CA2065403C - Transdermal delivery device having delayed onset - Google Patents
Transdermal delivery device having delayed onsetInfo
- Publication number
- CA2065403C CA2065403C CA002065403A CA2065403A CA2065403C CA 2065403 C CA2065403 C CA 2065403C CA 002065403 A CA002065403 A CA 002065403A CA 2065403 A CA2065403 A CA 2065403A CA 2065403 C CA2065403 C CA 2065403C
- Authority
- CA
- Canada
- Prior art keywords
- layer
- active compound
- skin
- compound
- laminated
- 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.)
- Expired - Fee Related
Links
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Classifications
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- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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- A61F13/00—Bandages or dressings; Absorbent pads
- A61F13/02—Adhesive bandages or dressings
- A61F13/0259—Adhesive bandages or dressings characterised by the release liner covering the skin adhering layer
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- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F13/00—Bandages or dressings; Absorbent pads
- A61F2013/00361—Plasters
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Abstract
A transdermal delivery device has a reservoir containing an active compound, which is kept separate from the delivery lay-ers of the device until administration. At the time of administration, the reservoir is laminated to the delivery layers, or is ruptured to place the active compound, vehicle, and/or permeation enhancers in contact with the delivery layers, which results in adminis-tration of the active compound to the skin after a delay period.
Description
WO91/03998 ZO~S~3 PCT/US90/05198 TRANSDERMAL DELIVERY DEVICE
HAVING DELAYED ONSET
Description Technical Field This invention relates to devices and methods for administering biologically active compounds through the skin, i.e., transdermally. More specifically, the invention relates to a device and method for transdermal delivery having a delayed onset of delivery.
Backqround of the Invention The delivery of compounds through the skin provides many advantages. Primarily, transdermal deliv-ery provides a comfortable, convenient, and noninvasive means for delivering drugs. By avoiding administration through the gastrointestinal tract, one may employ com-pounds which would otherwise be degraded, metabolically deactivated, or poorly absorbed. Additionally, one eliminates the complications of gastrointestinal irrita-tion. Transdermal delivery using a continuous-release type of device also allows one to terminate administra-tion immediately should the need arise, e.g., in the event of an adverse drug reaction, or over-elevation of drug plasma concentration.
Drug delivery devices may generally be classi-fied as either "matrix" or "reservoir" in construction.
A matrix or monolithic device generally comprises a drug-permeable solid polymer, having a drug dispersed ,~
W O 91/03998 ~ PC~r/US90/05198 2065~3 throughout. Matrix devices may be formed from erodible or non-erodible polymers (transdermal devices are typically non-erodible). Reservoir devices generally comprise a depot of essentially pure drug (or drug with excipient) surrounded by a rate-controlling membrane, where the rate of drug diffusion through the membrane controls the rate of release. Combinations of matrix reservoirs with rate-controlling membranes have also been proposed. The typical design criteria are to provide a substantially constant and continuous release rate, and to provide a release rate capable of delivering a therapeutically effective amount of the compound.
Additionally, the device must be non-irritating, and is preferably designed to be of a convenient size.
The conventional transdermal device is designed with the goal of delivering a therapeutic compound at a substantially constant rate ("zero-order" delivery).
However, administration of some compounds at a constant, continuous rate may cause drug tolerance to develop. In order to prevent tolerance, a transdermal patch-type device must be removed periodically to interrupt continuous delivery. This in turn creates additional problems of patient compliance and design of the patch adhesive (which must adhere to the skin continuously), and fails to accommodate the patient's circadian rhythms.
Nitroglycerin is a vasodilator currently administered for coronary disorders, especially angina pectoris and congestive heart failure. As nitroglycerin cannot be administered orally, it is typically adminis-tered sublingually, or via transdermal patch. Commer-cially available patches, such as Transderm Nitro0 and Nitro-Dur0, provide essentially constant plasma concen-trations of nitroglycerin over a 24 hour period, and are changed daily. However, recent studies suggest that continuous administration of nitroglycerin induces tol-WO9l/03998 2~65~ PCT/~ISgo/05198 erance, with concomitant loss of efficacy in the patient.European Patent Application No. 0290262 (published 9 November 1988) describes a transdermal device which provides a delayed onset of administration of nitrate drugs to the skin. It consists of a backing layer, a rupturable pod sandwiched between the backing and a nonwoven fabric layer, an initially drug impermeable barrier membrane, an adhesive layer and a release liner. The pod is constructed of two layers that have rupturable seals about their peripheries so as to define a lumen that contains the drug and an activator liquid that is capable of plasticizing the barrier membrane and making it increasingly permeable to drugs.
Although this device enables delayed nitrate drug administration which is dependent upon the plasticization of the barrier membrane, it suffers several important and practical drawbacks. In this regard, the delay is achieved through use of an activator liquid. The use of an activator complicates the formulation, economics, and regulatory approval of the device. Further, the drug release kinetics of the device are complicated because they depend on the permeability of the barrier membrane which varies with the degree of membrane plasticization.
Among the purposes of one embodiment of the present invention are to provide a delayed onset transdermal drug delivery device that (1) does not involve an activator liquid, and (2) has a release profile subject to fewer variables. The purposes of another embodiment of the invention is to provide a delayed onset transdermal drug delivery device that does not involve a rupturable drug reservoir but instead is effected through assembly of components of the device just prior to device use.
~4~ 206~403 Summary of the Invention Embo-limente of the invention as described hereinafter can provide a continuous, constant transdermal release of an active substance, wherein the onset of release is delayed from 1-24 hours, depending on the length of time that the drug is 5 delivered. This provides a "wash out" period, during which the plasma concentration of any compound rem~ining in the patient's system from application of the previous device is allowed to drop to near baseline levels.
Accordingly in one example, a patient may wear the patch for 24 hours, replacing the patch with a fresh patch prior to going to sleep. The wash out period 10 thus occurs during the patient's sleep, and is followed by effective plasma concentrations of the active compound during the waking hours.
According to a first aspect of the invention there is provided a kit for preparing a device for ~-imini~tçring an active compound tr~n~dçrm~lly to a subject's skin, having a delayed onset of delivery, said kit comprising: a first layer comprising a 15 polymeric matrix impregnated with said active compound, said compound and matrix being selected to obtain a first compound diffusion coefficient of about 10-5 to about 10-1 cm2/sec in said matrix; a second layer not in contact with said first layer, comprising an adhesive capable of a&ering to said first layer and to said subject's skin, said second layer having a second diffusion coefficient of about 10-5 to about 20 10-1 cm2/sec in said matrix, wherein said second layer is substantially devoid of said active compound.
According to a second aspect of the invention there is provided a controlled release device for ~lministering an active compound to a subject comprising: a first having a polymeric matrix impregn~ted with an active compound, said compound and25 matrix being selected to obtain a first compound diffusion coefficient of about 10-5 to about 10-1 cm2/sec in said matrix; a second layer having an a&esive capable of adhering to said first layer and to said subject's skin, said second layer having a second diffusion coefficient of about 10-5 to about 10-1 cm2/sec in said matrix, said s- 2065403 second layer being subst~nti~lly devoid of said active compound; wherein the first and second layers are arranged for use in a method of ~rlmini~tering the active compound to the subject in which a l~min~te of the first and second layers is applied to the skin of the subject before the active compound equilibrates in the l~min~te.
According to a third aspect of the invention there is provided a device for ~lmini~tering an active compound tr~n~dçrm~lly following application to a subject's skin, having a delayed onset of delivery, said device comprising: (a) a contact layer comprising a skin contact adhesive which is permeable to said active compound; (b) a backing layer comprising a thin, flexible m~tçri~l which is substantially impermeable to said active compound, which is l~min~ted to said contact layer, and together with said contact layer defines a reservoir void between said contact layer and said backing layer; and within said reservoir void, a rupturable capsule Co~ g said active compound.
A
20~iS403 Brief DescriPtion of the Drawinqs Figure 1 shows a schematic cross-section of a presently preferred embodiment of the invention, wherein the active compound is sequestered within a rupturable capsule.
Figure 2 is a schematic cross-section of a kit embodiment of the invention which is laminated by the user. The layers depicted are thin solid films, prefer-ably flexible and/or elastomeric, and are laminated together immediately prior to application by the user.
The view depicted illustrates a cross-section of the device with the protective release liner and liner/carrier in place.
Figure 3 shows a perspective view of the kit embodiment after removal of the upper release liner, just prior to lamination.
Figure 4 depicts a schematic cross section of the kit embodiment immediately after lamination, follow-ing removal of the liner/carrier.
Figure 5 is a schematic cross section of another presently preferred embodiment, having a ruptur-able capsule formed as part of the drug reservoir of the device.
Figure 6 is a cross section of a dispensing device, suitable for dispensing devices of the invention as shown in Figure 1 or Figure 5.
Figure 7 depicts graphically the results of the experiment reported in Example 1.
Figure 8 depicts graphically the results of the experiment reported in Example 2.
Figure 9 depicts graphically the results of the experiments reported in Example 3.
