AU682813B2 - Subsaturated transdermal delivery device - Google Patents

Description

1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPE C I F I CATION FOR A STANDARD PATENT

ORIGINAL

~1 4.

of Applicant: a* *4 4 4 *4 *'.**ctual Inventors: o* S.e.

':"':Address for Service: Invention Title: Invention Title: ALZA CORPORATION James Lee Osborne, Melinda K. Smart (previously Melinda Nelson), David James Enscore, Su II Yum, Robert M. Gale and Patricia S. Campbell.

SHELSTON WATERS Clarence Street SYDNEY NSW 2000 "SUBSATURATED TRANSDERMAL DELIVERY DEVICE" Details of Original Application No. 38521/89 The following statement is a full description of this invention, including the best method of performing it known to us:- Subject matter disclosed but not claimed herein is disclosed and claimed in copending application No.

38521/89 of which this application is a divisional application.

This invention relates to transdermal delivery devices intended to deliver biologically active agents through skin at substantially constant rates for extended periods of time and more particularly to such devices in which the active agent to be delivered is present in the device at a concentration below saturation.

BACKGROUND OF THE INVENTIONI Transdermal delivery devices for the delivery of a wide variety of biologically active agents have been known for sometime and representative systems are disclosed in U.S. Patents 3,598,122, 3,598,123, 3,742,951, 4,031,894, 4,060,084, 4,144,317, 4,201,211 and a 4,379,454 which are incorporated herein by reference. Such devices generally comprise an impermeable backing, a drug or active agent i reservoir, a rate controlling membrane and a contact adhesive layer which can be laminated or heat sealed together to produce a transdermal delivery device. Although subsaturated systems are known, see patent 4,379,454, for example, it is generally desirable that the agent reservoir comprise the agent to be delivered in a suitable carrier at a concentration above the saturation o concentration in the carrier. This is done to maintain a unit 25 activity source of the agent so that the delivery rate of the agent will remain substantially constant over the intended administration o: period; the amount of agent originally present over saturation being the depot or reservoir for the dose of agent ultimately delivered.

If the concentration of the agent drops below unit activity during the delivery period, the rate of agent delivery will also tend to decrease. It is also generally desirable to minimize the residual agent in the device after use and, to accomplish this, devices normally utilize a carrier, which has a limited solubility for the agent to be delivered. Although such typical devices have been found useful for the delivery of a wide variety of agents, we have encountered significant problems in producing devices intended to deliver an agent which is capable of dissolving or plasticizing medically acceptable contact adhesives. Such agents are usually, but not always, oily, nonpolar materials, liquid at ambient temperatures, and are either solvents for medically acceptable contact adhesives or are highly soluble therein and cause such adhesives to loose their adhesiveness. In the latter case, the agent, may not actually solvate the adhesive but instead plasticize the adhesive and cause it to swell, loose its cohesiveness and adhesiveness, and degrade its other physical properties. As used herein, an agent is a "solvent" for medically acceptable adhesives, and such adhesives are "soluble" in such agents if the agent either dissolves or plasticizes such adhesives as described above.

Agents which are such solvents may be drugs, permeation enhancers or other transdermally deliverable substances.

Representatives of such agents are drugs such as benztropine base, an anticholinergic useful in the treatment of Parkinsonism, the 15 antispasmolytic drugs secoverine and dexsecoverine, nicotine, useful in the withdrawal from smoking, and arecoline, a cholinergic and as anthelmintic agent. Representative permeation enhancers include o a polyethylene glycol monolaurate (PGML), glycerol monolaurate (GML), and glycerol monooleate (GMO) and ethanol. Although ethanol is not an oily, nonpolar liquid, it is an example of a material which, in high concentrations, can act as solvent for certain medically acceptable contact adhesives.

Regardless of the initial concentration of the agent in the reservoir and adhesive layers, the devices will equilibrate upon standing. Thus, if the agent is a solvent for the adhesive layer, we have found that substantial quantities migrate from the reservoir througn the rate controlling membrane and into the adhesive layer prior to use. The migration will continue until the thermodynamic activity of the agent in the adhesive equals the 30 activity of the agent in the reservoir. Thus, a substantial amount of agent can migrate into the adhesive layer and uii be released onto the skin in an uncontrolled manner before the rate controlling membrane can exert any effect on the agent remaining in the reservoir. Also, high concentrations of agent in the adhesive layer and in direct contact with the skin may cause irritation or produce undesirably high plasma levels during the initial period after application to the skin and prior to depletion of the initial -4" loading of agent in the contact adhesive layer. In addition to the deleterious effects on a patient that way be caused by high concentrations of agent in the adhesive, certain adhesives tend to lose their adhesive properties when they are dissolved or plasticized by the agent being delivered.

s The present invention provides, according to one aspect thereof, a medical device j for the transdermal adm~inistration of nicotine, said device being adapted to deliver nicotine during a predetermined nicotine administration period of at least about eight hours, said device comprising, in combination: 9o a) nicotine ;,esez-voir means comprising said nicotine dissolved in a solvent at a 1 concentration less than saturation and containing sufficient nicotine to administer :nicotine at a steady-state administration rate in the range of 250-4000 jig/lw during a portion of said administration period; b) nicotine release rate controlling membrane means disposed in the path of nicotine migration~ from said reservoir to the skin; said means maintaining the steadystate administration rate of nicotine from said device substantially constant and withia the range of 250-4000 g/ar for a portion of said administration period; and c) adhesive means disposed in the path of nicotine migration from said release1 rate controlling membrane means to the skin.

