CA2315890C - Rate controlling membranes for controlled drug delivery devices - Google Patents

Rate controlling membranes for controlled drug delivery devices Download PDF

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Publication number
CA2315890C
CA2315890C CA002315890A CA2315890A CA2315890C CA 2315890 C CA2315890 C CA 2315890C CA 002315890 A CA002315890 A CA 002315890A CA 2315890 A CA2315890 A CA 2315890A CA 2315890 C CA2315890 C CA 2315890C
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Prior art keywords
membrane
rate controlling
drug
reservoir
hours
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CA002315890A
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French (fr)
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CA2315890A1 (en
Inventor
Lothar W. Kleiner
Robert Martin Gale
Randall G. Berggren
Gilbert T. Tong
Guohua Chen
Keith E. Dionne
Paul R. Houston
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Intarcia Therapeutics Inc
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Intarcia Therapeutics Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal 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
    • A61K9/7084Transdermal 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system

Abstract

This invention provides rate controlling membranes for controlled drug delivery devices that are stable over time and exhibit more predictable and consistent membrane functionality. According to another aspect, the membranes have enhanced permeability. According to the invention, the rate controlling membrane of a controlled drug delivery device is subjected to a pre-treatment annealing process wherein it is subjected to an elevated temperature for a predetermined time period and subsequently cooled to ambient conditions before incorporation into a controlled drug delivery device.

Description

6 This invention relates to the field of drug delivery devices which 7 incorporate a rate controlling membrane in order to control the rate of release 8 of a drug from the device to a patient. More particularly, the invention is 9 directed to rate controlling membranes for drug delivery devices characterized by being subjected to an annealing process in accordance with the present 11 invention. The rate controlling membranes of this invention exhibit improved 12 membrane functionality particularly with respect to storage time.

16 The use of rate controlling membranes to control delivery of a drug 17 from a drug delivery device is well known. For exampie, transdermal drug 18 delivery devices including rate controlling membranes are disclosed in U.S.
19 Patent Nos. 3,797,494, 4,031,894, 4,201,211, 4,379,454, 4,436,741, 4,588,580, 4,615,699, 4,661,105, 4,681,584, 4,698,062, 4,725,272, 21 4,832,953, 4,908,027, 5,004,610, 5,310,559, 5,342,623, 5,344,656, and 22 5,364,630. As 23 disclosed in these patents, various materials, including ethylene vinyl acetate 24 copolymers and polyethylene, may be used to form rate controlling membranes useful for transdermal drug delivery systems. Additional 26 materials useful for forming rate controlling membranes for transdermal drug 27 delivery devices are disclosed in K.P.R. Chowdary et al. "Preparation and 28 Evaluation of Cellulose Acetate Films as Rate Controlling Membranes for 29 Transdermal Use" Indian Drugs 29 (7).

1 For a selected membrane material, after conversion of the polymer 2 pellet to the membrane, the necessary rate control for a transdermal drug 3 delivery,device is provided by varying the composition, pore size, or thickness 4 of the rate controlling membrane, adjusting the viscosity of the drug formulation to be administered by appropriate formulation, or impregnating 6 the pores of the membranes with a diffusive medium as disclosed in US
7 Patent No. 3,797,494 listed above. The rate controliing membrane is then 8 incorporated into a transdermal drug delivery device without any other 9 additional treatment thereof.
Diffusional and osmotically driven fluid-imbibing dosage forms 11 incorporating rate controlling membranes are also known in the art. For 12 example, U.S. Patent Nos. 3,845,770 and 3,916,899, 13 disclose a device comprising a wall that surrounds a compartment 14 containing a drug for delivery to a patient. The wall of the device is permeable to the passage of fluid. Drug is released from the device by fluid 16 being imbibed through the wall into the device at a rate determined by the 17 permeability of the wall and the osmotic pressure gradient across the wall.
18 Other diffusional and osmotic fluid-imbibing dosage forms are disclosed in 19 U.S. Patent Nos. 3,987,790, 4,111,202, 4,111,203, 4,203,439, 4,327,725, 4,612,008, 4,865,845, 5,034,229, 5,057,318, 5,059,423, 5,110,596, 21 5,112,614, 5,137,727, 5,234,692, and 5,234,693.

23 Additionally, US Patent Nos. 4,931,295, 5,024,842, and 5,160,743 24. disclose a dosage form comprising a coat surrounding a drug. The coat comprises a water soluble overcoat polymer and a subcoat. The overcoat 26 and the subcoat are annealed to provide a continuous, insoluble membrane 27 or film that surrounds the drug and which dissolves in an aqueous 28 environment of use.

29 One problem associated with prior art rate controlling membranes formed from thermoplastic polymers is that they often encounter 1 morphological changes after processing over long periods of time due to 2 phase separation of domain structures. These morphological changes can 3 alter the membrane functionality. For example, the water permeation or water 4 uptake rate through the membrane of fluid-imbibing devices may vary over time, leading to inconsistent performance of the device.
6 Another problem associated with prior art rate non-annealed rate 7 controlling membranes used in controlled drug delivery devices is that the 8 permeability of the membrane may vary over the storage period, particularly 9 when such devices are exposed to elevated temperatures. If this occurs, the system would not have a drug release rate which is stable as a function of 11 storage time. This is particularly undesirable where, for example, the 12 permeability of the rate controlling membrane to the drug is increased beyond 13 a preferred range due to exposure of the system to elevated temperatures.
14 Variations in the rate of administration of drugs can effect efficacy and cause undesirable side effects. As can be appreciated by one of ordinary skill 16 in the art, variations in the functionality of rate controlling membranes of drug 17 delivery devices over storage may arise in any device which incorporates a 18 rate controlling membrane and can pose a significant problem.

BRIEF DESCRIPTION OF TERMS

22 As used herein, the term "drug" is to be construed in its broadest sense 23 to mean any material which is intended to produce some biological, 24 beneficial, therapeutic, or other intended effect, such as permeation enhancement, for example, on the organism to which it is applied.
26 As used herein, the term "individual" intends a living mammal and 27 includes, without limitation, humans and other primates, livestock and sports 28 animals such as cattle, pigs and horses, and pets such as cats and dogs.
29 As used herein, the term "membrane functionality" refers to properties of the membrane which affect the desired degree of rate control of the drug 1 delivery device in which the membrane is used and includes for example, 2 drug permeability, water permeability, and/or water uptake.
3 As used herein, the term "transdermal" intends both percutaneous and 4 transmucosal administration, i.e., passage of drug through skin or mucosal tissue into the systemic circulation.

9 According to this invention, rate controlling membranes intended for use in controlled drug delivery devices are pretreated by an annealing 11 process prior to or subsequent to incorporation of the membrane into the drug 12 delivery device. The annealing process of this invention provides rate 13 controlling membranes which exhibit consistent membrane functionality over 14 time. In one embodiment, the annealed rate controlling membranes of this invention comprise enhanced permeability compared to non-annealed 16 membranes that is more predictable with respect to thermal transients, 17 particularly throughout storage over time. According to another embodiment, 18 rate controlling membranes subjected to the annealing process of this 19 invention maintain a permeability within a preferred range even after being subjected to elevated temperatures.
21 Accordingly, it is an aspect of this invention to provide rate controlling 22 membranes for use in controlled drug delivery devices that overcome the 23 disadvantages associated with those of the prior art.
24 Another aspect of the invention is to provide rate controlling membranes which exhibit consistent membrane functionality over time.
26 Another aspect of this invention is to provide rate controlling 27 membranes for transdermal drug delivery systems that have more predictable 28 drug permeabilities with respect to thermal transients.

1 Another aspect of this invention is to provide rate controlling 2 membranes for transdermal drug delivery devices that have drug 3 permeabilities that are stable as a function of storage time.
4 Another aspect of this invention to provide rate controlling membranes 5 for transdermal drug delivery devices that provide enhanced drug 6 permeability.

7 Yet another aspect of this invention is to provide rate controlling 8 membranes for fluid-imbibing drug delivery devices which exhibit consistent 9 water permeability and water uptake over a storage period.
Therefore, the invention comprises the following aspects, either alone 11 or in combination:
12 A rate controlling membrane for a controlled drug delivery device 13 characterized by being subjected to an elevated temperate of about 30 C to 14 about 5 C below the melting temperature of the membrane polymer for a predetermined period of about 1- 250 hours and subsequently incorporated 16 into the delivery device.
17 The membrane material may be selected from the group consisting of 18 ethylene vinyl acetate copolymers, polyethylene, copolymers of ethylene, 19 polyolefins including ethylene oxide copolymers such as Engage@ (DuPont Dow Elastomers), polyamides, cellulosic materials, polyurethanes, polyether 21 blocked amides copolymers such as PEBAX (Elf Atochem North America, 22 Inc.), and polyvinyl acetate.
23 The device may be a transdermal drug delivery device comprising a 24 drug reservoir layer between a backing layer and a contact adhesive layer, wherein rate controlling membrane is on the skin-proximal side of the drug 26 reservoir layer. The drug reservoir may also contain one or more permeation 27 enhancers and/or other excipients.
28 The device may be a transdermal drug delivery device comprising a 29 backing layer, a permeation enhancer reservoir containing a permeation enhancer on the skin proximal side of the backing layer, a drug reservoir layer 1 containing at least one drug to be transdermally administered on the skin 2 proximal side of the permeation enhancer reservoir, and a means for 3 maintaining said drug device in drug transmitting relation with the skin, 4 wherein the rate controlling membrane is positioned between the permeation enhancer reservoir and the drug reservoir.
6 Alternatively, the membrane may be positioned in sealing relationship 7 with an internal surface of one end of an impermeable reservoir of a fluid-8 imbibing drug delivery device, wherein the fluid imbibing drug delivery device 9 comprises an impermeable reservoir containing a piston that divides the reservoir into a drug containing chamber and a water-swellable agent 11 containing chamber, wherein the water-swellable agent containing chamber is 12 provided with an outlet which accommodates the membrane. The agent 13 containg layer may comprise leuprolide.
14 The membrane may be cooled to ambient conditions before being incorporated into the delivery device.
16 Additionally, the invention is directed to a method for processing rate 17 controlling membranes used in controlled drug delivery devices comprising:
18 a) exposing the membrane to a predetermined temperature of 19 from about 30 C to about 5 C below the melting temperature of the membrane polymer;
21 b) maintaining the membrane at the predetermined temperature 22 for a period of time of from about 1 to 250 hours; and 23 c) incorporating said membrane into a controlled drug delivery 24 device.
These and other aspects, features, and advantages of this invention 26 will be more apparent from the following detailed description and drawings.

