CA1261267A

CA1261267A - Transdermal system for timolol

Info

Publication number: CA1261267A
Application number: CA000497479A
Authority: CA
Inventors: Joseph V. Bondi; Alice E. Loper; Edward M. Cohen
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1984-12-17
Filing date: 1985-12-12
Publication date: 1989-09-26
Also published as: US4752478A; JPS61145113A; EP0186071A3; DE3584766D1; EP0186071B1; DK581685D0; ES8702153A1; DK581685A; ES550011A0; ATE69720T1; EP0186071A2; JPH0684304B2

Abstract

TITLE OF THE INVENTION
TRANSDERMAL SYSTEM FOR TIMOLOL

ABSTRACT OF THE INVENTION
A method and device for administering timolol for an extended period is described. By the method and device, transdermal application of timolol may be accomplished with substantially no irritation to the skin.

Description

qi`7 TIl'LE OF INVENTION
. . . _ TRANSDERMAL SYSTEM FOR TIMOLOL

The present invention relates to transdermal application of timolol, more particularly to a method and device for application over an extended period of time with a minimal amount of the undesirable side effect of irritation and/or erythema of the skin.

BACKGROUND OF THE INVENTION
_ Transdermal methods have been devised for administering controlled quantities of systemically active drugs. However, to be useful, the drug must be permeable through the skin. Even if permeable, the method may still not be useful because of irritation caused to the skin. This is especially important with certain drugs in which the continuous supplying of a therapeutic drug over an extended period of time is highly desirable. Unfortunately,

2~

, 04910/0825~ - 2 - 1720~

some drugs such as timolol while adaptable to therapy via a transdermal system by virtue of being absorb-able through the skin, heretofore have not been adaptable to long term therapy because of the irritation caused to the skin. By "extended period"
as herein employed is meant time which is long enough to be measured in numbers of days.

STATEMENT OF THE INVENTION
According to the present invention it has been discovered that the drug timolol may be administered transdermally over an extended period to obtain efficient beta blockade with substantially no irritation or very minimal irritation to the skin by supplying said timolol at a controlled low zero order rateO By employing an appropriate controlled rate of delivery to the skin, it has been found that thera-peutic doses of timolol may be supplied over an extended period of time.
DESCRIPTION OF THE_INVENTION
There has been discovered a method of administering timolol transdermally over an extended period with substantially no irritation to the skin.
By supplying timolol at a zero order rate of not greater than 20 micrograms per square centimeter per hour (20 mcg/cm2/hr~. A useful range is in the order of from about 7 mcg/cm2/hr to about 15 mcg/cm /hr, with a preferred range of from about 7 mcg/cm /hr to about 13 mcg/cm2/hr with about 12 mcg/cm2/hr being most preferred. The lower range for administration accomodates patients with high dermal sensitivity. When the preferred rates are employed, it has been found that there is minimal irritation and by adjusting the size of the patch to provide the amount necessary for the essential therapeutic dose, an excellent complete ~-blockade can be achieved, as can be seen, for example, in a significant reduction in exercise heart rate.
The method of the present invention is most readily carried out by means of a transdermal delivery system and the patch or bandage through which it is effected and which comprises an aspect of the present invention. As herein employed the expression "transdermal delivery system" is employed to refer to the essential components for carrying out the present invention, namely, the backing member, the drug reservoir and the rate-controlling member.
By the expression "transdermal patch" or "transdermal bandage" is meant the transdermal delivery system plus a means to attach the system to the skinO The transdermal system and transdermal patch are described with reference to the drawings.-Figure 1 is a fragmentary enlarged cross-sectional view depicting the essential component elements of a transdermal delivery system of a transdermal patch~
Fi~ures la, lb, lc, ld, and le are frag-mentary enlarged cross-sectional views of several embodiments of component elements of a transdermal delivery system.
Figure 2 is a cross-sectional view illus-trating one embodiment of a transdermal patch.
Figure 3 is a cross-sectional view illustrating another embodiment a transdermal patchO

.. . . . . .