ZO~i54~3 Modes of Carrying Out The Invention A. Definitions The term "active compound" as used herein refers to any substance which may be administered to an animal to obtain a beneficial effect. Active compounds may be drugs, for example, vasodilators such as nitro-glycerin, amyl nitrate, isosorbide dinitrate or mono-nitrate and the like, L-DOP~, analgesics, antiinflam-matories, antihistamines, antibiotics, antihypertens-ives, hormones, and the like, which are useful for pre-venting or ameliorating a given disorder. other active compounds include contraceptives (e.g., estradiol, levo-norgestrel, 3-ketodesogestrel, gestodene, and the like), vitamins, appetite suppressants, nicotine, caffeine and other stimulants, growth promoters (particularly when administered to livestock), and the like. Suitable active compounds within the scope of this invention are capable of diffusion or absorption through the skin.
The term "mammals" includes animals such as humans, livestock including cattle, sheep, goats, horses, small animals such as dogs, cats, and mice, wildlife and zoo animals such as elephants, lions, tigers, antelope, and the like. The term ~animal" refers to mammals and birds, including domestic fowl such as chickens, geese, ducks, turkeys, game hens, and the like.
The term "liquid carrier" refers to a solvent compatible with the reservoir matrix and adhesive lay-ers, as well as with skin, in which the active compound is soluble. The active compound will preferably be mod-erately soluble in the carrier. Suitable carriers gen-erally enhance the release rate of active compound from devices of the invention. Exemplary carriers include lower alcohols such as methanol, ethanol, propanol, iso-propanol, and the like, glycols such as propylene glycol Z~6~103 and the like, glycol ethers and esters, dimethylsulf-oxide, tetrahydrofuran, acetone, and the like.
The term "delayed onset" as used herein refers to the situation where no active compound is released from the device of the invention until some time after the device is applied to the skin. For a 24 hour patch, this delay period will typically be 1-18 hours, prefer-ably about 12 hours in duration. Patches designed for longer duration (e.g., a weekly patch) may have cor-respondingly longer delay periods.
B. General Method Figure 1 depicts a presently preferred deviceof the invention, having a rupturable capsule containing the active compound prior to administration. This embodiment 20 comprises an optional wick layer 23, which is capable of diffusing the active compound, but which does not act as a reservoir: the wick layer preferably does not absorb the active compound to a significant degree, and thus does not retain a substantial amount of the compound. The wick layer is preferably formed from a non-woven fabric, and must be capable of adhering to the adjacent layers under conditions of use (e.g., when saturated with active compound and vehicle). A
non-permeable backing layer 21 forms the outer surface of the device, and prevents loss of the active compound through the upper surface. The backing layer is prefer-ably occlusive, waterproof, drug-proof (for at least the administration period of the device), and suitable for lamination to the adjacent layer. Backing layer 21 may be heat-sealed or crimped onto the adjacent layer, forming a perimeter region 22, which seals the reservoir area 27 formed by the void between backing layer 21 and the adjacent layer 23.
W O 91/03998 PC~r/US90/05198 z~ 03 Backing layer 21 and the layer adjacent 23 are laminated together to form a reservoir volume 27. The reservoir volume is a space that contains rupturable capsule 30, comprising the active compound 33, option-ally a vehicle, permeation enhancer, solubilizer, and thelike, sealed within a non-permeable film wall material 31. Capsule 30 is maintained in an intact state, so that no active compound 33 is within the reservoir volume, exposed to the wick layer (or other layer) prior to administration. The capsule may be fabricated from any material which is impermeable to the active compound and its vehicle, and which may be ruptured when desired to release the active compound (and carrier if present) and activate the device. The ability to use a completely impermeable capsule allows one to employ compounds which are normally precluded from use in transdermal devices due to their volatility. Because the volatile compound will be completely contained within the internal cap-sule, one may employ vehicles and enhancers such as ethanol, acetone, methanol, ethyl acetate and the like, or use active compounds such as nicotine, without loss of compound from the device prior to administration. Non-rupturable devices of the prior art must be permeable to the compounds contained therein, and thus tend to lose any volatile components during shipping and storage prior to administration. (Even if the volatile components are contained with the prior art device within a pouch, the components will not be distributed properly within the device at the time of administration.) Rupturable cap-sules may have a rupturable seal at a seam (or otherdeliberately weakened portion of the wall), or may be prepared from a fragile or frangible material (for example, glass, silica, crystalline or brittle polymers, etc.), either crushable or having a scored portion to allow rupture by flexing the patch. Thus, in a pres-XQ65~03 ently preferred embodiment, the capsule is formed from analuminum foil-laminated heat seal film having a ruptur-able heat seal 32. This film is flexible, and comprises a layer of aluminum (about 0.3-1 mil) with a heat seal layer comprising EVA, polypropylene, or modified polyethylene (about 0.3-0.8 mil). However, the capsule may be fashioned from any frangible or friable container or film. For example, a thin glass capsule or brittle (e.g., crystalline) polymer may alternatively be employed. If desired, the capsule may be scored or necked to enhance breaking. The capsule may be attached to the backing layer 21 or the layer adjacent the back-ing layer (23, 24, or 25), or may be simply encapsulated within the reservoir volume 27 in loose form.
Underlying the reservoir and wick layer are a microporous membrane layer 24 and a contact adhesive layer 25. Layer 2~ contributes structural integrity to the device, as well as a means to delay the permeation of drug through the device to the skin. Its pores are preferably empty prior to the rupture of the reservoir;
in other words, the microporous membrane is substantially devoid of active compound and vehicle prior to rupture of the reservoir. Further, microporous membrane layer 24 is not plasticized by any component of the active compound formulation. Suitable films for the layer 24 include, without limitation, microporous films of about 0.5-3.0 mil in thickness composed of, for example, polypropylene (e.g., Celgard, available from Celanese), polyethylene (available from, e.g., 3M), or polytetrafluoroethylene (for example Teflon, available from Gore-tex).
Skin contact adhesive layer 25 is a pressure-sensitive adhesive suitable for application to human skin. The adhesive selected must also be compatible with the active compound and its vehicle, and must be suitable for lamination to the upper layers.
206~03 Presently preferred contact layer adhesives include acrylic, silicone, polyisobutylene, polyurethane, SIS, and SBS pressure sensitive adhesives. The layer may range in thickness from about 0.5 to about 5.0 mil. The adhesive layer is preferably protected prior to administration by means of a release liner 2C, which is generally a thin film or sheet which has been treated to allow easy removal from the adhesive layer. In this device, the active compound is sequestered within a non-permeable capsule prior to activation: accordingly, the release liner need only protect the contact adhesive, without regard for the nature of the active compound since the release liner is not exposed to the active compound during storage. In other words, the release liner need not be impermeable to the active compound, thus making available a wider range of materials. Thus, siliconized or fluorocarbon-treated paper or polystyrene may be used, in place of more expensive polymer films such as polyester or polycarbonate, which might otherwise be required. The thickness of the release liner is not critical, and may be determined by aesthetic criteria.
In general, the release liner must exhibit sufficient thickness and structural integrity that it may be peeled or stripped easily from the contact adhesive layer, preferably in one or two pieces. A thickness of about 3 mil is generally sufficient.
As this embodiment sequesters the active com-pound completely prior to activation, it is much simpler to package than devices in which the active compound is not sequestered. I.e., the package need not be impermeable to the active compound, as the compound will be completely contained within the device. Thus, one may employ simple cardboard or plastic containers, paper or plastic pouches, and the like. If desired, the release liner may be provided in the form of a long strip with Z06~03 multiple perforations spaced at appropriate intervals, such that the device of the invention may be provided on "tear-off" rolls or accordion-pleated stacks. Thus, a sufficient number of devices to treat a patient for a month can be provided on one strip, or within one con-tainer. Additionally, each device can then be numbered or dated, to aid patients in compliance. For example, on the fourth day of the month, the patient can determine if he or she has already applied the device for the day by determining whether or not the device marked "4" has been removed yet. This is a significant advantage for devices which are applied on a daily or weekly basis over an extended period of time.
Another embodiment of the invention is shown in Figure 5. In this variation, the rupturable capsule is provided as part of the backing layer 21, rather than as a separate layer 31. In this case, an impermeable layer 3~ is laminated to the wick layer 23, and a rupturable membrane or film 3S is provided to separate the reservoir volume 27 in contact with the wick layer from the sequestered portion.
Finally, the device may be packaged in a con-tainer which provides for capsule rupture and/or release liner removal automatically upon removal. Such a device is depicted in Figure 6. The container may be a box ~6 of any suitable shape, having pressure means ~1 and ~2 above and below an aperture ~8 sized to admit the device ~ after capsule rupture. A plurality of devices are provided on a long carrier strip 26, wound in a roll around a wide-diameter spool ~5 (wide enough to avoid premature capsule rupture due to flexing). To dispense the device, the carrier passes through pressure means and ~2, rupturing the capsule, and then passes through aperture ~8. The pressure means may be a pair of pres-sure rollers as depicted, a roller opposed to a flat ZOÇ~4~3 surface, or simply two flat surfaces having a separation decreasing in the direction of travel as the device is dispensed. The pressure means is preferably a cam-shaped roller. The pressure means may optionally be tensioned by means of a spring or other device (not shown). The device may further comprise means for separating the carrier/liner 26 from the device, such as roller ~3. In this embodiment, carrier 26 may be ejected through a separate aperture ~9. The spool ~5 may optionally comprise an axle ~7 affixed to the interior of the enclosure ~6. If desired, the axle 47 may be further connected to a handle or crank (not shown), by which the carrier roll may be advanced and the devices of the invention dispensed. Alternatively, the devices may be dispensed by simply pulling the carrier strip 26 until the device is ejected. In this embodiment, the carrier selected must be strong enough to pull the device through the pressure means. The pressure means must be far enough from the carrier separation means ~3 (if present) that the device has completely passed the pressure means and the capsule ruptured prior to separation from the carrier. Other devices not pictured may easily be constructed. For example, the roll of patches may be replaced with an accordion-folded stack of patches on a pleated carrier. The pressure means may be crank operated rather than the supply roll (particularly when the pressure means are rollers). In the event a frangible, scored capsule is used, the device may be designed to bend the capsule until ruptured. Other variations will be apparent to those of ordinary skill in the art.
