CA1333689C - Transdermal drug delivery device - Google Patents
Transdermal drug delivery deviceInfo
- Publication number
- CA1333689C CA1333689C CA000577093A CA577093A CA1333689C CA 1333689 C CA1333689 C CA 1333689C CA 000577093 A CA000577093 A CA 000577093A CA 577093 A CA577093 A CA 577093A CA 1333689 C CA1333689 C CA 1333689C
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- Canada
- Prior art keywords
- therapeutic agent
- skin
- activating
- nicotine
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
Abstract
A diffusional drug delivery device is described which can provide for stability of the adhesive and system components, elimination of the initial burst of drug and hence irritation, and to provide for delayed onset of therapeutic effect along with delivery of a therapeutic agent at an optimum rate. The therapeutic agent in a first form which is suitable for storage, and the anhydrous activating means are inert when in an anhydrous environment. Moisture activates the system whereby the activating means provides an acidic or basic solution and the first form of the therapeutic agent is converted to a second form which is suitable for absorption through the skin or mucosa.
Description
zIMPROVED TRANSDERMAL DRUG DELIVERY DEYICE 1333G89 3Field of the Invention This invention relates to the transdermal delivery of drugs or other biologically active agents and particularly to novel 6 methods and compositions for providing stable systems under 7 storage conditions. Still more particularly, this invention 8 relates to novel methods and compositions for delaying the onset 9 of drug delivery for transdermal systems.
11Background of the Invention 13The transdermal route of parenteral delivery of drugs 1~ provides many advantages and transdermal systems for delivering a 1~ wide variety of drugs or other beneficial agents are described in 16 U.S.Pat.Nos. 3,598,122, 3,598,123, 4,286,592, 4,314,557, 17 4.379.454 and 4,568,343 for examp1e .
11Background of the Invention 13The transdermal route of parenteral delivery of drugs 1~ provides many advantages and transdermal systems for delivering a 1~ wide variety of drugs or other beneficial agents are described in 16 U.S.Pat.Nos. 3,598,122, 3,598,123, 4,286,592, 4,314,557, 17 4.379.454 and 4,568,343 for examp1e .
2~
2In these devices, a drug or other active agent is released 3by diffusion from a reservoir through the agent releasing surface 4of the device to the biological environment at which the device 5is applied. Such devices perform well in the administration of 6many agents but are not suitable for the administration of an 7agent whose dosage regime requires that the onset of therapeutic 8effect be delayed for a significant period of time after gapplication of the device at the site of delivery. This is 10because the concentration of the therapeutic agent at the surface 11through which the agent is released, at the time of application, 12is typically at or above saturation and is capable of delivering 13at a rate that can give rise to therapeutic blood levels. In some 14cases, the initial rate of release is unacceptably high and a 15method for reducing this initial "burst" of agent delivery is 16described in U.S.Patent No. 3,923,939 to Baker et al. Even in 17this patent, the agent releasing surface of the diffusional 18embodiment does contain agent and delivery commences immediately 1gin the manner described above.
20Non-diffusional devices are known which do not immediately 21present drug to the biological environment when installed, such 22as devicés which contain material in breakable microcapsules, or 23fluid imbibing pumps, such as that described in U.S.Patent No.
244,655,766 of Theeuwes et al. Diffusional delivery devices known 25to the art however, do not possess this capability.
26The devices of this invention are particularly useful in 27providing a predetermined delayed onset of therapeutic effect for any desired time period after application to the skin. Thus a device could be removed and a new one applied simultaneously, wherein the desired drug-free interval is obtained.
One of the advantages of a continuous release dosage form, such as a transdermal drug delivery device, 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.
This advantage is lost when removal and application occur at different times or where onset of a therapeutic effect is desired at an inconvenient time such as shortly prior to arousal from 11 sleep. It is not possible, using concurrent application and 12 removal of diffusional delivery devices known in the art, to 13 substantially delay the onset of transdermal drug delivery from 14 the time of application, such as bedtime, until shortly prior to arousal.
16 Additionally, a common problem encountered with state of the 17 art systems is how to deal with unstable active agents, 18 especially those that tend to degrade the adhesive and other 19 system components. Therefore, there is a continuing need for a transdermal therapeutic system that provides stability of the 21 adhesive and all components during storage.
23 Summarv of the Invention An object of this invention is to provide a diffusional 26 drug delivery device which provides for delayed onset of drug 27 administration.
A further object of this invention is to provide a diffusional drug delivery device which does not deliver an 3 initial burst of drug and hence is less likely to cause irritation.
Another object of this invention is to stabilize an active 6 drug by storing it within a transdermal therapeutic system, in 7 form suitable for storage.
8 A further object of this invention is to provide a 9 diffusional delivery device where the adhesive and other components are protected from degradation by using a drug which 11 in a first form is suitable for storage, said form being more 12 compatible with the system components upon prolonged exposure.
13 A further object of this invention is to provide for the 14 maintenance of drug potency and device efficacy during prolonged storage periods, whereby the device is inactive while stored, and 16 active when applied to the skin.
17 A still further object of this invention is to provide a 18 diffusional delivery device which continuously releases 19 drug into a biological environment after a period of no drug delivery.
21 These and other objects, features, and advantages have been 22 demonstrated by the present invention wherein a controlled 23 release medical device for the delivery of at least one 24 therapeutic agent in a pre-determined delivery rate pattern to a biological environment is comprised of, in combination: reservoir 26 means containing a therapeutic agent which in a first form is 27 suitable for storage and which in a second form is suitable for 4 absorption through the skin or mucosa by reaction with a solution formed by an activating agent and moisture available from the body, the reservoir means having a surface substantially impermeable to therapeutic agent in its first form and permeable 7 to therapeutic agent in its second form, through which the 8 second skin absorbable form of therapeutic agent is released to g the biological environment; and activating means containing an activating agent wherein said activating agent in a first state 11 is anhydrous and in a second state is in solution with moisture supplied by the bodyi whereby the therapeutic agent is changed 12 from its first to its second form by the activating means in its 13 second state and whereby the passage of therapeutic agent to the 14 biological environment by diffusion is impeded until the agent changes forms.
16 The present invention also relates to a tr~n~dçrm~l drug delivery device, comprising 17 a nicotine layer, having a skin-facing side and a skin-distal side, said layer cont~ining a 18 sufficient quantity of nicotine to m~int~in a flux of nicotine from said device for total time 19 period of 13 hours or more; an occlusive backing layer in contact with and covering said 20 layer on said skin-distal side, and rate-controlling means for controlling diffusion of 21 nicotine from said skin-facing side at a first flux of greater than zero but less than about 22 140 llg/cm2fh in any hour for a first time period of greater than zero but less than 5 hours, 23 then at a second flux between about to and about 280 ~g/cm2/h for a second time period 24 of 13 hours or more.
1333~89 2Furthermore, in another embodiment, the present invention relates to a transdermal 3 drug delivery device, comprising a nicotine layer, having a skin-facing side and a skin-distal 4 side, said layer cont~inin~ a sufficient quantity of nicotine to m~int~in a flux of nicotine 5 from said device for a total time period of 12 hours or more; an occlusive backing layer in 6 contact with and covering said layer on said skin-distal side; and rate-controlling means for 7 controlling diffusion of nicotine from said skin-facing side at a first flux less than about 40 8 llg/cm2/h for a first time period of greater than zero but less than about 13 hours, then at 9 a second flux no greater than about 180 ~lg/cm2/h for a second time period of 9 hours or 10 more.
1~
15Brief DescriDtion of the Drawing 16In the drawings, which are not drawn to scale, but rather 1~are set forth to illustrate the various embodiments of the 18invention and wherein like reference numerals designate like 19parts, the drawings are as follows:
20Figures 1, 2 and 3 are schematic cross-sectional views of 21embodiments of the transdermal drug delivery system of this 22invention, where the drug in a storage suitable form and 23the activating agent in its first state are in separate 24 reservoirs;
25Figures 4, 5 and 6 are schematic cross-sectional views of 2~
28 5a ;.
2 embodiments of the transdermal drug delivery system of this 3 invention, where the drug in a storage suitable form and the 4 activating agent in its first state are in the same reservoir;
Figure 7 is a schematic cross-sectional view of an 6 embodiment of the transdermal drug delivery system of this 7 invention where the activating agent in its second state is 8 microencapsulated;
g Figures 8 and 9 are schematic cross-sectional views of embodiments of the transdermal drug delivery system of this 11 invention, where the drug in its first state is in a non-aqueous 12 medium; and 13 Figures 10 and 11 are graphs illustrating the release rate 14 of nicotine from transdermal drug delivery systems according to this invention.
17 Description of the Preferred Embodiment 18 Therapeutic agents suitable for transdermal administration 19 exist in various forms, some of which are more suitable for storage and some of which are more suitable for administration 21 through skin or mucosa. For example, a therapeutic agent may 22 exist in a free base form, a free acid form, a salt form, an 23 ester form, a non-covalent complex or an ionic complex, as for 24 example, agents may exist as the phosphates or glycinates as ion pairs.
26 Many therapeutic agents such as fluorouracil, barbitol, 27 furosemide, albuterol, apomorphine, benzocaine, acetylsalicylic .
2 acid, scopolamine, clonidine, phenylpropanolamine, 3 chlorpheniramine, pilocarpine and ephedrine, for example, are 4 extremely stable in the salt form, such as the sodium, calcium and magnesium cation salts, and the hydrobromide, hydrochloride, 6 maleate, nitrate and sulfate anion salts. These agents, however, 7 may be readily absorbable through the skin only in either the 8 free base form, the free acid form or the ester form, for g example. In the past, therefore, transdermal delivery devices storing the agent in the form suitable for absorption through the 11 skin could have an undesirably short storage life. Similarly 12 those storing the agent in a form suitable for storage could have 13 an undesirable low agent delivery rate through skin.
14 According to this invention, a therapeutic agent delivery device is provided in which the therapeutic agent is converted 16 from the storage suitable form to the delivery suitable or 17 absorbable form after the device is placed into its environment 18 of use in contact with the skin or mucosa as a result of moisture 19 entering the device form the environment of use.
Along with stabilizing an otherwise active compound (drug) 21 by storing it within the system in a stable form suitable for 22 storage, for example in its salt form, this invention has the 23 advantage of protecting the adhesive and other system components 24 from any adverse reactions that are likely to occur upon prolonged exposure to the active drug, as would be the case under 26 storage conditions.
27 An additional advantage of the transdermal drug delivery 1333~89 system of this invention is the delayed drug delivery and control of the initial excess burst of drug. In this manner, a means for delayed onset is provided which gives a drug-free period in plasma during continuous application of a transdermal drug delivery system.
With reference to the Figures, the devices shown, represent for purposes of illustration, transdermal delivery devices 8 because these are the preferred embodiments of this invention. It must be recognized however, that this invention is applicable to delivery devices generally and in non-transdermal applications, 11 certain components such as the adhesive and backing layers can be 12 omitted. A transdermal delivery device according to this 13 invention may include an impermeable backing member, a 14 therapeutic agent reservoir containing a first storage suitable form of the therapeutic agent which is subsequently converted to 16 a second deliverable form which is suitable for absorption 17 through the skin or mucosa, and an anhydrous activating means 18 which contains an acid or a base activating agent which forms a 19 solution with moisture available from the body and converts the 20 first storage suitable form of the drug to the second deliverable 21 form.
22 It is believed that this invention has utility in connection 23 with the delivery of drugs within the broad class normally 24 delivered through body surfaces and membranes, including skin and mucosa. As used herein, the expressions "drug" and "therapeutic 26 agent" are used interchangeably and are intended to have their 27 broadest interpretation as any therapeutically active substance 1333~89 2 which is delivered to a living organism to produce a desired, 3 usually beneficial, effect. ln general, this includes therapeutic 4 agents in all of the major therapeutic areas including, but not limited to those disclosed in U.S.Pat.No.s 3,598,122, 3,598,123, 6 4,286,592, 4,314,557, 4,379,454 and 4,568,343 .