' i'7 Referring to the drawings, there is shown a transdermal delivery system 10 which comprises an impermeable backing member 11, a drug reservoir member 12 consisting of the drug 13 dispersed in carrier 14, and a rate controlling member 15, said system which together with a means to attach the system to the skin forms a transdermal patch or bandage. The rate controlling member may be (a) a microporous membrane 15a as seen in Figure la, (b) a diffusion controlling membrane 15b as seen in Figure lb, (c) a rate controlling adhesive as seen in Figure lc, (d) a combination of a microporous membrane 15a and an adhesive layer having rate controlling properties 15c which together perform the rate controlling function as seen in Figure ld, or (e) may be a combination of a diffusion controlling membrane 15b and a rate controlling adhesive layer 15c as seen in Figure le. When an adhesive is contributing to or performing a rate controlling function, the adhesive in these instances is performing a dual function of rate control and of attaching the transdermal delivery system to the skin.
Figure 2 depicts an embodiment of a transdermal patch in which the drug reservoir is a solid. Figure 3 depicts an embodiment in which the drug reservoir is a semisolid or vintment ~herein the face of the backing member contiguous to the drug reservoir is joined at the edges to the face of the microporous membrane contiguous to the drug reservoir. The edges are joined preferably by heat-sealingr but also may be sealed by crimping, using sealants, and by other means for effecting a seal.

'7 The impermeable backing member 11 is preferably of a polyester occlusive film. Other materials s~itable for a backing include foil, polyethylene coated foil, polyethylene~ Mylar~
polyester, polypropylene and the like.
The drug reservoir is a dispersion of timolol in a carrier. The carrier may be a solid, i.e., of a non-mobile or non-flowable material or may be of a semi-solid preparation often referred to as ointments. Suitable semi-~olid carriers include gelled mineral oil e.g., mineral oil gelled with 5 percent polyethylene (commercially available as Plexi Gel 50W from Parke Davis), polyisobutylene, aluminum stearate, or even propylene glycol, or fatty acid esters. Solid carriers include silicone, acrylic adhesive, plasticized polyvinyl chloride, and the like. By "drug reservoir composition" is meant timolol in one of the aforementioned carriers.
Membrane l5a, a microporous membrane, may be of any porous material permitting the passage of the drug and is inclusive of microporous polypropylene, microporous nylon, microporous polycarbonate and the like. The membrane layer may be a single layer or may be of multiple layers of selected microporous materials which have been laminated together. The drug passes through the micropores which are filled with mineral oil or other carrier material during fabrication. The control effected by the membrane is not by the dissolution of the drug in the membrnae material but merely in travel through the pores.
Membrane 15b, a diffusion controlling membrane, may be of materials in which the timolol , , ~. : . ;, .. ' , dissolves and is inclusive of silicone, ethylene vinyl acetate and polyurethane.
When the rate controlling member is an adhesive rate controlling member 15c, the preferred adhesive is selected from a class of rubber based adhesives. Other adhesives include suitable medical grade adhesive which permits migration. Examples of such adhesives include polymers of esters with acrylic acid, copolymers of the esters with other acrylic derivatives such as acrylic acids, acryl~
amides, elastomeric silicone polymers, vinyl polymers such as polyvinyl alcohols, polyvinylpyrrolidones, polyvinyl acetates, blends of cellulose derivatives and natural gums such as guar gum, pectin and the like. When the adhesive is to be employed solely as attachment means for a patch, an adhesive having no rate-controlling properties is employed. Generally, such adhesives are acrylate based adhesive systems.
The rate of travel of ~he drug is controlled by several factors, the porosity or diffusion coefficient of the drug in the membrane, thickness of the membrane or the rate controlling adhesive, and the solubility of the drug in the carrier material of the drug reservoir.
The size oP the patch depends on the required surface area of the drug which in turn depends on the amount of drug which must be delivered employing a rate of delivery which is no greater than about ~0 mcg/cm2/hr. Generally, a suitable patch can be fabricated in the size range of about 13 to about 30 square centimeters~ A smaller patch would usually necessitate a higher rate of delivery thereby '~ ~

rendering the use likely to be accompanied by irritation. A larger patch would be undesirable from the standpoint of inconvenience to the patient to wear s~ch a large device. By proper selection of size and delivery rate, a patch can be found which is suitable for supplying the necessary therapeutic dose while accomodating to the patient's particular skin sensitivity.
The transdermal patch may be fabricated by uniformly applying a drug reservoir composition to a backing member, thereafter applying a rate-controlling member, and if necessary, i.e., when rate-controlling member is a membrane and non-adhesive, applying an adhesive composition. If the drug reservoir is semi-solid, then a membrane must be employed and the membrane must be sealed to the backing layer before applying ~he adhesive. After application of the adhesive, the bandage may be cut to the desired size. It is to be understood that in the preferred article of the present invention, an adhesive layer is the means for attaching the bandage to the skin. However, a separate bandage material may be employed to attach the transdermal delivery system of the present invention to the skin.
Thus, initially a selection is made of the drug reservoir composition and the rate controlling member, and the determination of flux is made in vitro. For the determination of flux, a dispersion of timolol in the selected carrier is placed behind the selected membrane material in a diffusion cell and rate of release into an isotonic phosphate buffer is determined. If a constant rate of release into a ; , .