6a In accordance with an aspect of the present invention there is provided a rate controlling membrane, comprising a polymer, for a controlled drug delivery device characterized by being subjected to an elevated temperature of 30 C to 5 C
below the melting temperature of the membrane polymer for a predetermined period of 1 -hours and subsequently incorporated into the delivery device.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the membrane comprises a polymer selected from the group consisting of ethylene vinyl acetate copolymers, polyethylene, ethylene copolymers, ethylene oxide copolymers, polyamides, cellulosic materials, polyurethanes, polyether blocked amides copolymers, and polyvinyl acetate.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the membrane comprises ethylene vinyl acetate copolymer.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention the ethylene vinyl acetate copolymer comprises a vinyl acetate content of 4-18%.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the membrane is characterized by a DSC profile having a primary peak at 94-99 C and a secondary peak at greater than 50 C.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the ethylene vinyl acetate copolymer comprises a vinyl acetate content of 5-12%.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the device is a transdermal drug delivery device comprising a drug reservoir layer between a backing layer and a contact adhesive layer, the rate controlling membrane is on a skin-proximal side of the drug reservoir layer.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the device is a transdermal drug delivery device comprising a backing layer, a permeation enhancer reservoir containing a permeation enhancer on a skin proximal side of the backing layer, a drug reservoir layer containing at least one drug to be transdermally administered on the skin proximal side of the permeation enhancer reservoir, and a means for maintaining the drug device 6b in drug transmitting relation with skin, wherein the rate controlling membrane is positioned between the permeation enhancer reservoir and the drug reservoir.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the drug reservoir comprises a drug selected from the group consisting of testosterone, estradiol, and fentanyl.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the membrane is positioned in sealing relationship with an internal surface of one end of an impermeable reservoir of a fluid-imbibing drug delivery device, wherein the fluid-imbibing drug delivery device comprises the impermeable reservoir, a piston that divides the reservoir into a drug containing chamber and a water-swellable agent containing chamber, wherein the water-swellable agent containing chamber is adjacent the membrane.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the drug containing chamber comprises leuprolide.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the membrane comprises a polymer selected from the group consisting of polyurethanes or polyether blocked amides copolymers.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the elevated temperature is 45-80 C and the predetermined period is 1-75 hours.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the elevated temperature is 52-72 C and the predetermined time is 2-36 hours.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the elevated temperature is 55-75 C and the predetermined time is 12-48 hours.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention wherein the membrane is cooled to ambient conditions before being incorporated into the deliver device.
In accordance with an aspect of the present invention there is provided a method for processing rate controlling membranes used in controlled drug delivery devices comprising: exposing the membrane to a predetermined temperature from 30 C to 6c below the melting temperature of the membrane polymer; maintaining the membrane at the predetermined temperature for a period of time of from 1-250 hours; and incorporating the membrane into a controlled drug delivery device.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the predetermined temperature is from 45 C to 80 C.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane is maintained at the predetermined temperature for a period of time of from 1 to 75 hours.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane is cooled to ambient conditions over a period of time of 0.1-150 hours prior to incorporating the membrane into the device.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane is incorporated into a transdermal drug delivery device and comprises an increased drug permeability compared to a non-annealed membrane comprising the same polymer.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane comprises a polymer selected from the group consisting of ethylene vinyl acetate copolymers, polyethylene, ethylene copolymers, ethylene oxide copolymers, polyamides, cellulosic materials, polyurethanes, polyether blocked amides copolymers, and polyvinyl acetate.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane comprises ethylene vinyl acetate copolymer, a high density polyethylene, or polyurethane.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane comprises ethylene vinyl acetate copolymer comprising a vinyl acetate content of 4-18%.

6d In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane comprises ethylene vinyl acetate copolymer comprising a vinyl acetate content of 5-12%.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the predetermined temperature is 52-72 C and the period of time is 2-36 hours.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the predetermined temperature is 55-75 C and the period of time is 12-48 hours.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane is allowed to set at ambient conditions for a period of at least 12 hours after processing prior to exposing the membrane to the predetermined temperature.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane is allowed to set at ambient conditions for a period of at least 48 hours after processing prior to exposing the membrane to the predetermined temperature.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane is positioned in sealing relationship with an internal surface of one end of an impermeable reservoir of a fluid-imbibing drug deliver device, wherein the fluid imbibing drug delivery device comprises the impermeable reservoir, a piston that divides the reservoir into an active agent containing chamber and a water-swellable agent containing chamber, wherein the water-swellable agent containing chamber is adjacent the membrane.
In accordance with an aspect of the present invention there is provided a rate controlling membrane of the present invention a method of the present invention wherein the membrane is plug-shaped.

4 FIG. 1 is a cross-sectional view of one embodiment of a transdermal therapeutic drug delivery device which may be used in accordance with the 6 present invention.
7 FIG. 2 is a cross-sectional view of another embodiment of a 8 transdermal therapeutic drug delivery device which may be used in 9 accordance with the present invention.
FIG. 3 is a cross-sectional view of yet another embodiment of a 11 transdermal therapeutic drug delivery device which may be used in 12 accordance with this invention.
13 FIG. 4 is a cross-sectional view of one embodiment of a fluid-imbibing 14 drug delivery device which may be used in accordance with the present invention.
16 FIG. 5 is a DSC profile for a non-annealed ethylene vinyl acetate film 17 comprising 9% vinyl acetate wherein the DSC profiie is examined at a 18 temperature range of -50 - 150 C heated at a rate of 10 C/min.
19 FIG. 6 is a DSC profile for an annealed ethylene vinyl acetate film comprising 9% vinyl acetate wherein the DSC profile is examined at a 21 temperature range of -50 -150 C heated at a rate of 100 C/min.
22 FIG. 7 is a plot of the in vitro skin flux of fentanyl from systems 23 according to this invention with annealed and non-annealed rate controlling 24 membranes.
FIG. 8 is a plot of the in vitro skin flux of ethanol from systems 26 according to this invention with annealed and non-annealed rate controlling 27 membranes.
28 FIG. 9 is a plot of the in vitro skin flux of fentanyl vs. the annealing 29 temperature.

1 FIG. 10 is a plot depicting water uptake of annealed and non-annealed 2 polyurethane membranes.

3 FIG. 11 is a plot depicting water uptake vs. annealing time of 4 polyurethane plug membranes.
FIG. 12 is a plot depicting system weight gain vs. time for systems 6 comprising annealed and non-annealed membranes.
7 FIG. 13 is a plot depicting average system release rate vs. time from 8 systems comprising annealed and non-annealed membranes.
9 FIGS. 14 and 15 are plots depicting water uptake vs. annealing temperature for various polyurethane membranes at dry or 1% moisture 11 conditions in the annealing oven.
12 FIG. 16 is a plot depicting the effect of annealing temperature and 13 moisture content on the melt temperature of the hard segment of 14 polyurethane.

18 According to this invention, rate controlling membranes for controlled 19 drug delivery systems are subjected to an annealing process which comprises subjecting the rate controlling membranes to an annealing 21 temperature (Te) for a specified time after conversion of the polymer pellet to 22 the membrane or during the conversion process itself. The membranes are 23 maintained at the annealing temperature for a predetermined period of time, 24 and subsequently cooled to ambient conditions over a time period ranging from 0.1 to 150 hours, preferably 0.1 - 48 hours. The membranes are then 26 incorporated into a controlled drug delivery system.
27 Proper annealing conditions are selected in accordance with the 28 particular polymer membrane based upon its thermal properties including its 29 glass transition temperature, T9, and melting point, Tnõ molecular weight, molecular weight distribution, and crystallization kinetics. A wide range of 1 annealing conditions can be selected. The annealing temperature T. is above 2 T. and below Tn, of the membrane material. The most rapid annealing 3 process occurs at a T. halfway between T. and T,õ. The largest crystal 4 formation is observed at a T. just below Tm. The preferred annealing temperature according to this invention is within the range of above about 300 6 C and at least 50 C below Tm of the polymer membrane material, more 7 preferably about 45 C to 80 C. The membrane is preferably maintained at 8 the annealing temperature for a period of time of about 1 to 250 hours, more 9 preferably about 1 to 75 hours. According to a preferred embodiment, it is preferable to allow the membrane to set at room temperature for relaxation for 11 a predetermined period prior to the annealing step.
12 A preferred embodiment is directed to rate controlling membranes that 13 are more predictable with respect to thermal transients. According to this 14 embodiment, the permeability of rate controlling membranes subjected to the annealing process of this invention is maintained below a predetermined 16 maximum level after exposure of the system to thermal transients. Membrane 17 annealing according to this embodiment provides predetermined delivery 18 rates for predetermined administration intervals within an overall 19 administration period.
A particularly preferred embodiment according to this aspect of the 21 invention is directed to rate controlling membranes comprising an ethylene 22 vinyl acetate (EVA) copolymer. The desired membrane permeability is 23 achieved by proper selection of the vinyl acetate (VA) content of the 24 copolymer in addition to selection of the proper annealing conditions. In general, the membrane permeability decreases as the VA content of an EVA
26 membrane decreases. Preferred annealing conditions according to this 27 embodiment comprise an annealing temperature of about 45 - 750 C, most 28 preferably about 52 C - 72 C, for a period of about 1 hour - 72 hours, most 29 preferably 2-36 hours, and a VA content of 4- 18%, most preferably 5- 12%.