8 This invention has particular utility in connection with the g delivery of all sympathomimetic drugs (bronchodilators) including but not limited to terbutaline, salbutamol and ephedrine. These 11 drugs are placed in a system according to this invention in a 12 storage suitable, preferably salt form, such as terbutaline 13 sulfate, salbutamol sulfate and ephedrine hydrochloride, 14 respectively. Additionally, this invention is useful in delivering ergot alkaloids such as ergonovine and ergotamine, 16 present in a storage suitable form as a salt such as ergonovine 17 mesylate and ergotamine tartrate. Both the sympathomimetrics and 18 the ergot alkaloids in their active forms, have a tendency to be lg unstable and so this invention is particularly suitable since it uses a storage suitable form of the drug such as a salt, thereby 21 providing a stable system.
22 This invention also finds utility in connection with the 23 delivery of drugs such as benztropine, nicotine and secoverine.
24 These drugs in their active form, tend to degrade the components of the system, including the adhesive, upon prolonged exposure 26 such as is the case under storage conditions. The storage 27 suitable forms, in particular the salt forms, of these drugs however, do not adversely affect the system's components.
Therefore, benztropine mesylate, nicotine tartrate and secoverine hydrochloride can be placed in the system of this invention, to provide delivery of their respective drugs.
5As stated above, this invention also eliminates the initial 6 burst of drug. This is particularly beneficial in delivering 7 drugs that have a tendency in large doses, to irritate the skin.
8 These drugs include benztropine, secoverine and nicotine, as 9 noted above, along with beta-blockers such as propranolol and timolol. Storage suitable forms of the latter two drugs are the 11 salt forms propranolol hydrochloride and timolol hydrochloride, 12 respectively.
13A diffusional delivery device, in its broadest sense, 14 comprises at least one reservoir means from which at least one therapeutic agent or drug passes by diffusion to the agent 16releasing surface of the device and from there into the 17biological environment to which it is applied.
18In the preferred embodiment of this invention, a therapeutic 19agent is transdermally administered to the skin or mucosa, said 20agent being stored in the diffusional delivery device in a first 21form suitable for storage, hereinafter referred to as the storage 22suitable form. Preferably, a salt form of an acid or a base drug 23is used. Typical examples include, without limitation, nicotine 24salt, secoverine salt and benztropine salt. The therapeutic agent 25is converted during delivery from its reservoir, into a second 26form which is suitable for absorption through skin or mucosa, by 27reacting with the activating agent which is in solution with 1333~89 2 moisture supplied by the body, said second form hereinafter 3 referred to as the deliverable form. While the therapeutic agent 4 in its deliverable form is able to permeate the layers of the system and ultimately the skin itself, the storage suitable form 6 of the therapeutic agent can not. The inability of the 7 therapeutic agent in its first form to permeate the system and 8 the skin ensures that the therapeutic agent will remain within g the reservoir until the onset of delivery is desired, at which time an activating means converts the therapeutic agent to its 11 deliverable form. Typically, the second or deliverable form of 12 the therapeutic agent is a free base form or a free acid form.
13In order that premature reaction be prevented, the 14therapeutic agent and the activating agent are maintained in an 15anhydrous environment prior to use. Within these broad 16limitations, the specific structure of the administration device 17is not critical to this invention. The therapeutic agent and the 18activating agent may be dispersed within an anhydrous matrix, 19either as a solid, non-aqueous liquid or gel, or mixed with 20suitable anhydrous carriers, permeation enhancers and the like as 21is known in the art. The devices are preferably in the form of an 22adhesive patch or the like but can also be in the form suitable 23for application to the skin or mucosa such as anhydrous ointment, 24gel or matrix, for example. If desired, means for controlling the 25release rate can also be used, as is known in the art.
26The delivery system of this invention can be used to provide 27delayed delivery of more than one drug, if desired. If the drugs to be delivered have the same storage suitable form, for example, either the salt of a base drug or the salt of an acid drug, both drugs remain within the reservoir until the onset of delivery is desired, at which time they are converted to their deliverable form by the activating means. Since these deliverable forms are suitable for absorption through skin, the drugs are co-delivered.
7 This invention can also be used to provide a system where a first drug is continuously delivered, said delivery commencing 9 immediately upon placement of the system on skin, and a second drug is delivered after a predetermined delay. This can be 11 accomplished by utilizing a first drug which is a neutral or non-12 salt formable drug such as hydrocortisone, capable of permeating 13 the layers of the system. The second drug is in the storage 14 suitable form, for example, the salt form of an acid or base drug which can not permeate the layers in that form. Moisture from the 16 skin activates the activating means which converts the second 17 drug from its storage suitable form to its deliverable form. This 18 conversion process creates the delay between application of the 19 system and onset of delivery of the second drug.
Alternately, this invention can provide a system that will 21 deliver a first drug and subsequently a second drug, and delivery 22 of the first drug ceases when delivery of the second drug 23 commences. The first drug can be the free form of an acid drug 24 and the second, the salt form of a base drug. Alternately, the first drug can be the free form of a base drug and the second, 26 the salt form of an acid drug. In either case, the system is 27 permeable to the passage of drug in its free form and 2 substantially impermeable to passage of drug in its salt form.
3 When the system is placed upon the skin, delivery of the free 4 form of the drug commences. Meanwhile, moisture available from the body diffuses into the activating means, converting the 6 activating agent to its second state and the activating agent now 7 in solution migrates into the drug reservoir, converting the 8 salt form of the second drug into its free form and likewise g converting the free form of the first drug into its salt form.
Thus, delivery of the second drug, now in its free form, 11 commences and since the first drug is now in its salt form and 12 therefore impermeable, its delivery ceases.
13This invention can provide delayed delivery in a variety of 14 embodiments, which are best described with relation to the Figures. Figures 1, 2, and 3 illustrate embodiments of the 16invention which have the reservoir means separate from the 17 activating means. The simplest of these is shown in Figure 1.
18 System 10 is comprised of drug reservoir means 12 and activating 19 means 14. The system is also provided with an impermeable backing 20layer 16, an in-line pharmaceutically acceptable contact adhesive 2118 and a strippable release liner 20, which is removed prior to 22application to the skin. The various layers are laminated or 23otherwise assembled into a bandage having a predetermined size 24and shape as is known to the art.
25The drug reservoir 12 is in the form of a matrix or carrier 26having a storage suitable form of the drug to be delivered, 27dispersed throughout. The system components are substantially impermeable to the passage of the storage suitable form of the drug but permeable to the second form of the drug, which is suitable for absorption through the skin or mucosa.
Activating means 14 is a layer comprised of an anhydrous activating agent which can be either an acid or a base dispersed 6 in a matrix or carrier. Suitable acids include without 7 limitation, citric acid, succinic acid, oxalic acid, succinic anhydride, phthalic acid, phthalic anhydride, sodium bisulfate 9 and salicylic acid. Likewise, suitable bases include without limitation~ Na2C3~ NaHC3~ K2C3~ KHC03, Na3P04, Na2HP04, sodium 11 oxalate, sodium succinate, sodium citrate, sodium salicylate, and 12 all other salts of organic acids.
13 When the system 10 is first placed on the patient's skin, 14 the system- or skin-impermeable storage suitable form of the drug in reservoir 12 is sequestrated from the activating means 14 and 16 reservoir 12 is substantially free of activating agent. Likewise, 17 the activating means 14 is substantially free of drug, both the 18 storage suitable and the deliverable form. This is due to the 19 fact that in an anhydrous environment such as is the case at storage conditions, the drug in its first form, in reservoir 12 21 and the activating agent in activating means 14 are for the most 22 part, non-reactive.
23 In accordance with a preferred embodiment of the invention, 24 the activating means 14 is activated by moisture, which is readily available from the site of administration such as the 26 cutaneous surface, particularly in occluded regions. Means 14 may 27 alternatively be moistened by dipping into a liquid containing 2 vessel immediately prior to application. In operation, this 3 moisture migrates into the system 10 from the skin surface or 4 other source, typically by osmosis or diffusion, passing through the adhesive layer 18 and then to the activating means 14 where 6 it mixes with the acid or base contained therein. The acid or 7 base forms an acidic or basic solution and migrates into the salt 8 drug layer, reacting with the salt drug to convert it into its g free form which then passes freely through layers 14 and 18 and then through the skin.
11 The drug releasing surfaces of certain embodiments of our 12 invention are characterized by being substantially free of drug 13 at the time they are applied to the body. As used herein, the 1~ expression "substantially free of drug" means either free of drug or containing an amount of drug insufficient to establish 16 untoward effects on skin (eg. irritation) or to establish and 17 maintain therapeutically effective drug delivery rates at the 18 time of application to the delivery site. In this manner, the 19 adhesive layer 18 is substantially free of drug.
Figure 2 illustrates another embodiment of the invention 21 where the laminated system 22 is provided with a rate controlling 22 membrane 24 positioned between the drug reservoir 12 and the 23 activating means 14. Membrane 24 controls the rate at which 24 activating agent diffuses from means 14 into reservoir 12.
Therefore, the rate at which the storage suitable form of the 26 drug is converted and subsequently delivered, is also controlled, 27 indirectly.
Membrane 24 is fabricated of a material such that it is substantially impermeable to the passage of the first form of the drug and to the contents of layer 12, and substantially permeable to the passage of the activating agent in solution with water or other biological fluid, and also permeable to drug in its second form. This rate controlling membrane may be fabricated from permeable, semipermeable or microporous materials which are known in the art to control the rate of agents and/or fluids into and out of delivery devices. It is preferable that the in vitro flux of agent in solution across membrane 24 is less than the rate 11 (per cm2) that said agent goes into solution. However, this 12 invention also contemplates use of a membrane having an in vitro 13 flux greater than or equal to that rare that agent goes into 14 solution.
Figure 3 illustrates an embodiment similar in construction 16 to that of Fig. 2. Laminated system 26 also has a rate 17 controlling membrane 28. However, in system 26, the membrane 28 18 is interposed between the activating means 14 and the adhesive 19 18. In this embodiment, the membrane 28 controls the rate at which moisture enters the system, and therefore the rate at which 21 the activ~ating means 14 becomes hydrated.
22 Membrane 28 is fabricated from a material such that it is 23 substantially impermeable to the passage of the activating agent 24 and other components of activating means 14, and substantially permeable to the passage of drug in its second form. The membrane 26 is preferably of a material such that the in vitro flux of 27 moisture across membrane 28 is less than the in vitro flux of 2 moisture through the skin.
3 Figures 4, 5 and 6 illustrate embodiments of the invention q where the drug reservoir and the activating means are combined, ie. there is a single reservoir containing both the drug in its 6 storage suitable form and the activating agent.
7 In Fig. 4, system 30 is comprised of a reservoir 32 and a 8 rate controlling membrane 34. Membrane 34 controls the rate at g which moisture enters reservoir 32. The reservoir 32 is formed by dry blending the drug in its first form, and an activating agent, 11 without any carrier vehicle or nonaqueous vehicle. The first form 12 of the drug can not permeate membrane 34 until moisture is 13 available from the skin or other source. When moisture becomes 14 available, it passes through membrane 34 and into the reservoir 32 where the activating agent becomes hydrated and converts the 16 first form to the second form of the drug, which then can pass 17 through membrane 34 and adhesive 18. Backing member 16, instead 18 of being flat, forms an envelope or pouch in which the reservoir 19 32 is held. This configuration is especially suitable for use when the reservoir 32 is not self-supporting.
21 Figure 5 illustrates a laminated system 36 having a single 22 reservoir 38 where the drug in its first form and the activating 23 agent are dispersed throughout a matrix or carrier. In Figure 6, 24 laminated system 40 has a rate controlling membrane 34 positioned between the drug/agent reservoir 38 and the adhesive 18.
26 The embodiments of Fig.s 1-6 rely on external moisture to 27 activate the system, whereby moisture from the skin forms an aqueous solution with the activating agent which can then convert the drug from its first storage suitable form into its second deliverable form. Figure 7 provides a system where the activating agent in an aqueous solution is actually placed into the system 42, thereby avoiding the need for an external source of moisture.
System 42 is comprised of an agent reservoir 44 where an aqueous solution of activating agent is microencapsulated in wax.