According to another aspect of the invention, there is provided a transdermal patchF comprising: a) a nicotine depot layer having a skin-facing side and a skin-distal side, said depot layer containing nicotine dissolved in a solvent at a concentration less than t 71 1-of# VI~I~d ~bVU t9~ S~31U'1 N.LS3-I V010d TST ""N 26SESBE 9 T9 SN31W NOIS13HS M-C;r 46-180/0 saturation and in a sufficient quantity to maintain useful flux of nicotine from, said patch for a total time~ period of at least about 10 hours or more; b) an occlusive backing layer in contact with and covering said depot layer on said skin-distal side; S c) a rate controlling membrane means for controlling diffusion of nicotine from the skin-facing side of said reservoir at a firt flux of greater than 0 but less than 1017 1ig/cm 2 averaged over any hour fbr a first time period of greater than 0 but less than 4 *fr *hours, then at a second flux in the range of 23-800 p±g/cmn/hr for a secoi~d time period ofI 6 hours or more; and d) adhesive means disposed in the path of nicotine migration from said rat, controlling membrane means to the skin.

According to a further aspect of the invention, there is provided a transdennal 0 patch comprising: 9a) a nicotine reservoir layer having a skin-facing side and a skin-distal side, is said reservoir layer containing nicotine dissoivcd in a solvent at a concentration Jess than saturation and in a sufficient quantity to maintain a usefu flux of nicotine from said patch for a period of 8 hours or more; b) an occlusive backing layer in contact with and covering said reservoir layer on said skin-distal side; c) nicotinj~ permeable rate controlling membrane means for controlling diffusion of nicotine from said skin-facing side at a flux between 23 and 800 Jig/cm'T/hr for a period of 8 hours or more; and ~RA4/ 69 T I GOO-d TGT*ON 26SESeE 9 T9 S8231UM NOIS-L9HS MltsT LG/BO/2T -6d) adhesive means disposed in the path of nicotie migration from said rate controlling memnbrane means to the skin.

Thie invention also provides a method for administering nicotine to an individual in need of such administration, comprising applying to the skin of said, individual a transderrnal patch, said patch comprising: a) a nicotine reservoir layer having a skin-facing, side and skin-distal side, said reservoir layer containing nicotine dissolved in a solvent at a concentration less than saturation and in a sufficient quantity to maintain a useful flux of nicotine from said patch for a total time period of at least 10 hours; 1.

]0 b) an occlusive backing layer in contact with and covering said reservoir layer on said skin-distal side; nicotine permeable rate controlling membrane means for coii-trolling diffusion of nicotine from the ski-facing side of said reservoir at a first flux of greater than0 bu les thn 117 J~g/m 2 aeraed over any hour for a first time period of greater than 0 but less than 4 hours, then at a second flux in the range of 23-800 4~g/cm 2 /hr for a second time period of 6 hours or more; nd d) adhesive means disposed in the path of nicotine migration from said rate controlling membrane meanS to the skin.

A futher method of the invention lies in a m~ethod of administering nicotine to an individual in need of such administration comprising applying to the skin of said individual a transdermed patch, said patch comprisixg: a) a nicotine reservoir layer having a skin-facing side and a skin-distal side, I said reservoir layet containing nicotitie dissolved in a solvent at a concentration less than 7~ 4U 900cd IST *ON 26SESSE 9 T9 SJB(' NOIS1BE4; LV;S saturation and in a sufficient quantity to nmiainin a useful flux of nicotine from said patch for a period of 8 hours or more; b) an occlusive backing layer in~ contact with and covering said reservoir layer on said skin-distal side;J0 c) nicotine permeable rate controlling membrane means for controlling diff-usion of nicotine from said skin-facing side at a flux between 23 and 800 ig/cm~fr for a period of 8 hours or more; and adhesive means disposed in the path of nicotine migration from said rate Aoding to orne oithe of the invention, there is provided a rate controlled,& subsuturated trasdermal delivery device having an in-line adhesive which delivers an agent which is a solvent of the in-line adhesive and which exhibits improved release .p *0*4 characteristics. In certain embodiments of our invention a substantially constant release *too* rate ove' a substantial portion of a predetermined administration period can be obtained, is The device utilizes a subsaturated reservoir containing a~ sufflolent amount of agent to prevent the activity from decreasing by more than about 75%, and preferably no more than about 25% during the predetermined delivery period. The device is also preferablyI designed sueb that no more than, and preferably substantially less than, half of the tobt agent loading in the device is in the adhesive and '4Y, 0 400d rGT*0N GSES92 9 T9 <-SN3UM NOJ.S1HS OT' 46/0/ rate controlling membrane layers after equilibration and prior to use.

