CA2115570A1 - Transdermal drug delivery device using a membrane-protected microporous membrane to achieve delayed onset - Google Patents
Transdermal drug delivery device using a membrane-protected microporous membrane to achieve delayed onsetInfo
- Publication number
- CA2115570A1 CA2115570A1 CA002115570A CA2115570A CA2115570A1 CA 2115570 A1 CA2115570 A1 CA 2115570A1 CA 002115570 A CA002115570 A CA 002115570A CA 2115570 A CA2115570 A CA 2115570A CA 2115570 A1 CA2115570 A1 CA 2115570A1
- Authority
- CA
- Canada
- Prior art keywords
- layer
- underlying
- drug
- polymer
- reservoir
- 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.)
- Abandoned
Links
Classifications
-
- 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
-
- 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 delayed onset transdermal drug delivery device (11) exhibiting a delay period of at least eight hours comprising a laminated composite of (A) a top backing layer (12); (B) a pressure rupturable layer (13) underlying (B); (C) a reservoir of a solution of drug (14) in a liquid vehicle between (A) and (B) underlying layer (13) is a hard, solid body (15) to which finger pressure may be applied to facilitate the rupture of layer (13); (D) a wick layer (16) underlying (B) for dispersing the drug once (B) is ruptured;
(E) a first adhesive layer (17) underlying (D) that is permeable to the drug; (F) a first polymer membrane (18) that is permeable to drug but substantially impermeable to the adhesive of (E); (G) a microporous membrane (19) underlying (F) which is itself impermeable to the drug and whose pores are unfilled; (H) a second polymer membrane (20) that underlies the microporous membrane (19) that is permeable to drug but substantially impermeable to the adhesive of (I) below; and (I) a second adhesive layer (21) underlying (H) that is permeable to the drug.
(E) a first adhesive layer (17) underlying (D) that is permeable to the drug; (F) a first polymer membrane (18) that is permeable to drug but substantially impermeable to the adhesive of (E); (G) a microporous membrane (19) underlying (F) which is itself impermeable to the drug and whose pores are unfilled; (H) a second polymer membrane (20) that underlies the microporous membrane (19) that is permeable to drug but substantially impermeable to the adhesive of (I) below; and (I) a second adhesive layer (21) underlying (H) that is permeable to the drug.
Description
~"~ W093/03692 2 1 1 5 ~ 7 o PCT/US92/06839 TRANSDERMAL DRUG DELIVERY ~EVICE USING A MEM~RANE-PRQTE~TED MICRQPOROUS MEMBRANE TO ACHIEV~ DELAYED ONSET
De~cri~tion Technical Field This invention i9 in the general field of transdermal drug delivery and relates specifically to devices from which drug is released in a delayed pattern from the time the device is placed on the skin. Devices that release drug in such a pattern are commonly referred to as "delayed onset" devices.
Rackqround Earnest efforts to develop tran dermal drug delivery devices that provide drug to the patient in a controlled pattern began i~ the late 19608 and early 1~70s. The principal pattern of deli~ery that was investigated was substantially constant rate deli~ery in which delivery began at or shortly after the de~ice was applied to th~e skin, rose to a desired level, and stayed at that level for a sustained time period. These efforts re~ulted in numerous patents being issued for de~ices of various structures that achieved or closely mimicked constant rate delivery. See, for in~tance, U.S. 3,598,122; 3,598,123; 3,797,494; and 4,286,592.
Nitroglycerin i(NTG) is among the many drugs that has been a~m~ni~tered transdermally. Among the U.S. patents describing transdermal NTG delivery are U.S. 3,742,951; 4,533,540; 4,559,222; 4,618,699;
4,681,584; 4,654,209; 4,655,766; 4,661,441; 4,751,087;
4,776,850;, 4,778,678; 4,784,857; and 4,786,282. None of U~Ds3t~s2 PCT/US92/~3' ~
211~570 -2-these patents concern delayed onset nitroglycerin delivery. Further, the initial commercial transdermal NTG devices (the Transdenm-Nitro and Nitro-Dur de~ices) are continuous rather than delayed-onset deli~ery de~ices.
In the mid-1980s a number of clinical studies raised questions about the efficacy of NTG therapy provided by the then available commercial transdermal devices that administered NTG in a continuous pattern.
Specifically, continuous administration was tending to cause tolerance and hemodynamic attenuation. This led clinicians to conclude that the ideal regimen for administering NTG would include an overnight ~washout period" during which no NTG was administered.
Correlatively, it led developers of transdermal devices to propose delayed onset devices for administering NTG.
U.S. 4,956,181 describes a delayed on~et de~ice for administering NTG. Its device consists of a backing layer, a rupturable pod sandwiched between the backing and a nonwoven fabric layer, a barrier membrane, an adhesive layer, and a relea~e liner. The rupturable pod contains NTG and an activator liquid that is capable of plasticizing the barrier membrane and increasing its permeability~to NTG. Once the pod is ruptured, drug and activator migrate down through the barrier membrane, with the activator causing the membrane to become increasingly permeable to the drug. While this patent indicates that an effective delay of up to 12 hr may be achieved, the examples of the patent describe de~ices that achieve only a 4-6 hr delay.~ ;
An object of the present invention is to pr~vide a delayed onset device for administering NTG that provides at least a six and preferably an eight hour delay in administration. The device of the invention 211~ .j 7 0 PCT/US92/06839 does not use plasticization of a barrier membrane as a delay mechanism.
