WO1990000416A1

WO1990000416A1 - Moisture activated transdermal delivery device

Info

Publication number: WO1990000416A1
Application number: PCT/US1989/002711
Authority: WO
Inventors: Eun Soo Lee; David Edgren; Su Il Yum
Original assignee: Alza Corporation
Priority date: 1988-07-14
Filing date: 1989-06-20
Publication date: 1990-01-25
Also published as: DK66390A; AU4038089A; US4917895A; EP0380638A1; DK66390D0; JPH03500301A; KR900701346A

Abstract

An agent delivery device (10) is described which can provide shelf life stability of the system components, elimination of the initial burst of agent and delayed onset of delivery of a therapeutic agent. A metal layer (20) and an activating means (22) are inert when dry. Moisture activates the system (10) to cause the activating means (22) to erode the metal layer permitting the therapeutic agent to be released.

Description

MOISTURE ACTIVATED TRANSDERMAL DELIVERY DEVICE

Field of the Invention This invention relates to the transdermal delivery of drugs or other biologically active agents and particularly to novel methods and compositions for delaying the onset of drug delivery and for maintaining system stability during storage.

Background of the Invention The transdermal route of parenteral delivery of agents such as drugs, permeation enhancers, nutrients, hormones and other substances which are administered to a subject to produce a desired, usually beneficial, effect (hereafter referred to in their broadest senses as "agents") provides many advantages and transdermal systems for delivering a wide variety of drugs or other beneficial agents are described in U.S.Pat.Nos. 3,598,122, 3,598,123, 4,144,317, 4,286,592, 4,314,557, 4,379,454, 4,568,343 and 4,601,105 for example, all of which are incorporated herein by reference.

In these devices, the agent is released from a reservoir through the agent releasing surface of the device to the biological environment at which the device is applied. Such devices perform well in the administration of many agents but are not ideal for the administration of an agent whose dosage regime requires that the onset of therapeutic effect be delayed for a significant period of time after application of the device at the site of delivery. This is because the concentration of the active agent at the surface through which the agent is released, at the time of application, is typically at or above saturation and is capable of delivering agent at a rate that can give rise to therapeutic blood levels or can cause irritation of the skin. In some cases, the initial rate of release is unacceptably high and a method for reducing this initial "burst" of agent delivery is described in U.S.Patent No. 3,923,939 to Baker et al . Even in this patent, the agent releasing surface of the diffusional embodiment does contain agent and delivery commences immediately in the manner described above. The devices of this invention are particularly useful in administering agents which require an interruption in administration as a result of specific dosage requirements or to prevent tolerance from developing, For example, it has been suggested to administer nitroglycerin in a manner such that there is a drug free interval during sleep and administration commences shortly before awakening.

One of the advantages of transdermal delivery is the improvement in patient compliance that is obtained from the concurrent removal of one device and application of a new device at the same time which produces continuous administration of the agent when existing devices are used. According to this invention devices can be removed and replaced simultaneously while still providing interruption in administration and commencement of administration at an inconvenient time such as shortly prior to arousal from sleep. Another problem encountered with transdermal delivery devices systems is how to deal with active agents that are unstable in the presence of other components of a transdermal delivery device or that interact adversely with the adhesive of other components of the delivery device.

Summary of the Invention An object of this invention is to provide an agent delivery device which provides for delayed onset of agent administration. A further object of this invention is to provide an agent delivery device which does not deliver an initial burst of agent. Another object of this invention is to provide a delivery system where the adhesive and other components are isolated from the agent during storage.

These and other objects, features, and advantages have been demonstrated by the present invention wherein a medical device for administration of an agent to a biological environment according to a predetermined pattern comprises in combination: reservoir means containing agent and having a surface through which the agent is released to the biological environment; a metal layer disposed between the reservoir means and the biological environment, wherein said metal layer in a first state, is substantially impermeable to the passage of said agent and in a second state is permeable to said agent; and activating means by which the metal layer is changed from said first to said second state; whereby the passage of agent to the biological environment is impeded until the metal layer changes state.