Preferred embodiments of our invention are rate-controlled drug delivery devices having in-line adhesives for the controlled delivery of drugs which are solvent for the in-line adhesive such as the smoke cessation aid, nicotine, the anticholinergic, benztropine, and the tertiary amine secoverine, 1cyclohexyl-4-C[ethyl(p-methoxy-alpha-methylphenylethyl) 10 amino]-butazone, an anti-spasmodic agent described in

*O

U.S. Patents 3,996,245 and 4,125,623 which are

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incorporated herein by reference. The active, isomer of secoverine is hereinafter referred to as SI** "dexsecoverine".

1n Other preferred embodiments can be used to deliver drugs in connection with permeation enhancers such as ethanol, PGML, GML and GMO for example. Attempts to produce transdermal delivery devices for these agents and enhancers by following the aforementioned teachings of 20 the prior art were unsuccessful based on a combination of the above considerations. It is also expected that similar problems will be encountered with respect to other agents which are solvents for medical adhesives and this invention will have utility with such other agents.

The invention will be readily apparent from the following description with reference to the accompanying drawings wherein: 9 Figure 1 is a cross section through an embodiment of the transdermal delivery devices according to this invention; Figure 2 is a cross section through another embodiment of a transdermal delivery device according to this invention; Figures 3, 5, 6 and 7 are plots in vitro release rates directly into a sink at 32 0 C (Fig. 3) or 359C (Figs. 5, 6 and 7) vs. time for embodiments of this 10 invention; and I* Figure 4 compares plots of its in vitro in release

CC

rates at 32 0 C directly into a sink vs. time with the in t vitro at 32 0 C through human cadaver skin into a sink vs.

64 time obtained from an embodiment of this invention.

Referring now to Figures 1 and 2 (like reference numerals referring to common elements), transdermal Sdelivery devices 1 and 10 according to this invention are 49CC shown. Devices 1 and 10 are formed of an impermeable backing 2, an agent reservoir 3, an agent release rate 20 controlling membrane 4, a contact adhesive 5 permeable to the agent, and a release liner 6 adapted to be removed from the adhesive layer prior to application to the skin 6 of the subject to whom the agent is to be administered.

As noted above, the agent to be delivered is a solvent for the adhesive forming the adhesive layer 5. In this regard, the reservoir may contain more than one agent according to this invention provided that at least one oF -the agents is a solvent for the adhesive. Typically, one of the agents could be a drug and another agent could be a permeation enhancer or another drug, for example.

The embodiments of Figure.s 1 and 2 differ in that the agent reservoir 3 of the embodimn3nt of Figure 1 is less viscous than the reservoir 3 of Figure 2 such that the impermeable backing 2 is bonded at its periphery to the rate controlling membrane 4 to form a pouch fully enclosing reservoir 3 to prevent it from flowing or oozing. In the embodiment of Figure 2 the reservoir 3 has sufficient viscosity to maintain its structural integrity without a peripheral or circumferential seal. Although Figures 1 and 2 relate to laminated devices, other arrangements of the adhesive, reservoir s: and rate controlling membranes are usable and include, for example, an adhesive having microcapsules of the agent within a rate *b controlling membrane dispersed therethrough as shown in aforementioned patent No. 3,598,123.

According to this inventionj transdermal delivery devices I and 10 are intended to be applied to a patient for a predetermined administration period, typically from about 1-7 days. During the administration period it would be desirable to control the amount of goes*:agent that is released from the device so that the agent can be administered to the patient in a predetermined and controlled *manner, 'he in vitro agent release rate or flux from a traidermai delivery device directly into an infinite sink as a function of time can be considered to consist of two phases, a first, initial "transient" phase, and a second, subsequent "steady-state" delivery .phase. During the initial transient phase, the agent is released .6 at a high rate as a result of the initial loading of the agent in the adhesive and rate controlling membrane layers 5 and 4, respectively. This initial pulse release decreases relatively rapidly as a function of tf" 2 until the initial loading of agent in the adhesive layer is depleted and the "steady-state" phase in which agent is being delivered from reservoir 3 commences, shown in Figure 5 and 6 represents the time at which the initial transient phase ends and the steady state delivery phase commences. The variation of release rate with time during the steady-state phase depends on the structure of the device. Simple monoliths of the prior art exhibit a theoretical variation of release rate as a function of t"11 2 whereas prior art devices having unit activity reservoirs and release rate-controlling membranes exhibit theoretical release rates that vary with they remain constant. Devices according to this invention exhibit a theoretical release rate which varies as a function of tn where 'M n -1 0 and preferred embodiments exhibit in vitro release rates which approach those obtained from zero order devices.