1 Differential scanning calorimetry (DSC) analysis may be used to 2 determine the extent of membrane annealing and may be performed by 3 procedures well known in the art. According to the preferred embodiments 4 comprising an EVA copolymer rate controlling membrane, significant changes 5 in the DSC profile are noted at annealing temperatures greater than about 6 60 C. At these temperatures, as seen in Figs. 5 and 6, the primary peak (Tm) 7 is observed at about 98 C and remains substantially consistent at various 8 annealing temperatures. However, the secondary peak, observed to appear 9 at about 51 C for a non-annealed EVA membranes (9% vinyl acetate) (FIG.
10 5), appears at a higher temperature upon annealing at temperatures of about 11 400 C and greater (second peak at 71 C for an EVA (9% vinyl acetate) 12 membrane annealed at 60 C for 2 hours as seen in Fig. 6). Preferred 13 embodiments for EVA copolymer rate controlling membranes are directed to 14 rate controlling membranes exhibiting DSC profiles having the secondary peak at a temperature within the range of about 51 - 80 C, most preferably 16 56.- 75 C. Additionally, a third, less significant peak is observed for 17 annealed EVA, preferably within the range of about 32 - 40 C.
18 According to the preferred embodiments comprising polyurethane 19 membranes, DSC analysis showed that an increase in annealing temperature caused a slight increase in the melting temperature. Similarly, a slight 21 increase in moisture content from 0 to 1% caused a slight increase in melting 22 temperature. It is preferred according to this embodiment to anneal at dry 23 conditions.
24 Rate controlling membranes subjected to the annealing process of this invention overcome the disadvantages of those of the prior art. According to 26 one embodiment, membrane annealing according to this invention 27 surprisingly results in rate controlling membranes having enhanced 28 permeabilities to drugs compared to membranes not treated in accordance 29 with this invention. This is contrary to expectations of lower drug permeabilities due to the higher density of the annealed rate controlling 1 membrane. For example, the density and crystallinity of a polymer are 2 among the factors influencing the polymer's permeability coefficient. In 3 general, the higher the density and crystallinity, the lower the permeability 4 coefficient and the resulting membrane permeability. See "Permeability and Diffusion Data" Polymer Handbook, 3rd Edition, J. Bradley & E.H. Immergut, 6 J. Wiley, 1989, p. 435. While not being limited to any particular theory, the 7 inventor's believe that, according to this embodiment, the annealing process 8 of this invention enhances significantly the mobility of the amorphous phase 9 interconnecting the crystalline regions of the annealed membranes, thus leading to the enhanced permeability observed from the annealed 11 membranes.
12 A preferred embodiment of the present invention is directed to rate 13 controlling membranes used in transdermal drug delivery devices as shown in 14 FIG. 1. In FIG. 1, a transdermal therapeutic system 1 according to this invention comprises a pouch formed from an impermeable backing 2, rate 16 controlling membrane 3, and a contact adhesive layer 4, covered by a 17 removable protective release liner 5. The impermeable backing is configured 18 to provide a central volume which contains a drug reservoir 6 in the form of a 19 gel having dissolved and suspended drug therein. Means other than the in-line contact adhesive layer 4 may be used for maintaining the system on the 21 skin such as a peripheral ring of adhesive outside the path of drug flow from 22 the system to the skin. Adhesive overlays or other fastening means such as 23 belts and elastic arm bands are also contemplated.
24 Referring now to FIG. 2, a multilaminate type of transdermal therapeutic system according to this invention is shown. Device 10 26 comprises a drug reservoir 12 preferably in the form of a matrix containing 27 both the drug and a permeation enhancer, if used, dispersed therein.
28 Reservoir 12 is sandwiched between a backing layer 14, which is preferably 29 impermeable to both the drug and the permeation enhancer mixture, and rate controlling membrane 16. In FIG. 2, the drug reservoir 12 is formed of a 1 material, preferably a polymeric material, that is sufficiently viscous to 2 maintain its shape. The device 10 adheres to the surface of the skin 17 by 3 means of the contact adhesive layer 18. With certain formulations, an 4 adhesive overlay or other fastening means may be preferable to the in-line contact adhesive. The adhesive for layer 18 should be chosen so that it is 6 compatible with system components and the skin and does not interact with 7 the drug or other system component in any way to alter functionality. The 8 adhesive layer 18 may optionally contain enhancer and/or drug. A removable 9 liner (not shown) is normally provided along the exposed surface of adhesive layer 18 and is removed prior toapplication of device 10 to the skin 17.
11 Figure 3 illustrates another embodiment of the invention, device 20, 12 shown in placement on the skin 27. In this embodiment, the transdermal drug 13 delivery device 20 comprises multi-laminate drug formulation/enhancer 14 reservoir 21 having at least two zones 22 and 24. Zone 22 consists of a drug reservoir substantially as described with respect to FIG. 2. Zone 24 16 comprises a permeation enhancer reservoir which is preferably made from 17 substantially the same matrix as is used in zone 22. Zone 24 comprises a 18 permeation enhancer dispersed throughout and is free of any drug in excess 19 of saturation. Rate-controlling membrane 23 for controlling the release rate of the permeation enhancer from zone 24 to zone 22 is placed between the two 21 zones. A rate-controlling membrane (not shown) for controlling the release 22 rate of the enhancer and/or drug from zone 22 to the skin may also optionally 23 be utilized and would be present between the skin 27 and zone 22:
24 Superimposed over the drug formulation/enhancer reservoir 21 of device 20 is an impermeable backing 25 and an adhesive overlay 26. Backing layer 25 26 is preferably impermeable to the drug and permeation enhancer and is 27 preferably slightly larger than zone 24 in order to prevent the materials in 28 zone 24 from adversely interacting with the adhesive in overlay 26. Other 29 fastening means may be utilized such as an in-line contact adhesive as described above. In addition, a removable liner (not shown) would preferably 1 be provided on the device prior to use and removed prior to application of the 2 device 20 to the skin 27_ 3 The rate controlling membranes may be fabricated from permeable, 4 semi-permeable, or microporous materiais which are known in the art to control the rate of drugs into and out of delivery devices or are disclosed in 6 the aforementioned patents.
7 Suitable materials include, but are not limited to, polyolefins including 8 polyethylene, polyvinyl acetate and ethylene vinyl acetate copolymers. High 9 density polyethylene and ethylene vinyf acetate copolymers represent preferred rate controlling membrane materials according to the present 11 invention.
12 Various materials suited for the fabrication of the various layers of the 13 transdermal devices of FIGS. 1-3 are known in the art or are disclosed in the 14 aforementioned patents For example, the matrix making up the drug reservoir I permeation enhancer 16 reservoir of Figures 1-3 can be a gel or polymer and may comprise an 17 aqueous or non-aqueous composition. For example, suitable matrix materials 18 include, without (imitation, natural and synthetic rubbers or other polymeric 19 material, thickened mineral oil, silicone fluids, polysiloxanes, polyacrylates, ethylene vinyl acetate copolymers, or petroleum jelly.
21 In addition to any drug and permeation enhancer, the matrix, if needed, 22 may also contain stabilizers, dyes, pigments, inert fillers, tackifiers, excipients 23 and other conventional components of transdermal delivery devices as are 24 known in the art. The transdermal therapeutic devices of the present invention are prepared in a manner known in the art, such as by those procedures, for 26 example, described in the patents listed previously herein.
27 Another preferred embodiment, depicted in Fig. 4, is directed to 28 providing membranes for use in diffusional or osmotically driven drug delivery 29 devices such as fluid-imbibing devices described in the patents listed above and in U.S. Patent No. 5,217,227.