Referring to Figures l and 5, capsule 31 is ruptured by applying pressure so that the active com-pound is released from the capsule into the reservoir volume 27. This may be accomplished by placing the device on a flat surface and pressing the capsule with a finger or thumb, or by some external pressure such as passing the device through a suitable mechanical pres-sure device, such as a pair of rollers (similar to a mangle as found on old cloths washing machines), or by bending or flexing the patch to cause rupture of a weak-ened or scored area. The release liner 26 is removed from contact layer 25, and the device applied to a suit-able area of intact skin, for example the upper arm, thigh, chest, lower abdomen, and the like. Alterna-tively, the device may be applied to the skin prior to activation by rupturing the capsule. Upon rupture, the active compound and vehicle are released from the cap-sule, and diffuse through the adjacent layers. The wick layer acts to spread the active compound over the entire available underlying layer, providing for an even flow across the area of the device. The compound diffuses through the wick layer, the microporous membrane layer, and into the contact layer, where it accumulates until sufficient concentration has developed that diffusion into the patient's skin begins at a significant rate.
Due to the fact that the intermediate layers are not equilibrated with the compound, a substantial delay occurs prior to significant diffusion into the skin.
~igure 2 shows another embodiment of the invention 1, having a polymeric matrix reservoir layer 12 containing an active compound 13 and optionally a liquid carrier 19. This reservoir layer is laminated permanently to an impermeable backing layer 11, which prevents loss of active compound from the "non-contact"
side of the device, and which may additionally provide some degree of structural support. Although layers 11 and 12 are shown here as distinct layers, the backing layer may be formed from a portion of the matrix reser-voir layer by suitable treatment, such as heat, chemical crosslinking, radiation, and the like, so as to render the surface substantially impermeable to the active com-pound and carrier (if present). Layer 11 is preferably supported by a liner/carrier 17. The reservoir layer 12 is preferably protected on its other side (opposite backing 11) by a releasable protective liner 16. A con-tact adhesive layer 1~ is provided which is not in con-tact with said reservoir layer 12, and may serve as the delay layer. Adhesive layer 1~ is substantially free of active compound 13, although it may contain a liquid carrier, permeation enhancer or the like if desired. An additional release liner 15 may be laminated to adhesive layer 14 if desired. The release liner 15 and adhesive layer 14 are supported by a liner/carrier, preferably the same liner/carrier 17 which supports reservoir 12 and backing 11. The adhesive layer 1~ is preferably protected on its upper surface (opposite optional release liner 15) by an additional releasable protective liner, preferably an extension of said protective liner 16. An additional delay layer (not shown) may be laminated between contact adhesive layer 1~ and protective liner 16, if desired.
To use the device of Figure 2, the protective liner 16 is first removed from the upper surface of the device. The exposed surface of adhesive layer 14 is then laminated to the exposed surface of reservoir layer 12.
In devices wherein both layer 12 and layer 14 are supported by the same carrier 17, this lamination is preferably assisted by means of a crease or fold line 18, as shown in Figure 3. Lamination is accomplished by simply folding the device along the fold line, and pressing layer 14 onto layer 12. It is preferred that the reservoir-backing sublaminate and the adhesive-liner sublaminate be arranged on the liner/carrier so that folding the liner/carrier along the crease insures that W09t/03998 PCT/~IS90/05198 206~03 the completed device layers will overlap completely.
This results in the configuration shown in Figure 4. At this point, liner/carrier 17 is removed from layer 1~ (or release liner 15 if present). If release liner 15 is present, it also is removed, and the exposed adhesive layer 1~ applied to the subject's skin. Carrier 17 is then removed from backing layer 11, leaving the device comprising layers 11, 12, and 1~ on the subject's skin.
Active compound 13 (and optionally liquid carrier l9) then begins to diffuse into layer 14, and finally into the subject's epidermis. A substantial time delay occurs before the active compound begins to diffuse into the epidermis at a significant rate, due to the fact that layer 1~ is not equilibrated with reservoir 12 at the time of application.
The devices of the invention are particularly suited for repeated administration. When used to admin-ister nitroglycerine (e.g., for treatment of congestive heart failure) or nicotine (e.g., to reduce cigarette craving), a device of the invention is preferably applied shortly before retiring for the evening. Due to the delayed onset of release, little or no compound is released while the subject is sleeping. Instead, com-pound is released at or just before time for the subject to wake up, when the compound is most needed. The device continues to release active compound over the next sixteen hours. Then, the device is removed, and is replaced with a fresh device. Thùs, the plasma level of active compound may decline to baseline during the sub-ject's sleep, so that tolerance or undesirable sideeffects do not develop. In the case of appetite sup-pressants, it is preferred to apply a device of the invention shortly before breakfast. Thus, the subject is able to eat a healthy breakfast, with appetite sup-pression occurring several hours later, when most needed.
~654(3~
Backing layer 11 and 21 is preferably made of asheet or film of a preferably flexible elastomeric material that is substantially impermeable to the active compound. The layer is preferably on the order of 0.01 to 0.08 mm in thickness, and may optionally be pigmented (e.g., to resemble the subject's skin color). Ideally, the layer is fabricated from a material that permits the device to mimic the contours of the skin and to be worn comfortably on areas of skin such as joints or other points of flexure normally subjected to mechanical strain. This reduces the possibility of disengaging or losing the device due to differences in flexibility or resiliency of the skin and the device. Exemplary elastomeric polymers useful for preparing backing layer 11 include polyether block amide copolymers (e.g., PEBAX~
copolymers), polyethylene methylmethacrylate block copolymers ( ~ ) such as NUKRELL~polymers, polyurethanes such as PELLATHANE or ESTANE polymers, silicone elastomers, polyester block copolymers such as HYTREL~
rubber-based polyisobutylene, styrene, and styrene-buta-diene and styrene-isoprene copolymers. Flexible polymers include polyethylene, polypropylene, and polyesters such as polyester terephthalate (PET~, which may be provided as films or laminates. One may also use laminates or combinations of any of the above materials.
The polymeric matrix reservoir 12 is composed of a polymeric material in which the active compound is poorly to moderately soluble, and capable of diffusing the active compound at a high rate. The reservoir layer must also be capable of adhering to the adjacent layers, to prevent delamination. Thus, selection of the par-- ticular material will depend in part upon the active compound (and its vehicle, e.g., solubilizers, permeation enhancers, etc.) selected, and the adhesives employed.
Devices of the invention employing a rupturable capsule 20~;5403 preferably contain the active compound in the form of a liquid or gel. The vehicle must be capable of flowing following rupture of the sequestering capsule.
Typically, the vehicle will comprise silicone fluid, PGML, propylene glycol, other carriers such as lactose, and the like.
The contact adhesive layer 1~ and 25 is gener-ally fabricated from an active compound-permeable poly-mer which adheres to both the reservoir matrix and to mammalian skin without irritation. Exemplary materials for forming layer 1~ and 25 include without limitation polysiloxanes, polyisobutylenes, polyacrylates, poly-urethanes, plasticized ethylene-vinyl acetate copoly-mers, low molecular weight polyether block amide copolymers (PEBAX copolymers), and mixtures thereof. The particular material used will depend upon the diffusion coefficient of the active compound (and optionally the liquid carrier) in the adhesive layer, and the diffusion coefficient in the reservoir layer. Generally, both diffusion coefficients should be in the range of about 10-5 to about 10 10 cm /sec.
The various carriers and release liners may be formed from any material having the desired degree of flexibility and impermeability. These liners are gener-ally rendered "strippable~' from the contact adhesivelayer using silicone or fluorocarbon surface treatments.
The devices of the invention are generally prepared by standard thin-film lamination techniques.
C. Exam~les The examples presented below are provided as a further guide to the practitioner of ordinary skill in the art, and are not to be construed as limiting the invention in any way.
20fi5403 -Exam~le 1 (In Vitro Delayed Flux Determination) Water based acrylic adhesive (Flexcryl 1625, 69% solids) was coated onto a 0.075 mm thick siliconized polyester film at a thickness of 0.25 mm. The adhesive coating was cured at 75C for 30 min in order to remove all of the water; cured thickness was 0.01 mm (10 mg/cm2). A disc of the cured adhesive was die-cut and laminated to the stratum corneum side of a disc of human cadaver epidermis. The skin/adhesive composite was mounted on a glass diffusion cell (effective flux area 0.713 cm2) with the skin side facing the receptor com-partment. A measured volume of receiver solution (0.9%
NaCl and 0.01~ NaN3 in deionized water) was placed in the receptor compartment. The donor was 1.5 g of a nitroglycerin suspension consisting of 2.5 wt% nitro-glycerine; 48.8 wt% Dow 360 silicone fluid, 350 cts;
23.8 wt% propylene glycol monolaurate (Gattefasse); and 24.7 wt% lactose. The nitroglycerin suspension was placed in the donor compartment directly in contact with the adhesive. The donor compartment was then occluded, and the cell maintained at 32C. Samples of the receiv-ing solution were taken periodically and analyzed by HPLC
to determine the amount of nitroglycerin permeated per unit time. The experiment was repeated exactly, substituting Nitro-Dur0, a commercially-available nitro-glycerin transdermal device, for the adhesive layer and nitroglycerin vehicle.