Brief Description of the Drawings In the drawings, which are not drawn to scale, but rather are- set forth to illustrate the various embodiments of the invention and wherein like reference numerals designate like parts, the drawings are as follows:

Figure 1 is a schematic cross-sectional view of one embodiment of the transdermal drug delivery system of this invention;

Figure 2 is a graphic representation of the drug release rate profile of the system illustrated in Fig. 1; and

Figures 3, 4, 5. 6, 7, and 8 are schematic cross-sectional views of other embodiments of this invention.

Description of the Invention Embodiment This invention utilizes a metal barrier to prevent release of the agent from the delivery device until the desired time after application of the device to the biological environment. At that time, the metal barrier has been eroded to permit passage of the agent to the environment. Because of the very low permeability of metals, agent does not diffuse through the metal barrier in its first state until the metal barrier has been substantially converted to its second state. Once this occurs, the agent can commence passing at the desires rate thereby providing for a sharp and predictable onset of administration. Although, for purposes of illustration this invention will be described with respect to transdermal delivery devices, it must be recognized that this invention is applicable to agent delivery devices generally and in non-transdermal applications, certain components such as the adhesive and backing layers can be omitted. This invention also finds utility in connection with the delivery of agents such as benztropine, nicotine and secoverine, which tend to degrade other components of the delivery device upon prolonged exposure such as is the case under storage conditions. By using a metal barrier to keep the agent in its reservoir during storage, the degradation problem is avoided. This invention also provides delayed onset of drug delivery. This is useful in the delivery of drugs such as nitroglycerin where a typical regimen involves concurrent application and removal of transdermal delivery systems and delivery from the freshly applied system is not immediately desired. This invention also eliminates any initial burst of drug.

This is particularly beneficial in delivering agents that, at high fluxes, have a tendency to irritate the skin. These drugs include benztropine, secoverine and nicotine, as noted above, along with beta-blockers such as propranolol and timolol. In a preferred embodiment of this invention, a metal layer and an anhydrous activating means are disposed between the agent reservoir and the surface through which the agent is released from the device. The metal layer is disposed between the agent reservoir and the activating means and the activating means will typically be substantially free of agent. Water causes the activating means to react with the metal layer eroding it from its first dry, un-eroded state, having a low agent permeability, to the second eroded state having high agent permeability. Because metals are substantially impermeable to most agents there will normally be at least a factor of two, and preferably at least an order of magnitude difference in permeability between the first and second states.

In order to prevent premature erosion of the metal layer, the system is maintained in an anhydrous condition prior to use. Within these broad limitations, the specific structure of the drug delivery device is not critical to this invention.

As used herein, the expression "changes state" refers to the change occurring to the metal layer where in a first state, the metal is a barrier to drug diffusion and in a second state, it allows drug to diffuse therethrough. The term "erosion" is used herein to define various processes that can result in this change of state. Therefore, "erosion" is interpreted broadly to include, without limitation, corrosion, oxidation, dissolution ionization, disintegration and electrolytic reactions.

A transdermal delivery device of this invention is shown in Figure 1. The device 10 is comprised of an agent reservoir 12 formed of an agent dispersed within a matrix or carrier which may or may not be anhydrous, either as a solid, liquid or gel. The agent reservoir 12 may also contain stabilizers, thickeners, permeation enhancers or other additives well known in the art.

Reservoir 12 is covered by an impermeable backing 14 and the system 10 may be held in place by means of an in-line pharmaceutically acceptable contact adhesive 16 or other means such as an adhesive overlay or belt buckle or strap for example. A strippable release liner 18, adapted to be removed prior to application would normally be included in the packaged product. The device 10 further comprises a metal layer 20, an activating means 22 and, if desired, a rate controlling membrane 24. The various layers are laminated or otherwise assembled into a bandage having a predetermined size and shape as is known to the art.