1 These devices can be implanted into an individual 2 to release the drug in a controlled manner for a predetermined administration 3 period. In general, these devices work by imbibing fluid from .the outside 4 environment and releasing corresponding amounts of the drug. The volumetric delivery rate of these systems is determined by the design, 6 dimensions, and material properties of the rate controlling membrane and is 7 tightly correlated to the water uptake of the membrane materials. The higher 8 the water uptake of the membrane materials, the higher the water permeation 9 rate through the membrane.
For some membrane materials, for example high water uptake 11 hydrophilic polyurethane, the amorphous domain of the soft segments plays 12 an important role in controlling water uptake, hence water permeation rate, of 13 the membrane. It is expected that after processing, material membrane 14 functionality such as water uptake and water permeation rate may change over time as phase separation occurs. Membrane annealing according to this 16 invention accelerates morphological changes and stabilizes membrane 17 performance, thus providing consistent and predictable membrane 18 functionality. With semi-crystalline materials such as polyurethane, annealing 19 also accelerates the phase separation of hard and soft segments such that crystalline (hard) segments come together to form micro-crystalline regions 21 distributed within the continuous amorphous (soft) non-crystalline region.
22 Membranes annealed according to this embodiment exhibit water uptake and 23 water permeability which are more stable than non-annealed membranes.
24 After annealing, the membrane is incorporated into a fluid-imbibing device as depicted in Figure 4. Fluid-imbibing device 30 comprises an 26 impermeable reservoir 32 divided into two chambers by a piston 34. The first 27 chamber 36 is adapted to contain a drug and the second chamber 38 is 28 adapted to contain a fluid-imbibing agent. Preferred fluid-imbibing agents are 29 NaCI with appropriate tableting agents such as povidone, magnesium stearate, sodium carboxy methyicellulose, water, and sodium polyacrylate.

1 Other suitable fluid imbibing agents are the osmagents and osmopolymers 2 described in, for example, U.S. Patent No. 5,413,572.
3 Membrane 40 is positioned in seaiing relationship with an 4 interior surface of one end of the impermeable reservoir. The membrane can 5 be a sheet-like layer or can be formed into any desired shape by well know 6 procedures such as injection molding, extrusion, and the like. A preferred 7 embodiment comprises a membrane plug as depicted in FIG 4. In the 8 embodiment depicted in Fig. 4, fluid-imbibing device 30 additionally 9 comprises flow path 42 formed between threaded back-diffusion regulating 10 outlet 44 and threads 46 on the interior surface of reservoir 32.
11 The membrane 40 controls the rate at which fluid is imbibed into the 12 device and is typically comprised of a polymeric material including, but not 13 limited to, plasticized cellulosic materials, enhanced polymethylmethacrylate 14 such as hydroxyethylmethacrylate (HEMA), and thermoplastic elastomeric 15 materials such as polyurethanes and polyamides, polyether-polyamide 16 copolymers, polyether blocked amides copolymers such as PEBAX@, 17 thermoplastic copolyesters, and the like. Thermoplastic elastomeric materials 18 are preferred as such materials span a wide range of water uptake and water 19 permeability values, are injection moldable and easily processed, swell upon hydration, and are available in durometers widely used for gaskets and seals.
21 Blended or non-blended polyurethanes are particularly preferred 22 membrane materials. Tecophilic , a high water uptake, medical grade, 23 aliphatic, polyether polyurethane, manufactured by Thermedics Inc., Woburn 24 MA, is a part icularly preferred membrane material.
Preferred membrane functionality according to this embodiment such 26 as water uptake and water permeability can be obtained by either blending 27 low and high water uptake materials or by direct synthesis of materials of 28 varying water uptake. For example, Tecophilic consists of aliphatic "hard 29 segments" and different proportions of polyethylene glycol (PEG) and polytetramethylene glycol (PTMG) "soft segments", which proportions of PEG

1 and PTMG can be varied during polymer synthesis to provide the desired 2 water uptake and water permeation. Generally, higher water uptake and 3 higher permeability materials comprise a higher proportion of PEG. Various 4 materials for the fabrication of the other components of the fluid-imbibing device of Fig. 4 are known in the art or are disclosed in the aforementioned 6 patents previously incorporated by reference.
7 Preferred annealing temperatures according to this embodiment are 8 about 50 C -100 C, preferably about 50 C - 80 C, and most preferably about 9 55 C - 75 C. The annealing time is about 1-250 hours, preferably about 4 -72 hours, and most preferably about 12 - 48 hours. Prior to annealing, the 11 membranes are stored at room temperature for relaxation, preferably for at 12 least 12 hours - 7 days, and more preferably for at least about 2 - 3 days after 13 processing. The combination of allowing time for membrane relaxation 14 followed by annealing result in the membrane achieving steady-state functionality at a much quicker rate. Membrane annealing according to this 16 embodiment also enhances the mechanical strength of the membrane.
17 It is believed that this invention has utility in connection with the 18 delivery of a wide variety of drugs. It is to be understood that more than one 19 drug may be delivered by the devices of this invention. For example, suitable drugs for administration by the devices of this invention are disclosed in the 21 aforementioned patents and patent applications previously incorporated by 22 reference. In general, practice of this invention includes devices to be used to 23 deliver therapeutic drugs in all of the major areas, including, but not limited to, 24 ACE inhibitors, adenohypophoseal hormones, adrenergic neuron blocking drugs, adrenocortical steroids, inhibitors of the biosynthesis of adrenocortical 26 steroids, alpha-adrenergic agonists, alpha-adrenergic antagonists, selective 27 alpha-two-adrenergic agonists, analgesics, antipyretics and anti-inflammatory 28 drugs, androgens, local and general anesthetics, antiaddictive drugs, 29 antiandrogens, antiarrhythmic drugs, antiasthmatic drugs, anticholinergic drugs, anticholinesterase drugs, anticoagulants, antidiabetic drugs, 1 antidiarrheal drugs, antidiuretic, antiemetic and prokinetic drugs, antiepileptic 2 drugs, antiestrogens, antifungal drugs, antihypertensive drugs, antimicrobial 3 drugs, antimigraine drugs, antimuscarinic drugs, antineoplastic drugs, 4 antiparasitic drugs, antiparkinson's drugs, antiplatelet drugs, antiprogestins, antithyroid drugs, antitussives, antiviral drugs, atypical antidepressants, 6 azaspirodecanediones, barbituates, benzodiazepines, benzothiadiazides, 7 beta-adrenergic agonists, beta-adrenergic antagonists, selective beta-one-8 adrenergic antagonists, selective beta-two-adrenergic agonists, bile salts, 9 drugs affecting volume and composition of body fluids, butyrophenones, drugs affecting calcification, calcium channel blockers, cardiovascular drugs, 11 catecholamines and sympathomimetic drugs, cholinergic agonists, 12 cholinesterase reactivators, dermatological drugs, diphenylbutylpiperidines, 13 diuretics, ergot alkaloids, estrogens, ganglionic blocking drugs, ganglionic 14 stimulating drugs, hydantoins, drugs for control of gastric acidity and treatment of peptic ulcers, hematopoietic drugs, histamines, histamine 16 antagonists, 5-hydroxytryptamine antagonists, drugs for the treatment of 17 hyperlipoproteinemia, hypnotics and sedatives, immunosupressive drugs, 18 laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular 19 blocking drugs, organic nitrates, opioid analgesics and antagonists, pancreatic enzymes, phenothiazines, LHRH and its analogues such as 21 leuprolide, progestins, prostaglandins, drugs for the treatment of psychiatric 22 disorders, retinoids, sodium channel blockers, drugs for spasticity and acute 23 muscle spasms, succinimides, thioxanthines, thrombolytic drugs, thyroid 24 drugs, tricyclic antidepressants, inhibitors of tubular transport of organic compounds, drugs affecting uterine motility, vasodilators, vitamins and the 26 like.
27 The following examples are offered to illustrate the practice of the 28 present invention and are not intended to limit the invention in any manner.

i3 3 Transdermal therapeutic systems comprising an aqueous ethanolic gel 4 were prepared according to the following procedure. Fentanyl base was added to a mixture of 95% ethanol and purified water. 2% of hydroxyethyl 6 cellulose gelling agent was added slowly to the solution with stirring and 7 mixed until a smooth gel was obtained (approximately 1 hour). A 0.05 mm 8 thick contact adhesive layer was formed on a release liner for the system by 9 solution casting an amine resistant silicone medical adhesive (XCF 2992, Dow Coming, Midland MI) onto the polyester film from a solution in heptane.
11 An annealed or non-annealed rate controlling membrane comprised of 12 EVA (9% VA) was pressure laminated to the exposed adhesive as set forth in 13 the system configuration shown in Table 1 below. The rate controlling 14 membranes subjected to an annealing process according to this invention (systems 2 and 4) were maintained at about 60 C for a period of time of 16 about 24 hours and subsequently allowed to cool to ambient conditions for 2 17 days before being pressure laminated to the adhesive.

19 Table 1 SYSTEM CONFIGURATION

SYSTEM MEMBRANE ANNEALING MEMBRANE THICKNESS
(symbol in Fig. 7) ~Rrrf~'G~ --~~~
1 (") NO q 2(0) YES -71, Z
3 (m) NO ''g 4 (A) YES

22 A backing member comprised of a multilaminate of polyester thylene, 23 aluminum, polyester and EVA (Scotchpak 1220, 3M Co., St. Paul, MN) was 24 also provided and the aqueous gel was pouched between the backing member and the release liner/adhesive/rate controlling membrane on a rotary AMENDED SHEET

1 heat-seal machine. Sealed pouches in sizes of 5 cm2 were die cut and 2 immediately pouched to avoid loss of ethanol. The pouched systems were 3 allowed to equilibrate for at least two weeks in order to reach equilibrium 4 concentration of the drug and ethanol in the rate controlling and adhesive layers.

