AU666208B2 - Transdermal delivery device - Google Patents

Description

666208 1

AUSTRALIA

PATENTS ACT 1990 C O M P T, E T E SPECIFICATION C 0 M PL E T FOR A, STANDARD PATENT

ORIGINAL

0 Name of Applicant: r.* 99.

Actual Inventors: A e 9 9 o r Address for Service: 9 ALZA CORPORATION James Lee OSBORNE, Melinda K. SMART David James ENSCORE, Sue II YUM, Robert M. GALE and Patricia S. CAMPBELL SHELSTON WATERS Clarence Street SYDNEY NSW 2000 "TRANSDERMAL DELIVERY DEVICE" Invention Title: Details of Original Application No. 85852/91 dated 15th October 1991 The following statement is a full description of this invention, including the best method of performing it known to us:- 2 Subject matter disclosed but not claimed herein is disclosed and claimed in copending application Nos.

38521/89 and 85852/91 of which this application is a divisional application of 85852/91.

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 device in which the active agent to be delivered is present in the 10 device at a concentration below saturation.

BACKGROUND OF THE INVENTION 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. Patent 3,598,122, 3,598,123, 3,742,951, 4,031,894, 4,060,084, 4,144,317, 4,201,211 and 4,379,454 which are incorporated herein by reference. Such devices generally comprise an impermeable backing, a drug or active agent 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 concentration in the carrier. This is done to maintain a unit activity source of the agent so that the delivery rate of the agent will remain 3 substantially constant over the intended administration 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 1 0 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 coos 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, f. e 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, .a-y 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.

4 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 the treatment of Parkinsonism, the antispasmolytic drugs secoverine and dexsecoverine, nicotine, useful in the withdrawal from smoking, and arecoline, a cholinergic and anthelmintic agent. Representative permeation enhancers include polyethylene glycol monolaurate (PGML), 10 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 e 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 through 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 activity of the agent in the reservoir. Thus, a substantial amount of agent can migrate into che adhesive layer and will 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 agent plasma levels during the initial period after application to the skin and prior to depletion of the initial loading of agent in the contact adhesive layer.

In addition to the deleterious effects on a patient that may 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.

The present invention provides a transdermal nicotine delivery device for delivering nicotine during a predetermined administration period and utilizing an in-line adhesive comprising, in combination:an agent reservoir containing nicotine d,issolved therein at an initial equilibrated thermodynamic activity no greater than 0.50 and at an initial equilibrated loading sufficient to prevent the thermodynamic activity of nicotine in said 20 reservoir from decreasing by more than 75% during said administration period; and S(b) in-line adhesive means for maintaining said agent reservoir in agent transmitting relationship to the skin, said adhesive means having a high 25 nicotine solubility.

as.

-6- According to another aspect of the invention, there is provided a trancdermal delivery device utilizing an in-line adhesive having a high nicotine solubility for delivering nicotine during a predetermined administration period comprising an agent reservoir containing nicotine dissolved therein at a concentration lss than saturation with said in-line adhesive disposed in the path of nicotine migration from said reservoir to the skin, the improvement comprising: an initial equilibrated activity of nicotine in said reservoir does not exceeding 0.50; and the initial equilibrated loading of nicotine in said reservoir being sufficient to prevent the activity of nicotine from decreasing by more than 75% during said administration period.

Preferably, the transdermal nicotine delivery device utilized in the method of the present invention comprises a nicotine release rate controlling means •which may be disposed in the path of nicotine migration 999**9 20 from the agent reservoir to the skin.

9 9 ~Preferably, the nicotine is administered to the patient at an administration rate of about 250 to 4000 pg/hr during a substantial portion of the predetermined administration period.

25 Preferably, the reservoir contains sufficient nicotine to administer nicotine for an administration period of at least about 16 hours or more. The device may L° i also comprise an occlusive backing layer in contact with and covering the depot layer on the skin-distal side.

Preferably the rate controlling means can control the diffusion of nicotine from the skin facing side of the reservoir at a first flux of greater than 0 but less than about 1017 Pg/cm 2 /hr averaged over any hour for a first time period of greater than 0 but less than about 4 hours, then at a second flux in the range of about 23-800 g/cm2/hr for a second time period of 6 hours or more. Preferably, the second flux is from 23-800 Pg/cm 2 /hr for a period of 8 hours or more.

According to a further aspect the invention provides a method for transdermally administering nicotine from a transdermal delivery device of the present invention, which method comprises applying the device to the skin of a subject.