~isclosure of the Invention Thiq invention i8 a device for administ~ring a drug transdermally following application of the device to a subject~s skin wherein the delivery of drug is delayed at least about six hours after said application compri-sing in combination: (a) a nonrupturable backing layer forming the top surface of the device; (b) a pressure rupturable reservoir underlying (a) and containing the drug dissolved in a liquid vehicle; (c) a wick layer underlying (b) for dispersing the drug once the reservoir is ruptured; (d) a layer of a drug permeable polymer underlying (c); 5e) a first polymer membrane layer underlying (d) that is penmeable to the drug, but substantially impermeable to the adhesive polymer of (d);
(f) a microporous membrane underlying (e); (g) a second polymer membrane layer underlying (f) that is permeable to the drug; (h) a layer of a drug permeable adhe~ive polymer underlying (g); wherein the second polymer membrane layer i~ substantially impenmeable to the adhe~ive polymer of (h) and wherein it initially takes at least about 8iX hours for the drug to diffuse to the skin 25-- from the reservoir once the reservoir is ruptured and the device is applied to the skin.
rief Descri~tion of the ~rawin~s - Figure 1 is a sectional view of an embodiment of the invention for administering NTG. The drawing is not to scale. The thicknesses of the layer~ of the - embodiment are exaggerated for the purpo~es of illustration.
Figure 2 is a graph of the results of the te~ts described in the Example.
W093/03~92 PCT/US92/~83~
Modes for Carryina Out the Invention The drawing shows a preferred embodiment, generally designated 11, of the delayed onset device of the invention. The top surface of the de~ice i8 defined by backing layer 12. It i9 made of a material or --combination of materials that is substantially impermeable to the soIution of NTG in the liquid vehicle, does not absorb significant amounts of the NTG solution, and is capable of being sealingly bonded (e.g., by heat sealing or crimping) at its periphery to the underlying microporous m~mhrane layer 19 (described below). In addition, the mechanical properties of the backing should be such that it does not rupture coincident with the rupture of the underlying rupturable layer 13. It is also preferably flexible and/or elastomeric. Examples of materials from which the backing layer may be formed are elastomeric polymers such as polyether block amide copolymers (e.g., P~BAX copolymer~), polyethylene methyl methacrylate block copolymer~, (e.g., NURREL~ polymers), polyurethanes (e.g., PE~THANE polymer~), silicone elastomers, polyester block eopolymers such as HYTRE~, rubber-based polyisobutylene, ~tyrene, and styrene-butadiene and styrene-i~oprene eopolymers. Flexible polymers-include polyethylene, polypropylene, and polyesters such as polyester terephthalate (P$T), which may be provided as films or laminates. The thickness of the backing layer will normally be in the range of 0.01 to 0.15 mm, more normally 0.02 to 0.1 mm. m e backing may optionally be pigmented (e.g., to resemble skin color).
~ - ~acking layer 12 has a cavity that ~erves as a re~ervoir or container for a liquid formulation of NTG, generally de~ignated 14. Formulation 14 compri~e~ NTG in a liquid vehicle. Example~ of ~uitable liquid carriers are lower alkanol~ ~uch as methanol, ethanol, -~ W093/03692 2 1 1 5 ~ 7 0 PCT/US92/~839 isopropanol, glycols such as propylene glycol, and the like. Propylene glycol i~ preferred. The fonmulation may also contain additional ingredients such as a dye which may ser~e as an indicator of rupture of the reservoir. The NTG will normally compri3e 2 to 20~ by weight of the formulation, more normally S to 10~ by weight. The total amount of NTG in the reservoir will normally be S0 to 300 mg, more normally 100 to 150 mg.
Directly underlying the ca~ity and backing layer is a pre~sure-rupturable layer 13. Laye~ 13 is sealed to the overlying backing layer 12 (and underlying layers to the microporous membrane layer 19) about the periphery of the cavity containing the NTG formulation 14. ~ayer 13 is also impermeable to the NTG formulation and serves as the basal wall of the reservoir. It is made of a material that may be ruptured with normal finger pressure such as aluminum foil coated with a heat sealable layer of ethylene vinyl acetate copolymer, polypropylene or polyethylene. Underlying layer 13 in registry with the reservoir is a hard, solid (incompress-ible) body 15 to which finger pressure may be applied to facilitate the rupture or tearing of layer 13 below the reservoir to release the liquid formulation of NTG from the reservoir.. The body is smaller in dimension than the ca~ity containing the NTG solution.;- It will ~ypically be made from hard materials such as polycarbonate, poly-propylene, or high density polyethylene.
Immediately below the rupturable layer 13 is a wick layer 16 that is capable of dispersing or spreading the liguid fonmulation of NTG tra~ersely or parallel to the basal surface of the de~ice. The wick layer does not absorb or retain any substantial amount of the NTG formu-lation and functions merely to spread the fonmulation across the de~ice. It is not a barrier to diffu~ion of the NTG from the reservoir to the ~kin surface. The wick WOs3~ g2 PCT/US92/0683~-;
211S57~ -6-layer i8 preferably made from a nonwo~en polymeric fabric such as spun-bonded polyester. It will normally have a basis weight of 0.2 to 1 oz./yard2, preferably 0.4 to 0.6 oz./yard2. The wick layer must be capable of adhering to the adjoining layers of the de~ice under conditions of use (i.e., in the presence of adsorbed NTG formulation) and be sealable (e.g., by heat) to the overlying layers and to the underlying microporous membrane.
Underlying the wick layer 16 i9 a first layer of a polymer adhesive layer 17 that i8 permeable to the NTG formulation. The diffusion coefficient of NT~ in this layer will normally be 1 x 10-7 to 1 x 1o~8 cm/sec.
It~ thicknes~ will normally be 0.02 to 0.3 mm, more usually 0.02 to 0.15 mm.
lS Underlying adhesive }ayer 17 is a dense (not microporous) polymer membrane layer 18. The purpose of layer 18 is to deter or prevent the adhesive of layer 17 from migrating into the pores of the underlying microporou membrane layer 19 while at the ~ame time permitting the drug to permeate therethrough.