6 The peelable liner of the laminate was removed and the fentanyl 7 releasing surface was placed against the stratum corneum side of a disc of 8 human epidermis which had been blotted dry just prior to use. The excess 9 epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device covered with epidermis was 11 then mounted on a Teflon holder of a release rate rod using nylon mesh 12 and metal string. The rod was then reciprocated in a fixed volume of receptor 13 solution (0.05M phosphate buffer, pH 6.5) at 35 C.
14 At given time intervals, the entire receptor solution was removed from the test tubes and replaced with an equal volume of fresh receptor solutions 16 previously equilibrated at 35 C. The receptor solutions were stored in capped 17 vials at 4 C until assayed for fentanyl base or ethanol content by HPLC
18 analysis. From the drug concentration and the volume of the receptor 19 solutions, the area of permeation and the time interval, the flux of the drug was calculated as follows: (drug concentration X volume of receptor)/(area x 21 time) = flux ( g/cm` hr).
22 Figure 7 depicts the in vitro flux of fentanyl through skin from the 23 systems prepared as set forth above. As seen in Figure 7, the systems 24 comprising the annealed rate controlling membranes demonstrated a higher flux of fentanyl therethrough as compared to the non-annealed systems.
26 There was significantly less variation of drug fluxes between the systems 27 comprising the annealed membranes as compared to the variation in fluxes 28 observed among the systems comprising non-annealed membranes.
29 Figure 8 depicts the in vitro flux of ethanol through skin from the systems prepared as set forth above. As seen in Figure 8, the systems 1 comprising the annealed rate controlling membranes demonstrated a more 2 consistent, higher flux of ethanol therethrough as compared to the systems 3 with non-annealed membranes.

7 Systems comprising 2 mil, 3 mil, or 3.5 mil EVA (9% VA) membranes 8 and a surface area of 10 .cm2 were prepared according to the procedure set 9 forth in Example 1. The 2.0 mil EVA membranes in roll form were annealed 10 in a sauna room at 60 C for 2-34 hours, while the 3.0 and 3.5 mil EVA
11 membranes were annealed in an oven at 60 C for two hours. The release 12 rates of fentanyl and ethanol from systems comprising annealed membranes 13 were then measured and compared to release rates measured from control 14 systems comprising non-annealed membranes.
15 Release rates were measured by placing the systems in closed jars 16 containing a fixed amount of a receptor solution (0.05M phosphate buffer, pH
17 6.5) at 35 C. At given time intervals, the entire receptor solution was removed 18 from the jars and replaced with an equal volume of fresh receptor solutions 19 previously equilibrated at 35 C. The receptor solutions were stored in capped 20 vials at 4 C until assayed for fentanyl base or ethanol content by HPLC
21 analysis. From the drug concentration and the volume of the receptor 22 solutions, the area of permeation and the time interval, the flux of the drug 23 was calculated as follows: (drug concentration X volume of receptor)/(area x 24 time) = flux ( g/cm2 = hr). The average in vitro release rate of fentanyl and ethanol are shown in Table 2.

3 Average Release Rates of Fentanyl and Ethanol 4 from Annealed vs. Non-annealed Systems MEMBRANE FENTANYL RELEASE RATE ( g/cm hr) ETHANOL RELEASE RATE
( g/cm2 = hr ) 2 mil control 3.6 35 2 mil annealed 4.6 47 3 mil control 3.3 20 3 mil annealed 4.0 39 3.5 mil control 3.2 29 3.5 mil annealed 4.6 35 9 The effect of annealing temperature on fentanyl flux was studied.
Systems were made according to the procedure set forth in Example 1. The 11 rate controlling membranes were annealed at various temperatures ranging 12 from 45 - 80 C for two hours. The flux of fentanyl from these systems was 13 then measured by the skin flux experiments described in Example 1. The 14 results are shown in Figure 9, which is a plot of the average fentanyl flux ( g/cm2 - hr) over the period 2-29 hours following application of the system vs.
16 temperature of the annealing process. As seen in Figure 9, the average flux 17 of fentanyl during the 2-29 hour period increased substantially linearly with 18 increasing annealing temperature.

22 The effect of storage on the permeability stability of an EVA membrane 23 was investigated. Donor solutions were prepared by adding fentanyl base to 24 a mixture of 95% ethanol and purified water. 2% of hydroxyethyl cellulose gelling agent was added slowly to the solution with stirring and mixed until a 26 smooth gel was obtained (approximately 1 hour). Flux experiments were 27 performed to measure the flux of fentanyl from the donor solution through SUBSTITUTE SHEET (RULE 26) 1 annealed EVA film containing 9% vinyl acetate (EVA 9) and compared to 2 fentanyl flux through a non-annealed EVA 9 membrane. The EVA 9 3 membranes were annealed at 600 C for 2 hours. Membrane 1 was annealed 4 15 months prior to the flux experiment while membrane 2 was annealed on the day of the flux experiment.
6 The experiment was carried out using standard glass diffusion cells 7 which consist of a donor compartment and a receptor compartment. The rate 8 controlling membrane was placed in each diffusion cell in a horizontal position 9 between a lower capped receptor compartment and an upper capped donor compartment. The receptor compartment has both a venting tube (uncapped) 11 and a sampling port (capped). An 0-ring was positioned between the 12 membrane and the donor compartment, and a clamp held the compartments 13 together. The receptor solution, 0.05M phosphate buffer, pH 6.5, was added 14 to each receptor compartment. The cells were placed in a temperature controlled water bath shaker at 35 C and allowed to come to temperatUre 16 before the donor solution was added. The donor solution comprised fentanyl 17 gel with a large excess of fentanyl in order to maintain constant steady state 18 flux throughout the 30 hour sampling period.
19 At each time interval, the receptor solution was removed from the test cell and replaced with an equal volume of fresh receptor solution previously 21 equilibrated at 35 C. The receptor solutions for each time interval were then 22 assayed for fentanyl by HPLC analysis to calculate the permeation rate of 23 fentanyl through the membrane from the donor solutions. From the drug 24 concentration and the volume of the receptor solutions, the area of permeation and the time interval, the flux of the drug through the rate 26 controlling membranes was calculated as follows: (drug concentration X
27 volume of receptor)/(area x time) = flux ( g/cm2 - hr).

3 Effect of Storage on EVA 9 Membrane Permeability MEMBRANE ANNEALLING FENTANYL FLUX
( g/cm2 - hr) membrane 1 600 C for 2 hours 11.0 membrane 2 60 C for 2 hours 10.8 membrane 3 none 6.5 As seen in Table 3, the permeability of membrane 1 was stable after 6 15 months storage at room temperature.

Tests were done to study the effects of annealing on high density 11 polyethylene (HDPE) films using nicotine as a model drug. Drug reservoirs 12 were prepared by mixing 60 wt% ethylene vinyl acetate (39% vinyl acetate) 13 and 40 wt% nicotine base and were allowed to equilibrate to room 14 temperature. 10 cm2 patches were prepared by placing approximately 0.4 grams of the drug reservoir on the heat sealable (silver side) of a Scotchpak 16 polyester backing using a syringe. HDPE resins (LR723, LR734 and LS901, 17 Millenium, Texas) were cast into films which were then heated in an oven at 18 70 C for a period of two hours. An HDPE film to be tested was placed over 19 the drug reservoir mixture, and a piece of Teflon film was placed over the HDPE film and the films were heat sealed together. Finished systems were 21 cut from the prepared laminate by hand punching around the heat sealed 22 zone.
23 In vitro release rate experiments were performed to measure the 24 release of nicotine through annealed HDPE film and compared to nicotine release through a non-annealed HDPE membrane. The release liner was 26 removed and the device was then mounted on a Teflon holder of a release 1 rate rod using Nylon mesh and metal wire. The rod was then reciprocated in 2 a fixed volume of receptor solution (distilled water) at 32 C.

3 At given time intervals, the entire receptor solution was removed from 4 the test tubes and replaced with an equal volume of fresh receptor solutions previously equilibrated at 32 C. The nicotine concentration in the distilled 6 water receptor was measured by UV absorption at 260 nm. From the drug 7 concentration and the volume of the receptor solutions, the area of 8 permeation and the time interval, the flux of the drug was calculated as 9 follows: (drug concentration X volume of receptor)/(area x time) = flux ( g/cm2 hr). The results are shown in Table 4.

13 Nicotine Flux ( g/cm2 = hr) Through 14 Annealed and Non-Annealed HDPE Films HDPE Resin Film Treatment Thickness (mii) Nicotine Flux LP 5102 Non-annealed 1.90 31.47 LP 5102 Annealed 1.90 44.13 LR 723 Non-annealed 2.40 20.67 LR 723 Annealed 2.40 26.19 LR 734 Non-annealed 2.13 11.41 LR 734 Annealed 2.13 15.15 LS 901 Non-annealed 1.23 19.09 LS 901 Annealed 1.23 22.78 16 As seen from Table 4, the systems comprising annealed membranes 17 resulted in a greater flux of nicotine than systems comprising non-annealed 18 rate controlling membranes.