Figure 7 shows the results of this test. Solid circles indicate the amount per cm2 per hour (in micrograms) for the above-described composite. Open circles indicate the results obtained using Nitro-Dur~.
As shown in the Figure, Nitro-Dur0 reached essentially peak flux rate by 2-4 hours after administration, whereas Z~)6~03 the composition of the invention delayed full onset to 4.5-5 hours after administration.
ExamDle 2 (In Vitro Delayed Flux Determination) Water based acrylic adhesive (Flexcryl 1625, 69% solids) was coated onto a 0.075 mm thick siliconized polyester film at a thickness of 0.125 mm. The adhesive coating was cured at 75C for 30 min in order to remove all of the water; cured thickness was 0.05 mm (5 mg/cm ). A disc of the cured adhesive was die-cut and laminated to the stratum corneum side of a disc of human cadaver epidermis. The skin/adhesive composite was mounted on a glass diffusion cell (effective flux area 0.713 cm2) with the skin side facing the receptor com-partment. A measured volume of receiver solution (0.9%
NaCl and 0.01~ NaN3 in deionized water) was placed in the receptor compartment. The donor was 1.5 g of a nitroglycerin suspension consisting of 2.3 wt% nitro-glycerine; 75.0 wt% Dow 360 silicone fluid, 350 cts;
and 22.5 wt% lactose. The nitroglycerin suspension was placed in the donor compartment directly in contact with the adhesive. The donor compartment was then occluded, and the cell maintained at 32C. Samples of the receiv-ing solution were taken periodically and analyzed by HPLC
to determine the amount of nitroglycerin permeated per unit time. The experiment was repeated exactly, substituting Nitro-Dur~ for the adhesive layer and nitroglycerin vehicle.
Figure 8 shows the results of this test. Solid circles indicate the amount per cm2 per hour (in micrograms) for the above-described composite. Open circles indicate the results obtained using Nitro-Dur~.
As shown in the Figure, Nitro-~ur~ reached essentially peak flux rate by 2-4 hours after administration, whereas W O 91/03998 PC~r/~'S90/05198 - .zo6~4~3 the composition of the invention delayed full onset to 5-6 hours after administration.
Example 3 (In Vitro Delayed Flux Determination) (A) Water based acrylic adhesive (Flexcryl 1625, 69% solids) was coated onto a 0.075 mm thick siliconized polyester film at a thickness of 0.125 mm.
The adhesive coating was cured at 75C for 30 min in order to remove all of the water; cured thickness was 0.05 mm (5 mg/cm2). A disc of the cured adhesive was die-cut and laminated to the stratum corneum side of a disc of human cadaver epidermis. Next, a disc of 2 mil microporous polypropylene membrane (Celgard 2400, avail-able from Celanese/Hoecht) was laminated to the contact adhesive as a delay membrane. The skin/adhesive compos-ite was mounted on a glass diffusion cell (effective flux area 0.713 cm2) with the skin side facing the receptor compartment. A measured volume of receiver solution (0.9% NaCl and 0.01% NaN3 in deionized water) was placed in the receptor compartment. The donor was 1.5 g of a 10 wt% nitroglycerin solution in propylene glycol. The nitroglycerin solution was placed in the donor compartment directly in contact with the adhesive. The donor compartment was then occluded, and the cell maintained at 32C. Samples of the receiving solution were taken periodically and analyzed by HPLC to deter-mine the amount of nitroglycerin permeated per unit time.
The experiment was repeated exactly, substituting Nitro-Dur~ for the adhesive layer and nitroglycerin vehicle.
(B) The procedure described in part A above was repeated exactly, substituting a microporous poly-propylene membrane/non-woven polypropylene laminated film (Celgard 4410) for the Celgard 2400 membrane.
WO91/03998 PCT/~S90/05198 ;~06~03 (C) Figure 9 shows the results of these tests.
The solid circles depict the results using patch "A"
(with Celgard 2400). The open circles depict the results from patch "B" (using Celgard 4410). The solid squares indicate the results obtained using Nitro-Dur~. As shown in the ~igure, Nitro-Durg reached a high flux rate by 2-4 hours after administration, whereas the composition of the invention delayed significant onset to 8-12 hours after administration.
HAVING DELAYED ONSET
Description Technical Field This invention relates to devices and methods for administering biologically active compounds through the skin, i.e., transdermally. More specifically, the invention relates to a device and method for transdermal delivery having a delayed onset of delivery.
Backqround of the Invention The delivery of compounds through the skin provides many advantages. Primarily, transdermal deliv-ery provides a comfortable, convenient, and noninvasive means for delivering drugs. By avoiding administration through the gastrointestinal tract, one may employ com-pounds which would otherwise be degraded, metabolically deactivated, or poorly absorbed. Additionally, one eliminates the complications of gastrointestinal irrita-tion. Transdermal delivery using a continuous-release type of device also allows one to terminate administra-tion immediately should the need arise, e.g., in the event of an adverse drug reaction, or over-elevation of drug plasma concentration.
Drug delivery devices may generally be classi-fied as either "matrix" or "reservoir" in construction.
A matrix or monolithic device generally comprises a drug-permeable solid polymer, having a drug dispersed ,~
W O 91/03998 ~ PC~r/US90/05198 2065~3 throughout. Matrix devices may be formed from erodible or non-erodible polymers (transdermal devices are typically non-erodible). Reservoir devices generally comprise a depot of essentially pure drug (or drug with excipient) surrounded by a rate-controlling membrane, where the rate of drug diffusion through the membrane controls the rate of release. Combinations of matrix reservoirs with rate-controlling membranes have also been proposed. The typical design criteria are to provide a substantially constant and continuous release rate, and to provide a release rate capable of delivering a therapeutically effective amount of the compound.
Additionally, the device must be non-irritating, and is preferably designed to be of a convenient size.
The conventional transdermal device is designed with the goal of delivering a therapeutic compound at a substantially constant rate ("zero-order" delivery).
However, administration of some compounds at a constant, continuous rate may cause drug tolerance to develop. In order to prevent tolerance, a transdermal patch-type device must be removed periodically to interrupt continuous delivery. This in turn creates additional problems of patient compliance and design of the patch adhesive (which must adhere to the skin continuously), and fails to accommodate the patient's circadian rhythms.
Nitroglycerin is a vasodilator currently administered for coronary disorders, especially angina pectoris and congestive heart failure. As nitroglycerin cannot be administered orally, it is typically adminis-tered sublingually, or via transdermal patch. Commer-cially available patches, such as Transderm Nitro0 and Nitro-Dur0, provide essentially constant plasma concen-trations of nitroglycerin over a 24 hour period, and are changed daily. However, recent studies suggest that continuous administration of nitroglycerin induces tol-WO9l/03998 2~65~ PCT/~ISgo/05198 erance, with concomitant loss of efficacy in the patient.European Patent Application No. 0290262 (published 9 November 1988) describes a transdermal device which provides a delayed onset of administration of nitrate drugs to the skin. It consists of a backing layer, a rupturable pod sandwiched between the backing and a nonwoven fabric layer, an initially drug impermeable barrier membrane, an adhesive layer and a release liner. The pod is constructed of two layers that have rupturable seals about their peripheries so as to define a lumen that contains the drug and an activator liquid that is capable of plasticizing the barrier membrane and making it increasingly permeable to drugs.
Although this device enables delayed nitrate drug administration which is dependent upon the plasticization of the barrier membrane, it suffers several important and practical drawbacks. In this regard, the delay is achieved through use of an activator liquid. The use of an activator complicates the formulation, economics, and regulatory approval of the device. Further, the drug release kinetics of the device are complicated because they depend on the permeability of the barrier membrane which varies with the degree of membrane plasticization.
Among the purposes of one embodiment of the present invention are to provide a delayed onset transdermal drug delivery device that (1) does not involve an activator liquid, and (2) has a release profile subject to fewer variables. The purposes of another embodiment of the invention is to provide a delayed onset transdermal drug delivery device that does not involve a rupturable drug reservoir but instead is effected through assembly of components of the device just prior to device use.
~4~ 206~403 Summary of the Invention Embo-limente of the invention as described hereinafter can provide a continuous, constant transdermal release of an active substance, wherein the onset of release is delayed from 1-24 hours, depending on the length of time that the drug is 5 delivered. This provides a "wash out" period, during which the plasma concentration of any compound rem~ining in the patient's system from application of the previous device is allowed to drop to near baseline levels.
Accordingly in one example, a patient may wear the patch for 24 hours, replacing the patch with a fresh patch prior to going to sleep. The wash out period 10 thus occurs during the patient's sleep, and is followed by effective plasma concentrations of the active compound during the waking hours.
According to a first aspect of the invention there is provided a kit for preparing a device for ~-imini~tçring an active compound tr~n~dçrm~lly to a subject's skin, having a delayed onset of delivery, said kit comprising: a first layer comprising a 15 polymeric matrix impregnated with said active compound, said compound and matrix being selected to obtain a first compound diffusion coefficient of about 10-5 to about 10-1 cm2/sec in said matrix; a second layer not in contact with said first layer, comprising an adhesive capable of a&ering to said first layer and to said subject's skin, said second layer having a second diffusion coefficient of about 10-5 to about 20 10-1 cm2/sec in said matrix, wherein said second layer is substantially devoid of said active compound.