According to yet another aspect the present invention provides a method for transdermally administering nicotine from a transdermal delivery device of the present invention which method comprises: 20 applying said device to the skin of a subject *e when the thermodynamic activity of said nicotine in said reservoir does not exceed 0.50; and removing the device from the skin before the activity decreases by more than The invention also provides a method for administering nicotine to an individual in need of such

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-8administration which method comprises: applying to the skin of said individual upon waking, a transdermal device according to the first aspect of the invention which comprises a nicotine reservoir containing a sufficient quantity of nicotine to maintain a useful transdermal flux of nicotine from said device for a total time period of at least 16 hours; maintaining said device in nicotine transmitting relationship to the skin during waking hours; and 10 removing said device prior to sleep.

According to another embodiment of the invention, there is provided a rate controlled, subsaturated transdermal delivery device which can be utilized in the method defined, having an in-line adhesive which 9 G 15 delivers an agent which is a solvent for the in-line adhesive and which exhibits improved release characteristics. In certain embodiments of our invention a substantially constant release rate over a substantial portion of a predetermined administration period can be obtained. The device used in the present invention may utilize a subsaturated reservoir containing a sufficient amount of agent to prevent the activity from decreasing by more than about 75% and preferably no more than about 25% during the predetermined administration period. The device is also V~T, preferably designed such that no more than, and preferably substantially less than, half of the total agent loading in the device is in the I 9 adhesive and 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 Patents 3,996,245 and 4,125,623 which are incorporated herein by reference. The active, isomer of secoverine is hereinafter referred to as 2 "dexsecoverine".

Other preferred embodiments can be used to deliver drugs in connection with permeation enhancers such as a ethanol, PGML, GML and GMO for example. Attempts to produce transdermal delivery devices for these agents and *4 enhancers by following the aforementioned teachings of 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: 10 Figure 1 is a cross section through an embodiment of the transdermal delivery devices according to the 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 :(Figs. 5, 6 and 7) vs. time for embodiments of this 10 invention; and 'Figure 4 compares plots of its in vitro in release rates at 32°C directly into a sink vs. time with the in vitro at 32 0 C through human cadaver skin into a sink vs.

time obtained from an embodiment of this invention.

Referring now to Figures 1 and 2 (like reference .numerals referring to common elements), transdermal 9 9 delivery devices 1 and 10 according to this invention are ab"e shown. Devices I and 10 are formed of an impermeable backing 2, an agent reservoir 3, an agent release rate 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 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 11 of the agents could be a drug and another agent could be a permeation enhancer or another drug, for example.

The embodiments of Figures 1 and 2 differ in that the agent reservoir 2 of the embodiment 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 10 has sufficient viscosity to maintain its structural S"integrity without a peripheral or circumferential seal.

e Although Figures 1 and 2 relate to laminated devices, other arrangements of the adhesive, reservoir and rate '"2controlling membranes are usable and include, for example, an adhesive having microcapsules of the agent within a rate controlling membrane dispersed therethrough oo, as shown in aforementioned patent No. 3,598,123.

According to this invention, transdermal delivery Sdevices 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 agent that is released from the device so that the agent can be administered to the patient in a predetermined and controlled manner. The in vitro agent release rate or flux from a transd3rmal delivery device directly into an infinite sink as a function of time can be considered to consist of two phases, a first, initial "transient" 12 phase, and a second, subsequent "steady-state" delivery phase. During the initial transient phase, the agent is released 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 t 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 ,te.o 10 commences.

t shown in Figures 5 and 6 represents the time :I ss 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 whereas prior art devices having unit activity reservoirs and release rate-controlling membranes exhibit theoretical release rates that vary with to, they remain constant.

Devices according to this invention exhibit a theoretical release rate which varies as a function of t n where n 0 and preferred embodiments exhibit in vitro release rates which approach those obtained from zero order devices.

According to preferred embodiments of this invnntion, the steady-state in vitro release rate can be maintained substantially constant from the termination of -13the initial transient phase until the expiration of the predetermined administration period. As used herein, 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 to mean any material 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 colicentration at which irritation problems or unacceptably high initial transdermal agent fluxes, for S' 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 the invention, preferably have the :o following characteristics: 14 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 is less than S4. The reservoir 3 comprises the agent dissolved in a l:ots: 10 diluent with respect to which rate controlling membrane 4 9.44 is substantially impermeable; 5. In preferred embodiments the initial loading of the agent in reservoir 3 is sufficient to prevent the

V

activity of the agent in the reservoir from decreasing by more than about 75% and preferably no more than about St" during the predetermined period of administration; and r• g t6. In preferred embodiments the thicknesses of the adhesive, 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.