22 The effect of the vinyl acetate content on the permeability of EVA rate 23 controlling membranes using testosterone as the model drug was 24 investigated. A reservoir gel comprising 26 wt.% testosterone, 1-2 wt.%
hydroxypropyl cellulose, and the remainder 95% ethanol was prepared by 1 mixing testosterone, 95% ethanol and adding hydroxypropyl cellulose with 2 mixing.
3 A contact adhesive composition was made by mixing polyisobutylene 4 (MW 1,200,000), polyisobutylene (MW 35000) and light mineral oil. A 50 5 micron thick layer of the contact adhesive was cast onto a 75 micron thick film 6 of siliconized polyethylene terephthalate peelable liner. The contact adhesive 7 side of the resulting two layer subassembly was laminated to a 50 micron 8 thick film of annealed or non-annealed ethylene vinyl acetate (EVA) 9 copolymer of various vinyl acetate content as set forth in Table 5. The 10 annealed EVA membranes were heated at 42 C for 5 days. The gelled 11 testosterone-ethanol mixture was placed on the EVA membrane. A backing 12 member comprised of aluminized polyethylene terephthalate with an EVA
13 heat sealable coating was laid over the gels and heat-sealed to the EVA
14 copolymer using a rotary heat seal machine. Finished systems were die-cut 15 from laminate using a circular punch and placed in sealed pouches to prevent 16 loss of volatile components.
17 The peelable liner of the laminate was removed and the system was 18 then mounted on a Teflon rod. A known volume of receptor solution (0.10%
19 phenoVH20) was then placed in a test tube and was equilibrated at 35 C.
20 The Teflon rod with the attached system was then placed in a water bath at 21 35 C. Mixing was accomplished by attachment to a motor which caused 22 constant vertical mixing.
23 At given time intervals, the entire receptor solution was removed from 24 the test tubes and replaced with an equal volume of fresh receptor solutions 25 previously equilibrated at 35 C. The receptor solutions were stored in capped 26 vials at 4 C until assayed for testosterone content by HPLC analysis. From 27 the drug concentration and the volume of the receptor solutions, the area of 28 permeation and the time interval, the flux of the drug was calculated as 29 follows: (drug concentration X volume of receptor)/(area x time) = flux ( g/cm2 - hr).

3 Average Release Rate of Testosterone Through 4 Annealed and Non-Annealed EVA Membranes of Varying VA Content % Vinyl Acetate AVG (12-30 hr) AVG (12-30 hr) (VA) Testosterone release rate Testosterone release rate through non-annealed through annealed membrane ( g/cm2 - hr) membrane ( g/cm2 = hr) 12.2 1.39 1.56 9 1.04 1.22 9 1.02 1.21 6.6 0.46 0.50 8 10 cm2 systems containing fentanyl were prepared as set forth in 9 Example 1. EVA membranes (thickness of 50 micron) comprising 6.6% VA
were compared to systems comprising 9 % VA. The systems were exposed 11 to various thermal stresses prior to conducting in vitro release rate studies 12 following the procedure set forth in Example 1 to determine if membrane 13 permeability exceeded a preferred maximum limit after thermal stressing.
14 The preferred maximum release from the system is less than 34.5 g/cm2 - hr for the period 0-2 hours after application, less than 6.8 g/cm2 - hr for the 16 period 2-12 hours after application, and less than 4.7 g/cm2 - hr for the period 17 12 - 24 hours after application. As seen in Table 6, the annealed EVA 9 18 membrane exceeded the predetermined limits for the 0-2 and 2-12 hr 19 intervals while the annealed EVA 6.6 membrane was within these limits after thermal stressing at 50 C for one day.

2 Release Rate of Fentanyl After Heat Stressing % VA Heat Stress 0-2 hr 2-12 hr release 12-24 hr release release ( g/cm2 - hr) ( g/cm2 - hr) ( g/cm2 - hr) 6.6 none 6.1 1.8 1.45 9 none 12.9 3.6 2.76 6.6 none 7.5 3.49 2.78 annealed 6.6 45 C, 16 hrs 27.4 6.4 3.8 annealed 6.6 45 C, 40 hrs 27.8 6.3 3.95 annealed 6.6 50 C, 4 hrs 22.1 5.75 3.85 annealed 6.6 50 C, 16 hrs 24.8 6.4 4.0 annealed 6.6 50 C, 24 hrs 27.3 6.26 3.59 annealed 9 50 C, 24 hrs 41.0 8.9 3.6 annealed 6 Tests were performed to observe annealing effects on water uptake of 7 polyurethane membranes. Polyurethane membranes (blend of 65%
8 Tecophilic(D HP-60D-35 and 35% Tecoflex EG-85A, Thermedics, Inc.) were 9 heated at 52 C for 0, 4, 8, 16, 24, and 32 hours and thereafter weighed and stored in sealed bags at room temperature. The membranes were then 11 placed in 15 ml of water at 37 C for 7 days, removed, and blotted dry to 12 remove any surface water prior to weighing. Water uptake was calculated as:
13 Water uptake (H20%) = ( WW / Wd )x 100 where W. is the membrane weight 14 after being removed from water and Wd is the dry membrane weight after the heat treatment. Fig. 10 shows the water uptake of annealed and non-16 annealed membranes as a function of time prior to testing. As seen in Fig.
17 10, the annealed membranes exhibited much more consistent water uptake 1 values compared to non-annealed membranes. Figure 11 shows the water 2 uptake as function of annealing time.

6 Tests were performed to observe annealing effects on water 7 permeability of polyurethane membranes by measuring the weight gain of 8 devices depicted in FIG. 4 incorporating annealed and non-annealed 9 membranes. Two sets of polyurethane membrane plugs (Tecophilic HP-60D-35, Thermedics, Inc.) were formed by injection molding. One set was 11 annealed at 65 C for 24 hours and the other set was not subjected to 12 annealing. One half of each set of the membranes were immediately 13 fabricated into systems for weight gain testing (day 1) and the other half were 14 stored for 28 days at which time systems were fabricated and tested for weight gain. The piston 34 and reservoir 32 were lightly lubricated with 16 silicone medical fluid. The piston 34 was then inserted into the open end of 17 chamber 36. Membrane plug 40 was then inserted by lining up the plug with 18 the reservoir and gently pushing the plug until it was fully engaged in the 19 reservoir. The system was then placed in a test medium (370 C deionized water) and the weight of the system was measured gravimetrically as a 21 function of time. In order to prevent water from seeping into the formulation 22 chamber through the oriflce, the system was inserted into a form-fitting hole 23 cut into the lid of a vacutainer such that the membrane end is enclosed in the 24 vacutainer and the orifice end protrudes out of the container. The vacutainer was then filled with test medium which surrounded the membrane end of the 26 system. The entire assembly was placed in a secondary vial which was 27 sealed and placed in a 37 C water bath. System weight gain was measured 28 by removing the system from the vacutainer, wiping it dry, weighing it, and 29 then returning the system to the water bath filled vacutainer which was then replaced in the heated water bath. The weight gain rate is calculated as OW /

1 At =[WM - W(,_,)] /[t(i) - tn.,)] where %) is the system weight at time t(;). The 2 results are depicted in Figure 12.

6 Release rates from systems comprising annealed and non-annealed 7 membranes were compared. Membranes were prepared and placed in 8 systems according to Example 9. Half of each set of the membranes were 9 immediately fabricated into systems and tested for release rate (day 1) and the other half were stored for 28 days at which time systems were fabricated 11 and tested for release rate. The systems were filled with a blue dye solution 12 consisting of 1-2% blue dye in 98-99% water. Testing was performed by 13 placing dye filled systems in glass test-tubes filled with pre-warmed liquid (35 14 ml of distilled water or phosphate buffered saline solution). Periodic sampling was performed over 130 days by transferring the systems into fresh pre-filled, 16 pre-warmed test-tubes and measuring the amount of dye in the old test-tubes.
17 The release rate was determined by measuring the absorbance of the 18 surrounding release media using a spectrophotometer. Standard setting for 19 blue dye is 630 nm and a standard curve for all formulations was prepared.
Release rate ( l/day) was determined by comparing the absorbance of 21 release media to the standard curve. The results are depicted in Figure 13.

The effect of annealing temperature and moisture content on water 26 uptake of annealed membrane plugs was investigated. Polyurethane (HP-27 60D-35, HP-6013-20, Thermedics, Inc.) membrane plugs were formed by 28 injection molding. The membrane plugs were then annealed for 24 hours at 29 50 C, 65 C, or 80 C at moisture conditions of 0 or 1%. Water uptake was determined by the procedure set forth in Example 8. Figure 14 depicts the 1 results for the HP-60D-35 membranes and Figure 15 depicts the results for 2 the HP-60D-20 membranes. Figure 16 shows the effect on the melting 3 temperature of the hard segment of polyurethane at these annealing 4 temperatures and moisture conditions.
5 Having thus generally described our invention and described certain 6 specific embodiments thereof, including the embodiments that applicants 7 consider the best mode of practicing their invention, it should be readily 8 apparent that various modifications to the invention may be made by workers 9 skilled in the art without departing from the scope of this invention which is 10 limited only by the following claims.