Activating means 22 is comprised of a material which is inert or non- reactive with the metal in the anhydrous condition and which can erode the metal in the presence of water, to produce reaction products which do not adversely affect the skin. The activating means will typically be a weak oxidizing agent, weak acid or weak base. It is often advantageous to control the pH of the activating means, as the erosion rates of metals in aqueous media can be strongly dependent upon pH. The inclusion of an appropriate buffer therefore yields greater control over the delay time and also allows the pH to be maintained within a non irritating, biocompatible window of about 2-10 and preferably within the range of about 3-9. The matrix of the activating means is anhydrous and may be a solid or a non-aqueous liquid or gel. The activating means may also contain additives such as a drying agent to ensure that moisture does not prematurely activate the system. Suitable matrix materials include without limitation, natural and synthetic rubbers or other polymeric materials, thickened mineral oil or petroleum jelly. The activating means may also contain other materials such as dyes, pigments, inert fillers, permeation enhancers, excipients and conventional components of pharmaceutical products or transdermal therapeutic systems known to the art.

Rate controlling membrane 24 may be fabricated from permeable, semipermeable or microporous materials which are known in the art to control the rate of agents or fluids into and out of del very devices as are described in the aforementioned patents.

Device 10 can also operate without a rate controlling membrane 24 or the metal layer 20 can be designed to provide the rate control. The activating means 22 can be caused to form pits in the metal layer by appropriate masking of portions of the metal layer exposed to the activating means. Thus, in effect the metal layer can be formed into a rate controlling microporous membrane.

The delay or pulsed drug delivery attainable by our invention is preferably based upon an oxidation-reduction reaction where the activating means acts as an oxidizing agent with respect to the metal comprising layer 20. The relative strength of a material as an oxidizing agent is defined by its oxidation potential, a value assigned based upon a scale where the oxidation potential of the hydrogen half reaction:

H₂ + 2H₂0 > 2H₃0⁺+2e^" is arbitrarily assigned a value of zero. Substances having a higher oxidation potential will be oxidized by a substance having a lower oxidation potential. Substances such as metals having high oxidation potential are commonly referred to as reducing agents and substances such as oxygen or fluorine containing materials have a low oxidation potential and are referred to as oxidizing agents. Suitable materials for the metal layer are those having a relatively high oxidation potential and which are stable when dry, even if in direct contact with the activating means. However, in the presence of water as a vapor or liquid, the metal should react in a known manner with the activating means without producing reaction products which adversely affect the skin. The metal layer 20 is formed by thinly coating the rate controlling membrane 24 with a suitable metal. The metal can be applied by any of numerous methods which are known in the art, a typical example being vapor deposition.

Suitable materials for the metal layer include without limitation, metals such as magnesium within Group II A, metals such as silver and copper in Group I B and zinc in Group II B, metals such as titanium within Groups III A through VII B inclusive, metals such as iron and nickel in Group VIII, metals such as aluminum in Group III A and tin in Group IV A. The properties of these metals- are described in detail in the literature. See The Encyclopedia of Chemistry, editor George L. Clark, "Metals," pp. 643-648, Second Edition (1966) and Van Nostrand Reinhold Encyclopedia of Chemistry, editor Douglas M. Considine, "Metals," pp.569-570, Fourth Edition (1984).

As used herein, the term "metal" is also intended to include alloys. Alloys offer a high degree of control on the erosion rate and therefore on delay time. Electrode potentials, which are a measure of reactivity, and the erosion rate of alloys by the process of corrosion, have been reported. E.H.Dix Jr., R.H.Brown and W.W.Binger, "The Resistance of Aluminum Alloys to Corrosion", in METALS HANDBOOK VI, 916, American Society of Metals (8th ed). A small change in alloy composition results in a significant change in the erosion rate. For example, 6061 aluminum having 0.6% iron erodes five times faster than 6061 aluminum having 0.004% iron.

Suitable activating means include weak oxidizing agents and weak acids such as potassium phosphate monobasic (KH₂P0₄), sodium bitartrate, citric acid, sodium bisulfate, sodium phosphate monobasic, cupric chloride, sodium chloride, ammonium persulfate and the like. A suitable activating means is potassium phosphate monobasic (KH₂P0₄) whose aqueous solutions have a pH within the range of 4-7. A mildly acidic eroding agent contained within the activating means such as that attained with KH₂P0₄ is relatively harmless to human skin, as the natural pH of the human body is itself si ightly acidic.