According to preferred embodiments of this invention, the steady-state in vitro release rate can be maintained substantially constant from the termination of the initial transient phase until the expiration of the predetermined administration period. As used ~I5herein, the in vitro agent delivery rate is considered to be "substantially constant" if the steady-state rate does not vary more than about and preferably no more than during the steady state administration period.

As used herein, the term "agent" is used in its broadest sense 4,20 to mean any macerial which is to be delivered into the body of a human or animal to produce a beneficial therapeutic or other intended effect, such as permeation enhancement, for example, and is not limited to drugs and pharmaceutical products. The maximum allowable concentration of the agent in the adhesive will be determined by such factors as the agent concentration at which the adhesive properties are impaired, the agent concentration at which irritation problems or unacceptably high initial transdermal agent fluxes, for example, are observed. When such undesirable effects occur) it is necessary that the initial activity of the agent in the adhesive be at a lower level. Because the device will equilibrate on standing, the activity (but not necessarily the concentration) of the agent in the adhesive will ultimately be the same as the activity of the agent in the reservoir layer.

Transdermal delivery devices, according to embodiments of our invention, have the following characteristics 1. The devices utilize an in-line adhesive to maintain the device on the skin; 2. The agent to be delivered is a solvent for the in-line adhesive; 3. The initial equilibrated concentration of the agent in the reservoir 3 and the adhesive 5 is below saturation, expressed alternatively, the activity 4s less than 4. The reservoir 3 comprises the agent dissolved in a diluent with respect to which rate controlling membrane 4 is substantially impermeable; In preferred embodiments the initial loading of the agent in reservoir 3 is sufficient to prevent the activity of the agent in the reservoir from decreasing by more than about 75% and preferably no more than about 25% during the predetermined period of administration; and 6. In preferred embodiments the thicknesses of the adhesive, rate controlling membrane and reservoir layers are selected so that S' 15 at least 50% and, preferably at least 75% of the initial equilibrated agent loading is in the reservoir layer.

To design a system according to our invention, the permeability of skin to the agent to be delivered, the amount of agent required 0* to saturate the agent binding sites in the skin, the maximum activity of agent in the adhesive layer that can be tolerated withotut loss of adhesive properties and without producing undesirable initial drug pulses, skin irritation or undesirable o* sensations would be determined by suitable in vitro and in vivo tests. Having determined the maximum allowable activity of agent 25 in the adhesive; a somewhat lower initial activity would typically be employed to provide for a factor of safety. In some instances, such as in the initial administration of the agent or where i intermittent, as opposed to continuous, delivery periods are prescribed, the initial loading of agent in the adhesive layer 5 and rate controlling membrane 4 may correspond approximately to the amount of agent needed to saturate the agent binding sites in the skin below the delivery device.

In preferred embodiments the equilibrated agent loading in the reservoir layer 3 is selected to be sufficient to enable the total dose of agent delivered during the predetermined administration period to be delivered while maintaining the decrease in activity of the agent in the non-permeating solvent forming reservoir 3 within 13 the limits noted above. The total loading of agent in each layer of the device can be readily varied without changing the activity simply by increasing or decreasing the thickness of the adhesive layer 5 and/or reservoir layer 3, and also by appropriate selection of the total surface area of the device through which agent is delivered. Because the rate controlling membrane can only act as a release rate limiting element on agent which is in the reservoir; the reservoir thickness should S! 10 be selected, with respect to the thicknesses of the rate

S*

controlling membrane and the adhesive layers, such that at least half, and preferably substantially more, of the 6) initial equilibrated agent loading is in the reservoir.

i* The rate controlling membrane 4 would be selected such that the flux of the agent through the membrane into an infinite sink is preferably no greater than the in j* vitro flux of the agent through skin (which would produce about 50% device control) and preferably substantially *0 less. If the skin flux is greater than the membrane flux 20 by a factor of about 2.4, for example, approximately of the rate control is obtained from the device.

.a Suitable materials from which the various layers of the device according to this invention can be made are known to the art and many are described in the aforementioned U.S. patents.

Having thus generally described our invention, the following description and examples will illustrate how variations of the above described parameters affect the administration of the agent.

Device according to our invention can be used for the transdermal administration of nicotine to skin or mucosa. The following calculations can be used to estimate the characteristics required for such a transdermal nicotine delivery device.

Studies with nicotine releasing gum (Nicorette\), have determined that the target blood level of nicotine for reducing the urge to smoke is approximately 12-15 nanograms/ml and that the clearance of nicotine from the body occurs at about 18 ml/min-kg.

0e In order to deliver adequate amounts of nicotine from a reasonably sized system, the target steady-state 0, in vivo delivery rates are within the range of 250-4000 °0 S 15 pg/hr with a typical rate being about 1000 pg/hr.