Accordingly, thi~ membrane i9 penmeable to the drug but su~stantially impermeable to the adhesive of the overlying layer. It may be made of polymers ~uch as ethylene-vlnyl acetate copolymers, low density polyethylene, ethylene polypropylene diene, polyester copolymer,-and polyether amide copolymers. It will normally be about 0.01 to 0.2 mm thick, more usually 0.01 to 0.10 mm thick.
--~ The next layer is the microporous membrane layer 19. The-material from which the membrane itself is made is substantially impermeable to the NTG formulation.
Examples of microporou~ materials are microporous polypropylene (OE ~GARD, Hoechst-Celane~e), microporous polyethylene (COTRAN, 3M), and microporous polytetrafluoroethylene ~TEFLON, Gortex). The membrane W093/03692 2 1 1 5 ~ 7 o PCT/US92/~839 will typically have a pore volume in the range of 10~ to 60~. The pore~ of the layer are initially unfilled. The thickness of the microporous membrane layer will normally be 0.001 to 0.1 mm.
Immediately underlying microporous membrane 19 i9 a second dense polymer membrane layer 20. It serves to deter or prevent the adhesive of a second underlying adhesiv~ layer 21 from back-migrating into the pores of the microporous membrane while at the same time permitting the drug to permeate therethrough.
Accordingly, it too is permeable to the drug but substantially impenmeable to the adhesive of layer 21.
Since it functions in the same manner as membrane 18, it may be made from the same polymers and be of the same thickness as membrane 18.
A~ indicated, a second adhesive layer 21 underlies the second membrane layer 20. The second adhesive layer may have the same or different composition as the first layer. The thicknes,s of the second adhesive layer will normally be 0.02 to 0.3 mm, more usually 0.02 to 0.15 mm. Examples of adhesives from which the adhesive layers 17 and 21 may be made are polysiloxanes, ~polyacrylates, polyurethanes, and ethylene-~inyl acetate copolymers.
2S ~ A standard release liner layer 22 underlie~ the second adhesive layer.
T~he delayed onset devices of the present invent~on are designed to be worn for a one-day period and then~replaced. In the case of NTG, the devices will norm,ally be placed on the skin shortly before the individual goes to sleep at night. ~hus, the period during which the wearer recei~es insignificant NTG will coincide roughly with the wearer's sleeping hours;
,whereas the period~during which delivery i8, effected will coincide roughly with the wearer~s waking hours. -l~hi~
W093/0~92 PCT/US92/~83~
De~cri~tion Technical Field This invention i9 in the general field of transdermal drug delivery and relates specifically to devices from which drug is released in a delayed pattern from the time the device is placed on the skin. Devices that release drug in such a pattern are commonly referred to as "delayed onset" devices.
Rackqround Earnest efforts to develop tran dermal drug delivery devices that provide drug to the patient in a controlled pattern began i~ the late 19608 and early 1~70s. The principal pattern of deli~ery that was investigated was substantially constant rate deli~ery in which delivery began at or shortly after the de~ice was applied to th~e skin, rose to a desired level, and stayed at that level for a sustained time period. These efforts re~ulted in numerous patents being issued for de~ices of various structures that achieved or closely mimicked constant rate delivery. See, for in~tance, U.S. 3,598,122; 3,598,123; 3,797,494; and 4,286,592.
Nitroglycerin i(NTG) is among the many drugs that has been a~m~ni~tered transdermally. Among the U.S. patents describing transdermal NTG delivery are U.S. 3,742,951; 4,533,540; 4,559,222; 4,618,699;
4,681,584; 4,654,209; 4,655,766; 4,661,441; 4,751,087;
4,776,850;, 4,778,678; 4,784,857; and 4,786,282. None of U~Ds3t~s2 PCT/US92/~3' ~
211~570 -2-these patents concern delayed onset nitroglycerin delivery. Further, the initial commercial transdermal NTG devices (the Transdenm-Nitro and Nitro-Dur de~ices) are continuous rather than delayed-onset deli~ery de~ices.
In the mid-1980s a number of clinical studies raised questions about the efficacy of NTG therapy provided by the then available commercial transdermal devices that administered NTG in a continuous pattern.
Specifically, continuous administration was tending to cause tolerance and hemodynamic attenuation. This led clinicians to conclude that the ideal regimen for administering NTG would include an overnight ~washout period" during which no NTG was administered.
Correlatively, it led developers of transdermal devices to propose delayed onset devices for administering NTG.
U.S. 4,956,181 describes a delayed on~et de~ice for administering NTG. Its device consists of a backing layer, a rupturable pod sandwiched between the backing and a nonwoven fabric layer, a barrier membrane, an adhesive layer, and a relea~e liner. The rupturable pod contains NTG and an activator liquid that is capable of plasticizing the barrier membrane and increasing its permeability~to NTG. Once the pod is ruptured, drug and activator migrate down through the barrier membrane, with the activator causing the membrane to become increasingly permeable to the drug. While this patent indicates that an effective delay of up to 12 hr may be achieved, the examples of the patent describe de~ices that achieve only a 4-6 hr delay.~ ;
An object of the present invention is to pr~vide a delayed onset device for administering NTG that provides at least a six and preferably an eight hour delay in administration. The device of the invention 211~ .j 7 0 PCT/US92/06839 does not use plasticization of a barrier membrane as a delay mechanism.
~isclosure of the Invention Thiq invention i8 a device for administ~ring a drug transdermally following application of the device to a subject~s skin wherein the delivery of drug is delayed at least about six hours after said application compri-sing in combination: (a) a nonrupturable backing layer forming the top surface of the device; (b) a pressure rupturable reservoir underlying (a) and containing the drug dissolved in a liquid vehicle; (c) a wick layer underlying (b) for dispersing the drug once the reservoir is ruptured; (d) a layer of a drug permeable polymer underlying (c); 5e) a first polymer membrane layer underlying (d) that is penmeable to the drug, but substantially impermeable to the adhesive polymer of (d);
(f) a microporous membrane underlying (e); (g) a second polymer membrane layer underlying (f) that is permeable to the drug; (h) a layer of a drug permeable adhe~ive polymer underlying (g); wherein the second polymer membrane layer i~ substantially impenmeable to the adhe~ive polymer of (h) and wherein it initially takes at least about 8iX hours for the drug to diffuse to the skin 25-- from the reservoir once the reservoir is ruptured and the device is applied to the skin.
rief Descri~tion of the ~rawin~s - Figure 1 is a sectional view of an embodiment of the invention for administering NTG. The drawing is not to scale. The thicknesses of the layer~ of the - embodiment are exaggerated for the purpo~es of illustration.