These microcapsules 46 can be broken and the solution released upon application of pressure or they can be melted and the solution released upon application of heat. The activating 11 solution then migrates through the microporous membrane 48 and 12 into the drug reservoir 12 where the drug in its first form is 13 converted to the second absorbable form of the drug, which is then delivered to the skin.
Microporous membrane 48 may be formed from polymers such as 16 polypropylene, polytetrafluorethylene, polycarbonates, 17 polyvinylchloride, cellulose acetate, cellulose nitrate and 18 polyacrylonitrile, for example.
19 The embodiments of Figures 8 and 9 illustrate placement of the storage suitable form of the drug in a non-aqueous medium as 21 compared to a polymeric matrix. Suitable materials for the non-22 aqueous medium include, without limitation, mineral oil, silicone 23 oil and petrolatum.
24 Fig. 8 shows system 50 having the drug/non-aqueous medium in reservoir 52. The system 54 of Fig. 9 has the same res~rvoir but 26 additionally has a microporous membrane 48 interposed between 27 reservoir 52 and the activating agent reservoir 14.
2Figure 10 is a graphical representation of the theoretical 3 release rate profile versus time for the system illustrated in 4 Fig. 3. The system 26 would be positioned on the skin at time zero. From time zero until time t, moisture from the skin would 6 diffuse through the rate controlling membrane 28, into the 7 activating layer 14 and acid or base in solution would migrate 8 into the drug layer 12 to convert the drug in its first form to g its second absorbable form, which subsequently would diffuse through the layers to reach the skin surface. Shortly after time 11t, the drug would begin to actually be delivered into the 12 bloodstream. This is indicated by the rise on the curve in Fig.
13 10.
14The delay time (time zero until time t) depends upon both 15the water migration through the rate controlling membrane 28 and 16the activating layer 14.
17Various materials suited for the fabrication of the various 18layers are disclosed in the aforementioned patents. The polymer 19matrix of the drug reservoir 12, the activating agent reservoir 2014, and combined reservoir 38, are anhydrous and suitable 21materials include without limitation, natural and synthetic 22rubbers or other polymeric materials, thickened mineral oil or 23petroleum jelly. The preferred embodiment according to this 24invention is fabricated from an ethylene/vinylacetate (EVA) 25copolymer of the type described in U.S.Pat.No. 4,144,317, 26preferably those having a vinylacetate content in the range of 27about 18 to 60 weight percent. Particularly good results have been obtained using an EVA copolymer of about 40 weight percent vinylacetate content (40 w/O VA). The drug and/or agent is preferably dispersed through the matrix at a concentration in excess of saturation, the amount of the excess being a function of the intended useful life of the system.
In addition to the drug and/or agent, the matrix may also contain other materials such as dyes, pigments, inert fillers, permeation enhancers, excipients and conventional components of pharmaceutical products or transdermal therapeutic systems as is known to the art. The drug and/or the activating agent containing matrices may also contain a salt such as NaCl, which facilitates 12 the onset of drug delivery by osmotically drawing up moisture 13 from the skin.
14 One face surface of the drug reservoir bears a backing member 16. The purpose of the backing is to prevent passage of 16 the drug through the surface of the reservoir distant from the 17 adhesive layer. An ancillary purpose of the backing is to provide 18 support for the system, where needed. The backing layer can be 1g flexible or nonflexible and suitable materials include without limitation, cellophane, cellulose acetate, ethylcellulose, 21 plasticized vinylacetate-vinylchloride copolymers, polyethylene 22 terephthalate, nylon, polyethylene, polypropylene, metalized 23 polyester films, polyvinylidene chloride, coated flexible fibrous 24 backings such as paper and cloth and aluminum foil. Such backings can be in the form of precast films or fabrics which are bonded 26 to the reservoir by heat or adhesives and can be coated onto the 27 reservoir. Numerous other suitable materials are disclosed in 1~33689 2 U.S.Pat. No. 4,661,105 .
3 The composition and thickness of adhesive layer 18 are such 4 that layer 18 does not constitute a significant permeation barrier to the passage of drug. Adhesive layer 18 may also 6 contain a predetermined amount of the skin absorbable form of the 1 drug which serves to saturate the skin for more rapid therapeutic 8 effects where desired. Silicone compounds are commonly used as g adhesives, however numerous materials are known which possess the requisite strength and skin compatibility. An adhesive overlay or 11 other means for maintaining the device on the skin can be 12 employed instead of, or in combination with, adhesive lamina 18.
13 Suitable adhesive materials are noted in the aforementioned 14 patent.
In operation, liner 20 is removed and the system is placed 16 in direct contact with the skin. The releaseable liner is made 17 from materials which are substantially impermeable to the drug, 18 and any other components of the layers. The same materials that 19 are used to make the backing layer may be used to make the liner, provided they are made strippable such as by siliconizing.
21 The aforementioned patents describe a wide variety of 22 materials which can be used for fabricating the various layers of 23 the transdermal delivery systems according to this invention.
24 This invention therefore contemplates the use of materials other than those specifically disclosed herein, including those which 26 may hereafter become known to the art to be capable of performing 21 the necessary functions.
3 A test sample was designed to deliver nicotine according to 4 this invention. Nicotine which is transdermally administered to facilitate breaking the tobacco habit, is especially suited to 6 illustrate this invention. Nicotine in its active form tends to 7 degrade adhesives, especially those which are silicone based.
8 Also, nicotine delivered in a sudden burst may irritate the skin.
g Therefore, use of this invention to deliver nicotine provides a system with an improved shelf-life by storing the nicotine in its 11 salt form, and further provides elimination of the initial burst 12 of drug by storing nicotine in a form which is not readily 13 absorbed through mucous membrane and intact skin.
14 The drug reservoir was a polymeric matrix comprised of 60 %
nicotine tartrate and 40 % EVA 40 carrier, and was about 6.5 mils 16 thick. The activating layer was about 3.5 mils thick and was a 17 polymeric matrix comprised of 6070 Na2C03 and 40% EVA 40 carrier.
18 Sodium carbonate provides an aqueous solution which is strongly 19 alkaline. Thus, in this particular embodiment, the activating layer was a base.
21 The release rate was measured at 35C using a 1.5 mil 22 Hytrel- (Du Pont) membrane, which simulates water diffusion 23 through human skin. The release rate profile is illustrated in 24 Figure 10.
Prior to application to the Hytrel~ membrane, the activating 26 layer is anhydrous and therefore inert and is substantially 27 impermeable to the passage of drug and is thus substantially free of drug, both nicotine and nicotine tartrate. When the system is placed in contact with the Hytrel~ membrane, moisture migrates through the membrane and into the activating layer which then becomes hydrated and active.
Moisture entering the EVA polymeric matrix reacts with the solid Na2C03 to form a basic solution. Thus, the activating agent undergoes a change of state from a first anhydrous and inert state to a second hydrated and active state, where the activating agent is in solution.
The basic solution then diffuses through the activating 11 matrix and into the drug reservoir, where it reacts with the 12 solid nicotine tartrate to convert it to its free form, nicotine.13 The agent nicotine then passes freely through the activating 14 layer and then through the Hytrel~ membrane. The activating layerin its dry state is impermeable to the passage of nicotine 16 tartrate but in its hydrated state, is permeable to the passage 17 of nicotine.
A system was designed according to this invention and is 21 illustrated in Figure 7. The backing was standard Medpar2 and the22 system had the storage suitable form of the drug and the 23 activating agent (base) mixed in the same reservoir. The drug 24 reservoir was comprised of 42% nicot;ne tartrate, 18% Na2C03 and 40% EVA 40 carrier. The system had a PVA rate controlling 26 membrane about 1.5 mils thick and had a silicone adhesive layer.
27 The release rate of nicotine from this system at 35 C in a release medium of water, is presented in the following table:
Table I
4 Time. hrsAverage Release Rate. /ug/cm2/hr 2 72.64 4 29.55 6 6 45.84 8 52.60 7 13 112.51 g As is evidenced from the data presented, this system provides the desired delayed onset where the drug release rate during the 11 first 8 hours is minimal and gradually increases to a significant 12 level at 13 hours.
14 A test sample was designed to deliver nicotine. The drug reservoir was a polymeric matrix comprised of 40 % nicotine 16 tartrate, 50 % EVA 40 carrier and 10 % NaCl, and was about 8 mils 7 thick. The activating layer was about 3.5 mils thick and was a 18 polymeric matrix comprised of 60 % Na2C03 and 40 % EVA 40 19 carrier.
The release rate was measured using a 1.5 mil Hytrel 21 membrane and is graphically illustrated in Figure 11.
22 Having thus generally described our invention and described 23 in detail certain preferred embodiments thereof, it will be 24 readily apparent that various modifications to the invention may be made by workers skilled in the art without departing from the 26 scope of this invention which is limited only by the following 27 claims.
2In these devices, a drug or other active agent is released 3by diffusion from a reservoir through the agent releasing surface 4of the device to the biological environment at which the device 5is applied. Such devices perform well in the administration of 6many agents but are not suitable for the administration of an 7agent whose dosage regime requires that the onset of therapeutic 8effect be delayed for a significant period of time after gapplication of the device at the site of delivery. This is 10because the concentration of the therapeutic agent at the surface 11through which the agent is released, at the time of application, 12is typically at or above saturation and is capable of delivering 13at a rate that can give rise to therapeutic blood levels. In some 14cases, the initial rate of release is unacceptably high and a 15method for reducing this initial "burst" of agent delivery is 16described in U.S.Patent No. 3,923,939 to Baker et al. Even in 17this patent, the agent releasing surface of the diffusional 18embodiment does contain agent and delivery commences immediately 1gin the manner described above.
20Non-diffusional devices are known which do not immediately 21present drug to the biological environment when installed, such 22as devicés which contain material in breakable microcapsules, or 23fluid imbibing pumps, such as that described in U.S.Patent No.
244,655,766 of Theeuwes et al. Diffusional delivery devices known 25to the art however, do not possess this capability.
26The devices of this invention are particularly useful in 27providing a predetermined delayed onset of therapeutic effect for any desired time period after application to the skin. Thus a device could be removed and a new one applied simultaneously, wherein the desired drug-free interval is obtained.
One of the advantages of a continuous release dosage form, such as a transdermal drug delivery device, 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.
This advantage is lost when removal and application occur at different times or where onset of a therapeutic effect is desired at an inconvenient time such as shortly prior to arousal from 11 sleep. It is not possible, using concurrent application and 12 removal of diffusional delivery devices known in the art, to 13 substantially delay the onset of transdermal drug delivery from 14 the time of application, such as bedtime, until shortly prior to arousal.
16 Additionally, a common problem encountered with state of the 17 art systems is how to deal with unstable active agents, 18 especially those that tend to degrade the adhesive and other 19 system components. Therefore, there is a continuing need for a transdermal therapeutic system that provides stability of the 21 adhesive and all components during storage.
23 Summarv of the Invention An object of this invention is to provide a diffusional 26 drug delivery device which provides for delayed onset of drug 27 administration.
A further object of this invention is to provide a diffusional drug delivery device which does not deliver an 3 initial burst of drug and hence is less likely to cause irritation.
Another object of this invention is to stabilize an active 6 drug by storing it within a transdermal therapeutic system, in 7 form suitable for storage.
8 A further object of this invention is to provide a 9 diffusional delivery device where the adhesive and other components are protected from degradation by using a drug which 11 in a first form is suitable for storage, said form being more 12 compatible with the system components upon prolonged exposure.
13 A further object of this invention is to provide for the 14 maintenance of drug potency and device efficacy during prolonged storage periods, whereby the device is inactive while stored, and 16 active when applied to the skin.
17 A still further object of this invention is to provide a 18 diffusional delivery device which continuously releases 19 drug into a biological environment after a period of no drug delivery.