According to a second aspect of the invention there is provided a controlled release device for ~lministering an active compound to a subject comprising: a first having a polymeric matrix impregn~ted with an active compound, said compound and25 matrix being selected to obtain a first compound diffusion coefficient of about 10-5 to about 10-1 cm2/sec in said matrix; a second layer having an a&esive capable of adhering to said first layer and to said subject's skin, said second layer having a second diffusion coefficient of about 10-5 to about 10-1 cm2/sec in said matrix, said s- 2065403 second layer being subst~nti~lly devoid of said active compound; wherein the first and second layers are arranged for use in a method of ~rlmini~tering the active compound to the subject in which a l~min~te of the first and second layers is applied to the skin of the subject before the active compound equilibrates in the l~min~te.
According to a third aspect of the invention there is provided a device for ~lmini~tering an active compound tr~n~dçrm~lly following application to a subject's skin, having a delayed onset of delivery, said device comprising: (a) a contact layer comprising a skin contact adhesive which is permeable to said active compound; (b) a backing layer comprising a thin, flexible m~tçri~l which is substantially impermeable to said active compound, which is l~min~ted to said contact layer, and together with said contact layer defines a reservoir void between said contact layer and said backing layer; and within said reservoir void, a rupturable capsule Co~ g said active compound.
A
20~iS403 Brief DescriPtion of the Drawinqs Figure 1 shows a schematic cross-section of a presently preferred embodiment of the invention, wherein the active compound is sequestered within a rupturable capsule.
Figure 2 is a schematic cross-section of a kit embodiment of the invention which is laminated by the user. The layers depicted are thin solid films, prefer-ably flexible and/or elastomeric, and are laminated together immediately prior to application by the user.
The view depicted illustrates a cross-section of the device with the protective release liner and liner/carrier in place.
Figure 3 shows a perspective view of the kit embodiment after removal of the upper release liner, just prior to lamination.
Figure 4 depicts a schematic cross section of the kit embodiment immediately after lamination, follow-ing removal of the liner/carrier.
Figure 5 is a schematic cross section of another presently preferred embodiment, having a ruptur-able capsule formed as part of the drug reservoir of the device.
Figure 6 is a cross section of a dispensing device, suitable for dispensing devices of the invention as shown in Figure 1 or Figure 5.
Figure 7 depicts graphically the results of the experiment reported in Example 1.
Figure 8 depicts graphically the results of the experiment reported in Example 2.
Figure 9 depicts graphically the results of the experiments reported in Example 3.
ZO~i54~3 Modes of Carrying Out The Invention A. Definitions The term "active compound" as used herein refers to any substance which may be administered to an animal to obtain a beneficial effect. Active compounds may be drugs, for example, vasodilators such as nitro-glycerin, amyl nitrate, isosorbide dinitrate or mono-nitrate and the like, L-DOP~, analgesics, antiinflam-matories, antihistamines, antibiotics, antihypertens-ives, hormones, and the like, which are useful for pre-venting or ameliorating a given disorder. other active compounds include contraceptives (e.g., estradiol, levo-norgestrel, 3-ketodesogestrel, gestodene, and the like), vitamins, appetite suppressants, nicotine, caffeine and other stimulants, growth promoters (particularly when administered to livestock), and the like. Suitable active compounds within the scope of this invention are capable of diffusion or absorption through the skin.
The term "mammals" includes animals such as humans, livestock including cattle, sheep, goats, horses, small animals such as dogs, cats, and mice, wildlife and zoo animals such as elephants, lions, tigers, antelope, and the like. The term ~animal" refers to mammals and birds, including domestic fowl such as chickens, geese, ducks, turkeys, game hens, and the like.
The term "liquid carrier" refers to a solvent compatible with the reservoir matrix and adhesive lay-ers, as well as with skin, in which the active compound is soluble. The active compound will preferably be mod-erately soluble in the carrier. Suitable carriers gen-erally enhance the release rate of active compound from devices of the invention. Exemplary carriers include lower alcohols such as methanol, ethanol, propanol, iso-propanol, and the like, glycols such as propylene glycol Z~6~103 and the like, glycol ethers and esters, dimethylsulf-oxide, tetrahydrofuran, acetone, and the like.
The term "delayed onset" as used herein refers to the situation where no active compound is released from the device of the invention until some time after the device is applied to the skin. For a 24 hour patch, this delay period will typically be 1-18 hours, prefer-ably about 12 hours in duration. Patches designed for longer duration (e.g., a weekly patch) may have cor-respondingly longer delay periods.
B. General Method Figure 1 depicts a presently preferred deviceof the invention, having a rupturable capsule containing the active compound prior to administration. This embodiment 20 comprises an optional wick layer 23, which is capable of diffusing the active compound, but which does not act as a reservoir: the wick layer preferably does not absorb the active compound to a significant degree, and thus does not retain a substantial amount of the compound. The wick layer is preferably formed from a non-woven fabric, and must be capable of adhering to the adjacent layers under conditions of use (e.g., when saturated with active compound and vehicle). A
non-permeable backing layer 21 forms the outer surface of the device, and prevents loss of the active compound through the upper surface. The backing layer is prefer-ably occlusive, waterproof, drug-proof (for at least the administration period of the device), and suitable for lamination to the adjacent layer. Backing layer 21 may be heat-sealed or crimped onto the adjacent layer, forming a perimeter region 22, which seals the reservoir area 27 formed by the void between backing layer 21 and the adjacent layer 23.
W O 91/03998 PC~r/US90/05198 z~ 03 Backing layer 21 and the layer adjacent 23 are laminated together to form a reservoir volume 27. The reservoir volume is a space that contains rupturable capsule 30, comprising the active compound 33, option-ally a vehicle, permeation enhancer, solubilizer, and thelike, sealed within a non-permeable film wall material 31. Capsule 30 is maintained in an intact state, so that no active compound 33 is within the reservoir volume, exposed to the wick layer (or other layer) prior to administration. The capsule may be fabricated from any material which is impermeable to the active compound and its vehicle, and which may be ruptured when desired to release the active compound (and carrier if present) and activate the device. The ability to use a completely impermeable capsule allows one to employ compounds which are normally precluded from use in transdermal devices due to their volatility. Because the volatile compound will be completely contained within the internal cap-sule, one may employ vehicles and enhancers such as ethanol, acetone, methanol, ethyl acetate and the like, or use active compounds such as nicotine, without loss of compound from the device prior to administration. Non-rupturable devices of the prior art must be permeable to the compounds contained therein, and thus tend to lose any volatile components during shipping and storage prior to administration. (Even if the volatile components are contained with the prior art device within a pouch, the components will not be distributed properly within the device at the time of administration.) Rupturable cap-sules may have a rupturable seal at a seam (or otherdeliberately weakened portion of the wall), or may be prepared from a fragile or frangible material (for example, glass, silica, crystalline or brittle polymers, etc.), either crushable or having a scored portion to allow rupture by flexing the patch. Thus, in a pres-XQ65~03 ently preferred embodiment, the capsule is formed from analuminum foil-laminated heat seal film having a ruptur-able heat seal 32. This film is flexible, and comprises a layer of aluminum (about 0.3-1 mil) with a heat seal layer comprising EVA, polypropylene, or modified polyethylene (about 0.3-0.8 mil). However, the capsule may be fashioned from any frangible or friable container or film. For example, a thin glass capsule or brittle (e.g., crystalline) polymer may alternatively be employed. If desired, the capsule may be scored or necked to enhance breaking. The capsule may be attached to the backing layer 21 or the layer adjacent the back-ing layer (23, 24, or 25), or may be simply encapsulated within the reservoir volume 27 in loose form.
Underlying the reservoir and wick layer are a microporous membrane layer 24 and a contact adhesive layer 25. Layer 2~ contributes structural integrity to the device, as well as a means to delay the permeation of drug through the device to the skin. Its pores are preferably empty prior to the rupture of the reservoir;
in other words, the microporous membrane is substantially devoid of active compound and vehicle prior to rupture of the reservoir. Further, microporous membrane layer 24 is not plasticized by any component of the active compound formulation. Suitable films for the layer 24 include, without limitation, microporous films of about 0.5-3.0 mil in thickness composed of, for example, polypropylene (e.g., Celgard, available from Celanese), polyethylene (available from, e.g., 3M), or polytetrafluoroethylene (for example Teflon, available from Gore-tex).
Skin contact adhesive layer 25 is a pressure-sensitive adhesive suitable for application to human skin. The adhesive selected must also be compatible with the active compound and its vehicle, and must be suitable for lamination to the upper layers.
206~03 Presently preferred contact layer adhesives include acrylic, silicone, polyisobutylene, polyurethane, SIS, and SBS pressure sensitive adhesives. The layer may range in thickness from about 0.5 to about 5.0 mil. The adhesive layer is preferably protected prior to administration by means of a release liner 2C, which is generally a thin film or sheet which has been treated to allow easy removal from the adhesive layer. In this device, the active compound is sequestered within a non-permeable capsule prior to activation: accordingly, the release liner need only protect the contact adhesive, without regard for the nature of the active compound since the release liner is not exposed to the active compound during storage. In other words, the release liner need not be impermeable to the active compound, thus making available a wider range of materials. Thus, siliconized or fluorocarbon-treated paper or polystyrene may be used, in place of more expensive polymer films such as polyester or polycarbonate, which might otherwise be required. The thickness of the release liner is not critical, and may be determined by aesthetic criteria.