This range can be readily achieved according to our invention in a rate controlled device having a size in the range of about 5-50 cm 2 and typically about 15-20 0* 2 cm 2 A one day delivery period can readily be 20 obtained from subsaturated devices of this invention, and 0 administration periods of at least 8-10 hours and up to about 3 days can be attained by varying the thickness of 0 the reservoir.

An alternate embodiment of this invention would be a system capable of providing nicotine delivery for 16 hours to be applied each day upon waking, worn all day, and removed and discarded just prior to sleep. This would be repeated for as long as nicotine delivery is desired.

Total nicotine loading in a transdermal delivery device of this invention is preferably at least about mg with the equilibrated concentration of nicotine in the reservoir composition being within the range of 5-50 wt%, corresponding to an activity within the range of 0.05-0.50. Reaction of the skin to nicotine is flux dependent and to minimize skin reaction and it is preferred to maintain the flux below about 200 g/cm 2 -hr and preferably below 120 pg/cm -hr S* in the steady state phase. Typically the flux will be in S* 0the range of about 30 to 70 pg/cm 2 -hr.

The equilibrated nicotine loading in the reservoir Re layer is preferably selected to be sufficient to enable the total dose of nicotine delivered during the predetermined administration period to be delivered while maintaining the decrease in activity of the nicotine in the reservoir the limits noted above. The total loading 20 of nicotine in each layer of the device can be readily varied without changing the activity, simply by S. increasing or decreasing the thickness of the adhesive layer and/or reservoir layer and also by appropriate selection of the total surface area of the device through which nicotine is delivered. Because the rate controlling membrane can only act as a release rate limiting element on the nicotine which is in the 16 reservoir, the reservoir thickness should be selected with respect to the thicknesses of the rate controlling membrane and the adhesive layers, such that at least half, and preferably substantially more, of the initial equilibrated nicotine loading is in the reservoir.

The preferred embodiments of this invention utilize an anhydrous reservoir formed of natural or synthetic rubbers or polymers as known to the art. When an ethylene/vinyl acetate copolymer (EVA) is selected it has a preferably VA content in the range of about 28-60% by wt.

9.

The rate controlling membrane may be of a dense polymer film that has the requisite permeability to 9.

nicotine. The membrane material would be selected such that the flux of the nicotine through the membrane into a sink is preferably no greater than the in in vitro flux of nicotine across skin (which would produce about system control) and preferably substantially less. The fractional control of nicotine delivered across skin (x) 20 from the rate controlled transdermal therapeutic system of this invention is given by the following relationship: x= J /J x net system which can be determined from the following equation: Jnet Jsystem [Jsystem Jskin] 1] 1 Thus if the skin flux is greater than the membrane or system flux by a factor of about 2.4, for example, the fractional control of nicotine flux from the system would 17 be: -l Jnet Jsystem 11 0.7 Therefore, approximately 70% of the rate control is obtained from the system. The flux of nicotine through skin varies somewhat from individual to individual and from body site to body site but generally appears to be in the range of about 400-800 pg/cm 2 /hr.

Preferably the rate controlling membrane is substantially impermeable to the diluent in which the nicotine in the reservoir is dissolved, although a low permeability to the diluent may not adversely affect the *e operation of the device. Examples of the types of polymer films that may be used to make the membrane 16 S are disclosed in U.S. Pat. Nos. 3,797,494 and 4,031,894, both of which are incorporated herein by reference.

Particularly suitable materials for use with the mixture are (EVA), low density polyethylene (LDPE) and high

O

density polyethylene (HDPE).

The composition and thickness of the adhesive layer 20 is selected so as not to constitute a significant o permeation barrier to the passage of nicotine. The S* adhesive material is selected from known materials having a high permeabilit to nicotine which is also such that it is compatible with nicotine at the activity chosen for the system. Amine resistant silicone adhesives are particularly suitable. These compounds may be modified with silicone oil to obtain the desired tack.

18 EXAMPLE 1 Transdermal delivery devices for the controlled delivery of nicotine were prepared utilizing a highly permeable, amine resistant adhesive available from Dow Corning (X7-2920), LDPE as the rate controlling membrane, EVA (40% VA) as the non-diffusible drug reservoir diluent, pigmented medium density polyethylene/aluminized polyester as the impermeable backing member and nicotine base as the source of nicotine. The devices had 4 mil LDPE rate controlling membranes, 6 mil drug reservoirs containing either 20 or 25 weight percent nicotine base I and a 2 mil adhesive layer. The in vitro fluxes of drug from these subsaturated transdermal nicotine devices through cadaver skin into aqueous sink at 35°C were S 15 determined and are shown in Table I. Nicotine flux data across skin was obtained from averaging the data generated by devices tested on two different skin donors.