;'7 perfect sink is obtained, i.e., no accumulation occurring after passage across the membrane, the measured flux may be described according to the following equation:

p S
J ____ h If the membrane is a porous membrane, E is membrane porosity, D is the diffusion coefficient of the drug through the reservoir material, Kp is 1, Cs is the drug concentration in the reservoir and h is the membrane thickness. If the membrane is a non-porous diffusion controlling membrane, E is 1, D is the diffusion coefficient of the drug in the membrane, Cs is the solubility of the drug in the reservoir and Kp is the partition coefficient between the drug in the membrane and the drug in the reservoir.
Thus, for a given reservoir and membrane of known porosity or diffusion coefficient with respect to drug and thickness, flux can be determined experimentally. Since D Kp which can be calculated from the above relationship will be constant for the same reservoir material and membrane, it is evident from the equation that the flux can be changed by modifying the thickness of the membrane. Depending on the rate desired, this can be accomplished by employing multiple thicknessesO Thus~ to decrease the flux to one third, a triple thickriess of the membrane would be employed~ When the rate control-ling member is an adhesive layer, flux can be .

, determined in a similar way after initially forming an adhesive layer by casting an adhesive composition onto a release liner, then drying to form an adhesive layer which then may perform as a membrane. After deter~ination of the relation of flux to a particular thickness of adhesive, controlled application of adhesive of the desired thickness may be employed in manufacture. Alternatively, an adhesive having the desired thickness may be manufactured separately and applied by laminating methods known in the art.
For other modifications, a combination of membranes may be employed. When different membranes are employed, the relationship among the resistance offered by the individual membranes and the net resistance may be represented by the formula:

+
Jnet Jl J2 where Jl and J2 are flux values for membranes 1 and 2. Thus, if a layer of membrane 1 and a layer of membrane 2 are employed, the resulting membrane would have flux represented Jnet obtained by calculation.
Conversely, desiring a particular flux~ the selection of a second membrane to be employed with the one already at hand can be accomplished readily. Thus, by combining membranes of different porosity, any desired flux may be readily attained.
The following examples illustrate the invention but are not to be construed as limiting:

P~7 Example I
A. Preparation of Patches Transdermal timolol patches of 10 centi-meters square in size, containing timolol in gelled mineral oil and designed to deliver approximately 32, 13.5 and 6.7 micrograms per square centimeter per hour (mc~/cm2/hr) through a microporous membrane were prepared.
As a first step in the preparation of the patches, commercially available membrane materials of known porosity and thickness were employed to determine the release rates for timolol through a single layer of each membrane into an isotonic phosphate buffer and to calculate the necessary combination of membranes to provide appropriate delivery rates. Commercial microporous polypropylene membrane (sold by Celanese Corporation under the tradename Celgard~2402~ of a thickness of 0.005 centimeter and a porosity of 38 percent was found experimentally to have a flux of 40 mcg/cm2/hr.
The concentration of timolol hemihydrate in solution in gelled mineral oil had previously been determined to be 7000 mcg/ml in the presence of excess solid.
Substituting these figures in the equation p S
h for measured flux, the term D Kp was calculated to be 7.5 x 10 cm/hr which would be constant for the membraneO By appropriate substitution, a membrane .

i 7 0491O/0825A - ll - 17208 having a flux of approximately 13.5 mcg/cm2/hr was determined to be one having three thicknesses of the membrane and a membrane having a flux of approxi-mately 6.7 mcg/cm2/hr was deterlmined to be one having six thicknesses of said membrane (Celgard 2402).
In a similar manner, commercial microporous polypropylene membrane having a thickness of 0.0025 centimeter and a porosity of 45 percent (Celgard 2500) was determined experimentally to have a flux of 160 mcg/cm2/hr. By substituting the fluxes of the two membranes into the equation:

+
Jnet Jl J2 the Jnet was found to be 35 mcg/cm2/hrO Thus, by using one layer of Celgard 2402 and one layer of Celgard 2500, a membrane having a flux oP about 32 mcg/cm2/hr was providedO
The patches then were prepared by (a) applying to each lO centimeter square of polyester coated aluminum foil backing material, approximately 250 milligram portions of 40 percent (weight/weight) timolol ointment ~timolol hemihydrate in a commercial gelled mineral oil of 5 percent polyethylene in heavy mineral oil), (b) placing the appropriate previously determined membrane on the timolol ointment, (c) applying pressuxe to uniformly spread the ointment constituting the drug reservoir between the backin~
and the membrane and (d) heat sealing the edges and cutting when necessary to a uniform size. In -addition to the foregoing, a placebo patch was prepared of gelled mineral oil for the drug reservoir and one layer of Celgard 2402 and one layer of Celgard 2500 for the membrane.
The actual ln vitro delivery rates of the patches were determined by the U.S.P. Paddle Method.
The Paddle Method determination is an U.V. detection of released material. In this case, the timolol (as a free base) was released from the patches when the patches were subjected to pH 7.4 in isotonic phosphate buffer. In the determination, the patches were placed in the buffer solution in flasks fitted with paddles set 8 centimeters from the bottom and agitated at 32C. Samples were withdrawn over a seven day period and absorbance determined and compared with standard timolol solution at 294 nm.
The amount of timolol free base released from the patch was determined according to the formula:

Amount = Au x Ws x Du x 0.732 x P
As Ds- 100 where Au is UV absorbance of sample at 294 nm, As is absorbance of a timolol maleate standard at 294 nm, Ws is weight of timolol maleate standard (milligrams), Du is dilution factor for sample, 0.732 is conversion factor from timolol maleate to free base, Ds is dilution factor for standard and P is percent purity of standard.
Employing the foregoing methods, patches hereinafter designated A, B, C, and D were prepared designed to deliver timolol base at rates of 31~7, '7 O991o/0825A - 13 - 17208 13.2, 6.7, and 0 (placebo) mcg/cm2/hr respectively.
The actual in vitro delivery rates for the timolol containing patches determined as above described were 31.7 ( 10.3~), 13.3 (+1675%) and 8.6 (+2.7%) mcg/cm /hr.

~. Clinical Evaluation . _ Clinical evaluation was carried o~t on twelve human volunteers (subjects). In the study, four patches were placed in the deltoid region of the arms, two on each arm. The patches were held in place with commercially available medical grade polyurethene tape. In ten of the subjects, each of the four different patches were employed. In two of the subjects, one B (15 mcg/cm2/hr) patch and three placebo patches were employed.
The subjects were divided into two groups:
one group wore the patch or 96 hours (4 days) and the other group wore the patch for 168 houxs (7 days). At the end of 96 hours or 168 hours, the patches were removed and each pa-tch analyzed for timolol content as an indication of timolol not delivered from the patches. The difference between the initial timolol content of the patch (determined by accurate weight determination of the ointment in each patch) and the timolol remaining was taken as an estimate of timolol delivered and employed to determine apparent rate of delivery (flux). ~or determining the timolol remaining a~ the site of application, the tape, the patch, and gauze wipings of the skin were combined and timolol extracted therefrom with chloroform and the timolol partitioned ... .

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i'7 into O.lN H2S04 and determined by high pressure liquid chromatographic analysis at 294 nm against timolol standard according to standard methods. The skin at the time of removal of the patch was examined for erythema and scored employing the Draize method.
(A visual scoring method, c.f. Rothman, S., "Physiology and Biochemistry of the Skin", p. 54, University of Chicago Press, 19!54.) Another observation was made 24 hours later. The results are seen in Tables I and II. It is seen that there is greater indication of erythema 24 hours after removal than at the time of removal and therefore in determining the rate for adminis-tering a therapeutically effective amount of timolol in a long term application without irritation, the determination must be made at twenty-four hours or some time after removal of the patch.

; 7 TABLE I
96 Hour Study Flux Draize Scores ... _ . .. ..
(Estimated) 96 Hour 96 + 24 ~our Subject (mcg/cm2/hr) Reading Reading A BC A B C D A B C D
I 24.4 15.8 16.3 1 1 1 0 3 1 0 0 II 20.3 12.6 4.1 0 0 2 1 0 0 0 0 10III 19.9 12.5 3.0 0 0 0 0 3 3 2 0 IV 28.4 8.3 4.3 0 0 1 0 2 2 0 0 V 31.6 19.9 19.2 0 0 1 0 1 1 1trace VI -- 18.8 -- 0* 1~5 1* 1 1.5* 2.5 0~5* 0.5 * Asterisks indicate placebo scores. Subject VI had 1 timolol (Patch B~ and 3 placebo patches (A, C, D) applied.