Figure 2 is a graph of the results of the te~ts described in the Example.
W093/03~92 PCT/US92/~83~
Modes for Carryina Out the Invention The drawing shows a preferred embodiment, generally designated 11, of the delayed onset device of the invention. The top surface of the de~ice i8 defined by backing layer 12. It i9 made of a material or --combination of materials that is substantially impermeable to the soIution of NTG in the liquid vehicle, does not absorb significant amounts of the NTG solution, and is capable of being sealingly bonded (e.g., by heat sealing or crimping) at its periphery to the underlying microporous m~mhrane layer 19 (described below). In addition, the mechanical properties of the backing should be such that it does not rupture coincident with the rupture of the underlying rupturable layer 13. It is also preferably flexible and/or elastomeric. Examples of materials from which the backing layer may be formed are elastomeric polymers such as polyether block amide copolymers (e.g., P~BAX copolymer~), polyethylene methyl methacrylate block copolymer~, (e.g., NURREL~ polymers), polyurethanes (e.g., PE~THANE polymer~), silicone elastomers, polyester block eopolymers such as HYTRE~, rubber-based polyisobutylene, ~tyrene, and styrene-butadiene and styrene-i~oprene eopolymers. Flexible polymers-include polyethylene, polypropylene, and polyesters such as polyester terephthalate (P$T), which may be provided as films or laminates. The thickness of the backing layer will normally be in the range of 0.01 to 0.15 mm, more normally 0.02 to 0.1 mm. m e backing may optionally be pigmented (e.g., to resemble skin color).
~ - ~acking layer 12 has a cavity that ~erves as a re~ervoir or container for a liquid formulation of NTG, generally de~ignated 14. Formulation 14 compri~e~ NTG in a liquid vehicle. Example~ of ~uitable liquid carriers are lower alkanol~ ~uch as methanol, ethanol, -~ W093/03692 2 1 1 5 ~ 7 0 PCT/US92/~839 isopropanol, glycols such as propylene glycol, and the like. Propylene glycol i~ preferred. The fonmulation may also contain additional ingredients such as a dye which may ser~e as an indicator of rupture of the reservoir. The NTG will normally compri3e 2 to 20~ by weight of the formulation, more normally S to 10~ by weight. The total amount of NTG in the reservoir will normally be S0 to 300 mg, more normally 100 to 150 mg.
Directly underlying the ca~ity and backing layer is a pre~sure-rupturable layer 13. Laye~ 13 is sealed to the overlying backing layer 12 (and underlying layers to the microporous membrane layer 19) about the periphery of the cavity containing the NTG formulation 14. ~ayer 13 is also impermeable to the NTG formulation and serves as the basal wall of the reservoir. It is made of a material that may be ruptured with normal finger pressure such as aluminum foil coated with a heat sealable layer of ethylene vinyl acetate copolymer, polypropylene or polyethylene. Underlying layer 13 in registry with the reservoir is a hard, solid (incompress-ible) body 15 to which finger pressure may be applied to facilitate the rupture or tearing of layer 13 below the reservoir to release the liquid formulation of NTG from the reservoir.. The body is smaller in dimension than the ca~ity containing the NTG solution.;- It will ~ypically be made from hard materials such as polycarbonate, poly-propylene, or high density polyethylene.
Immediately below the rupturable layer 13 is a wick layer 16 that is capable of dispersing or spreading the liguid fonmulation of NTG tra~ersely or parallel to the basal surface of the de~ice. The wick layer does not absorb or retain any substantial amount of the NTG formu-lation and functions merely to spread the fonmulation across the de~ice. It is not a barrier to diffu~ion of the NTG from the reservoir to the ~kin surface. The wick WOs3~ g2 PCT/US92/0683~-;
211S57~ -6-layer i8 preferably made from a nonwo~en polymeric fabric such as spun-bonded polyester. It will normally have a basis weight of 0.2 to 1 oz./yard2, preferably 0.4 to 0.6 oz./yard2. The wick layer must be capable of adhering to the adjoining layers of the de~ice under conditions of use (i.e., in the presence of adsorbed NTG formulation) and be sealable (e.g., by heat) to the overlying layers and to the underlying microporous membrane.
Underlying the wick layer 16 i9 a first layer of a polymer adhesive layer 17 that i8 permeable to the NTG formulation. The diffusion coefficient of NT~ in this layer will normally be 1 x 10-7 to 1 x 1o~8 cm/sec.
It~ thicknes~ will normally be 0.02 to 0.3 mm, more usually 0.02 to 0.15 mm.
lS Underlying adhesive }ayer 17 is a dense (not microporous) polymer membrane layer 18. The purpose of layer 18 is to deter or prevent the adhesive of layer 17 from migrating into the pores of the underlying microporou membrane layer 19 while at the ~ame time permitting the drug to permeate therethrough.
Accordingly, thi~ membrane i9 penmeable to the drug but su~stantially impermeable to the adhesive of the overlying layer. It may be made of polymers ~uch as ethylene-vlnyl acetate copolymers, low density polyethylene, ethylene polypropylene diene, polyester copolymer,-and polyether amide copolymers. It will normally be about 0.01 to 0.2 mm thick, more usually 0.01 to 0.10 mm thick.