21 These and other objects, features, and advantages have been 22 demonstrated by the present invention wherein a controlled 23 release medical device for the delivery of at least one 24 therapeutic agent in a pre-determined delivery rate pattern to a biological environment is comprised of, in combination: reservoir 26 means containing a therapeutic agent which in a first form is 27 suitable for storage and which in a second form is suitable for 4 absorption through the skin or mucosa by reaction with a solution formed by an activating agent and moisture available from the body, the reservoir means having a surface substantially impermeable to therapeutic agent in its first form and permeable 7 to therapeutic agent in its second form, through which the 8 second skin absorbable form of therapeutic agent is released to g the biological environment; and activating means containing an activating agent wherein said activating agent in a first state 11 is anhydrous and in a second state is in solution with moisture supplied by the bodyi whereby the therapeutic agent is changed 12 from its first to its second form by the activating means in its 13 second state and whereby the passage of therapeutic agent to the 14 biological environment by diffusion is impeded until the agent changes forms.
16 The present invention also relates to a tr~n~dçrm~l drug delivery device, comprising 17 a nicotine layer, having a skin-facing side and a skin-distal side, said layer cont~ining a 18 sufficient quantity of nicotine to m~int~in a flux of nicotine from said device for total time 19 period of 13 hours or more; an occlusive backing layer in contact with and covering said 20 layer on said skin-distal side, and rate-controlling means for controlling diffusion of 21 nicotine from said skin-facing side at a first flux of greater than zero but less than about 22 140 llg/cm2fh in any hour for a first time period of greater than zero but less than 5 hours, 23 then at a second flux between about to and about 280 ~g/cm2/h for a second time period 24 of 13 hours or more.
1333~89 2Furthermore, in another embodiment, the present invention relates to a transdermal 3 drug delivery device, comprising a nicotine layer, having a skin-facing side and a skin-distal 4 side, said layer cont~inin~ a sufficient quantity of nicotine to m~int~in a flux of nicotine 5 from said device for a total time period of 12 hours or more; an occlusive backing layer in 6 contact with and covering said layer on said skin-distal side; and rate-controlling means for 7 controlling diffusion of nicotine from said skin-facing side at a first flux less than about 40 8 llg/cm2/h for a first time period of greater than zero but less than about 13 hours, then at 9 a second flux no greater than about 180 ~lg/cm2/h for a second time period of 9 hours or 10 more.
1~
15Brief DescriDtion of the Drawing 16In the drawings, which are not drawn to scale, but rather 1~are set forth to illustrate the various embodiments of the 18invention and wherein like reference numerals designate like 19parts, the drawings are as follows:
20Figures 1, 2 and 3 are schematic cross-sectional views of 21embodiments of the transdermal drug delivery system of this 22invention, where the drug in a storage suitable form and 23the activating agent in its first state are in separate 24 reservoirs;
25Figures 4, 5 and 6 are schematic cross-sectional views of 2~
28 5a ;.
2 embodiments of the transdermal drug delivery system of this 3 invention, where the drug in a storage suitable form and the 4 activating agent in its first state are in the same reservoir;
Figure 7 is a schematic cross-sectional view of an 6 embodiment of the transdermal drug delivery system of this 7 invention where the activating agent in its second state is 8 microencapsulated;
g Figures 8 and 9 are schematic cross-sectional views of embodiments of the transdermal drug delivery system of this 11 invention, where the drug in its first state is in a non-aqueous 12 medium; and 13 Figures 10 and 11 are graphs illustrating the release rate 14 of nicotine from transdermal drug delivery systems according to this invention.
17 Description of the Preferred Embodiment 18 Therapeutic agents suitable for transdermal administration 19 exist in various forms, some of which are more suitable for storage and some of which are more suitable for administration 21 through skin or mucosa. For example, a therapeutic agent may 22 exist in a free base form, a free acid form, a salt form, an 23 ester form, a non-covalent complex or an ionic complex, as for 24 example, agents may exist as the phosphates or glycinates as ion pairs.
26 Many therapeutic agents such as fluorouracil, barbitol, 27 furosemide, albuterol, apomorphine, benzocaine, acetylsalicylic .
2 acid, scopolamine, clonidine, phenylpropanolamine, 3 chlorpheniramine, pilocarpine and ephedrine, for example, are 4 extremely stable in the salt form, such as the sodium, calcium and magnesium cation salts, and the hydrobromide, hydrochloride, 6 maleate, nitrate and sulfate anion salts. These agents, however, 7 may be readily absorbable through the skin only in either the 8 free base form, the free acid form or the ester form, for g example. In the past, therefore, transdermal delivery devices storing the agent in the form suitable for absorption through the 11 skin could have an undesirably short storage life. Similarly 12 those storing the agent in a form suitable for storage could have 13 an undesirable low agent delivery rate through skin.
14 According to this invention, a therapeutic agent delivery device is provided in which the therapeutic agent is converted 16 from the storage suitable form to the delivery suitable or 17 absorbable form after the device is placed into its environment 18 of use in contact with the skin or mucosa as a result of moisture 19 entering the device form the environment of use.
Along with stabilizing an otherwise active compound (drug) 21 by storing it within the system in a stable form suitable for 22 storage, for example in its salt form, this invention has the 23 advantage of protecting the adhesive and other system components 24 from any adverse reactions that are likely to occur upon prolonged exposure to the active drug, as would be the case under 26 storage conditions.
27 An additional advantage of the transdermal drug delivery 1333~89 system of this invention is the delayed drug delivery and control of the initial excess burst of drug. In this manner, a means for delayed onset is provided which gives a drug-free period in plasma during continuous application of a transdermal drug delivery system.
With reference to the Figures, the devices shown, represent for purposes of illustration, transdermal delivery devices 8 because these are the preferred embodiments of this invention. It must be recognized however, that this invention is applicable to delivery devices generally and in non-transdermal applications, 11 certain components such as the adhesive and backing layers can be 12 omitted. A transdermal delivery device according to this 13 invention may include an impermeable backing member, a 14 therapeutic agent reservoir containing a first storage suitable form of the therapeutic agent which is subsequently converted to 16 a second deliverable form which is suitable for absorption 17 through the skin or mucosa, and an anhydrous activating means 18 which contains an acid or a base activating agent which forms a 19 solution with moisture available from the body and converts the 20 first storage suitable form of the drug to the second deliverable 21 form.
22 It is believed that this invention has utility in connection 23 with the delivery of drugs within the broad class normally 24 delivered through body surfaces and membranes, including skin and mucosa. As used herein, the expressions "drug" and "therapeutic 26 agent" are used interchangeably and are intended to have their 27 broadest interpretation as any therapeutically active substance 1333~89 2 which is delivered to a living organism to produce a desired, 3 usually beneficial, effect. ln general, this includes therapeutic 4 agents in all of the major therapeutic areas including, but not limited to those disclosed in U.S.Pat.No.s 3,598,122, 3,598,123, 6 4,286,592, 4,314,557, 4,379,454 and 4,568,343 .
8 This invention has particular utility in connection with the g delivery of all sympathomimetic drugs (bronchodilators) including but not limited to terbutaline, salbutamol and ephedrine. These 11 drugs are placed in a system according to this invention in a 12 storage suitable, preferably salt form, such as terbutaline 13 sulfate, salbutamol sulfate and ephedrine hydrochloride, 14 respectively. Additionally, this invention is useful in delivering ergot alkaloids such as ergonovine and ergotamine, 16 present in a storage suitable form as a salt such as ergonovine 17 mesylate and ergotamine tartrate. Both the sympathomimetrics and 18 the ergot alkaloids in their active forms, have a tendency to be lg unstable and so this invention is particularly suitable since it uses a storage suitable form of the drug such as a salt, thereby 21 providing a stable system.
22 This invention also finds utility in connection with the 23 delivery of drugs such as benztropine, nicotine and secoverine.
24 These drugs in their active form, tend to degrade the components of the system, including the adhesive, upon prolonged exposure 26 such as is the case under storage conditions. The storage 27 suitable forms, in particular the salt forms, of these drugs however, do not adversely affect the system's components.
Therefore, benztropine mesylate, nicotine tartrate and secoverine hydrochloride can be placed in the system of this invention, to provide delivery of their respective drugs.
5As stated above, this invention also eliminates the initial 6 burst of drug. This is particularly beneficial in delivering 7 drugs that have a tendency in large doses, to irritate the skin.
8 These drugs include benztropine, secoverine and nicotine, as 9 noted above, along with beta-blockers such as propranolol and timolol. Storage suitable forms of the latter two drugs are the 11 salt forms propranolol hydrochloride and timolol hydrochloride, 12 respectively.
13A diffusional delivery device, in its broadest sense, 14 comprises at least one reservoir means from which at least one therapeutic agent or drug passes by diffusion to the agent 16releasing surface of the device and from there into the 17biological environment to which it is applied.
18In the preferred embodiment of this invention, a therapeutic 19agent is transdermally administered to the skin or mucosa, said 20agent being stored in the diffusional delivery device in a first 21form suitable for storage, hereinafter referred to as the storage 22suitable form. Preferably, a salt form of an acid or a base drug 23is used. Typical examples include, without limitation, nicotine 24salt, secoverine salt and benztropine salt. The therapeutic agent 25is converted during delivery from its reservoir, into a second 26form which is suitable for absorption through skin or mucosa, by 27reacting with the activating agent which is in solution with 1333~89 2 moisture supplied by the body, said second form hereinafter 3 referred to as the deliverable form. While the therapeutic agent 4 in its deliverable form is able to permeate the layers of the system and ultimately the skin itself, the storage suitable form 6 of the therapeutic agent can not. The inability of the 7 therapeutic agent in its first form to permeate the system and 8 the skin ensures that the therapeutic agent will remain within g the reservoir until the onset of delivery is desired, at which time an activating means converts the therapeutic agent to its 11 deliverable form. Typically, the second or deliverable form of 12 the therapeutic agent is a free base form or a free acid form.
13In order that premature reaction be prevented, the 14therapeutic agent and the activating agent are maintained in an 15anhydrous environment prior to use. Within these broad 16limitations, the specific structure of the administration device 17is not critical to this invention. The therapeutic agent and the 18activating agent may be dispersed within an anhydrous matrix, 19either as a solid, non-aqueous liquid or gel, or mixed with 20suitable anhydrous carriers, permeation enhancers and the like as 21is known in the art. The devices are preferably in the form of an 22adhesive patch or the like but can also be in the form suitable 23for application to the skin or mucosa such as anhydrous ointment, 24gel or matrix, for example. If desired, means for controlling the 25release rate can also be used, as is known in the art.
26The delivery system of this invention can be used to provide 27delayed delivery of more than one drug, if desired. If the drugs to be delivered have the same storage suitable form, for example, either the salt of a base drug or the salt of an acid drug, both drugs remain within the reservoir until the onset of delivery is desired, at which time they are converted to their deliverable form by the activating means. Since these deliverable forms are suitable for absorption through skin, the drugs are co-delivered.
7 This invention can also be used to provide a system where a first drug is continuously delivered, said delivery commencing 9 immediately upon placement of the system on skin, and a second drug is delivered after a predetermined delay. This can be 11 accomplished by utilizing a first drug which is a neutral or non-12 salt formable drug such as hydrocortisone, capable of permeating 13 the layers of the system. The second drug is in the storage 14 suitable form, for example, the salt form of an acid or base drug which can not permeate the layers in that form. Moisture from the 16 skin activates the activating means which converts the second 17 drug from its storage suitable form to its deliverable form. This 18 conversion process creates the delay between application of the 19 system and onset of delivery of the second drug.
Alternately, this invention can provide a system that will 21 deliver a first drug and subsequently a second drug, and delivery 22 of the first drug ceases when delivery of the second drug 23 commences. The first drug can be the free form of an acid drug 24 and the second, the salt form of a base drug. Alternately, the first drug can be the free form of a base drug and the second, 26 the salt form of an acid drug. In either case, the system is 27 permeable to the passage of drug in its free form and 2 substantially impermeable to passage of drug in its salt form.
3 When the system is placed upon the skin, delivery of the free 4 form of the drug commences. Meanwhile, moisture available from the body diffuses into the activating means, converting the 6 activating agent to its second state and the activating agent now 7 in solution migrates into the drug reservoir, converting the 8 salt form of the second drug into its free form and likewise g converting the free form of the first drug into its salt form.
Thus, delivery of the second drug, now in its free form, 11 commences and since the first drug is now in its salt form and 12 therefore impermeable, its delivery ceases.
