the scopolamine reservoir lamina through which scopolamine base is released from the reservoir lamina after the bandage is affixed to the skin, a contact adhesive lamina adjacent and below the microporous membrane lamina by which the bandage is affixed to the skin, characterized by: the reservoir lamina being comprised of about 0.2 to about 3 mg scopolamine base dispersed in a gelled mixture of mineral oil of about 10 to about 100 cp at 25°C and polyisobutene; the tortuosity, porosity and thickness of the membrane lamina, the concentration gradient of scopol-amine base across the membrane, and the diffusion coefficient of scopolamine base in the mineral oil are such that scopolamine base is released through the membrane lamina at a substantially constant rate in the range of about 0.3 to about 10 mcg per hour; and the contact lamina being comprised of about 10 to about 200 mcg scopolamine base per cm effective surface area dispensed in said gelled mixture.

2. The therapeutic system of claim 1 further characterized in that the mineral oil constitutes 35% to 65% by weight of the gelled mixture and the polyisobutene constitutes 35% to 65% by weight of the gelled mixture.

3. The therapeutic system of claim 2 further characterized in that the polyisobutene is a blend of a first polyisobutene having a viscosity average molecular weight of 35,000 to 50,000 and a second polyisobutene having a vis-cosity average molecular weight of 1,000,000 to 1,500,000.

4. The therapeutic system of claim 3 further characterized in that the mineral oil constitutes 35% to 65% by weight of the gelled mixture, the first polyisobutene constitutes 10% to 40% by weight of the gelled mixture and the second polyisobutene constitutes 20% to 40% by weight of the gelled mixture.

5. The therapeutic system of claim 1 further characterized in that the microporous membrane lamina has a porosity of about 0.1 to 0.85, a tortuosity of about 1 to 10 and a thickness of about 10-3 to 10-2 cm.

6. The therapeutic system of claim 5 further characterized in that the microporous membrane lamina is made of polypropylene.

7. The therapeutic system of claim 6 further characterized in that the backing lamina is made of aluminized polyethylene terephthalate.

8. The therapeutic system of claim 1, 2 or 3 including a strippable coating lamina that is substantially impermeable to the components of the contact adhesive lamina and is adapted to be stripped off the bandage before the bandage is affixed to the skin.

9. A process for making the therapeutic system of claim 1 characterized by: casting a scopolamine base reservoir lamina onto a backing lamina; casting a contact adhesive lamina onto a strippable coating lamina; interposing a microporous membrane lamina between the two castings; and laminating the two castings and interposed microporous membrane lamina together.