--~ The next layer is the microporous membrane layer 19. The-material from which the membrane itself is made is substantially impermeable to the NTG formulation.
Examples of microporou~ materials are microporous polypropylene (OE ~GARD, Hoechst-Celane~e), microporous polyethylene (COTRAN, 3M), and microporous polytetrafluoroethylene ~TEFLON, Gortex). The membrane W093/03692 2 1 1 5 ~ 7 o PCT/US92/~839 will typically have a pore volume in the range of 10~ to 60~. The pore~ of the layer are initially unfilled. The thickness of the microporous membrane layer will normally be 0.001 to 0.1 mm.
Immediately underlying microporous membrane 19 i9 a second dense polymer membrane layer 20. It serves to deter or prevent the adhesive of a second underlying adhesiv~ layer 21 from back-migrating into the pores of the microporous membrane while at the same time permitting the drug to permeate therethrough.
Accordingly, it too is permeable to the drug but substantially impenmeable to the adhesive of layer 21.
Since it functions in the same manner as membrane 18, it may be made from the same polymers and be of the same thickness as membrane 18.
A~ indicated, a second adhesive layer 21 underlies the second membrane layer 20. The second adhesive layer may have the same or different composition as the first layer. The thicknes,s of the second adhesive layer will normally be 0.02 to 0.3 mm, more usually 0.02 to 0.15 mm. Examples of adhesives from which the adhesive layers 17 and 21 may be made are polysiloxanes, ~polyacrylates, polyurethanes, and ethylene-~inyl acetate copolymers.
2S ~ A standard release liner layer 22 underlie~ the second adhesive layer.
T~he delayed onset devices of the present invent~on are designed to be worn for a one-day period and then~replaced. In the case of NTG, the devices will norm,ally be placed on the skin shortly before the individual goes to sleep at night. ~hus, the period during which the wearer recei~es insignificant NTG will coincide roughly with the wearer's sleeping hours;
,whereas the period~during which delivery i8, effected will coincide roughly with the wearer~s waking hours. -l~hi~
W093/0~92 PCT/US92/~83~
pattern of delivery provides NTG when most needed--upon awakening and through the day--and allows the level of NTG in the wearer~s circulation to wash out or decline during sleep 90 that tolerance to NTG is lensened.
In use, the de~ice is removed from its packaging and gripped such that a force may be applied from the basal surface against the solid body lS to cause the solid body to penetrate and rupture layer 13. The release liner layer is then removed and the deYice i~
placed on the skin with the basal layer of the second adhesive layer 21 in drug-delivery contact with the skin surface. The rupturing of layer 13 permits the liquid NTG formulation 14 to be released onto the wick layer 16.
The adsorbent properties of the wick layer cause the liquid to be dispersed across (parallel to the basal ~urface) the device. The liquid then diffuses through the first adhe~ive layer, the first membrane layer, the pores of the microporou~ membrane layer, the second membrane layer and the second adhesive layer. The NTG is released from the basal surface of the ~econd adhesive layer into the skin. The extent of the delayed onset will depend upon the diffusion coefficients of the polymers forming the first and second adhe~ive layers, and first and second membrane layers, the thicknesses of those layers, the porosity characteristics of the microporous membrane, and the thickness of the microporous membrane. With the ranges of these parameters given above a delay of at least eight hours i9 achieved before skin flux of NTG reaches about 2 ~g/cm2/hr. During the delay period the NlG skin flux ranges between 0 and about 2 ~g/cm2/hr. After the delay period the skin flux rises steadily over the remainder of the 24-hour wearing period to a skin flux level of about - - 5 to 20 ~g/cm2/hr. These levels of skin flux are a~
measured by the in vitro diffusion; all-studies de~cribed ~ W093/03692 2 1 1 ~ 5 7 o PCT/USg2/0683~
in the Examples, infra. The drug delivery area of the device (i.e., the basal surface) is normally in the range of 10-50 cm2, preferably lS-25 cm2.
The devices of the invention may be made by conventional lamination techniques. By way of example, a cavity of desired size is formed in a backing layer. The cavity is filled with a 10~ solution of NTG in propylene glycol. The rupturable foil layqr i8 then placed over the cavity. Two sheets of release liner are then coated on one side with adhesive to the desired thickness. One of these sheets is laminated to the wick layer and the release liner i9 removed. A microporous membrane i9 then l~minated on each side to a polymer membrane and one side of that ~ubassembly is laminated to the exposed side of the adhesive layer and the other adhesive-release liner subassembly is laminated to the other side of the microporou~ membrane suba~sembly. Finally the backing-NTG reservoir, rupturable layer subassembly i8 laminated to the wick layer onto which a 1 cm diameter, 2 mm thick disc of polycarbonate has been placed and the assembly is heat-sealed about the periphery of the cavity, thereby heat-sealing the backing through to the microporous membrane layer. `
- The following example further describes the invention. m is example is not-intended to limit the invention in any manner. - :
- Exam~le Water-based acrylic adhesive (Flexcryl 1625, 69~ solids) was coated onto a 0.003" thick siliconized polyester release liner film at a thickne~s of 0.005~.
The adhesive coating was cured at 70C for 30 min in order to remove all of the water; cured thickness wa~
0.002~ (5 mg/cm2). Two ~uch films were prepared.
W093/0~92 PCT/US92/0683 ~
2115~7~ -lo-Ethylene-vinylacetate copolymer (Vynathene, containing 40~ by wt ~inyl acetate~ was dissolved in toluene and coated onto a 0.003 n thick siliconized polyester release liner film at a thickness of 0.002".
5 This coating wa~ also cured at 70C for 30 min in order to remGve all of the solvent; cured thickness was less than 0.0005". Two such films were prepared.