13This invention can provide delayed delivery in a variety of 14 embodiments, which are best described with relation to the Figures. Figures 1, 2, and 3 illustrate embodiments of the 16invention which have the reservoir means separate from the 17 activating means. The simplest of these is shown in Figure 1.
18 System 10 is comprised of drug reservoir means 12 and activating 19 means 14. The system is also provided with an impermeable backing 20layer 16, an in-line pharmaceutically acceptable contact adhesive 2118 and a strippable release liner 20, which is removed prior to 22application to the skin. The various layers are laminated or 23otherwise assembled into a bandage having a predetermined size 24and shape as is known to the art.
25The drug reservoir 12 is in the form of a matrix or carrier 26having a storage suitable form of the drug to be delivered, 27dispersed throughout. The system components are substantially impermeable to the passage of the storage suitable form of the drug but permeable to the second form of the drug, which is suitable for absorption through the skin or mucosa.
Activating means 14 is a layer comprised of an anhydrous activating agent which can be either an acid or a base dispersed 6 in a matrix or carrier. Suitable acids include without 7 limitation, citric acid, succinic acid, oxalic acid, succinic anhydride, phthalic acid, phthalic anhydride, sodium bisulfate 9 and salicylic acid. Likewise, suitable bases include without limitation~ Na2C3~ NaHC3~ K2C3~ KHC03, Na3P04, Na2HP04, sodium 11 oxalate, sodium succinate, sodium citrate, sodium salicylate, and 12 all other salts of organic acids.
13 When the system 10 is first placed on the patient's skin, 14 the system- or skin-impermeable storage suitable form of the drug in reservoir 12 is sequestrated from the activating means 14 and 16 reservoir 12 is substantially free of activating agent. Likewise, 17 the activating means 14 is substantially free of drug, both the 18 storage suitable and the deliverable form. This is due to the 19 fact that in an anhydrous environment such as is the case at storage conditions, the drug in its first form, in reservoir 12 21 and the activating agent in activating means 14 are for the most 22 part, non-reactive.
23 In accordance with a preferred embodiment of the invention, 24 the activating means 14 is activated by moisture, which is readily available from the site of administration such as the 26 cutaneous surface, particularly in occluded regions. Means 14 may 27 alternatively be moistened by dipping into a liquid containing 2 vessel immediately prior to application. In operation, this 3 moisture migrates into the system 10 from the skin surface or 4 other source, typically by osmosis or diffusion, passing through the adhesive layer 18 and then to the activating means 14 where 6 it mixes with the acid or base contained therein. The acid or 7 base forms an acidic or basic solution and migrates into the salt 8 drug layer, reacting with the salt drug to convert it into its g free form which then passes freely through layers 14 and 18 and then through the skin.
11 The drug releasing surfaces of certain embodiments of our 12 invention are characterized by being substantially free of drug 13 at the time they are applied to the body. As used herein, the 1~ expression "substantially free of drug" means either free of drug or containing an amount of drug insufficient to establish 16 untoward effects on skin (eg. irritation) or to establish and 17 maintain therapeutically effective drug delivery rates at the 18 time of application to the delivery site. In this manner, the 19 adhesive layer 18 is substantially free of drug.
Figure 2 illustrates another embodiment of the invention 21 where the laminated system 22 is provided with a rate controlling 22 membrane 24 positioned between the drug reservoir 12 and the 23 activating means 14. Membrane 24 controls the rate at which 24 activating agent diffuses from means 14 into reservoir 12.
Therefore, the rate at which the storage suitable form of the 26 drug is converted and subsequently delivered, is also controlled, 27 indirectly.
Membrane 24 is fabricated of a material such that it is substantially impermeable to the passage of the first form of the drug and to the contents of layer 12, and substantially permeable to the passage of the activating agent in solution with water or other biological fluid, and also permeable to drug in its second form. This rate controlling membrane may be fabricated from permeable, semipermeable or microporous materials which are known in the art to control the rate of agents and/or fluids into and out of delivery devices. It is preferable that the in vitro flux of agent in solution across membrane 24 is less than the rate 11 (per cm2) that said agent goes into solution. However, this 12 invention also contemplates use of a membrane having an in vitro 13 flux greater than or equal to that rare that agent goes into 14 solution.
Figure 3 illustrates an embodiment similar in construction 16 to that of Fig. 2. Laminated system 26 also has a rate 17 controlling membrane 28. However, in system 26, the membrane 28 18 is interposed between the activating means 14 and the adhesive 19 18. In this embodiment, the membrane 28 controls the rate at which moisture enters the system, and therefore the rate at which 21 the activ~ating means 14 becomes hydrated.
22 Membrane 28 is fabricated from a material such that it is 23 substantially impermeable to the passage of the activating agent 24 and other components of activating means 14, and substantially permeable to the passage of drug in its second form. The membrane 26 is preferably of a material such that the in vitro flux of 27 moisture across membrane 28 is less than the in vitro flux of 2 moisture through the skin.
3 Figures 4, 5 and 6 illustrate embodiments of the invention q where the drug reservoir and the activating means are combined, ie. there is a single reservoir containing both the drug in its 6 storage suitable form and the activating agent.
7 In Fig. 4, system 30 is comprised of a reservoir 32 and a 8 rate controlling membrane 34. Membrane 34 controls the rate at g which moisture enters reservoir 32. The reservoir 32 is formed by dry blending the drug in its first form, and an activating agent, 11 without any carrier vehicle or nonaqueous vehicle. The first form 12 of the drug can not permeate membrane 34 until moisture is 13 available from the skin or other source. When moisture becomes 14 available, it passes through membrane 34 and into the reservoir 32 where the activating agent becomes hydrated and converts the 16 first form to the second form of the drug, which then can pass 17 through membrane 34 and adhesive 18. Backing member 16, instead 18 of being flat, forms an envelope or pouch in which the reservoir 19 32 is held. This configuration is especially suitable for use when the reservoir 32 is not self-supporting.
21 Figure 5 illustrates a laminated system 36 having a single 22 reservoir 38 where the drug in its first form and the activating 23 agent are dispersed throughout a matrix or carrier. In Figure 6, 24 laminated system 40 has a rate controlling membrane 34 positioned between the drug/agent reservoir 38 and the adhesive 18.
26 The embodiments of Fig.s 1-6 rely on external moisture to 27 activate the system, whereby moisture from the skin forms an aqueous solution with the activating agent which can then convert the drug from its first storage suitable form into its second deliverable form. Figure 7 provides a system where the activating agent in an aqueous solution is actually placed into the system 42, thereby avoiding the need for an external source of moisture.
System 42 is comprised of an agent reservoir 44 where an aqueous solution of activating agent is microencapsulated in wax.
These microcapsules 46 can be broken and the solution released upon application of pressure or they can be melted and the solution released upon application of heat. The activating 11 solution then migrates through the microporous membrane 48 and 12 into the drug reservoir 12 where the drug in its first form is 13 converted to the second absorbable form of the drug, which is then delivered to the skin.
Microporous membrane 48 may be formed from polymers such as 16 polypropylene, polytetrafluorethylene, polycarbonates, 17 polyvinylchloride, cellulose acetate, cellulose nitrate and 18 polyacrylonitrile, for example.
19 The embodiments of Figures 8 and 9 illustrate placement of the storage suitable form of the drug in a non-aqueous medium as 21 compared to a polymeric matrix. Suitable materials for the non-22 aqueous medium include, without limitation, mineral oil, silicone 23 oil and petrolatum.
24 Fig. 8 shows system 50 having the drug/non-aqueous medium in reservoir 52. The system 54 of Fig. 9 has the same res~rvoir but 26 additionally has a microporous membrane 48 interposed between 27 reservoir 52 and the activating agent reservoir 14.
2Figure 10 is a graphical representation of the theoretical 3 release rate profile versus time for the system illustrated in 4 Fig. 3. The system 26 would be positioned on the skin at time zero. From time zero until time t, moisture from the skin would 6 diffuse through the rate controlling membrane 28, into the 7 activating layer 14 and acid or base in solution would migrate 8 into the drug layer 12 to convert the drug in its first form to g its second absorbable form, which subsequently would diffuse through the layers to reach the skin surface. Shortly after time 11t, the drug would begin to actually be delivered into the 12 bloodstream. This is indicated by the rise on the curve in Fig.
13 10.
14The delay time (time zero until time t) depends upon both 15the water migration through the rate controlling membrane 28 and 16the activating layer 14.
17Various materials suited for the fabrication of the various 18layers are disclosed in the aforementioned patents. The polymer 19matrix of the drug reservoir 12, the activating agent reservoir 2014, and combined reservoir 38, are anhydrous and suitable 21materials include without limitation, natural and synthetic 22rubbers or other polymeric materials, thickened mineral oil or 23petroleum jelly. The preferred embodiment according to this 24invention is fabricated from an ethylene/vinylacetate (EVA) 25copolymer of the type described in U.S.Pat.No. 4,144,317, 26preferably those having a vinylacetate content in the range of 27about 18 to 60 weight percent. Particularly good results have been obtained using an EVA copolymer of about 40 weight percent vinylacetate content (40 w/O VA). The drug and/or agent is preferably dispersed through the matrix at a concentration in excess of saturation, the amount of the excess being a function of the intended useful life of the system.
In addition to the drug and/or agent, the matrix may also contain other materials such as dyes, pigments, inert fillers, permeation enhancers, excipients and conventional components of pharmaceutical products or transdermal therapeutic systems as is known to the art. The drug and/or the activating agent containing matrices may also contain a salt such as NaCl, which facilitates 12 the onset of drug delivery by osmotically drawing up moisture 13 from the skin.
14 One face surface of the drug reservoir bears a backing member 16. The purpose of the backing is to prevent passage of 16 the drug through the surface of the reservoir distant from the 17 adhesive layer. An ancillary purpose of the backing is to provide 18 support for the system, where needed. The backing layer can be 1g flexible or nonflexible and suitable materials include without limitation, cellophane, cellulose acetate, ethylcellulose, 21 plasticized vinylacetate-vinylchloride copolymers, polyethylene 22 terephthalate, nylon, polyethylene, polypropylene, metalized 23 polyester films, polyvinylidene chloride, coated flexible fibrous 24 backings such as paper and cloth and aluminum foil. Such backings can be in the form of precast films or fabrics which are bonded 26 to the reservoir by heat or adhesives and can be coated onto the 27 reservoir. Numerous other suitable materials are disclosed in 1~33689 2 U.S.Pat. No. 4,661,105 .
3 The composition and thickness of adhesive layer 18 are such 4 that layer 18 does not constitute a significant permeation barrier to the passage of drug. Adhesive layer 18 may also 6 contain a predetermined amount of the skin absorbable form of the 1 drug which serves to saturate the skin for more rapid therapeutic 8 effects where desired. Silicone compounds are commonly used as g adhesives, however numerous materials are known which possess the requisite strength and skin compatibility. An adhesive overlay or 11 other means for maintaining the device on the skin can be 12 employed instead of, or in combination with, adhesive lamina 18.
13 Suitable adhesive materials are noted in the aforementioned 14 patent.
In operation, liner 20 is removed and the system is placed 16 in direct contact with the skin. The releaseable liner is made 17 from materials which are substantially impermeable to the drug, 18 and any other components of the layers. The same materials that 19 are used to make the backing layer may be used to make the liner, provided they are made strippable such as by siliconizing.
21 The aforementioned patents describe a wide variety of 22 materials which can be used for fabricating the various layers of 23 the transdermal delivery systems according to this invention.
24 This invention therefore contemplates the use of materials other than those specifically disclosed herein, including those which 26 may hereafter become known to the art to be capable of performing 21 the necessary functions.
3 A test sample was designed to deliver nicotine according to 4 this invention. Nicotine which is transdermally administered to facilitate breaking the tobacco habit, is especially suited to 6 illustrate this invention. Nicotine in its active form tends to 7 degrade adhesives, especially those which are silicone based.