TABLE I Drug Flux with Drug Flux with 20 Time 20 wt% drug 25 wt% drug (hr) (pg/cm 2 -hr) (pg/cm 2 -hr) 2 87.9 133.2 4 65.8 104.6 6 52.6 85.0 8 47.5 73.2 23.25 33.4 52.8 27.25 27.9 45.2 30.75 23.1 40.3 EXAMPLE II Subsaturated nicotine transdermal delivery devices (1 cm 2 were fabricated having a nicotine loading of 19 about 5 pg/cm 2 comprising a 30 wt% ni-otine/70 wt% EVA 40 reservoir composition (0.30 nicotine activity), a 2 mil rate controlling membrane and a 2 mil amine resistant adhesive layer (Dow Corning X7-2920 with 5 wt% silicone fluid). The in vitro release rate at directly into an aqueous sink is shown in Figure 3. A device according to this example having a surface area of about 20 cm 2 applied to human subjects on a daily basis, should provide transdermal delivery of nicotine at administration rates sufficient to assist in the cessation of smoking.

*g The previous examples related to nicotine delivery devices; the following examples illustrate embodiments of this invention for transdermally administering other agents.

Secoverine normally exists as a racemic mixture of d and 1-isomers, the d-isomer, dexsecoverine, being the Sbiologically active ingredient. We have determined that dexsecoverine diffuses through normal skin at 20 substantially the same rate as the racemic mixture and therefore, if dexsecoverine is used as the agent in the reservoir, the agent flux through the skin need be only about one half that which would otherwise be required if racemic secoverine were delivered.

EXAMPLE III Transdermal delivery devices for the controlled delivery of dexsecoverine were prepared utilizing Dow Corning DC 355 silicone adhesive as the highly permeable medical adhesive, EVA VA) as the rate controlling membrane, EVA (40% VA) as the non-diffusible drug reservoir diluent, pigmented medium density polyethylene/aluminized polyester as the impermeable backing member and racemic secoverine or dexsecoverine as the source of dexsecoverine. Secoverine and dexsecoverine are extremely soluble (essentially miscible) in the EVA (40% VA) diluent and thus the weight percent concentration in the diluent corresponds approximately to the thermodynamic activity. Secoverine o 0 .and dexsecoverine are solvents for the adhesive and form solutions therewith at concentrations of 300 mg/cm or 15 more. Adverse effects on adhesive properties have been observed when agent concentration reached about 3 mg/cm "Thus, according to the preferred dexsecoverine delivering embodiments of this invention, it is desirable 20 to maintain the agent concentration in the adhesive below about 45 mg/cm which corresponds to an activity of about 0.15 in the drug reservoir and the adhesive .layers. The thickness of the adhesive and rate controlling layers in the subsaturated system were selected to provide an initial pulse of about 225 pg/cm 2 to saturate the agent binding sites in the skin, the contribution to the pulse of each such layer 21 being dependent on the thickness of the layer and the solubility of the agent in each layer. A thicker layer would provide a higher initial pulse and a thinner layer would provide a smaller initial pulse for the same initial activity. One or 1.3 mil LDPE and 2 or 4 mil EVA VA) rate control membranes were utilized in the preferred embodiments and drug reservoirs of approximately 5-20 mils were tested. A 5 mil thickness was sufficient to prevent the activity of the agent in the reservoir 3 from decreasing by more than 30% during a four-day administration period. The in vitro release rates of various subsaturated dexsecoverine systems are compared to the characteristics for unit activity systems in Table II. In Figure 4 the upper group of curves shows 15 the in vitro release rates at 32 0 C vs. time in hours directly into an aqueous sink and the lower group curves show the flux through cadaver skin at 32 0 C vs. time in hours into an aqueous sink from racemic secoverine systems and illustrate the effect of varying reservoir 20 thicknesses on in vitro release rates and flux.

S

22

TABLP:JI

DrUg Sourceg Drug Activity 1.00 0.06 Membrane LO)PE EVA (9%VA) *0 a

B*

a.

a S a a a.

a a *5 3 a 9* U S 9

S.

S

9*SUOa

S

*599 *a *5 5*SO a a a *Sa* SO n so a. a *aS~SG a Membrane Thickness (mils) 1.0 4.0 Adhes i,,e Thickness (mi is) 1.7 1.8 Reservo4 r Thickness 20 (mils) 10.0 Initial Burst (pg/cm 2 25 from membrane 170 142 from adhesive 1325 84 TOTAL 1495 226 Avg. Steady State In vitro ReleasF :-dte at 32 0 C (pcg/crn 2 /hr) 57 3.5 Dexsgecoverine S e oovKeriLne 0.15 0.10 0.20 0.20 0.20 LDPE EVA IJDPE LDPD, LDPE (9 %VA) 1.0 2.0 1.3 1.3 1.3 1.7 1.4 1.7 1.7 1.7 5 5.0 5.0 5.0 20.0 26 199 225 118 109 227 8.2 22 Range (over 24-96 hr) 60-54 75-5.5 10-7 24-18 40 We have detormined that to achieve anti-spasmodic activity from the continuous transdermal administration of secoverine, approximately 1 to 10 nanograms/nl of dexsecoverine should be maintained in the plasma. We have also discovered that the permeability of average human skin when exposed to unit activity sources of either secoverine or dexsecoverine appears to be in the range of approximately 20 to 60 g/cm 2 /hr. In order to deliver adequate amounts of a drug from a reasonably sized system, a target steady-state in vivo delivery rate of dexsecoverine from 10-40 pg/hr was selected which can be readily achieved according to our invention in a rate controlled device of reasonable size of from about 5 to cm 2 Delivery periods of about 3-5 days can be obtained from subsaturated devices of Table 2, and administration periods of up to about 7 days can be IQ attained by increasing the thickness of the reservoir to S* about 10 mils.