To design a system according to our invention, the permeability of skin to the agent to be delivered, the amount of agent required to saturate the agent binding sites in the skin, the maximum activity of agent in the adhesive layer than can be tolerated without loss of adhesive properties and without producing undesirable initial drug pulses, skin irritation or undesirable 15 sensations would be determined by suitable in vitro and in vivo tests. Having determined the maximum allowable activity of agent 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 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 r r 1 0 correspond approximately to the amount of agent needed to ee Ot saturate the agent binding sites in the skin below the par om. delivery device.

In preferred embodiments the equilibrated agent *4 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 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 be selected, with respect to the thicknesses of the rate controlling membrane and the adhesive layers, such that 16 at least half, and preferably substantially more, of the initial equilibrated agent loading is in the reservoir.

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 vitro flux of the agent through skin (which would produce about 50% device control) and preferably substantially less. If the skin flux is greater than the membrane flux by a factor of about 2.4, for example, 10 approximately 70% of the rate control is obtained from the device. Suitable materials from which the various no.o 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 *see eo"e 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.

17 In order to deliver adequate amounts of nicotine from a reasonably sized system, the target steady-state in vivo delivery rates are within the range of 250-4000 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 cm 2 A one day delivery period can readily be obtained from subsaturated devices of this invention, and T"O 10 administration periods of at least 8-10 hours and up to 6* a about 3 days can be attained by varying the thickness of 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 "0 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 from 0.15 to 0.50 and preferably from 0.2 to 0.40. 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 pg/cm 2 /hr and preferably below 120 yg/cm 2 /hr in the steady state phase. Typically the 18 flux will be in the range of about 30 to P.g/cm 2 /hr.

The equilibrated nicotine loading in the reservoir 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 of nicotine in each layer of the device can be readily 10 varied without changing the activity, simply by 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 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.

The rate controlling membrane may be of a dense polymer film that has the requisite permeability to -19nicotine. 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) from the rate controlled transdermal therapeutic system of this invention is given by the follow;.ng relationship: x net system which can be determined from the following equation: net /system system /skin] 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 be: Jnet /system 1] -1 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 25 permeability to the diluent may not adversely affect the operation of the device. Examples of the types of polymer films that may be used to make the membrane 16 in U.S. Pat. Nos. 3,797,494 and 4,031894, are disclosed in U.S. Pat. Nos. 3,797,494 and 4,031,894, piS^

I

20 both of which are incorporated herein by reference.

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

The composition and thickness of the adhesive layer is selected so as not to constitute a significant permeation barrier to the passage of nicotine. The adhesive material is selected from known materials having a high permeability to nicotine which is also such that 10 it is compatible with nicotine at the activity chosen for 4.

*the system. Amine resistant silicone adhesives are particularly suitable. These compounds may be modified with silicone oil to obtain the desired tack.

EXAMPLE 1 .4 4 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 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 0 C were determined and are shown in Table I. Nicotine flux data 21 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 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 15 Subsaturated nicotine transdermal delivery devices (1 cm were fabricated having a nicotine loading of about 5 mg/cm 2 comprising a 30 wt% nicotine/70 wt% EVA 40 reservoir composition (0.30 nicotine activity), a 0 2 mil rate controlling membrane and a 2 mil amine resistant adhesive layer (Dow Corning X7-2920 with 5 wt% 20 silicone fluid). The in vitro release rate at 35 0

C

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.

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

22 Secoverine normally exists as a racemic mixture of d and 1-isomers, the d-isomer, dexsecoverine, being the biologically active ingredient. We have determined that dexsecoverine diffuses through normal skin at 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.

1 0 EXAMPLE III 0 Transdermal delivery devices for the controlled delivery of dexsecoverine were prepared utilizing Dow Corning DC 355 silicone adhesive as the highly permeable a medical adhesive, EVA VA) as the rate controlling membrane, EVA (40% VA) as the non-diffusible drug reservoir diluent, pigmented medium density a 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 and dexsecoverine are solvents for the adhesive and form solutions therewith at concentrations of 300 mg/cm 3 or more. Adverse effects on adhesive properties have been observed when agent concentration reached about mg/cm 3 23 Thus, according to the preferred dexsecoverine delivering embodiments of this invention, it is desirable to maintain the agent concentration in the adhesive below about 45 mg/cm 3 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 10 skin, the contribution to the pulse of each such layer 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 to. a 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 9 0to. preferred embodiments and drug reservoirs of approximately 5-20 mils were tested. A 5 mil thickness Swas 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 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 24 systems and illustrate the effect of varying reservoir thicknesses on in vitro release rates and flux.