8 Also, nicotine delivered in a sudden burst may irritate the skin.
g Therefore, use of this invention to deliver nicotine provides a system with an improved shelf-life by storing the nicotine in its 11 salt form, and further provides elimination of the initial burst 12 of drug by storing nicotine in a form which is not readily 13 absorbed through mucous membrane and intact skin.
14 The drug reservoir was a polymeric matrix comprised of 60 %
nicotine tartrate and 40 % EVA 40 carrier, and was about 6.5 mils 16 thick. The activating layer was about 3.5 mils thick and was a 17 polymeric matrix comprised of 6070 Na2C03 and 40% EVA 40 carrier.
18 Sodium carbonate provides an aqueous solution which is strongly 19 alkaline. Thus, in this particular embodiment, the activating layer was a base.
21 The release rate was measured at 35C using a 1.5 mil 22 Hytrel- (Du Pont) membrane, which simulates water diffusion 23 through human skin. The release rate profile is illustrated in 24 Figure 10.
Prior to application to the Hytrel~ membrane, the activating 26 layer is anhydrous and therefore inert and is substantially 27 impermeable to the passage of drug and is thus substantially free of drug, both nicotine and nicotine tartrate. When the system is placed in contact with the Hytrel~ membrane, moisture migrates through the membrane and into the activating layer which then becomes hydrated and active.
Moisture entering the EVA polymeric matrix reacts with the solid Na2C03 to form a basic solution. Thus, the activating agent undergoes a change of state from a first anhydrous and inert state to a second hydrated and active state, where the activating agent is in solution.
The basic solution then diffuses through the activating 11 matrix and into the drug reservoir, where it reacts with the 12 solid nicotine tartrate to convert it to its free form, nicotine.13 The agent nicotine then passes freely through the activating 14 layer and then through the Hytrel~ membrane. The activating layerin its dry state is impermeable to the passage of nicotine 16 tartrate but in its hydrated state, is permeable to the passage 17 of nicotine.
A system was designed according to this invention and is 21 illustrated in Figure 7. The backing was standard Medpar2 and the22 system had the storage suitable form of the drug and the 23 activating agent (base) mixed in the same reservoir. The drug 24 reservoir was comprised of 42% nicot;ne tartrate, 18% Na2C03 and 40% EVA 40 carrier. The system had a PVA rate controlling 26 membrane about 1.5 mils thick and had a silicone adhesive layer.
27 The release rate of nicotine from this system at 35 C in a release medium of water, is presented in the following table:
Table I
4 Time. hrsAverage Release Rate. /ug/cm2/hr 2 72.64 4 29.55 6 6 45.84 8 52.60 7 13 112.51 g As is evidenced from the data presented, this system provides the desired delayed onset where the drug release rate during the 11 first 8 hours is minimal and gradually increases to a significant 12 level at 13 hours.
14 A test sample was designed to deliver nicotine. The drug reservoir was a polymeric matrix comprised of 40 % nicotine 16 tartrate, 50 % EVA 40 carrier and 10 % NaCl, and was about 8 mils 7 thick. The activating layer was about 3.5 mils thick and was a 18 polymeric matrix comprised of 60 % Na2C03 and 40 % EVA 40 19 carrier.
The release rate was measured using a 1.5 mil Hytrel 21 membrane and is graphically illustrated in Figure 11.
22 Having thus generally described our invention and described 23 in detail certain preferred embodiments thereof, it will be 24 readily apparent that various modifications to the invention may be made by workers skilled in the art without departing from the 26 scope of this invention which is limited only by the following 27 claims.
Claims (17)
1. A controlled release medical device for delivery of at least one therapeutic agent in a pre-determined delivery rate pattern to a biological environment comprising, in combination:
reservoir means containing a therapeutic agent which in a first form is suitable for storage and in a second form is suitable for absorption through the skin or mucosa, and said reservoir means having a surface substantially impermeable to said therapeutic agent in said first form and permeable to said therapeutic agent in said second form and through which the second form of said therapeutic agent is released to the biological environment; and activating means containing an activating agent wherein said activating agent in a first state is anhydrous, and in a second state is hydrated and in solution;
whereby the therapeutic agent is changed from its first to its second form by the activating means in its second state and whereby the passage of therapeutic agent to the biological environment by diffusion is impeded until the therapeutic agent changes form.
reservoir means containing a therapeutic agent which in a first form is suitable for storage and in a second form is suitable for absorption through the skin or mucosa, and said reservoir means having a surface substantially impermeable to said therapeutic agent in said first form and permeable to said therapeutic agent in said second form and through which the second form of said therapeutic agent is released to the biological environment; and activating means containing an activating agent wherein said activating agent in a first state is anhydrous, and in a second state is hydrated and in solution;
whereby the therapeutic agent is changed from its first to its second form by the activating means in its second state and whereby the passage of therapeutic agent to the biological environment by diffusion is impeded until the therapeutic agent changes form.
2. The device of claim 1 wherein the activating means is moistened by cutaneous liquids, whereby said activating agent is changed from said first to said second state.
3. The device of claim 1 wherein said reservoir means is a matrix having a therapeutic agent dispersed throughout, said means being substantially free of activating agent, and said activating means is a matrix having an activating agent dispersed throughout, said means being substantially free of therapeutic agent.
4. The device of claim 1 which further comprises:
rate controlling means for controlling the rate at which said activating means becomes hydrated when placed at its environment of use.
rate controlling means for controlling the rate at which said activating means becomes hydrated when placed at its environment of use.
5. The device of claim 1 which further comprises :
rate controlling means for controlling the rate at which said activating agent in its second state diffuses into said reservoir means.
rate controlling means for controlling the rate at which said activating agent in its second state diffuses into said reservoir means.
6. The device of claim 1 wherein said reservoir means and said activating means comprise a single reservoir having a therapeutic agent and activating agent contained therein, in a dry blend.
7. The device of claim 1 wherein said reservoir means and said activating means comprise a single reservoir having a therapeutic agent and activating agent contained therein, dispersed throughout a matrix.
8. The device of claim 1 wherein said reservoir means is comprised of a therapeutic agent in a non-aqueous medium, said means being substantially free of activating agent, and said activating means is a matrix having an activating agent dispersed throughout, said means being substantially free of therapeutic agent.
9. The device of claim 1 wherein said reservoir means is comprised of a first and a second therapeutic agent which are co-delivered.
10. The device of claim 1 wherein said first therapeutic agent is a non-salt drug and said second therapeutic agent in a first form is a salt form of a drug, and delivery of the second therapeutic agent is delayed until a change of state occurs.
11. The device of claim 1 wherein said reservoir means is comprised of a first and a second therapeutic agent, where delivery of the second therapeutic agent commences when delivery of the first therapeutic agent ceases.
12. The device of claim 1 wherein said therapeutic agent is selected from the group consisting of fluorouracil, barbitol, furosemide, albuterol, apomorphine, benzocaine, acetylsalicylic acid, scopolamine, clonidine, phenylpropanolamine, chlorpheniramine, pilocarpine, terbutaline, salbutamol, ephedrine, ergonovine, ergotamine, benztropine, nicotine, secoverine, propranolol and timolol.
13. A transdermal drug delivery device, comprising a nicotine layer, having a skin-facing side and a skin-distal side, said layer containing a sufficient quantity of nicotine to maintain a flux of nicotine from said device for a total time period of 13 hours or more;
an occlusive backing layer in contact with and covering said layer on said skin-distal side;
and rate-controlling means for controlling diffusion of nicotine from said skin-facing side at a first flux of greater than zero but less than about 140 µg/cm2/h in any hour for a first time period of greater than zero but less than 5 hours, then at a second flux between about 20 and about 280 µg/cm2/h for a second time period of 7 hours or more.
an occlusive backing layer in contact with and covering said layer on said skin-distal side;
and rate-controlling means for controlling diffusion of nicotine from said skin-facing side at a first flux of greater than zero but less than about 140 µg/cm2/h in any hour for a first time period of greater than zero but less than 5 hours, then at a second flux between about 20 and about 280 µg/cm2/h for a second time period of 7 hours or more.
14. A transdermal drug delivery device according to claim 13 wherein the first flux is greater than zero but less than about 40 µg/cm2/h in any hour for a first time period of greater than zero but less than 3 hours, then at a second flux between about 40 and about 280 µg/cm2/h for a second time period of 12 hours or more.
15. A transdermal drug delivery device, comprising a nicotine layer having a skin-facing side and a skin-distal side, said nicotine layer containing a sufficient quantity of nicotine to maintain a flux of nicotine from said patch for a period of 12 hours or more;
an occlusive backing in contact with and covering said layer on said skin-distal side; and rate-controlling means for controlling diffusion of nicotine from said skin-facing side at a flux between about 20 and about 280 µg/cm2/h for a period of 13 hours or more.
an occlusive backing in contact with and covering said layer on said skin-distal side; and rate-controlling means for controlling diffusion of nicotine from said skin-facing side at a flux between about 20 and about 280 µg/cm2/h for a period of 13 hours or more.
16. A transdermal drug delivery device, comprising a nicotine layer, having a skin-facing side and a skin-distal side, said layer containing a sufficient quantity of nicotine to maintain a flux of nicotine from said device for a total time period of 12 hours or more;
an occlusive backing layer in contact with and covering said layer on said skin-distal side;
and rate-controlling means for controlling diffusion of nicotine from said skin-facing side at a first flux less than about 40 µg/cm2/h for a first time period of greater than zero but less than about 11 hours, then at a second flux no greater than about 180 µg/cm2/h for a second time period of 9 hours or more.
an occlusive backing layer in contact with and covering said layer on said skin-distal side;
and rate-controlling means for controlling diffusion of nicotine from said skin-facing side at a first flux less than about 40 µg/cm2/h for a first time period of greater than zero but less than about 11 hours, then at a second flux no greater than about 180 µg/cm2/h for a second time period of 9 hours or more.