Claims (31)

1. A rate controlling membrane, comprising a polymer, for a controlled drug delivery device characterized by being subjected to an elevated temperature of 30°C to 5°C below the melting temperature of the membrane polymer for a predetermined period of 1 -250 hours and subsequently incorporated into the delivery device.
2. A rate controlling membrane according to claim 1 wherein the membrane comprises a polymer selected from the group consisting of ethylene vinyl acetate copolymers, polyethylene, ethylene copolymers, ethylene oxide copolymers, polyamides, cellulosic materials, polyurethanes, polyether blocked amides copolymers, and polyvinyl acetate.
3. A rate controlling membrane according to any one of claims 1 or 2 wherein the membrane comprises ethylene vinyl acetate copolymer.
4. A rate controlling membrane according to claim 3 wherein the ethylene vinyl acetate copolymer comprises a vinyl acetate content of 4-18%.
5. A rate controlling membrane according to claim 4 wherein the membrane is characterized by a DSC profile having a primary peak at 94-99°C and a secondary peak at greater than 50°C.
6. A rate controlling membrane according to claim 5 wherein the ethylene vinyl acetate copolymer comprises a vinyl acetate content of 5-12%.
7. A rate controlling membrane according to any one of claims 1-6 wherein the device is a transdermal drug delivery device comprising a drug reservoir layer between a backing layer and a contact adhesive layer, the rate controlling membrane is on a skin-proximal side of the drug reservoir layer.
8. A rate controlling membrane according to any one of claims 1 to 6 wherein the device is a transdermal drug delivery device comprising a backing layer, a permeation enhancer reservoir containing a permeation enhancer on a skin proximal side of the backing layer, a drug reservoir layer containing at least one drug to be transdermally administered on the skin proximal side of the permeation enhancer reservoir, and a means for maintaining the drug device in drug transmitting relation with skin, wherein the rate controlling membrane is positioned between the permeation enhancer reservoir and the drug reservoir.
9. A rate controlling membrane according to any one of claim 7 or 8 wherein the drug reservoir comprises a drug selected from the group consisting of testosterone, estradiol, and fentanyl.
10. A rate controlling membrane according to any one of claims 1 to 6 wherein the membrane is positioned in sealing relationship with an internal surface of one end of an impermeable reservoir of a fluid-imbibing drug delivery device, wherein the fluid-imbibing drug delivery device comprises the impermeable reservoir, a piston that divides the reservoir into a drug containing chamber and a water-swellable agent containing chamber, wherein the water-swellable agent containing chamber is adjacent the membrane.
11. A rate controlling membrane according to claim 10 wherein the drug containing chamber comprises leuprolide.
12. A rate controlling membrane according to any one of claims 1-11 wherein the membrane comprises a polymer selected from the group consisting of polyurethanes or polyether blocked amides copolymers.
13. A rate controlling membrane according to claim 1 wherein the elevated temperature is 45-80°C and the predetermined period is 1-75 hours.
14. A rate controlling membrane according to claim 13 wherein the elevated temperature is 52-72°C and the predetermined time is 2-36 hours.
15. A rate controlling membrane according to claim 13 wherein the elevated temperature is 55-75°C and the predetermined time is 12-48 hours.
16. A rate controlling membrane according to any one of claims 1-15 wherein the membrane is cooled to ambient conditions before being incorporated into the deliver device.
17. A method for processing rate controlling membranes used in controlled drug delivery devices comprising:

(a) exposing the membrane to a predetermined temperature from 30°C to 5°C
below the melting temperature of the membrane polymer;