TABLE II Drug Source Drug Activity Membrane 1.00 0.06 LDPE EVA (9%VA) Dexsecoverine 0.15 0.10 0.20 LDPE EVA LDPE (9%VA) Secoverine 0.20 0.20 LDPE LDPE 9 99 .9 9 0909 '.49 9~e '9.9 Membrane Thickness 10 (mils) 1.0 4 Adhesive Thickness (mils) 1.7 1 Reservoir Thickness (mils) 5 5 Initial Burst (pg/cm 2 from 20 membrane 170 142 from adhesive 1325 84 TOTAL 1495 226 Avg. Steady State In vitro Release Rate at 320C (pcg/cm 2 /hr) 57 3 ,0 1.0 2.0 1.3 1.3 1.3 .8 1.7 1.4 1.7 1.7 1.7 .0 5.0 5.0 20.0 10.0 49 9

S**

S00 99.9 26 199 225 118 109 227 .5 8.2 22 Range(over 24-96 hr) 60-54 75-5.5 10-7 24-18 We have determined that to achieve anti-spasmodic activity from the continuous transdermal administration of secoverine, approximately 1 to 10 nanograms/ml of dexsecoverine should be maintained in the plasma. We have also discovered that the permeability of average 25 human skin when exposed to unit activity sources of either secoverine or dexsecoverine appears to be in the range of approximately 20 to 60 pg/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 60 cm 2 Delivery periods of about 10 3-5 days can be obtained from subsaturated devices of Table 2, and administration periods of up to about 7 days *0@ oe: can be attained by increasing the thickness of the reservoir to about 10 mils.

06 *0 EXAMPLE IV

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Subsaturated transdermal delivery devices similar to those of Example III, but intended to deliver

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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 are fabricated using a highly permeable, amine resistant silicone adhesive available from Dow Corning, (X7-2920) or polyisobutylene/mineral oil adhesives, an impermeable backing, and an 8 mil-thick reservoir layer having an initial benztropine loading of 5, 10, and 20 weight percent equivalent to activities of 0.125, 0.25, and The approximate in vitro release rates directly into an aqueous bath at 32-35oC to be obtained from such -26devices, using 1 mil LDPE rate-controlling membranes, are 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 lg/cm 2 /hr and systems as described above can deliver benztropine in vivo at therapeutically useful rates of 10 to 40 ig/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 delivery devices for use in clinical testing were fabricated as set forth generally in Example IV from a 10% benztropine in 90% EVA reservoir composition into 5 cm 2 patches using mil LDPE rate controlling membranes and 1.8 mil amine 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 a daily basis, anticholinergically effective transdermal delivery of benztropine can be obtained.

EXAMPLE VI Transdermal nicotine delivery devices fabricated as set forth in Example IV were cut into fifteen square centimetre devices, using LMW:HMW PIB adhesive blends of V l -27- 90:10 and 85:15 having a nominal average administration rate of about 1 mg/hr.

These devices were used in clinical studies to evaluate their safety and efficacy as an aid to the withdrawal of smoking in healthy adult cigarette smokers, motivated to stop smoking. The devices were compared to placebos in blind studies for periods of four weeks in a pilot study and six weeks in a definitive study in different treatment regimes involving application upon waking in the morning with removal and reapplication 24 hours later and application upon waking and removal at bedtime, approximately 16 hours thereafter, followed by reapplication in the morning.

Safety was evaluated by noting any reactions that may have occurred during the study and efficacy was evaluated by determining the number and percentage of patients who smoked no cigarettes during the last two weeks of the pilot study and the last four weeks of the definitive study as ascertained by patient questionnaires and corroborated by measurement of expired carbon So: monoxide at levels of less than or equal to 8 parts per 6:00 *as: 0:64 25 million. Morning craving for cigarettes, incidents of insomnia and severity of withdrawal symptoms were also assessed. A follow-up after approximately 6 months on °0° those patients who smoked no cigarettes during the last se 0.

6 -28two weeks of the study was also made.