One of the a & esive film~ wa~ laminated to a polyester nonwoven (Reemay 2250). The relea~e liner was removed from the adhesive and one of the ethylene vinyl acetate copolymer films was laminated to the exposed adhesive surface. The release liner film was then removed from the ethylene vinyl acetate copolymer film and a microporous membrane (Celgard 2400 from Hoe~hst-Celanese) was laminated to the expo3ed surface. The~econd ethylene vinyl acetate copolymer film was then laminated to the exposed surface of the microporous membrane. The relea~e liner was remo~ed and the second adhesive film was laminated to the e~posed ethylene vinyl acetate copolymer film surface.
A disc of thi3 multilaminate wa~ die-cut and laminated to the stratum corneum side of a diqc of huma~
cadaver epidermi~. The skin~multilaminate compo~ite was mounted on a glas~ diffusion cell (effective flux area 0.71 cm2) with the skin side facing the receptor compartment. A measured ~olume of receiver solution (0.9% NaCl and 0.01~ Gentamicin in deionized water) was placed in the receptor compartment. The donor was 37 ~1 of a 10% nitroglycerin solution in propylene glycol ~SDM
27 from ICI Americas). The nitroglycerin ~olution was placed in the donor compartment directly in contact with the nonwo~en. The donor compartment was then occluded, and the cell mai~tained at 32C. Samples of the receiving solution were taken periodically and analyzed by HP~C to determine the amount of nitroglycerin ~ W093/0~92 2 1 1 ~ 5 7 0 PCT/US92/~39 permeated per unit time. The experiment was repeated exactly, substituting a commercially available nitroglycerin transdermal device, Nitro-Dur, for the multilaminate layer and nitroglycerin vehicle.
As shown in Fig. 2, Nitro-Dur reached substantial flux in 2-4 hr after administration, whereas the composite of the in~entions delayed full onset to 8 hr after administration.
~O While the invention has been exemplified in terms of an embodiment for administering NTG, it may also be used to administer other drugs in a delayed onset regimen. Drug~ which may be advantageously administered in such a regimen include other vasodilators, analgesics, contraceptives, appetite suppressants, growth factors, and the like. Other modifications of the above-described modes for carrying out the invention that are obvious to those of skill in the fields of transdermal drug delivery de~ice design, materials science, polymer chemistry and related fields are intended to be within the ~cope of the following cla~ms.
, , . . .
.
~ 35
In use, the de~ice is removed from its packaging and gripped such that a force may be applied from the basal surface against the solid body lS to cause the solid body to penetrate and rupture layer 13. The release liner layer is then removed and the deYice i~
placed on the skin with the basal layer of the second adhesive layer 21 in drug-delivery contact with the skin surface. The rupturing of layer 13 permits the liquid NTG formulation 14 to be released onto the wick layer 16.
The adsorbent properties of the wick layer cause the liquid to be dispersed across (parallel to the basal ~urface) the device. The liquid then diffuses through the first adhe~ive layer, the first membrane layer, the pores of the microporou~ membrane layer, the second membrane layer and the second adhesive layer. The NTG is released from the basal surface of the ~econd adhesive layer into the skin. The extent of the delayed onset will depend upon the diffusion coefficients of the polymers forming the first and second adhe~ive layers, and first and second membrane layers, the thicknesses of those layers, the porosity characteristics of the microporous membrane, and the thickness of the microporous membrane. With the ranges of these parameters given above a delay of at least eight hours i9 achieved before skin flux of NTG reaches about 2 ~g/cm2/hr. During the delay period the NlG skin flux ranges between 0 and about 2 ~g/cm2/hr. After the delay period the skin flux rises steadily over the remainder of the 24-hour wearing period to a skin flux level of about - - 5 to 20 ~g/cm2/hr. These levels of skin flux are a~
measured by the in vitro diffusion; all-studies de~cribed ~ W093/03692 2 1 1 ~ 5 7 o PCT/USg2/0683~
in the Examples, infra. The drug delivery area of the device (i.e., the basal surface) is normally in the range of 10-50 cm2, preferably lS-25 cm2.
The devices of the invention may be made by conventional lamination techniques. By way of example, a cavity of desired size is formed in a backing layer. The cavity is filled with a 10~ solution of NTG in propylene glycol. The rupturable foil layqr i8 then placed over the cavity. Two sheets of release liner are then coated on one side with adhesive to the desired thickness. One of these sheets is laminated to the wick layer and the release liner i9 removed. A microporous membrane i9 then l~minated on each side to a polymer membrane and one side of that ~ubassembly is laminated to the exposed side of the adhesive layer and the other adhesive-release liner subassembly is laminated to the other side of the microporou~ membrane suba~sembly. Finally the backing-NTG reservoir, rupturable layer subassembly i8 laminated to the wick layer onto which a 1 cm diameter, 2 mm thick disc of polycarbonate has been placed and the assembly is heat-sealed about the periphery of the cavity, thereby heat-sealing the backing through to the microporous membrane layer. `
- The following example further describes the invention. m is example is not-intended to limit the invention in any manner. - :
- Exam~le Water-based acrylic adhesive (Flexcryl 1625, 69~ solids) was coated onto a 0.003" thick siliconized polyester release liner film at a thickne~s of 0.005~.
The adhesive coating was cured at 70C for 30 min in order to remove all of the water; cured thickness wa~
0.002~ (5 mg/cm2). Two ~uch films were prepared.
W093/0~92 PCT/US92/0683 ~
2115~7~ -lo-Ethylene-vinylacetate copolymer (Vynathene, containing 40~ by wt ~inyl acetate~ was dissolved in toluene and coated onto a 0.003 n thick siliconized polyester release liner film at a thickness of 0.002".
5 This coating wa~ also cured at 70C for 30 min in order to remGve all of the solvent; cured thickness was less than 0.0005". Two such films were prepared.