At a pH of 4.5, the corrosion rate of zinc is about 25 mils (mil = 0.001 inch) per year. E.W.Horvick, "The Use of Zinc in

Corrosion Service", in METALS HANDBOOK VI, 1162, American Society for Metals (8th ed). In a transdermal drug delivery system according to this invention, a 0.4 micron layer of zinc, at a pH of 4.5 utilizing KH₂P0₄ as the eroding agent, would theoretically produce a delay time of about 5.6 hours as determined by the following equation: delay time = film thickness/erosion rate If a longer or a shorter delay time is desired, the thickness of the metal layer can be adjusted. For example, by decreasing the zinc thickness to 0.3 microns, the delay time decreases to 4.2 hours. Similarly, the delay time increases to 7.0 hours when a 0.5 micron thick zinc film is utilized.

Another suitable activating agent is sodium bitartrate. This is a weak acid and is especially suitable for use with a magnesium metal layer 20, since it rapidly erodes magnesium when in an aqueous environment.

The activating means may also contain small amounts of inorganic salts, to promote erosion of the metal layer. The salt can be non-oxidizing and acidic such as aluminum sulfate, zinc chloride and sodium acid tartrate; neutral such as sodium chloride and sodium iodide; or alkaline such as sodium borate and sodium phosphate. Additionally, the inorganic salt can be oxidizing and acidic such as ammonium persulfate and ferric sulfate; neutral such as sodium chlorate and sodium pyrophosphate; or alkaline such as calcium hypochlorite and sodium iodate. Refer to ASM Committee on Magnesium, "The Corrosion of Magnesium Alloys", in METALS HANDBOOK VI, 1086, American Society for Metals (8th ed).

In accordance with a preferred embodiment of the invention, the activating means 22 is activated by moisture, such as is readily available from the site of administration such as the cutaneous surface, particularly in occluded regions. Means 22 may alternatively be moistened by dipping into a liquid containing vessel immediately prior to application. In operation, moisture migrates into system 10 from the skin surface or other source, typically by osmosis or diffusion, passing through the adhesive layer 16 and into the activating means 22. The activating means hydrates and commences to erode the metal layer 20 at the metal layer-activating means interface 26. When the erosion is substantially completed agent will diffuse through the rate controlling membrane 24 and the eroded metal layer 20, and pass through layers 22 and 16 to the skin. Fig. 2 is a graphical representation of the theoretical release rate profile versus time (solid line) for the system illustrated in Fig. 1. The system 10 is positioned on the skin at time zero. From time zero until time t, moisture from the skin diffuses into, the activating means 22 and the metal layer 20 is eroded. At time t, the erosion is substantially complete and the agent begins to actually be released from the device. This is indicated by the rise on the solid line curve in Fig.2.

The graphical representation of Fig. 2 further illustrates the rapid onset of agent release attained according to this invention as compared to the gradual onset obtained when a hydratable polymeric material instead of a metal is used to produce the delay (dashed line) .

Another embodiment of the invention is shown in Fig. 3. Device 28 comprises rate controlling membrane 30 positioned between metal layer 20 and the activating means reservoir 22 which controls the rate at which hydrated activated means contacts metal layer 20. Thus, while the rate of agent leaving the reservoir is controlled by membrane 24, the actual onset of drug delivery is related to the rate at which the metal layer 20 erodes as controlled by means 30. In the embodiment illustrated in Fig. 4, device 32 shows the activating means mixed within the contact adhesive in a single layer 34. In operation, moisture migrates into the contact adhesive/activating means layer 34, hydrates the activating means which then erodes the metal layer 20. The erosion of metal layer 20 is followed by passage of drug from reservoir 12.

In the embodiment shown in Fig. 5, device has an activating means rate controlling membrane 30 positioned between the contact adhesive/activating means layer 34 and metal layer 20.