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TABLE I I
168 Hour Study Flux Draize Scores (Estimated) 168 Hour 168 + 24 Hour Subject (mcg/cm2/hr) Reading Reading A B C A B C D A B C D
.. . , ~
VII 19.2 14.3 9.7 0 0 0 1 1.5 1 1.5 VIII 28.8 18.4 8.0 1 1 0 0 2 2 1 0 10IX 29.9 27.7 5.9 1 1 0 1 1 2.5 0.5 0.5 X 21.6 13.0 9.4 1 1 1.5 1 0 1 0 0 XI 27.7 11.9 8.1 1 0 1 1 2 2.5 2 XII -- 12.2 -- 0* 0 0* 0 0* 1~5 1*

_ * Asterisk indicates placebo scoxes. Subject XII had 1 timolol (B) and 3 placebo patches (A, C, D) applied).

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'7 Example II
A similar study was carried out with patches contructed to have a delivery rate of 12 mcg/cm2/hr and in two sizes, 10 cm2 and 16 cm2 with an additional difference that after the fabrication of the patch, polyisobutylene/mineral oil (40/60) adhesive layer 3~5 mil thick was applied to the membrane surface.
The drug reservoir for Patch A, a 16 cm2 drug bearing patch consisted of timolol hemihydrate in gelled rnineral oil (25 percent w/w as free base in the 5 percent polyethylene in heavy mineral oil).
The drug reservoir for Patch Br a 10 cm2 drug bearing patch consisted of timolol hemihydrate in gelled mineral oil (12 percent w/w as free base).
Placebo patches, C (16 cm2) and D (10 cm2) were prepared also. The membrane employed was microporous polypropylene of porosity 38 percent and thickness of 0.02 centimeter (Celgard 4 ply 2400) for a theoretical release rate of 11.25 mcg/cm /hr. The actual in vitro release rate was determined using the ~.S.P.
Paddle Method described in Example I.
Clinical studies were carried out on twelve human subjects. On the first day of the study, 16 cm2 patches of types A and C were placed on the arms of subjects. On the fifth day (after 96 hours) 10 cm patches of types B and D or two D type patches were placed on the arms, also in the deltoid region. The initial patches were retained in place.
On the seventh day, seven days from the start of the study (168 hours3 and three days (72 hours) from the time of attachment of the 10 cm2 patch, the patches ; ~ , , '' - ' ~ ' ' .

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were removed. The in vivo release rate (flux) was determined in a manner described in Example I and the arms of the subjects were examined at the time of removal and 24 hours after removal and scored by the Draize method as described in Example I. The results are seen in Table II.
In addition to the study of wearability and skin flux, efficacy determinations were also carried out by making periodic determinations of reduction in exercise heart rate by bicycle ergometry. Tho~e subjects who did not show a 25 percent reduction at 96 hours were given the lO cm2 patch. Also others, randomly selected were given lO cm2 patches. The results (percent reduction in exercise heart rate) at 168 hours are included in the table together with the maximum probable daily dose calculated as follows:

Flux x Surface Area of Patch x 24 hours.

The results show effective reduction of exercise heart rate.

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- : , , Heart llax Flux Drai~eScores Rate Daily in ViYo Tim~ 168 168~24Rcduction Dose Sub.jectmC~/~m2/hr~hrs~hours hour~ (%)~ m~c 11 . 5 168 o 2 ~25 ( 7 . 8 7.4 72 1 1.5 2 17 . 7 168 0 o (20 ( 9 . 4 10.8 72 1 0

3 8 . 3 168 0 2 (26 ( 5 4 9.2 72 1 0 15 4 11 . 7 168 0 o (21 ( 4 . 5 -------- 7 2 ---------------- ( ( 11 . 7 168 0 o (25 ( 6 . 9 10.~ 72 1 0 6 7 . 8 16~ 1 2 (19 ~ 5 . 3 ~.6 72 1 0 7 9 . 4 168 1 0 (31 ( 3 . 6 8 ~.3 16~ 1 ~33 ( 5.3 9.2 72 0 0 30 9 8 . 1 168 1 1 (27 ( 5 . 5 5.B 72 0 0 ' :. ' ' ' "

. 7 04910tO825A - 20 - 17208 H~rt ~ax Flux D~aize Scores Rate Dall~
in vivo Time168 168~24 Reductlon Dose Subiect mc~cm2~hr (hrs~ hours hours (~) m~

10 lO.g 168 0 1.5 ( 28 ( 4.2 72 ---~

11 10.7 168 0.5 ( 2g ( ~.1 12 8.1 1~ 1 0 ( 17 ( 5.7 10.8 72 0 0 The maximum daily dose is based on the sum of the timolol received by the subject from the 16 cm2 ana 10 cm patches. *Indicates that these subjects did not requir~ a second patch at 96 hrs.