In general, the release liner must exhibit sufficient thickness and structural integrity that it may be peeled or stripped easily from the contact adhesive layer, preferably in one or two pieces. A thickness of about 3 mil is generally sufficient.
As this embodiment sequesters the active com-pound completely prior to activation, it is much simpler to package than devices in which the active compound is not sequestered. I.e., the package need not be impermeable to the active compound, as the compound will be completely contained within the device. Thus, one may employ simple cardboard or plastic containers, paper or plastic pouches, and the like. If desired, the release liner may be provided in the form of a long strip with Z06~03 multiple perforations spaced at appropriate intervals, such that the device of the invention may be provided on "tear-off" rolls or accordion-pleated stacks. Thus, a sufficient number of devices to treat a patient for a month can be provided on one strip, or within one con-tainer. Additionally, each device can then be numbered or dated, to aid patients in compliance. For example, on the fourth day of the month, the patient can determine if he or she has already applied the device for the day by determining whether or not the device marked "4" has been removed yet. This is a significant advantage for devices which are applied on a daily or weekly basis over an extended period of time.
Another embodiment of the invention is shown in Figure 5. In this variation, the rupturable capsule is provided as part of the backing layer 21, rather than as a separate layer 31. In this case, an impermeable layer 3~ is laminated to the wick layer 23, and a rupturable membrane or film 3S is provided to separate the reservoir volume 27 in contact with the wick layer from the sequestered portion.
Finally, the device may be packaged in a con-tainer which provides for capsule rupture and/or release liner removal automatically upon removal. Such a device is depicted in Figure 6. The container may be a box ~6 of any suitable shape, having pressure means ~1 and ~2 above and below an aperture ~8 sized to admit the device ~ after capsule rupture. A plurality of devices are provided on a long carrier strip 26, wound in a roll around a wide-diameter spool ~5 (wide enough to avoid premature capsule rupture due to flexing). To dispense the device, the carrier passes through pressure means and ~2, rupturing the capsule, and then passes through aperture ~8. The pressure means may be a pair of pres-sure rollers as depicted, a roller opposed to a flat ZOÇ~4~3 surface, or simply two flat surfaces having a separation decreasing in the direction of travel as the device is dispensed. The pressure means is preferably a cam-shaped roller. The pressure means may optionally be tensioned by means of a spring or other device (not shown). The device may further comprise means for separating the carrier/liner 26 from the device, such as roller ~3. In this embodiment, carrier 26 may be ejected through a separate aperture ~9. The spool ~5 may optionally comprise an axle ~7 affixed to the interior of the enclosure ~6. If desired, the axle 47 may be further connected to a handle or crank (not shown), by which the carrier roll may be advanced and the devices of the invention dispensed. Alternatively, the devices may be dispensed by simply pulling the carrier strip 26 until the device is ejected. In this embodiment, the carrier selected must be strong enough to pull the device through the pressure means. The pressure means must be far enough from the carrier separation means ~3 (if present) that the device has completely passed the pressure means and the capsule ruptured prior to separation from the carrier. Other devices not pictured may easily be constructed. For example, the roll of patches may be replaced with an accordion-folded stack of patches on a pleated carrier. The pressure means may be crank operated rather than the supply roll (particularly when the pressure means are rollers). In the event a frangible, scored capsule is used, the device may be designed to bend the capsule until ruptured. Other variations will be apparent to those of ordinary skill in the art.
Referring to Figures l and 5, capsule 31 is ruptured by applying pressure so that the active com-pound is released from the capsule into the reservoir volume 27. This may be accomplished by placing the device on a flat surface and pressing the capsule with a finger or thumb, or by some external pressure such as passing the device through a suitable mechanical pres-sure device, such as a pair of rollers (similar to a mangle as found on old cloths washing machines), or by bending or flexing the patch to cause rupture of a weak-ened or scored area. The release liner 26 is removed from contact layer 25, and the device applied to a suit-able area of intact skin, for example the upper arm, thigh, chest, lower abdomen, and the like. Alterna-tively, the device may be applied to the skin prior to activation by rupturing the capsule. Upon rupture, the active compound and vehicle are released from the cap-sule, and diffuse through the adjacent layers. The wick layer acts to spread the active compound over the entire available underlying layer, providing for an even flow across the area of the device. The compound diffuses through the wick layer, the microporous membrane layer, and into the contact layer, where it accumulates until sufficient concentration has developed that diffusion into the patient's skin begins at a significant rate.
Due to the fact that the intermediate layers are not equilibrated with the compound, a substantial delay occurs prior to significant diffusion into the skin.
~igure 2 shows another embodiment of the invention 1, having a polymeric matrix reservoir layer 12 containing an active compound 13 and optionally a liquid carrier 19. This reservoir layer is laminated permanently to an impermeable backing layer 11, which prevents loss of active compound from the "non-contact"
side of the device, and which may additionally provide some degree of structural support. Although layers 11 and 12 are shown here as distinct layers, the backing layer may be formed from a portion of the matrix reser-voir layer by suitable treatment, such as heat, chemical crosslinking, radiation, and the like, so as to render the surface substantially impermeable to the active com-pound and carrier (if present). Layer 11 is preferably supported by a liner/carrier 17. The reservoir layer 12 is preferably protected on its other side (opposite backing 11) by a releasable protective liner 16. A con-tact adhesive layer 1~ is provided which is not in con-tact with said reservoir layer 12, and may serve as the delay layer. Adhesive layer 1~ is substantially free of active compound 13, although it may contain a liquid carrier, permeation enhancer or the like if desired. An additional release liner 15 may be laminated to adhesive layer 14 if desired. The release liner 15 and adhesive layer 14 are supported by a liner/carrier, preferably the same liner/carrier 17 which supports reservoir 12 and backing 11. The adhesive layer 1~ is preferably protected on its upper surface (opposite optional release liner 15) by an additional releasable protective liner, preferably an extension of said protective liner 16. An additional delay layer (not shown) may be laminated between contact adhesive layer 1~ and protective liner 16, if desired.
To use the device of Figure 2, the protective liner 16 is first removed from the upper surface of the device. The exposed surface of adhesive layer 14 is then laminated to the exposed surface of reservoir layer 12.
In devices wherein both layer 12 and layer 14 are supported by the same carrier 17, this lamination is preferably assisted by means of a crease or fold line 18, as shown in Figure 3. Lamination is accomplished by simply folding the device along the fold line, and pressing layer 14 onto layer 12. It is preferred that the reservoir-backing sublaminate and the adhesive-liner sublaminate be arranged on the liner/carrier so that folding the liner/carrier along the crease insures that W09t/03998 PCT/~IS90/05198 206~03 the completed device layers will overlap completely.
This results in the configuration shown in Figure 4. At this point, liner/carrier 17 is removed from layer 1~ (or release liner 15 if present). If release liner 15 is present, it also is removed, and the exposed adhesive layer 1~ applied to the subject's skin. Carrier 17 is then removed from backing layer 11, leaving the device comprising layers 11, 12, and 1~ on the subject's skin.
Active compound 13 (and optionally liquid carrier l9) then begins to diffuse into layer 14, and finally into the subject's epidermis. A substantial time delay occurs before the active compound begins to diffuse into the epidermis at a significant rate, due to the fact that layer 1~ is not equilibrated with reservoir 12 at the time of application.
The devices of the invention are particularly suited for repeated administration. When used to admin-ister nitroglycerine (e.g., for treatment of congestive heart failure) or nicotine (e.g., to reduce cigarette craving), a device of the invention is preferably applied shortly before retiring for the evening. Due to the delayed onset of release, little or no compound is released while the subject is sleeping. Instead, com-pound is released at or just before time for the subject to wake up, when the compound is most needed. The device continues to release active compound over the next sixteen hours. Then, the device is removed, and is replaced with a fresh device. Thùs, the plasma level of active compound may decline to baseline during the sub-ject's sleep, so that tolerance or undesirable sideeffects do not develop. In the case of appetite sup-pressants, it is preferred to apply a device of the invention shortly before breakfast. Thus, the subject is able to eat a healthy breakfast, with appetite sup-pression occurring several hours later, when most needed.
~654(3~
Backing layer 11 and 21 is preferably made of asheet or film of a preferably flexible elastomeric material that is substantially impermeable to the active compound. The layer is preferably on the order of 0.01 to 0.08 mm in thickness, and may optionally be pigmented (e.g., to resemble the subject's skin color). Ideally, the layer is fabricated from a material that permits the device to mimic the contours of the skin and to be worn comfortably on areas of skin such as joints or other points of flexure normally subjected to mechanical strain. This reduces the possibility of disengaging or losing the device due to differences in flexibility or resiliency of the skin and the device. Exemplary elastomeric polymers useful for preparing backing layer 11 include polyether block amide copolymers (e.g., PEBAX~
copolymers), polyethylene methylmethacrylate block copolymers ( ~ ) such as NUKRELL~polymers, polyurethanes such as PELLATHANE or ESTANE polymers, silicone elastomers, polyester block copolymers such as HYTREL~
rubber-based polyisobutylene, styrene, and styrene-buta-diene and styrene-isoprene copolymers. Flexible polymers include polyethylene, polypropylene, and polyesters such as polyester terephthalate (PET~, which may be provided as films or laminates. One may also use laminates or combinations of any of the above materials.