G o EXAMPLE IV

S

*Subsaturated transdermal delivery devices similar *0 06 6 to those of Example III, but intended to deliver S. Sld 15 benztropine base are fabricated having an agent reservoir diluent of EVA (40% VA), and a 1 mil LDPE rate-controlling membrane. Benztropine base is soluble to about 650 mg/g of EVA (40% VA). 2.5 cm 2 devices 4e S are fabricated using a highly permeable, amine resistant 2Q silicone adhesive available from Dow Corning, (X7-2920) 6 *0*SSS or polyisobutylene/mineral oil adhesivesp an impermeable I backing, and an 8 mil-thick reservoir layer having an initial benzotropine loading of 5, 10, and 20 weight percent equivalent to activities of 0.125, 0.95, and 0.5. The approximate in vitro release rates directly into an aqueous bath at 32-35 0 C to be obtained from such devices, using I mil LDPE rate-controlling membranes, are 24 illustrated in Figure 5. The effect of using a 2-mil LDPE rate-controlling membrane is illustrated in Figure 6.

The permeability of average skin to benztropine is in the range of 70 to 90 pg/cm 2 /hr and systems as described above can deliver benztropine in vivo at therapeutically useful rates of 10 to 40 pg/hr. The size of the device can be selected to provide daily doses of about 0.4 to 4,5 mg for up to 4 days.

EXAMPLE V Benztropine transdermal del.':ary devices for use in clinical testing were fabricated as set forth generally 4' in Example IV from a 10% benztropine in 90% EVA *6 reservoir composition into 5 cm 2 patches using 1.5 mil 4 6 LDPE rate controlling membranes and 1.8 mil amine S 15 resistant adhesive layers. With a 5 mil reservoir layer the devices contained about 6.4 mg of benztropine and are intended for a 24 hour administration period. The in vitro release rate vs. time at 32°C into an aqueous sink is shown in Figure 7. When applied to human subjects on 20 a daily basis, anticholinergically effective transdermal 6 delivery of benztropine can be obtained.

S Having thus generally described our invention and preferred embodiments thereof, it is apparent that various modifications and substitutions will be apparent to workers skilled in the art, which can be made without departing from the scope of our invention which is limited only by the following claims.

Claims (2)

1. A medical device for the lxarzsdermal administration of nicotine, said device being adapted to deliver nicotine during a predetermined nicotinte administration period of at least about eight hours, said device cormprising, in combination: a) nicotine reservoir means comprising said nicotine dissolved in a solvent at a concentration less than satu'ration and containing sufficient nicotine to administer nicotine at a steady-state administration rate in the range of 250-4000 pLg/hr dwing a portion of said administration period; mmri~ en ipsdI h aho b) nicotine release ratecotoln ebatmendipsdIthpthf t nicotine thigration from said reservoir to the s'kin; said means maintaining the steady- :state administration rate of nicotine from said device substantially constant and within the range of 250-4000 pg/hr for a portion of said administration period; and t adhesive means disposed in the path of nicotine migration from said release ate controlling membrane means to the skin. is2, A transdermal patch comnprising: a) i, nicoine depot layer having a skin-facing side and a skin-distal aide, said depot layer containing nicotine dissolved in a solvent at a concentration less than U saturation and in a suficient quantity to maintain a usefal flux of nicotine from iU psftch for a total time period of at least about, 10 hours or more;- b) an occlusive backing layer in contact with and covering said depot layer on said skin,,istal side, o)a rate contmolling tnembvtme means for controlling diffusion of nicotine from the skin-facing side of said reservoir at a first flux of greater than 0 but less than 10 17 e.i