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Exam~le III
In vitro permeation of timolol through various adhesive and adhesive combination with auxiliary membrane as rate cont:rolling member were measured by applying 40 percent timolol hemihydrate in gelled mineral oil on a backing material and layered with an adhesive film with or without a microporous membrane material.
The adhesive films were prepared by mixing together an appropriate polymer with mineral oil, casting the mixture onto a silicone release paper and drying to obtain a film of the desired thickness.
The compositions of the films were as follows:
Film A 49~ low molecular weight polyiso-butylene (av. M.W. 10,500 by the Staudinger method) 21~ high molecular weight polyiso-butylene (av. M.W. 125,000 by the Staudinger method) 30~ mineral oil Film B 75% high molecular weight polyiso-butylene 25% mineral oil Film C 60% high molecular weight polyiso-butylene 40% mineral oil The auxiliary membrane, when employed, was microporous polypropylene of 38 percent porosity and thickness of 0.0025 centimeter.

, ,. . :

- ~.
-The results were as follows:

Auxiliary F'ilm Timolol Flow Film Membrane Thicknes,s ~ m2 ~

A No 0.058 cm. 47 B No 0.075 cm. 30 C Yes 0.080 cm. 24 B Yes 0.100 cm. 25 The results show that timolol flow can be controlled by employing an appropriate adhesive as a membrane and also by employing an adhesive in combination with a microporous membrane. The foregoing microporous polypropylene auxiliary membrane was previously found to release timolol from a similar reservoir at a rate of 80 mcg/cm2/hr.

Example IV
A rate controlling membrane providing suitable delivery rate for timolol therapy may be prepared from B film of Example III and Celgard 2402 film (38 percent porosity and O.OS centimeter thickness and having a flux of 40 mcg/cm2/hr). A
membrane so prepared would have a theoretical flux as determined by the series resistance equation of 17.1 mcg/cm /hr.

.

, , Jnet Jl J2

4~ 30 Jne~ = ~7.1 Example V
A transdermal patch is prepared by coating with the aid of heat a composition of a polyester occlusive film with a mixture of 40 percent timolol, 40 percent mineral oil and 20 percent high molecular weight polyisobutylene, allowing the coating to lS solidify and then applying to the surface thereof first a polyurethane film and thereater an adhesive film-forming composition 75 percent polyisobutylene and 25 percent mineral oil, drying and thereafter cutting to the desired 20 cm2 size.

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Claims

WHAT IS CLAIMED IS:

1. A transdermal delivery system suitable for administering timolol for an extended period which comprises:
(a) a backing member, said backing member being substantially impermeable to the drug, (b) a drug reservoir member, consisting essen-tially of tirnolol as the drug and carrier therefor, and (c) a rate controlling member, said member con-trolling the flow of timolol from the res-ervoir to the skin surface at a rate no greater than 20 micrograms per square centi-meter per hour.

2. A delivery system according to Claim 1, wherein the carrier for the drug is a gelled mineral oil.

3. A delivery system according to Claim 1, wherein the membrane is of laminated multilayers.

4. A delivery system according to Claim 1, wherein the rate controlling member is a membrane and said membrane is of microporous polypropylene, ethyl-ene vinyl acetate, silicone or polyurethane.

5. A transdermal patch suitable fox admin-istering timolol for an extended period which com-prises (a) a backing member of a material substantial-ly impermeable to timolol; (b) a drug reservoir member adjacent to and coextensive with one face of said backing member, said drug reservoir member conslsting essentially of timolol and a carrier therefor; (c) a rate controlling member superposed on the drug reser-voir member, said rate controlling member having the ability to control the flow of timolol at a zero order rate of no greater than 20 micrograms per square centimeter per hour and comprising at least one layer of a microporous membrane; and (d) an adhesive layer for affixing to the skin of a patient.

6. A patch according to Claim 5, wherein the carrier in the reservoir is gelled mineral oil and rate controlling member is (a) a film of polyisobutyl-ene and mineral oil or (b) microporous polypropylene membrane.

7. A patch according to Claim 5, wherein the carrier in the drug reservoir member is gelled mineral oil and the rate controlling member is a combination of (a) a film of polyisobutylene and mineral oil and (b) microporous polypropylene mem-brane.