The polymeric matrix reservoir 12 is composed of a polymeric material in which the active compound is poorly to moderately soluble, and capable of diffusing the active compound at a high rate. The reservoir layer must also be capable of adhering to the adjacent layers, to prevent delamination. Thus, selection of the par-- ticular material will depend in part upon the active compound (and its vehicle, e.g., solubilizers, permeation enhancers, etc.) selected, and the adhesives employed.
Devices of the invention employing a rupturable capsule 20~;5403 preferably contain the active compound in the form of a liquid or gel. The vehicle must be capable of flowing following rupture of the sequestering capsule.
Typically, the vehicle will comprise silicone fluid, PGML, propylene glycol, other carriers such as lactose, and the like.
The contact adhesive layer 1~ and 25 is gener-ally fabricated from an active compound-permeable poly-mer which adheres to both the reservoir matrix and to mammalian skin without irritation. Exemplary materials for forming layer 1~ and 25 include without limitation polysiloxanes, polyisobutylenes, polyacrylates, poly-urethanes, plasticized ethylene-vinyl acetate copoly-mers, low molecular weight polyether block amide copolymers (PEBAX copolymers), and mixtures thereof. The particular material used will depend upon the diffusion coefficient of the active compound (and optionally the liquid carrier) in the adhesive layer, and the diffusion coefficient in the reservoir layer. Generally, both diffusion coefficients should be in the range of about 10-5 to about 10 10 cm /sec.
The various carriers and release liners may be formed from any material having the desired degree of flexibility and impermeability. These liners are gener-ally rendered "strippable~' from the contact adhesivelayer using silicone or fluorocarbon surface treatments.
The devices of the invention are generally prepared by standard thin-film lamination techniques.
C. Exam~les The examples presented below are provided as a further guide to the practitioner of ordinary skill in the art, and are not to be construed as limiting the invention in any way.
20fi5403 -Exam~le 1 (In Vitro Delayed Flux Determination) Water based acrylic adhesive (Flexcryl 1625, 69% solids) was coated onto a 0.075 mm thick siliconized polyester film at a thickness of 0.25 mm. The adhesive coating was cured at 75C for 30 min in order to remove all of the water; cured thickness was 0.01 mm (10 mg/cm2). A disc of the cured adhesive was die-cut and laminated to the stratum corneum side of a disc of human cadaver epidermis. The skin/adhesive composite was mounted on a glass diffusion cell (effective flux area 0.713 cm2) with the skin side facing the receptor com-partment. A measured volume of receiver solution (0.9%
NaCl and 0.01~ NaN3 in deionized water) was placed in the receptor compartment. The donor was 1.5 g of a nitroglycerin suspension consisting of 2.5 wt% nitro-glycerine; 48.8 wt% Dow 360 silicone fluid, 350 cts;
23.8 wt% propylene glycol monolaurate (Gattefasse); and 24.7 wt% lactose. The nitroglycerin suspension was placed in the donor compartment directly in contact with the adhesive. The donor compartment was then occluded, and the cell maintained at 32C. Samples of the receiv-ing solution were taken periodically and analyzed by HPLC
to determine the amount of nitroglycerin permeated per unit time. The experiment was repeated exactly, substituting Nitro-Dur0, a commercially-available nitro-glycerin transdermal device, for the adhesive layer and nitroglycerin vehicle.
Figure 7 shows the results of this test. Solid circles indicate the amount per cm2 per hour (in micrograms) for the above-described composite. Open circles indicate the results obtained using Nitro-Dur~.
As shown in the Figure, Nitro-Dur0 reached essentially peak flux rate by 2-4 hours after administration, whereas Z~)6~03 the composition of the invention delayed full onset to 4.5-5 hours after administration.
ExamDle 2 (In Vitro Delayed Flux Determination) Water based acrylic adhesive (Flexcryl 1625, 69% solids) was coated onto a 0.075 mm thick siliconized polyester film at a thickness of 0.125 mm. The adhesive coating was cured at 75C for 30 min in order to remove all of the water; cured thickness was 0.05 mm (5 mg/cm ). A disc of the cured adhesive was die-cut and laminated to the stratum corneum side of a disc of human cadaver epidermis. The skin/adhesive composite was mounted on a glass diffusion cell (effective flux area 0.713 cm2) with the skin side facing the receptor com-partment. A measured volume of receiver solution (0.9%
NaCl and 0.01~ NaN3 in deionized water) was placed in the receptor compartment. The donor was 1.5 g of a nitroglycerin suspension consisting of 2.3 wt% nitro-glycerine; 75.0 wt% Dow 360 silicone fluid, 350 cts;
and 22.5 wt% lactose. The nitroglycerin suspension was placed in the donor compartment directly in contact with the adhesive. The donor compartment was then occluded, and the cell maintained at 32C. Samples of the receiv-ing solution were taken periodically and analyzed by HPLC
to determine the amount of nitroglycerin permeated per unit time. The experiment was repeated exactly, substituting Nitro-Dur~ for the adhesive layer and nitroglycerin vehicle.
Figure 8 shows the results of this test. Solid circles indicate the amount per cm2 per hour (in micrograms) for the above-described composite. Open circles indicate the results obtained using Nitro-Dur~.
As shown in the Figure, Nitro-~ur~ reached essentially peak flux rate by 2-4 hours after administration, whereas W O 91/03998 PC~r/~'S90/05198 - .zo6~4~3 the composition of the invention delayed full onset to 5-6 hours after administration.
Example 3 (In Vitro Delayed Flux Determination) (A) Water based acrylic adhesive (Flexcryl 1625, 69% solids) was coated onto a 0.075 mm thick siliconized polyester film at a thickness of 0.125 mm.
The adhesive coating was cured at 75C for 30 min in order to remove all of the water; cured thickness was 0.05 mm (5 mg/cm2). A disc of the cured adhesive was die-cut and laminated to the stratum corneum side of a disc of human cadaver epidermis. Next, a disc of 2 mil microporous polypropylene membrane (Celgard 2400, avail-able from Celanese/Hoecht) was laminated to the contact adhesive as a delay membrane. The skin/adhesive compos-ite was mounted on a glass diffusion cell (effective flux area 0.713 cm2) with the skin side facing the receptor compartment. A measured volume of receiver solution (0.9% NaCl and 0.01% NaN3 in deionized water) was placed in the receptor compartment. The donor was 1.5 g of a 10 wt% nitroglycerin solution in propylene glycol. The nitroglycerin solution was placed in the donor compartment directly in contact with the adhesive. The donor compartment was then occluded, and the cell maintained at 32C. Samples of the receiving solution were taken periodically and analyzed by HPLC to deter-mine the amount of nitroglycerin permeated per unit time.
The experiment was repeated exactly, substituting Nitro-Dur~ for the adhesive layer and nitroglycerin vehicle.
(B) The procedure described in part A above was repeated exactly, substituting a microporous poly-propylene membrane/non-woven polypropylene laminated film (Celgard 4410) for the Celgard 2400 membrane.
WO91/03998 PCT/~S90/05198 ;~06~03 (C) Figure 9 shows the results of these tests.
The solid circles depict the results using patch "A"
(with Celgard 2400). The open circles depict the results from patch "B" (using Celgard 4410). The solid squares indicate the results obtained using Nitro-Dur~. As shown in the ~igure, Nitro-Durg reached a high flux rate by 2-4 hours after administration, whereas the composition of the invention delayed significant onset to 8-12 hours after administration.
Claims (17)
1. A kit for preparing a device for administering an active compound transdermally to a subject's skin, having a delayed onset of delivery, said kit comprising:
a first layer comprising a polymeric matrix impregnated with said active compound, said compound and matrix being selected to obtain a first compound diffusion coefficient of about 10-5 to about 10-10 cm2/sec in said matrix;
a second layer not in contact with said first layer, comprising an adhesive capable of adhering to said first layer and to said subject's skin, said second layer having a second diffusion coefficient of about 10-5 to about 10-10 cm2/sec in said matrix, wherein said second layer is substantially devoid of said active compound.
a first layer comprising a polymeric matrix impregnated with said active compound, said compound and matrix being selected to obtain a first compound diffusion coefficient of about 10-5 to about 10-10 cm2/sec in said matrix;
a second layer not in contact with said first layer, comprising an adhesive capable of adhering to said first layer and to said subject's skin, said second layer having a second diffusion coefficient of about 10-5 to about 10-10 cm2/sec in said matrix, wherein said second layer is substantially devoid of said active compound.
2. The kit of claim 1, which further comprises:
a backing layer laminated to said first layer, wherein said backing layer is substantially impermeable to said compound.
a backing layer laminated to said first layer, wherein said backing layer is substantially impermeable to said compound.
3. The kit of claim 2 further comprises:
a backing layer laminated to said second layer.
a backing layer laminated to said second layer.
4. The kit of claim 2 which further comprises:
a release liner laminated to said second layer, opposite said backing layer.
a release liner laminated to said second layer, opposite said backing layer.
5. The kit of claim 1 which further comprises:
a backing layer laminated to said first and second layers, wherein said backing layer is substantially impermeable to said compound.
a backing layer laminated to said first and second layers, wherein said backing layer is substantially impermeable to said compound.
6. The kit of claim 5 which further comprises:
a release liner laminated to said first and second layers, opposite said backing layer.
a release liner laminated to said first and second layers, opposite said backing layer.