800.4 TGT 'ON IZSS! ASZ 9 T9 S8nlb" NOIS-13HS 80 151 46/oVET g.g/cni 2 P.veraged over anyv hour for a first time period of greater than 0 but less than 4 hours, then at a second flux in the range of 23- 800 pLg/cm 2 /hr for a second time period of 6 hours or more; and d) adhesive means disposed in the path of nicotine migration from~ said rate controllingm:erabrane means to the skin. 3I A transdernal patch comprising: a) a nicotine resrvoir layer having a skin-facing side and a skin-distal side, said reservoir layer colitai ing nicotine dissolved In a solvent at a concentration less than saturation~ and in a sufficient quantity to miaintain a useful flux o ,*nicotine from sad for a poriod Qof 8 hours or more; b) an occlusive backing laver in contact witiz nd cove~ig said reservoir layer on said skin-di,,tal side; nicotine permeable rate coi-'trolling membrane means for controlling diffusion of nicotine frorn said skin-facing side at a flux between 23 and 800 Ig/crr 2 /hr for a period of 8 hours or more; and d) adhesive means disposed in the path of nicotine milgration from said rate controlling membrane mean &o he skin. 4, The device of claim, 1, 2 or 3 wherein the initial equilibrated thermodynamic activity of nicoltine in said reservoir is betweeci 0.05 and 0,50. j The device of claim I wherein said adhesive has a high nicotine solubility. 6. The devico of claim 1, 2, 3, 4 or 5 wherein at least, 50% of the initial loading of the nicotine in the device is in the nicotine reservoir. (GI RA\ 600ld TST ION EGES' 9 TS 8*JL1MI NCO1SI-HS SV":Sr 4(5/4 C-. 27 7. The device of claim 1, 2, 3, 4, 5 or 6 wherein the initial equilik rated thermodynamic activity of nicotine in said reservoir and adhesive Lv.,;ers is in the range of 0.20-0,40. A 8. The device of elaim 1, 2, 3, 4, 5, 6 or 7 whereina the steady state flux of nicotine is in the range of 23-800 jtg/cWvk/hr. 9. ,The device of claim 1, 2, 3, 4, 5, 6 or 7 wherein the steady state of flux hs in the range of 23 -120 ).g/cm 2 /hr. 10. A method for administering nicotine to an indl, "ual in need of such a.administration, comprising applying to the skin of said individual a transderrnal patch, 4'A o said patch comprising: Ca) a nicotine reservoir layer having a isldn-facing side and skin-distal side, said reservoir layer containing nicotine dtissolved in a solvent at a concentraton less than saturation and in a sufficient quantity to maintain a useful flux of nicotine from said a4 40*04 patch for a total time period of at least 10 hours; 00 1 b) an occlusive backing layer in contact with and covering said reservir layer *on said kndsasie c) nicotine permeable rate controlling membrane means for controlling diffuion of nicotine from the skip,-facing side of said reservoir at a first flux of greater than 0 but less than 10 17 p.g/cm 2 averaged over any hour for a first time period of greater than 0 but less fhmn 4 hours, then at a second flux in the range of 23-800 Jgg/cnm 2 /hr for a second time period of 6 hours or more.- and d) adhesive means disposed In the path of nicotine migration from said rate controlling membrane means to the skin. T 13 Od E63 ON 9MSI3- 9 T9 S8fS.WM NQ.LS13-iS e6v8sr 146fB0.ICT -28- 11. A method of administering nicotine to an individual in need of such administration comprising applying to the skin of said individual a transdermal patch, said patch comprising: a) a nicotine reservoir layer having a skin-facing side and a skin-distal side, said reservoir layer containing nicotine dissolved in a solvent at a concentration less than saturation and in a sufficient quantity to maintain a useful flux of nicotine ftom said patch for v period of F ours or more; Sb) an occlusive backing layer in contact with and vovering said reservoir layer *on said skint-distal side; 4yl c) nicotine permieable rate controlling membrane means for controlling diffusion of nicotine from said skin-faing side at a flux between 23 and 800 p.g/cm 2 /hr for a period of 8 hours or mnore; and ci) adhesivo means disposed in the path of nicotine mnigration from said rate econtrolling membrane mneans to the skin. is 12, A rate-controlled transdermal delivery device substantially as hereinbefore I described with reference to any one of the accompanying drawings. jDATED this 13thi day of August 1997 L ALZA CORPOrZATION 4 Attorney: PAUL G. HARRISON Fellow Institute of Patent Attorneys of Australia SRA4/ t -U AIV TTOJ TGT*DN ESSCME 9 TS 4- SN31UM NOIS13HS 071ST 46/130/23 ABSTRACT Subsaturated, rate controlled delivery devices (1) for delivering an agent The initial equilibrated concentration of the agent in the agent reservoir and the adhesive is below saturation, The initial loading of the agent in reservoir is sufficient to prevent the activity of the agent in the reservoir (3) from decreasing by more than about 75% and preferably no more than about 25% during the predetermined period of S, administration. The thicknesses of the adhesive 10 rate controlling membrane and reservoir layers are selected so that at least 50% and, preferably at least 75% of the initial equilibrated agent loading is in the reservoir layer The devices are usable to deliver agents which are liquid at body temperatures such 15 as benzotropine, secoverine, nicotine, arecoline, polyethylene glycol monolaurate, glycerol monolaurate, glycerol monooleate and ethanol, for example. FIG. 1 I 0