In the embodiment of Fig. 6, the activating means is not initially incorporated into device 38. Rather, the activating means is sweat, available from the skin and the metal layer 20 is formed from nickel or nickel alloy. Sweat contains sodium chloride which acts as a weak oxidizing agent with respect to such nickel or nickel containing alloys. J.D.Hemingway and M.M.Molokhia, "The Dissolution of Metallic Nickel in Artificial Sweat", Contact Dermatitis 16, pgs. 99-105 (1987). In operation, release liner 18 is removed and system 38 positioned on the skin. Sweat available from the skin diffuses through the adhesive 16 and reacts with the metal layer 20, causing it to erode thus allowing for passage of drug from reservoir 12. - As shown in Fig. 7, this invention can also be used to provide multipulsed drug delivery by means of a relatively thin, multi-laminate device 40, which is provided with a plurality of activating means 22, metal layers 20 and agent reservoirs 12.

Each agent reservoir layer produces one pulse. System 40 as shown, will provide three pulses of drug delivery. However, this number is merely illustrative and more or fewer layers may be used. The device may,if desired, have a single agent rate controlling membrane positioned between the reservoir 12 and metal layer 20 closest to the skin. The system may also have one or more activating means rate controlling membranes positioned between the metal layers 20 and activating means 22 however, it must be recognized this will be a cumulative decrease in overall permeability for each additional layer in a device having a plurality of layers such as is the case with system 40.

In operation, moisture migrates through adhesive layer 16 and enters the first activating means 22. The hydrated activating means reacts with the first metal layer 20, eroding it to allow drug to diffuse from reservoir 12. The thickness and loading of agent in layer 20 is selected such that moisture will have migrated to the second activating means to repeat the erosion process after layer 20 has been substantially depleted of agent. As the second and subsequent metal layers are being eroded, there is a lapse in drug delivery, thus providing a pulsed system.

The embodiment of Fig. 7 is especially suited for a nitroglycerin regimen with, for example, a metal layer of magnesium or aluminum, and a slightly acidic eroding agent contained within the activating means. The metal forming layer 20 in the aforementioned embodiments may generate a gas such as hydrogen when it reacts with the hydrated activating means. The embodiments of this invention may be modified to handle any gas that may be evolved during erosion. The system may be equipped with a head space 42, as shown in Fig. 8. When the reservoir is a gel the head space can be introduced into the pouch as a bubble when the pouch is filled with gel. Alternately, a hole or vent can be made in the backing layer and covered with a tab to be removed immediately prior to application to the delivery surface. If an adhesive overlay is used to position the system on the surface, a gas permeable material can be used such as spun-bonded polyethylene film, commercially available as Tyveck^® from E.I. DuPont de Nemours and Company, Inc.

Example I A system 10 in accordance with Fig. 1, has a reservoir 12 comprised of a therapeutic agent dispersed throughout an EVA 40 polymeric matrix, a MEDPAR^® backing 14, a pharmaceutically acceptable in-line contact adhesive layer 16, a ethylene vinylacetate rate controlling membrane 24 thinly coated with magnesium layer 20 and an activating means 22 comprised of citric acid dispersed throughout an EVA 40 polymeric matrix.

In operation, moisture migrates into layer 22, reacting with the citric acid to generate hydrogen ions.

This particular embodiment provides for erosion of the metal layer by an acidic oxidation-reduction reaction where hydrogen ions migrate to the magnesium layer-activating means interface 26. There, the metal is oxidized to Mg⁺⁺ and the hydrogen ion reduced to H₂, which then evolves as a gas.

Example II

A system in accordance with Example I, is fabricated substituting cupric sulfate for the citric acid, so that when moisture migrates into activating means 22, the reaction would generate cuprous and sulfate ions. As with Example I, the metal layer is eroded by an oxidation-reduction reaction. The Cu⁺⁺ ions then migrate to the magnesium layer 20, where the metal is oxidized to Mg^"1-1" and the cuprous ions reduced to copper, forming an agent permeable deposit at the metal layer-activating means interface 26.

Example III A system 32 is fabricated in accordance with Fig. 4, wherein the agent reservoir 12 is comprised of a therapeutic agent dispersed throughout an EVA 40 polymeric matrix. The system can have a MEDPAR^® backing 14.