Based on the results of these studies it appears that the transdermal nicotine in both 16 and 24 hour regimes was more effective, as compared to the placebo, in both short term and long term smoking cessation and that the incidence of serious skin reaction was low. In a sensitization study using 2.5 cm 2 test samples formed from the formulation using the 90:10 adhesive blend described above only 3 out of 186 participants became sensitized.

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.

0 ft *00 o *o

Claims (17)

1. A transdermal nicotine delivery device for delivering nicotine during a predetermined administration period and utilizing an in-line adhesive comprising, in combination:- an agent reservoir containing nicotine dissolved therein at an initial equilibrated thermodynamic activity no greater than 0.50 and at an initial equilibrated loading sufficient to prevent the thermodynamic activity of nicotine in said reservoir from decreasing by more than 75% during said administration period; and b) in-line adhesive means for maintaining said agent reservoir in agent transmitting relationship to the skin, said adhesive means having a high nicotine solubility.

2. A device according to claim 1, wherein said initial equilibrated activity is in the range of from 0.05 to 0.50.

3. A device according to claim 1 or claim 2, wherein said initial equilibrated activity is in the range of from 0.20 to 0.40.

4. A device according to any one of the preceding claims, wherein said reservoir contains sufficient 0* nicotine to administer nicotine for an administration period of at least 16 hours. A transdermal delivery device utilizing an in-line k\ adhesive having a high nicotine solubility for delivering -I nicotine during a predetermined administration period comprising an agent reservoir containing nicotine dissolved therein at a concentration less than saturation with said in-line adhesive disposed in the path of nicotine migration from said reservoir to the skin, the improvement comprising: an initial equilibrated activity of nicotine in said reservoir does not exceeding 0.50; and the initial equilibrated loading of nicotine in said reservoir being sufficient to prevent the activity of nicotine from decreasing by more than during said administration period.

6. A device according to claim 5, wherein said initial equilibrated activity is in the range of from 0.05 to 0.50.

7. A device according to claim 5 or claim 6, wherein said initial equilibrated activity is in the range of fr(m 0.20 to 0.40.

8. A method for transdermally administering nicotine from a transdermal delivery device of any one of claims 1 to 7, which method comprises applying the device to the skin of a subject. «*9S

9. A method for transdermally administering nicotine ae 0 from a transdermal delivery device of any one of claims 1 4* to 7, which method comprises: applying said device to the skin of a subject when the thermodynamic activity of said nicotine in said reservoir does not exceed 0.50; and -31- removing said device from the skin before the activity decreases by more than A method according to claim 8 or claim 9, wherein when said device is applied to the skin the activity is in the range of from 0.05 to 0.50.

11. A method according to any one of claims 8 to wherein when said device is applied to the skin the activity is in the range of from 0.20 to 0.40.

12. A method for administering nicotine to an individual in need of such administration which method comprises: applying to the skin of said individual upon waking, a transdermal device according to any cne of claims 1 to 7 comprising a nicotine reservoir containing 0* a sufficient quantity of nicotine maintain a useful transdermal flux of nicotine from said device for a total time period of at least 16 hours; maintaining said device in nicotine transmitting relationship to the skin during waking 20 hours; and a removing said patch prior to sleep.

13. A method according to claim 12, wherein the time elapsed between application and removal of said device is about 16 hours.

14. A method according to claim 12 or claim 13, wherein nicotine is administered to said patient at an administration rate of about 250-4,000 pg/hr during a lv 0 1 cj substantial portion of the administration period. -32- A method according to any one of claims 12 to 14, wherein the average flux of nicotine over the administration period does not exceed 200 pg/cm 2 /hr.

16. A method according to any one of claims 12 to 14, wherein the average flux of nicotine over the administration period does not exceed 120 pg/cm2/hr.

17. A method according to claim 12 or claim 13, wherein the administration rate is maintained substantially constant over a substantial portion of said administration period.

18. A method according to claim 12 further comprising a nicotine release rate controlling means.

19. A method according to claim 18, wherein the means is a membrane which is dispersed in the path of nicotine *:0 migration from the agent reservoir to the skin.

20. A method according to claim 12 for administering nicotine to an individual in need of such administration •which method is substantially as herein described. DATED this 14th day of November, 1995 20 ALZA CORPORATION Attorney: IAN T. ERNST Fellow Institute of Patent Attorneys of Australia of SHELSTON WATERS 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 10 administration. The thicknesses of the adhesive 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 as benztropine, secoverine, nicotine, arecoline, polyethylene glycol monolaurate, glycerol monolaurate, S* glycerol monooleate and ethanol, for example. FIG. FIG. 1