17. A transdermal drug delivery device according to claim 16 wherein the first flux is less than about 10 µg/cm2/h and the first time period is the first hour.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/118,577 US4781924A (en) | 1987-11-09 | 1987-11-09 | Transdermal drug delivery device |
US07/118,577 | 1987-11-09 |
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Publication Number | Publication Date |
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CA1333689C true CA1333689C (en) | 1994-12-27 |
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---|---|---|---|
CA000577093A Expired - Lifetime CA1333689C (en) | 1987-11-09 | 1988-09-12 | Transdermal drug delivery device |
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US (2) | US4781924A (en) |
EP (1) | EP0316065B1 (en) |
JP (1) | JP2749832B2 (en) |
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CA (1) | CA1333689C (en) |
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Families Citing this family (92)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4965074A (en) * | 1985-03-05 | 1990-10-23 | Ciba-Geigy Corporation | Method of treating memory impairment |
ES2028074T3 (en) * | 1986-06-13 | 1992-07-01 | Alza Corporation | ACTIVATION BY MOISTURE OF A TRANSDERMIC PHARMACY SUPPLY SYSTEM. |
US6139868A (en) * | 1986-08-28 | 2000-10-31 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
US4908027A (en) * | 1986-09-12 | 1990-03-13 | Alza Corporation | Subsaturated transdermal therapeutic system having improved release characteristics |
US4917676A (en) * | 1986-11-20 | 1990-04-17 | Ciba-Geigy Corporation | User-activated transdermal therapeutic system |
US4911707A (en) * | 1987-02-13 | 1990-03-27 | Ciba-Geigy Corporation | Monolithic user-activated transdermal therapeutic system |
US4915950A (en) * | 1988-02-12 | 1990-04-10 | Cygnus Research Corporation | Printed transdermal drug delivery device |
US4906475A (en) | 1988-02-16 | 1990-03-06 | Paco Pharmaceutical Services | Estradiol transdermal delivery system |
US5004610A (en) * | 1988-06-14 | 1991-04-02 | Alza Corporation | Subsaturated nicotine transdermal therapeutic system |
US5364630A (en) * | 1988-06-14 | 1994-11-15 | Alza Corporation | Subsaturated nicotine transdermal therapeutic system |
IE62662B1 (en) * | 1989-01-06 | 1995-02-22 | Elan Corp Plc | Use of nicotine in the treatment of conditions susceptible to said treatment |
DE3905051A1 (en) * | 1989-02-18 | 1990-08-30 | Lohmann Therapie Syst Lts | THERAPEUTIC SYSTEM FOR DELAYED AND CONTROLLED TRANSDERMAL OR TRANSMUCOSAL ADMINISTRATION OF ACTIVE SUBSTANCES (I) |
DE3905050A1 (en) * | 1989-02-18 | 1990-08-30 | Lohmann Therapie Syst Lts | THERAPEUTIC SYSTEM FOR DELAYED AND CONTROLLED TRANSDERMAL OR TRANSMUCOSAL ADMINISTRATION OF ACTIVE SUBSTANCES (II) |
DE3908431A1 (en) * | 1989-03-15 | 1990-09-27 | Lohmann Therapie Syst Lts | TRANSDERMAL SYSTEM WITH STAGE SUBSTANCE DELIVERY AND USE FOR LOCAL OR SYSTEMIC DISPENSER |
DE3910543A1 (en) * | 1989-04-01 | 1990-10-11 | Lohmann Therapie Syst Lts | TRANSDERMAL THERAPEUTIC SYSTEM WITH INCREASED ACTIVE FLUID AND METHOD FOR THE PRODUCTION THEREOF |
ES2095929T3 (en) * | 1989-10-23 | 1997-03-01 | Theratech Inc | IONTOPHORETIC DEVICE USING A REGIME REGULATOR. |
DE4002281A1 (en) * | 1990-01-26 | 1991-08-01 | Lohmann Therapie Syst Lts | TRANSDERMAL THERAPEUTIC SYSTEM WITH TULOBUTEROL |
US5147654A (en) * | 1990-07-23 | 1992-09-15 | Alza Corporation | Oral osmotic device for delivering nicotine |
CA2120748A1 (en) * | 1991-10-16 | 1993-04-29 | Arto Olavi Urtti | Peroral drug delivery system |
GB2265088B (en) * | 1992-03-10 | 1996-02-07 | Kyosti Eero Antero Kontturi | Electrochemical device for drug delivery |
ZA937452B (en) * | 1992-10-15 | 1994-06-07 | Alza Corp | Delayed onset transdermal delivery device |
US5691377A (en) * | 1993-07-30 | 1997-11-25 | University Of Maryland Eastern Shore And University Of Maryland College Park | Use of N-methyl-aspartic acid for enhancing growth and altering body composition |
US5466465A (en) * | 1993-12-30 | 1995-11-14 | Harrogate Holdings, Limited | Transdermal drug delivery system |
DE4400769C2 (en) * | 1994-01-13 | 1996-07-18 | Lohmann Therapie Syst Lts | Method and device for producing a flat dosage form with a preparation containing active pharmaceutical ingredients |
EP0755244A1 (en) * | 1994-04-13 | 1997-01-29 | Novartis AG | Temporally controlled drug delivery systems |
GB2290964A (en) * | 1994-07-08 | 1996-01-17 | Arto Olavi Urtti | Transdermal drug delivery system |
DE4429663C2 (en) * | 1994-08-20 | 1997-09-11 | Lohmann Therapie Syst Lts | Transdermal therapeutic system with hydrolysis protection |
DE19610293C1 (en) * | 1996-03-15 | 1997-07-31 | Fraunhofer Ges Forschung | Electronically-breakable microencapsulation system for sensitive materials |
US6660295B2 (en) | 1997-09-30 | 2003-12-09 | Alza Corporation | Transdermal drug delivery device package with improved drug stability |
DE19814087A1 (en) | 1998-03-30 | 1999-10-14 | Lohmann Therapie Syst Lts | Moisture-activated therapeutic system |
DE19814083C2 (en) * | 1998-03-30 | 2002-02-07 | Lohmann Therapie Syst Lts | Process for the production of transdermal therapeutic systems using basic alkali metal salts for converting active substance salts into the free bases |
US6699497B1 (en) | 1998-07-24 | 2004-03-02 | Alza Corporation | Formulations for the transdermal administration of fenoldopam |
US6348210B1 (en) | 1998-11-13 | 2002-02-19 | Alza Corporation | Methods for transdermal drug administration |
KR100315465B1 (en) * | 1998-11-23 | 2002-02-19 | 성재갑 | Animal Insect Repellent Compositions Containing Water Soluble Polymer and Alcohol |
US9192780B2 (en) | 1998-11-30 | 2015-11-24 | L'oreal | Low intensity light therapy for treatment of retinal, macular, and visual pathway disorders |
US6936044B2 (en) * | 1998-11-30 | 2005-08-30 | Light Bioscience, Llc | Method and apparatus for the stimulation of hair growth |
US6887260B1 (en) | 1998-11-30 | 2005-05-03 | Light Bioscience, Llc | Method and apparatus for acne treatment |
US6283956B1 (en) * | 1998-11-30 | 2001-09-04 | David H. McDaniels | Reduction, elimination, or stimulation of hair growth |
US20060212025A1 (en) * | 1998-11-30 | 2006-09-21 | Light Bioscience, Llc | Method and apparatus for acne treatment |
ES2336054T3 (en) | 1998-12-18 | 2010-04-07 | Alza Corporation | TRANSPARENT DEVICE FOR THE TRANSDERMIC ADMINISTRATION OF NICOTINE. |
US6541021B1 (en) | 1999-03-18 | 2003-04-01 | Durect Corporation | Devices and methods for pain management |
US6835194B2 (en) * | 1999-03-18 | 2004-12-28 | Durect Corporation | Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners |
CA2367100A1 (en) * | 1999-04-01 | 2000-10-12 | Alza Corporation | Transdermal drug delivery devices comprising a polyurethane drug reservoir |
DE19925613A1 (en) * | 1999-06-04 | 2000-12-07 | Lohmann Therapie Syst Lts | Composite laminate and process for its manufacture |
US6586000B2 (en) | 1999-12-16 | 2003-07-01 | Dermatrends, Inc. | Hydroxide-releasing agents as skin permeation enhancers |
EP1239846A2 (en) * | 1999-12-16 | 2002-09-18 | Dermatrends, Inc. | Transdermal administration of phenylpropanolamine |
US6673363B2 (en) | 1999-12-16 | 2004-01-06 | Dermatrends, Inc. | Transdermal and topical administration of local anesthetic agents using basic enhancers |
US6582724B2 (en) | 1999-12-16 | 2003-06-24 | Dermatrends, Inc. | Dual enhancer composition for topical and transdermal drug delivery |
US6602912B2 (en) | 2000-06-30 | 2003-08-05 | Dermatrends, Inc. | Transdermal administration of phenylpropanolamine |
US6719997B2 (en) | 2000-06-30 | 2004-04-13 | Dermatrends, Inc. | Transdermal administration of pharmacologically active amines using hydroxide-releasing agents as permeation enhancers |
US7074803B2 (en) * | 2001-03-02 | 2006-07-11 | Durect Corporation | Opioid formulations |
US20020119187A1 (en) * | 2000-09-29 | 2002-08-29 | Cantor Adam S. | Composition for the transdermal delivery of fentanyl |
US6682757B1 (en) | 2000-11-16 | 2004-01-27 | Euro-Celtique, S.A. | Titratable dosage transdermal delivery system |
FR2822711B1 (en) * | 2001-03-28 | 2003-06-13 | Oreal | TREATMENT DEVICE COMPRISING AN ENVELOPE DEFINING A CAVITY IN WHICH A PART OF THE BODY MAY BE ENGAGED |
US20040102476A1 (en) * | 2002-11-25 | 2004-05-27 | Chan Tai Wah | High concentration formulations of opioids and opioid derivatives |
CN1784184A (en) | 2003-04-10 | 2006-06-07 | 光生物科学有限责任公司 | Photomodulation methods and devices for regulating cell proliferation and gene expression |
US20040258742A1 (en) * | 2003-04-11 | 2004-12-23 | Van Osdol William Woodson | Transdermal administration of N-(2,5-disubstituted phenyl)-N'-(3-substituted phenyl)-N'-methyl guanidines |
WO2005011606A2 (en) * | 2003-07-31 | 2005-02-10 | Light Bioscience, Llc | System and method for the photodynamic treatment of burns, wounds, and related skin disorders |
US7243788B2 (en) | 2003-10-22 | 2007-07-17 | Kimberly-Clark Worldwide, Inc. | Package for segregating and mixing substances |
NZ582975A (en) | 2004-10-21 | 2011-07-29 | Durect Corp | Transdermal delivery systems delivering sufentanil |
US8252319B2 (en) | 2004-10-21 | 2012-08-28 | Durect Corporation | Transdermal delivery system for sufentanil |
US20080269121A1 (en) * | 2005-02-25 | 2008-10-30 | The Board Of Regents Of The University Of Texas System | Methods and Compositions Involving A1c Subunit of L-Type Calcium Channels in Smooth Muscle Cells |
US8518926B2 (en) | 2006-04-10 | 2013-08-27 | Knopp Neurosciences, Inc. | Compositions and methods of using (R)-pramipexole |
US20070259930A1 (en) * | 2006-04-10 | 2007-11-08 | Knopp Neurosciences, Inc. | Compositions and methods of using r(+) pramipexole |
KR20090021169A (en) | 2006-05-16 | 2009-02-27 | 크놉 뉴로사이언시스 인코포레이티드 | Compositions of r(+) and s(-) pramipexole and methods of using the same |
EP2068968A2 (en) * | 2006-09-28 | 2009-06-17 | Med Institute, Inc. | Medical devices incorporating a bioactive and methods of preparing such devices |
WO2008039995A2 (en) * | 2006-09-28 | 2008-04-03 | Vance Products Incorporated, D/Ba Cook Urological Incorporated | Medical device including a bioactive in a non-ionic and an ionic form and methods of preparation thereof |
WO2008042227A1 (en) * | 2006-09-28 | 2008-04-10 | Med Institute, Inc. | Medical device including an anesthetic and method of preparation thereof |
US20090054333A1 (en) * | 2006-10-17 | 2009-02-26 | Antonio Giordano | Peptide inhibitors of cyclin-dependent kinase activity and uses thereof |
US8524695B2 (en) | 2006-12-14 | 2013-09-03 | Knopp Neurosciences, Inc. | Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same |
US20080228151A1 (en) * | 2007-02-28 | 2008-09-18 | Jie Zhang | Transdermal drug delivery with controlled heat for treating musculoskeletal pain and/or inflammation |
JP2010521496A (en) | 2007-03-14 | 2010-06-24 | ノップ ニューロサイエンシーズ、インク. | Synthesis of chiral purified substituted benzothiazolediamine |
WO2008150995A2 (en) * | 2007-06-01 | 2008-12-11 | Zars Pharma, Inc. | Transdermal drug delivery systems for delivering anti-inflammatory drugs |
DE102007041557B4 (en) * | 2007-08-29 | 2011-03-31 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing elongated hollow bodies |