One of the a & esive film~ wa~ laminated to a polyester nonwoven (Reemay 2250). The relea~e liner was removed from the adhesive and one of the ethylene vinyl acetate copolymer films was laminated to the exposed adhesive surface. The release liner film was then removed from the ethylene vinyl acetate copolymer film and a microporous membrane (Celgard 2400 from Hoe~hst-Celanese) was laminated to the expo3ed surface. The~econd ethylene vinyl acetate copolymer film was then laminated to the exposed surface of the microporous membrane. The relea~e liner was remo~ed and the second adhesive film was laminated to the e~posed ethylene vinyl acetate copolymer film surface.
A disc of thi3 multilaminate wa~ die-cut and laminated to the stratum corneum side of a diqc of huma~
cadaver epidermi~. The skin~multilaminate compo~ite was mounted on a glas~ diffusion cell (effective flux area 0.71 cm2) with the skin side facing the receptor compartment. A measured ~olume of receiver solution (0.9% NaCl and 0.01~ Gentamicin in deionized water) was placed in the receptor compartment. The donor was 37 ~1 of a 10% nitroglycerin solution in propylene glycol ~SDM
27 from ICI Americas). The nitroglycerin ~olution was placed in the donor compartment directly in contact with the nonwo~en. The donor compartment was then occluded, and the cell mai~tained at 32C. Samples of the receiving solution were taken periodically and analyzed by HP~C to determine the amount of nitroglycerin ~ W093/0~92 2 1 1 ~ 5 7 0 PCT/US92/~39 permeated per unit time. The experiment was repeated exactly, substituting a commercially available nitroglycerin transdermal device, Nitro-Dur, for the multilaminate layer and nitroglycerin vehicle.
As shown in Fig. 2, Nitro-Dur reached substantial flux in 2-4 hr after administration, whereas the composite of the in~entions delayed full onset to 8 hr after administration.
~O While the invention has been exemplified in terms of an embodiment for administering NTG, it may also be used to administer other drugs in a delayed onset regimen. Drug~ which may be advantageously administered in such a regimen include other vasodilators, analgesics, contraceptives, appetite suppressants, growth factors, and the like. Other modifications of the above-described modes for carrying out the invention that are obvious to those of skill in the fields of transdermal drug delivery de~ice design, materials science, polymer chemistry and related fields are intended to be within the ~cope of the following cla~ms.
, , . . .
.
~ 35
Claims (17)
1. A device for administering a drug transdermally following application of the device to a subject's skin wherein the delivery of drug is delayed at least about six hours after said application comprising in combination:
(a) a nonrupturable backing layer forming the top surface of the device;
(b) a pressure rupturable reservoir underlying (a) and containing the drug dissolved in a liquid vehicle;
(c) an adsorbent wick layer underlying (b) for dispersing the drug once the reservoir is ruptured;
(d) a layer of a drug permeable polymer adhesive underlying (c);
(e) a first polymer membrane layer underlying (d) that is permeable to the drug, but substantially impermeable to the adhesive polymer of (d);
(f) a microporous membrane underlying (e);
(g) a second polymer membrane layer underlying (f) that is permeable to the drug;
(h) a layer of a drug permeable adhesive polymer underlying (g);
wherein the second polymer membrane layer is substantially impermeable to the adhesive polymer of (h) and wherein it initially takes at least about six hours for the drug to diffuse to the skin from the reservoir once the reservoir is ruptured and the device is applied to the skin.
(a) a nonrupturable backing layer forming the top surface of the device;
(b) a pressure rupturable reservoir underlying (a) and containing the drug dissolved in a liquid vehicle;
(c) an adsorbent wick layer underlying (b) for dispersing the drug once the reservoir is ruptured;
(d) a layer of a drug permeable polymer adhesive underlying (c);
(e) a first polymer membrane layer underlying (d) that is permeable to the drug, but substantially impermeable to the adhesive polymer of (d);
(f) a microporous membrane underlying (e);
(g) a second polymer membrane layer underlying (f) that is permeable to the drug;
(h) a layer of a drug permeable adhesive polymer underlying (g);
wherein the second polymer membrane layer is substantially impermeable to the adhesive polymer of (h) and wherein it initially takes at least about six hours for the drug to diffuse to the skin from the reservoir once the reservoir is ruptured and the device is applied to the skin.
2. The device of claim 1 wherein the reservoir is defined by a cavity formed between the backing layer and a pressure rupturable layer overlying the wick layer.
3. The device of claim 2 including means for transmitting manually applied pressure to the pressure rupturable layer.
4. The device of claim 3 wherein the means is an incompressible body underlying the pressure rupturable layer.
5. The device of claim 4 wherein the pressure rupturable layer is a metal foil layer.
6. A delayed onset device for administering nitroglycerin transdermally to a subject's skin comprising in combination:
(a) a nonrupturable backing layer forming the top surface of the device;
(b) a pressure rupturable reservoir underlying (a) and containing nitroglycerin dissolved in propylene glycol;
(c) an adsorbent wick layer underlying (b) for dispersing the nitroglycerin once the reservoir is ruptured;
(d) a first layer of a nitroglycerin permeable adhesive polymer underlying (c);
(e) a first polymer membrane layer underlying (d) that is permeable to nitroglycerin, but substantially impermeable to the adhesive polymer of (d);
(f) a microporous membrane underlying (e) that is not plasticized, dissolved, or degraded by the contents of the reservoir;
(g) a second polymer membrane layer underlying (f) that is permeable to nitroglycerin;
(h) a second layer of a nitroglycerin permeable adhesive polymer underlying (g);
wherein the second polymer membrane layer is substantially impermeable to the adhesive polymer of (h) and wherein it initially takes at least about six hours for the nitroglycerin to diffuse to the skin from the reservoir once the reservoir is ruptured and the device is applied to the skin.