The delay portion of system 32 is comprised of an EVA 12 rate controlling membrane 24 thinly coated with an aluminum metal layer 20, and a contact adhesive/eroding agent layer 34 comprised of sodium carbonate and a copper compound such as CuCl₂ or CuS0₄.

In operation, moisture migrates into layer 34 reacting with the copper compound to generate cuprous ions. These ions then migrate to the metal layer/ activating means interface 26, where the aluminum is oxidized to Al⁺⁺⁺ and the copper ions are reduced to form an agent permeable copper deposit on the metal layer.

Example IV A system is fabricated as in accordance with Fig. 4 using zinc as the metal and citric acid as the activating means.

Moisture migrates into the layer 34 reacting with the citric acid contained therein to generate hydrogen ions which migrate to the zinc layer 20 where the zinc is oxidized to Zn^""^" and the hydrogen reduced and evolved as a gas.

Example V A nitroglycerin delivery devices are fabricated by pouching a drug reservoir composition comprising 55% wt of nitroglycerin/lactose 41.4% wt silicone fluid 20 cs 3.6% Cab-0-Sil silicon dioxide at a loading of 40 mg/cm² between an impermeable Medpar backing and a metalized rate controll ng membrane formed from a 2 mil EVA (9% VA) membrane coated by vapor deposition with 0.5 μm magnesium or a 1.5 mil EVA (12% VA) membrane coated by vapor deposition with 2.0 μm zinc. A 3 mil activating means layer comprised of silicone 355/silicone oil 100 cs and 30% wt of anhydrous sodium dihydrogen phosphate was deposited onto the metal layer. When placed on the skin of the chest and maintained in place by an adhesive overlay water from the skin will cause the metal layers to erode and release the nitroglycerin. A delay in the release of nitroglycerin of about 2 hours will be produced by the magnesium coating and a delay of about 3 hours will be produced by the zinc coating.

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

Claims

ClaimsWhat is claimed is:

1. A controlled release device for delivery of an agent in a predetermined delivery rate pattern to a biological environment comprising, in combination: agent reservoir means containing said drug and having a surface through which the agent within said reservoir is released to the biological environment; and a metal layer disposed between said surface and the biological environment, wherein said metal layer in a first state, is substantially impermeable to the passage of said drug, and in a second state is permeable to said drug; and whereby the passage of drug from the reservoir to the biological environment is prevented until the metal layer changes state.

2. The device of claim 1 further comprising activating means for changing said metal from said first state to said second state.

3. The device of claim 2 wherein, said activating means is in water receiving relationship to the biological^' environment.

4. The device of claims 1, 2 or 3 further comprising: rate controlling means for controlling the rate at which drug is released from said reservoir to said biological environment.

5. The device of claims 2 or 3 wherein said activating means comprises a material selected from the group consisting of weak acids, weak bases and weak oxidizing agents.

6. The device of claims 1, 2 or 3 further comprising: rate controlling means for controlling the rate at which said metal is converted from said first state to said second state.

7. The device of claim 1 wherein said metal layer is selected from a metal which reacts with sweat to change from its first state to its second state.

8. The device of claims 1, 2, 3 or 7 further comprising a plurality of agent reservoir means and a plurality of metal layers with a metal layer disposed between each reservoir means and the biological environment.

9. The device of claims 1, 2, 3 or 7 further comprising means for collecting gas evolved as said metal changes state.

10. The device of claims 1, 2, 3 or 7 wherein said drug is selected from the group consisting of nitroglycerin, benztropine, nicotine, secoverine, propranolol and timolol.

11. The device of claims 1, 2, 3 or 7 wherein the biological environment is skin and the device further comprises means for maintaining said device in agent transferring relationship to the skin.

12. A method of delivering an agent to a biological environment, comprising the steps of: placing a reservoir containing an agent to be delivered at the biological environment; interposing a metal barrier impermeable to said agent between the reservoir and the biological environment; and eroding said metal barrier to permit passage of said agent from said reservoir to the biological environment at a predetermined time after the reservoir is placed at the biological environment.

13. The method of claim 12 wherein said drug is selected from the group consisting of nitroglycerin, benztropine, nicotine, secoverine, propranolol and timolol.