DE102008013701A1 (en) * | 2008-03-11 | 2009-09-17 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system with stabilized membrane |
WO2010022140A1 (en) | 2008-08-19 | 2010-02-25 | Knopp Neurosciences, Inc. | Compositions and methods of using (r)-pramipexole |
US20100221313A1 (en) * | 2008-12-01 | 2010-09-02 | Innovative Pharmaceuticals, Llc | Transdermal reservoir patch |
AU2010262970A1 (en) * | 2009-06-19 | 2012-01-12 | Knopp Neurosciences, Inc. | Compositions and methods for treating amyotrophic lateral sclerosis |
DE102010024105A1 (en) * | 2010-06-17 | 2011-12-22 | Grünenthal GmbH | Transdermal administration of memantine |
CN103732611B (en) | 2011-01-10 | 2016-06-01 | 伊沃恩有限公司 | The purposes of beta-adrenergic inverse agonist for giving up smoking |
WO2013096816A1 (en) | 2011-12-22 | 2013-06-27 | Biogen Idec Ma Inc. | Improved synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds |
US9662313B2 (en) | 2013-02-28 | 2017-05-30 | Knopp Biosciences Llc | Compositions and methods for treating amyotrophic lateral sclerosis in responders |
US9682068B2 (en) | 2013-05-20 | 2017-06-20 | Mylan Inc. | Transdermal therapeutic system for extended dosing of pramipexole in treating neurological disorders |
US9468630B2 (en) | 2013-07-12 | 2016-10-18 | Knopp Biosciences Llc | Compositions and methods for treating conditions related to increased eosinophils |
PT3019167T (en) | 2013-07-12 | 2021-03-04 | Knopp Biosciences Llc | Treating elevated levels of eosinophils and/or basophils |
ES2813674T3 (en) | 2013-08-13 | 2021-03-24 | Knopp Biosciences Llc | Compositions and methods for treating plasma cell disorders and b-cell prolymphocytic disorders |
US9763918B2 (en) | 2013-08-13 | 2017-09-19 | Knopp Biosciences Llc | Compositions and methods for treating chronic urticaria |
US11541018B2 (en) | 2016-06-23 | 2023-01-03 | Corium, Llc | Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent |
CA3031945A1 (en) | 2016-07-27 | 2018-02-01 | Corium International, Inc. | Transdermal formulation and delivery method of low solubility or unstable unionized neutral drugs by in situ salt-to-neutral drug conversion of salt drug |
JP7071958B2 (en) | 2016-07-27 | 2022-05-19 | コリウム, インコーポレイテッド | Memantine transdermal delivery system |
US20180028461A1 (en) | 2016-07-27 | 2018-02-01 | Corium International, Inc. | Transdermal delivery systems with pharmacokinetics bioequivalent to oral delivery |
CA3086163A1 (en) | 2017-12-20 | 2019-06-27 | Corium, Inc. | Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point |
Family Cites Families (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE860152C (en) | 1951-06-24 | 1952-12-18 | Gustav Nowka | Ship propulsion through hydraulic reaction using a centrifugal pump |
US3252802A (en) | 1964-06-11 | 1966-05-24 | Canadian Patents Dev | Method of supplementing the feed of growing swine with nicotine |
US3598123A (en) * | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
US3598122A (en) * | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
US3734097A (en) | 1969-04-01 | 1973-05-22 | Alza Corp | Therapeutic adhesive tape |
US3901248A (en) | 1970-07-22 | 1975-08-26 | Leo Ab | Chewable smoking substitute composition |
US3877468A (en) | 1970-07-22 | 1975-04-15 | Leo Ab | Chewable tobacco substitute composition |
US3731683A (en) | 1971-06-04 | 1973-05-08 | Alza Corp | Bandage for the controlled metering of topical drugs to the skin |
US3742951A (en) | 1971-08-09 | 1973-07-03 | Alza Corp | Bandage for controlled release of vasodilators |
US3870593A (en) * | 1972-06-06 | 1975-03-11 | Minnesota Mining & Mfg | Stretch-oriented porous films and preparation and use thereof |
US3845217A (en) | 1972-11-16 | 1974-10-29 | Helsingborg L Ab | Buffered smoking substitute compositions |
US4177256A (en) * | 1973-04-25 | 1979-12-04 | Alza Corporation | Osmotic bursting drug delivery device |
US3870794A (en) | 1974-02-20 | 1975-03-11 | Foundation For Behavioral Rese | Treatment of certain emotional disorders with nicotine compounds |
US4125623A (en) | 1974-04-08 | 1978-11-14 | U.S. Philips Corporation | Spasmolytics |
NL178686C (en) | 1974-04-08 | 1986-05-01 | Duphar Int Res | METHOD FOR PREPARING OR MANUFACTURING SPASMOLYTICALLY ACTIVE PREPARATIONS AND METHOD FOR PREPARING N-ALKYL-N-SUBSTITUTED ALKYLBETA-PHENYLETHYLAMINES WITH SPASMOLYTIC ACTION |
US3923939A (en) * | 1974-06-07 | 1975-12-02 | Alza Corp | Process for improving release kinetics of a monolithic drug delivery device |
US3926188A (en) | 1974-11-14 | 1975-12-16 | Alza Corp | Laminated drug dispenser |
US4012221A (en) * | 1975-05-13 | 1977-03-15 | International Copper Research Association Inc. | Slow release copper toxicant compositions |
US4144317A (en) * | 1975-05-30 | 1979-03-13 | Alza Corporation | Device consisting of copolymer having acetoxy groups for delivering drugs |
US4562075A (en) | 1982-05-20 | 1985-12-31 | Nelson Research & Development Co. | Penetration enhancers for transdermal drug delivery of systemic agents |
US4031894A (en) | 1975-12-08 | 1977-06-28 | Alza Corporation | Bandage for transdermally administering scopolamine to prevent nausea |
US4060084A (en) | 1976-09-07 | 1977-11-29 | Alza Corporation | Method and therapeutic system for providing chemotherapy transdermally |
JPS5397422A (en) * | 1977-02-04 | 1978-08-25 | Canon Inc | Double priority camera |
US4201211A (en) | 1977-07-12 | 1980-05-06 | Alza Corporation | Therapeutic system for administering clonidine transdermally |
US4166111A (en) * | 1978-06-19 | 1979-08-28 | Environmental Chemicals, Inc. | Method and composition for the long term controlled release of a non-persistent organotin pesticide from an inert monolithic thermoplastic material |
US4748181A (en) | 1979-08-28 | 1988-05-31 | Foundation For Behavioral Research | Method for treating hypertension with nicotine |
US4286592A (en) * | 1980-02-04 | 1981-09-01 | Alza Corporation | Therapeutic system for administering drugs to the skin |
US4314557A (en) * | 1980-05-19 | 1982-02-09 | Alza Corporation | Dissolution controlled active agent dispenser |
US4379454A (en) * | 1981-02-17 | 1983-04-12 | Alza Corporation | Dosage for coadministering drug and percutaneous absorption enhancer |
US4661105A (en) * | 1981-06-29 | 1987-04-28 | Alza Corporation | Medical bandage for administering vasodilator drug |
US4484921A (en) * | 1982-02-01 | 1984-11-27 | Alza Corporation | Theophylline therapy utilizing osmotic delivery |
IE54286B1 (en) | 1983-01-18 | 1989-08-16 | Elan Corp Plc | Drug delivery device |
DE3344691A1 (en) | 1983-12-10 | 1985-06-20 | Bayer Ag, 5090 Leverkusen | ACTIVE GAS EXHAUST SYSTEMS |
US4704282A (en) | 1984-06-29 | 1987-11-03 | Alza Corporation | Transdermal therapeutic system having improved delivery characteristics |
US4588580B2 (en) | 1984-07-23 | 1999-02-16 | Alaz Corp | Transdermal administration of fentanyl and device therefor |
DE3586707T2 (en) | 1984-10-05 | 1993-02-11 | Hercon Lab | SYSTEM FOR TRANSDERMAL APPLICATION OF A MEDICINAL PRODUCT. |
US4573995A (en) | 1984-10-09 | 1986-03-04 | Alza Corporation | Transdermal therapeutic systems for the administration of naloxone, naltrexone and nalbuphine |
US4568343A (en) * | 1984-10-09 | 1986-02-04 | Alza Corporation | Skin permeation enhancer compositions |
DE3438284A1 (en) * | 1984-10-16 | 1985-03-07 | Hans-Harald von 2400 Lübeck Tilly | Nicotine-containing depot plaster |
US4597961A (en) * | 1985-01-23 | 1986-07-01 | Etscorn Frank T | Transcutaneous application of nicotine |
US4680172A (en) | 1985-03-05 | 1987-07-14 | Ciba-Geigy Corporation | Devices and methods for treating memory impairment |
US4643856A (en) | 1985-03-21 | 1987-02-17 | Moleculon, Inc. | Process of making gelled cellulose triacetate product |
US4665069A (en) | 1985-04-02 | 1987-05-12 | Barnett Rosenberg | Analgesic composition and method of relieving pain |
US4756710A (en) * | 1985-04-05 | 1988-07-12 | Merck & Co., Inc. | pH-Mediated drug delivery system |
US4920989A (en) | 1985-04-25 | 1990-05-01 | Regents Of The University Of California | Method and apparatus for aiding in the reduction of incidence of tobacco smoking |
US5016652A (en) | 1985-04-25 | 1991-05-21 | The Regents Of The University Of California | Method and apparatus for aiding in the reduction of incidence of tobacco smoking |
JPS61251619A (en) | 1985-04-30 | 1986-11-08 | Nitto Electric Ind Co Ltd | Nicotin-containing tape preparation |
US4655766A (en) * | 1985-08-01 | 1987-04-07 | Alza Corporation | Fluid imbibing pump with self-regulating skin patch |
US4715387A (en) | 1985-08-23 | 1987-12-29 | The Regents Of The Univ. Of California | Aerosol for use in the reduction of tobacco smoking |
EP0245480A1 (en) | 1985-11-14 | 1987-11-19 | ROSEN, David I. | Transdermal application of nicotine |
US4797284A (en) | 1986-03-12 | 1989-01-10 | Merck & Co., Inc. | Transdermal drug delivery system |
EP0251425B1 (en) | 1986-04-03 | 1993-06-16 | Hercon Laboratories Corporation | Article for administration of pharmacologically-active substances |
DE3629304A1 (en) | 1986-08-28 | 1988-03-24 | Lohmann Gmbh & Co Kg | TRANSDERMAL THERAPEUTIC SYSTEM, ITS USE AND METHOD FOR THE PRODUCTION THEREOF |
PT86138B (en) | 1986-11-20 | 1993-09-30 | Ciba Geigy Ag | PROCEDURE FOR TRANSDERMIC ACTIVATION OR TOPIC USING A TRANSDERMIC THERAPEUTIC SYSTEM ACTIVATED BY THE USER |
DE3743947A1 (en) | 1987-09-01 | 1989-03-09 | Lohmann Gmbh & Co Kg | DEVICE FOR THE CONTROLLED DELIVERY OF NICOTIN, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
US4839174A (en) | 1987-10-05 | 1989-06-13 | Pharmetrix Corporation | Novel transdermal nicotine patch |
-
1987
- 1987-11-09 US US07/118,577 patent/US4781924A/en not_active Ceased
-
1988
- 1988-09-12 CA CA000577093A patent/CA1333689C/en not_active Expired - Lifetime
- 1988-09-30 JP JP63247303A patent/JP2749832B2/en not_active Expired - Lifetime
- 1988-10-04 ES ES88309230T patent/ES2054818T3/en not_active Expired - Lifetime
- 1988-10-04 AT AT88309230T patent/ATE89755T1/en not_active IP Right Cessation
- 1988-10-04 EP EP88309230A patent/EP0316065B1/en not_active Expired - Lifetime
- 1988-10-04 IE IE299588A patent/IE63148B1/en not_active IP Right Cessation
- 1988-10-04 DE DE8888309230T patent/DE3881340T2/en not_active Expired - Lifetime
- 1988-10-11 DK DK567088A patent/DK567088A/en not_active Application Discontinuation
- 1988-11-08 PT PT88962A patent/PT88962B/en not_active IP Right Cessation
-
1990
- 1990-10-31 US US07/606,462 patent/USRE39588E1/en not_active Expired - Lifetime
-
1993
- 1993-05-27 GR GR920403266T patent/GR3007980T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
DK567088D0 (en) | 1988-10-11 |
EP0316065B1 (en) | 1993-05-26 |
ATE89755T1 (en) | 1993-06-15 |
PT88962A (en) | 1989-11-30 |
JP2749832B2 (en) | 1998-05-13 |
GR3007980T3 (en) | 1993-08-31 |
EP0316065A3 (en) | 1990-02-14 |
JPH01135717A (en) | 1989-05-29 |
IE63148B1 (en) | 1995-03-22 |
USRE39588E1 (en) | 2007-04-24 |
DK567088A (en) | 1989-05-10 |
US4781924A (en) | 1988-11-01 |
DE3881340T2 (en) | 1993-09-09 |
IE882995L (en) | 1989-05-09 |
PT88962B (en) | 1993-11-30 |
DE3881340D1 (en) | 1993-07-01 |
EP0316065A2 (en) | 1989-05-17 |
ES2054818T3 (en) | 1994-08-16 |
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Legal Events
Date | Code | Title | Description |
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MKEX | Expiry |