(a) a nonrupturable backing layer forming the top surface of the device;
(b) a pressure rupturable reservoir underlying (a) and containing nitroglycerin dissolved in propylene glycol;
(c) an adsorbent wick layer underlying (b) for dispersing the nitroglycerin once the reservoir is ruptured;
(d) a first layer of a nitroglycerin permeable adhesive polymer underlying (c);
(e) a first polymer membrane layer underlying (d) that is permeable to nitroglycerin, but substantially impermeable to the adhesive polymer of (d);
(f) a microporous membrane underlying (e) that is not plasticized, dissolved, or degraded by the contents of the reservoir;
(g) a second polymer membrane layer underlying (f) that is permeable to nitroglycerin;
(h) a second layer of a nitroglycerin permeable adhesive polymer underlying (g);
wherein the second polymer membrane layer is substantially impermeable to the adhesive polymer of (h) and wherein it initially takes at least about six hours for the nitroglycerin to diffuse to the skin from the reservoir once the reservoir is ruptured and the device is applied to the skin.
7. The device of claim 6 wherein the diffusion coefficient of nitroglycerin in the adhesive polymers of (d) and (h) are 1 x 10-7 cm/sec to 1 x 10-8 cm/sec.
8. The device of claim 7 wherein the adhesive polymer is an acrylic polymer.
9. The device of claim 6 wherein the skin flux during said at least about six hours is less than 2 µg/cm2/hr and thereafter rises to about 5 to 20 µg/cm2/hr.
10. The device of claim 6 wherein the reservoir is defined by a cavity formed between the backing layer and a pressure rupturable layer overlying the wick layer.
11. The device of claim 10 including means for transmitting manually applied pressure to the pressure rupturable layer.
12. The device of claim 11 wherein the means is an incompressible body underlying the pressure rupturable layer.
13. The device of claim 8 wherein the skin flux during said at least about six hours is less than 2 µg/cm2/hr and thereafter rises to about 5 to 20 µg/cm2/hr
14. The device of claim 1 wherein the drug is a vasodilator, analgesic, contraceptive, appetite depressant, or growth factor; the pressure rupturable reservoir is comprised of a metal foil coated with a layer of a heat-sealable polymer; the wick layer is nonwoven, the material forming the first and second polymer membrane layers is ethylene-vinyl acetate copolymer, low density polyethylene, ethylene-propylene diene, polyester copolymer, or polyether amide copolymer;
and the material forming the microporous membrane is polypropylene, polyethylene, or polytetrafluoroethylene.
and the material forming the microporous membrane is polypropylene, polyethylene, or polytetrafluoroethylene.
15. The device of claim 14 wherein the metal foil is aluminum foil and the heat-sealable polymer is ethylene vinylacetate copolymer, polyethylene, or polypropylene.
16. The device of claim 6 wherein the pressure rupturable reservoir is comprised of a metal foil coated with a layer of a heat-sealable polymer; the wick layer is nonwoven; the material forming the first and second polymer membrane layers is ethylene-vinyl acetate copolymer, low density polyethylene, ethylene-propylene diene, polyester copolymer, or polyether amide copolymer;
and the material forming the microporous membrane is polypropylene, polyethylene, or polytetrafluoroethylene.
and the material forming the microporous membrane is polypropylene, polyethylene, or polytetrafluoroethylene.
17. The device of claim 14 wherein the metal foil is aluminum foil and the heat-sealable polymer is ethylene vinylacetate copolymer, polyethylene, or polypropylene.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/748,935 US5273756A (en) | 1991-08-23 | 1991-08-23 | Transdermal drug delivery device using a membrane-protected microporous membrane to achieve delayed onset |
| US07/748,935 | 1991-08-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2115570A1 true CA2115570A1 (en) | 1993-03-04 |
Family
ID=25011540
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002115570A Abandoned CA2115570A1 (en) | 1991-08-23 | 1992-08-14 | Transdermal drug delivery device using a membrane-protected microporous membrane to achieve delayed onset |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5273756A (en) |
| EP (1) | EP0600023A4 (en) |
| JP (1) | JPH06510043A (en) |
| AU (1) | AU670410B2 (en) |
| CA (1) | CA2115570A1 (en) |
| FI (1) | FI940850A (en) |
| NO (1) | NO940589L (en) |
| NZ (1) | NZ244000A (en) |
| PT (1) | PT100807A (en) |
| WO (1) | WO1993003692A1 (en) |
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-
1991
- 1991-08-23 US US07/748,935 patent/US5273756A/en not_active Expired - Lifetime
-
1992
- 1992-08-14 CA CA002115570A patent/CA2115570A1/en not_active Abandoned
- 1992-08-14 JP JP5504461A patent/JPH06510043A/en active Pending
- 1992-08-14 WO PCT/US1992/006839 patent/WO1993003692A1/en not_active Application Discontinuation
- 1992-08-14 AU AU25037/92A patent/AU670410B2/en not_active Ceased
- 1992-08-14 EP EP92919052A patent/EP0600023A4/en not_active Withdrawn
- 1992-08-18 NZ NZ244000A patent/NZ244000A/en unknown
- 1992-08-24 PT PT100807A patent/PT100807A/en not_active Application Discontinuation
-
1994
- 1994-02-21 NO NO940589A patent/NO940589L/en unknown
- 1994-02-23 FI FI940850A patent/FI940850A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO940589D0 (en) | 1994-02-21 |
| AU670410B2 (en) | 1996-07-18 |
| EP0600023A1 (en) | 1994-06-08 |
| PT100807A (en) | 1994-05-31 |
| FI940850A (en) | 1994-03-09 |
| AU2503792A (en) | 1993-03-16 |
| WO1993003692A1 (en) | 1993-03-04 |
| JPH06510043A (en) | 1994-11-10 |
| EP0600023A4 (en) | 1995-06-14 |
| NO940589L (en) | 1994-04-13 |
| US5273756A (en) | 1993-12-28 |
| FI940850A0 (en) | 1994-02-23 |
| NZ244000A (en) | 1995-04-27 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Dead |