7. The kit of anyone of claims 1 to 6 wherein said active compound is selected from the group consisting of nitroglycerine and nicotine.
8. A controlled release device for administering an active compound to a subject comprising:
a first having a polymeric matrix impregnated with an active compound, said compound and matrix being selected to obtain a first compound diffusion coefficient of about 10-5 to about 10-10 cm2/sec in said matrix;
a second layer having an adhesive capable of adhering to said first layer and to said subject's skin, said second layer having a second diffusion coefficient of about 10-5 to about 10-10 cm2/sec in said matrix, said second layer being substantially devoid of said active compound;
wherein the first and second layers are arranged for use in a method of administering the active compound to the subject in which a laminate of the first and second layers is applied to the skin of the subject before the active compound equilibrates in the laminate.
a first having a polymeric matrix impregnated with an active compound, said compound and matrix being selected to obtain a first compound diffusion coefficient of about 10-5 to about 10-10 cm2/sec in said matrix;
a second layer having an adhesive capable of adhering to said first layer and to said subject's skin, said second layer having a second diffusion coefficient of about 10-5 to about 10-10 cm2/sec in said matrix, said second layer being substantially devoid of said active compound;
wherein the first and second layers are arranged for use in a method of administering the active compound to the subject in which a laminate of the first and second layers is applied to the skin of the subject before the active compound equilibrates in the laminate.
9. The device of claim 8 wherein said active compound is selected from nitroglycerin and nicotine.
10. A device for administering an active compound transdermally following application to a subject's skin, having a delayed onset of delivery, said devicecomprising:
(a) a contact layer comprising a skin contact adhesive which is permeable to said active compound;
(b) a backing layer comprising a thin, flexible material which is substantially impermeable to said active compound, which is laminated to said contact layer, and together with said contact layer defines a reservoir void between said contact layer and said backing layer; and within said reservoir void, a rupturable capsule containing said active compound.
(a) a contact layer comprising a skin contact adhesive which is permeable to said active compound;
(b) a backing layer comprising a thin, flexible material which is substantially impermeable to said active compound, which is laminated to said contact layer, and together with said contact layer defines a reservoir void between said contact layer and said backing layer; and within said reservoir void, a rupturable capsule containing said active compound.
11. The device of claim 10, which further comprises:
a wick layer comprising a porous fabric, laminated between said contact layer and said reservoir void.
a wick layer comprising a porous fabric, laminated between said contact layer and said reservoir void.
12. The device of claim 11 wherein said wick layer comprises a non-woven fabric.
13. The device of claim 10, 11, or 12 wherein the contact layer is an active compound permeable adhesive layer that is substantially devoid of active compound prior to rupture of the reservoir.
14. The device of claim 10 which further comprises:
an active compound permeable microporous membrane positioned between said reservoir void and said contact layer where said microporous membrane provides structural integrity.
an active compound permeable microporous membrane positioned between said reservoir void and said contact layer where said microporous membrane provides structural integrity.
15. The device of claim 10 which further comprises:
an active compound permeable delay membrane positioned between said reservoir void and said contact layer where said delay membrane delays the permeation of drug through the device to the skin.
an active compound permeable delay membrane positioned between said reservoir void and said contact layer where said delay membrane delays the permeation of drug through the device to the skin.
16. The device of claim 11 which further comprises:
an active compound permeable microporous membrane laminated between the wick layer and the contact adhesive layer.
an active compound permeable microporous membrane laminated between the wick layer and the contact adhesive layer.
17. The device of claim 14, 15, or 16 wherein the microporous membrane is fabricated from a material selected from the group consisting of polypropylene, polyethylene, polytetrafluoroethylene, polyurethane, dense polyacrylate, and dense polyisobutylene.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40747689A | 1989-09-14 | 1989-09-14 | |
US407,476 | 1989-09-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2065403A1 CA2065403A1 (en) | 1991-03-15 |
CA2065403C true CA2065403C (en) | 1996-06-18 |
Family
ID=23612266
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002065403A Expired - Fee Related CA2065403C (en) | 1989-09-14 | 1990-09-13 | Transdermal delivery device having delayed onset |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0491853A4 (en) |
JP (1) | JP2605183B2 (en) |
AU (1) | AU650851B2 (en) |
CA (1) | CA2065403C (en) |
FI (1) | FI921121A0 (en) |
WO (1) | WO1991003998A1 (en) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2542792B2 (en) * | 1992-11-05 | 1996-10-09 | ベクトン・ディッキンソン・アンド・カンパニー | User-operated iontophoretic device |
US5591767A (en) * | 1993-01-25 | 1997-01-07 | Pharmetrix Corporation | Liquid reservoir transdermal patch for the administration of ketorolac |
US5613958A (en) * | 1993-05-12 | 1997-03-25 | Pp Holdings Inc. | Transdermal delivery systems for the modulated administration of drugs |
JPH09505028A (en) * | 1993-07-09 | 1997-05-20 | シグナス,インコーポレイテッド | Methods and devices for providing percutaneous / buccal nicotine replacement therapy |
AU2703795A (en) * | 1994-06-23 | 1996-01-19 | Procter & Gamble Company, The | Treatment of nicotine craving and/or smoking withdrawal symptoms with a transdermal or transmucosal composition containing nicotine and caffeine or xanthine |
DE19736315A1 (en) * | 1997-08-21 | 1999-02-25 | Lohmann Therapie Syst Lts | Active agent containing device, for dermal use |
WO2005025549A2 (en) * | 2003-09-10 | 2005-03-24 | Noven Pharmaceuticals, Inc. | Multi-layer transdermal drug delivery device |
US8343538B2 (en) | 2004-10-08 | 2013-01-01 | Noven Pharmaceuticals, Inc. | Compositions and methods for controlling the flux of a drug from a transdermal drug delivery systems |
US20080167633A1 (en) * | 2005-04-11 | 2008-07-10 | Roberto Vannucci | Band-Aid With a Disinfectant Container |
CN101460156B (en) * | 2006-05-08 | 2011-06-08 | 帝国制药株式会社 | Tansdermally absorbable preparation comprising anti-dementia agent |
GB2438926A (en) * | 2006-06-07 | 2007-12-12 | Paul Marshall | Transdermal patch |
GB2443928A (en) * | 2006-11-08 | 2008-05-21 | Regen Therapeutics Plc | Transdermal pharmaceutical composition comprising Zolpidem |
GB2448855B (en) * | 2007-05-04 | 2010-10-20 | Mark Stephen Couchman | Pressure activated transdermal medicament delivery system |
FR2924349B1 (en) | 2007-12-03 | 2010-01-01 | Dbv Tech | ALLERGEN DISENSIBILITY METHOD |
GB201019761D0 (en) | 2010-11-22 | 2011-01-05 | Chowdhury Dewan F H | Multilayered transdermal patch |
EP3395337B1 (en) * | 2017-04-28 | 2023-06-14 | Nitto Denko Corporation | Transdermal absorption preparation precursor |
CN109646806A (en) * | 2018-12-17 | 2019-04-19 | 南京日光生物科技有限公司 | A kind of backbone patch and preparation method thereof with far infrared heating layer |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3703890A (en) * | 1970-08-10 | 1972-11-28 | Milton A Saunders Jr | Skin patch test device |
US4117841A (en) * | 1977-02-07 | 1978-10-03 | Anthony Perrotta | Medicated bandage pocket |
US4286592A (en) * | 1980-02-04 | 1981-09-01 | Alza Corporation | Therapeutic system for administering drugs to the skin |
ES2028074T3 (en) * | 1986-06-13 | 1992-07-01 | Alza Corporation | ACTIVATION BY MOISTURE OF A TRANSDERMIC PHARMACY SUPPLY SYSTEM. |
EP0249475A3 (en) * | 1986-06-13 | 1989-10-11 | Alza Corporation | Delayed percutaneous delivery |
EP0290262A3 (en) * | 1987-05-08 | 1990-12-12 | EASTMAN KODAK COMPANY (a New Jersey corporation) | Improved nitrate therapy for angina pectoris |
US4839174A (en) * | 1987-10-05 | 1989-06-13 | Pharmetrix Corporation | Novel transdermal nicotine patch |
US4812305A (en) * | 1987-11-09 | 1989-03-14 | Vocal Rodolfo S | Well medicine strip |
-
1990
- 1990-09-13 AU AU65153/90A patent/AU650851B2/en not_active Ceased
- 1990-09-13 JP JP2513760A patent/JP2605183B2/en not_active Expired - Lifetime
- 1990-09-13 CA CA002065403A patent/CA2065403C/en not_active Expired - Fee Related
- 1990-09-13 EP EP19900914848 patent/EP0491853A4/en not_active Withdrawn
- 1990-09-13 WO PCT/US1990/005198 patent/WO1991003998A1/en not_active Application Discontinuation
-
1992
- 1992-03-16 FI FI921121A patent/FI921121A0/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
FI921121A (en) | 1992-03-16 |
EP0491853A1 (en) | 1992-07-01 |
FI921121A0 (en) | 1992-03-16 |
AU6515390A (en) | 1991-04-18 |
AU650851B2 (en) | 1994-07-07 |
EP0491853A4 (en) | 1992-11-04 |
JP2605183B2 (en) | 1997-04-30 |
CA2065403A1 (en) | 1991-03-15 |
WO1991003998A1 (en) | 1991-04-04 |
JPH05500511A (en) | 1993-02-04 |
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