(b) maintaining the membrane at the predetermined temperature for a period of time of from 1-250 hours; and (c) incorporating the membrane into a controlled drug delivery device.
18. A method according to claim 17 wherein the predetermined temperature is from 45°C to 80°C.
19. A method according to claim 17 or 18 wherein the membrane is maintained at the predetermined temperature for a period of time of from 1 to 75 hours.
20. A method according to any one of claims 17 to 19 wherein the membrane is cooled to ambient conditions over a period of time of 0.1-150 hours prior to incorporating the membrane into the device.
21. A method according to any one of claims 17 to 20 wherein the membrane is incorporated into a transdermal drug delivery device and comprises an increased drug permeability compared to a non-annealed membrane comprising the same polymer.
22. A method according to any one of claims 17 to 21 wherein the membrane comprises a polymer selected from the group consisting of ethylene vinyl acetate copolymers, polyethylene, ethylene copolymers, ethylene oxide copolymers, polyamides, cellulosic materials, polyurethanes, polyether blocked amides copolymers, and polyvinyl acetate.
23. A method according to claim 22 wherein the membrane comprises ethylene vinyl acetate copolymer, a high density polyethylene, or polyurethane.
24. A method according to any one of claims 17 to 23 wherein the membrane comprises ethylene vinyl acetate copolymer comprising a vinyl acetate content of 4-18%.
25. A method according to claim 24 wherein the membrane comprises ethylene vinyl acetate copolymer comprising a vinyl acetate content of 5-12%.
26. A method according to any one of claims 17 to 25 wherein the predetermined temperature is 52-72°C and the period of time is 2-36 hours.
27. A method according to any one of claims 17 to 25 wherein the predetermined temperature is 55-75°C and the period of time is 12-48 hours.
28. A method according to any one of claims 17 to 27 wherein the membrane is allowed to set at ambient conditions for a period of at least 12 hours after processing prior to exposing the membrane to the predetermined temperature.
29. A method according to claim 28 wherein the membrane is allowed to set at ambient conditions for a period of at least 48 hours after processing prior to exposing the membrane to the predetermined temperature.
30. A method according to any one of claims 17 to 29 wherein the membrane is positioned in sealing relationship with an internal surface of one end of an impermeable reservoir of a fluid-imbibing drug deliver device, wherein the fluid imbibing drug delivery device comprises the impermeable reservoir, a piston that divides the reservoir into an active agent containing chamber and a water-swellable agent containing chamber, wherein the water-swellable agent containing chamber is adjacent the membrane.
31. A method according to claim 30 wherein the membrane is plug-shaped.
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Families Citing this family (158)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6440457B1 (en) * 1993-05-27 2002-08-27 Alza Corporation Method of administering antidepressant dosage form
US7833543B2 (en) * 1995-06-07 2010-11-16 Durect Corporation High viscosity liquid controlled delivery system and medical or surgical device
MY125870A (en) * 1997-07-25 2006-08-30 Alza Corp Osmotic delivery system flow modulator apparatus and method
JP4215188B2 (en) * 1997-12-22 2009-01-28 インターシア セラピューティクス,インコーポレイティド Rate-regulating membranes for devices that regulate drug delivery
AR013256A1 (en) * 1997-12-30 2000-12-13 Intarcia Therapeutics Inc ADMINISTRATION ARRANGEMENT FOR A CONTROLLED ADMINISTRATION OF A CHARITY AGENT, METHOD FOR FORMING AN ADMINISTRATION ARRANGEMENT, METHOD FOR MAKING AN ADMINISTRATION ARRANGEMENT AND METHOD OF CONTROLLING A SPEED OF FREEDOM.
US7258869B1 (en) 1999-02-08 2007-08-21 Alza Corporation Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicle
US7919109B2 (en) 1999-02-08 2011-04-05 Intarcia Therapeutics, Inc. Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles
US6835194B2 (en) * 1999-03-18 2004-12-28 Durect Corporation Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners
US6821281B2 (en) * 2000-10-16 2004-11-23 The Procter & Gamble Company Microstructures for treating and conditioning skin
US7828827B2 (en) 2002-05-24 2010-11-09 Corium International, Inc. Method of exfoliation of skin using closely-packed microstructures
DE10141650C1 (en) * 2001-08-24 2002-11-28 Lohmann Therapie Syst Lts Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
US7927613B2 (en) * 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
US7790905B2 (en) * 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
US20100311701A1 (en) * 2002-02-15 2010-12-09 Transform Pharmaceuticals, Inc Pharmaceutical Co-Crystal Compositions
AU2003213719A1 (en) 2002-03-01 2003-09-16 Regents Of The University Of Michigan Multiple-component solid phases containing at least one active pharmaceutical ingredient
MY135711A (en) * 2002-06-17 2008-06-30 Alza Corp Osmotic delivery system with early zero order push power engine
CN100360117C (en) * 2002-06-21 2008-01-09 转化医药公司 Pharmaceutical compositions with improved dissolution
CN100435880C (en) * 2003-02-28 2008-11-26 微创医疗器械(上海)有限公司 Medicament elution interventional medical apparatus and preparing method thereof
US20040202704A1 (en) * 2002-08-30 2004-10-14 Watson Pharmaceuticals, Inc. Transdermal delivery systems and methods
MXPA05004593A (en) * 2002-10-29 2005-07-26 Alza Corp Stabilized, solid-state polypeptide particles.
AU2003297464A1 (en) * 2002-12-19 2004-07-14 Alza Corporation Stable, non-aqueous, single-phase gels and formulations thereof for delivery from an implantable device
US7731947B2 (en) * 2003-11-17 2010-06-08 Intarcia Therapeutics, Inc. Composition and dosage form comprising an interferon particle formulation and suspending vehicle
US8183290B2 (en) * 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
EP2339328A3 (en) 2002-12-30 2011-07-13 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of celecoxib
EP1608339B8 (en) 2003-02-28 2012-04-25 McNeill-PPC, Inc. Pharmaceutical co-crystal of celecoxib-nicotinamide
US7207982B2 (en) * 2003-03-31 2007-04-24 Alza Corporation Osmotic pump with means for dissipating internal pressure
KR20060002922A (en) * 2003-03-31 2006-01-09 알자 코포레이션 Non-aqueous single phase vehicles and formulations utilizing such vehicles
KR20050120767A (en) * 2003-03-31 2005-12-23 알자 코포레이션 Osmotic delivery system and method for decreasing start-up times for osmotic delivery systems
US20040214893A1 (en) * 2003-04-11 2004-10-28 Matthew Peterson Gabapentin compositions
US7186863B2 (en) 2003-05-23 2007-03-06 Transform Pharmaceuticals, Inc. Sertraline compositions
EP1648363B1 (en) * 2003-07-03 2019-03-06 Corium International, Inc. Wound dressing, ingredient delivery device and iv hold-down, and method relating to same
CA2437639C (en) * 2003-08-11 2016-07-05 Valera Pharmaceuticals, Inc. Long term drug delivery devices with polyurethane based polymers and their manufacture
US7858110B2 (en) 2003-08-11 2010-12-28 Endo Pharmaceuticals Solutions, Inc. Long term drug delivery devices with polyurethane based polymers and their manufacture
US20090208540A1 (en) * 2003-08-11 2009-08-20 Indevus Pharmaceuticals, Inc. Implantable device for the delivery of naltrexone and methods of use thereof
AU2013200837B2 (en) * 2003-08-11 2015-08-27 Braeburn Pharmaceuticals, Inc. Manufacture of long term drug delivery devices with polyurethane based polymers
US7470266B2 (en) 2003-09-16 2008-12-30 I-Flow Corporation Fluid medication delivery device
WO2005030181A1 (en) * 2003-09-26 2005-04-07 Alza Corporation Controlled release formulations of opioid and nonopioid analgesics
NZ546183A (en) 2003-09-26 2011-04-29 Alza Corp Controlled release formulations exhibiting an ascending rate of release
ATE504288T1 (en) * 2003-09-26 2011-04-15 Alza Corp OROS PUSH STICK FOR THE CONTROLLED DELIVERY OF ACTIVE INGREDIENTS
EP1708684A2 (en) * 2003-09-26 2006-10-11 Alza Corporation Drug coating providing high drug loading and methods for providing the same
BRPI0414941A (en) 2003-09-30 2006-11-07 Alza Corp osmotically driven active agent dispensing device providing an upward release profile
US20070191815A1 (en) 2004-09-13 2007-08-16 Chrono Therapeutics, Inc. Biosynchronous transdermal drug delivery
US20050113410A1 (en) * 2003-11-03 2005-05-26 Mark Tawa Pharmaceutical salts of zafirlukast
MXPA06003065A (en) * 2003-11-06 2006-05-31 Alza Corp Modular imbibition rate reducer for use with implantable osmotic pump.
KR20060109926A (en) 2003-11-19 2006-10-23 메타베이시스 테라퓨틱스, 인크. Novel phosphorus-containing thyromimetics
EP2292213A1 (en) 2004-02-06 2011-03-09 Cephalon, Inc. Compositions comprising a polymorphic form of armodafinil
AU2005228145B2 (en) 2004-03-24 2011-03-03 Corium Pharma Solutions, Inc. Transdermal delivery device
US20060004037A1 (en) * 2004-03-25 2006-01-05 Transform Pharmaceuticals, Inc. Novel tricyclic compounds and related methods of treatment
US20050266087A1 (en) * 2004-05-25 2005-12-01 Gunjan Junnarkar Formulations having increased stability during transition from hydrophobic vehicle to hydrophilic medium
JP5017103B2 (en) * 2004-06-17 2012-09-05 トランスフオーム・フアーマシユーチカルズ・インコーポレーテツド Pharmaceutical co-crystal composition and related methods of use
WO2006015325A1 (en) * 2004-07-30 2006-02-09 Bay Materials, Llc Method of reducing stress relaxation in polymer articles and articles formed thereby
US8541026B2 (en) * 2004-09-24 2013-09-24 Abbvie Inc. Sustained release formulations of opioid and nonopioid analgesics
NZ582975A (en) 2004-10-21 2011-07-29 Durect Corp Transdermal delivery systems delivering sufentanil
US8252320B2 (en) 2004-10-21 2012-08-28 Durect Corporation Transdermal delivery system for sufentanil
US8779175B2 (en) 2004-10-25 2014-07-15 Synthonics, Inc. Coordination complexes, pharmaceutical solutions comprising coordination complexes, and methods of treating patients
US20060160783A1 (en) * 2004-12-30 2006-07-20 Transform Pharmaceuticals, Inc. Novel omeprazole forms and related methods
WO2006083761A2 (en) * 2005-02-03 2006-08-10 Alza Corporation Solvent/polymer solutions as suspension vehicles
WO2006084141A2 (en) * 2005-02-03 2006-08-10 Intarcia Therapeutics, Inc Suspension formulation of interferon
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide
US20060188558A1 (en) * 2005-02-18 2006-08-24 Mylan Technologies, Inc. Transdermal systems having control delivery system
US7959938B2 (en) * 2005-03-15 2011-06-14 Intarcia Therapeutics, Inc. Polyoxaester suspending vehicles for use with implantable delivery systems
US20060223786A1 (en) * 2005-04-01 2006-10-05 Smith David J Transdermal pain control method and device
WO2007002183A2 (en) * 2005-06-21 2007-01-04 Bausch & Lomb Incorporated Drug delivery device for implanting in the eye comprising a drug core and a preformed permeable crystalline polymeric disc
US20070027105A1 (en) 2005-07-26 2007-02-01 Alza Corporation Peroxide removal from drug delivery vehicle
US20110086086A1 (en) * 2005-07-26 2011-04-14 Pfizer Inc Transdermal system for varenicline
US7790671B2 (en) * 2005-10-07 2010-09-07 Codman & Shurtleff, Inc. Implantable pump for protein delivery for obesity control by drug infusion into the brain
US20100172989A1 (en) * 2006-01-21 2010-07-08 Abbott Laboratories Abuse resistant melt extruded formulation having reduced alcohol interaction
US20090317355A1 (en) * 2006-01-21 2009-12-24 Abbott Gmbh & Co. Kg, Abuse resistant melt extruded formulation having reduced alcohol interaction
US20090022798A1 (en) * 2007-07-20 2009-01-22 Abbott Gmbh & Co. Kg Formulations of nonopioid and confined opioid analgesics
US20070248657A1 (en) * 2006-04-25 2007-10-25 Smith David J Multi-compartment transdermal pain control device
NZ572003A (en) * 2006-05-30 2010-07-30 Intarcia Therapeutics Inc Two-piece, internal-channel osmotic delivery system flow modulator with spiral fluid channel
US7659344B2 (en) * 2006-06-08 2010-02-09 E. I. Du Pont De Nemours And Company Shaped articles containing poly(vinylpyrrolidone)-iodine complex
WO2008021133A2 (en) 2006-08-09 2008-02-21 Intarcia Therapeutics, Inc. Osmotic delivery systems and piston assemblies
US9114133B2 (en) 2006-08-25 2015-08-25 U.S. Dept. Of Veterans Affairs Method of improving diastolic dysfunction
US7538652B2 (en) * 2006-08-29 2009-05-26 International Business Machines Corporation Electrical component tuned by conductive layer deletion
PL2117521T3 (en) 2006-11-03 2012-11-30 Durect Corp Transdermal delivery systems comprising bupivacaine
AU2008209537B2 (en) * 2007-01-22 2013-01-31 Corium Pharma Solutions, Inc. Applicators for microneedle arrays
CA2894112C (en) 2007-02-09 2020-09-15 Metabasis Therapeutics, Inc. Novel antagonists of the glucagon receptor
ES2817249T3 (en) 2007-04-16 2021-04-06 Corium Inc Microneedle matrices obtained by dissolution and casting containing an active principle
NZ580447A (en) 2007-04-23 2011-06-30 Intarcia Therapeutics Inc Suspension formulations of insulinotropic peptides and uses thereof
ES2385231T3 (en) 2007-07-04 2012-07-19 Acino Ag Tank system with a closed membrane
CN101821276B (en) 2007-08-13 2016-08-31 症变治疗公司 Novel activators of glucokinase
WO2009048607A1 (en) * 2007-10-10 2009-04-16 Corium International, Inc. Vaccine delivery via microneedle arrays
JP5178132B2 (en) * 2007-10-11 2013-04-10 キヤノン株式会社 Image processing system and image processing method
US9226907B2 (en) 2008-02-01 2016-01-05 Abbvie Inc. Extended release hydrocodone acetaminophen and related methods and uses thereof
US8343140B2 (en) 2008-02-13 2013-01-01 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
ES2527670T3 (en) 2008-08-13 2015-01-28 Metabasis Therapeutics, Inc. Glucagon antagonists
CA2739179A1 (en) * 2008-09-30 2010-04-08 Endo Pharmaceuticals Solutions Inc. Implantable device for the delivery of histrelin and methods of use thereof
CN102202646A (en) * 2008-09-30 2011-09-28 Endo药物方法有限公司 Implantable device for the delivery of risperidone and methods of use thereof
CN106880596A (en) * 2008-10-15 2017-06-23 精达制药公司 Highly enriched drug particles, preparation, supensoid agent and its application
US20100221313A1 (en) * 2008-12-01 2010-09-02 Innovative Pharmaceuticals, Llc Transdermal reservoir patch
KR100911753B1 (en) * 2009-02-04 2009-08-10 (주)씨에스텍 A transdermal patch and a method of producing the same
HUP0900073A2 (en) * 2009-02-06 2010-11-29 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Process and equipment for inquiry medical product on dermal surface
ES2634667T3 (en) * 2009-04-24 2017-09-28 Corium International, Inc. Methods for manufacturing microprojection assemblies
NZ624569A (en) 2009-09-28 2016-01-29 Intarcia Therapeutics Inc Rapid establishment and/or termination of substantial steady-state drug delivery
ES2632431T3 (en) 2009-10-30 2017-09-13 Ntf Therapeutics, Inc. Enhanced Neurturin Molecules
CA2794565C (en) 2010-04-08 2018-08-21 Emory University Substituted androst-4-ene diones
EP2557924B1 (en) 2010-04-13 2019-06-12 Relmada Therapeutics, Inc. Dermal pharmaceutical compositions of 1-methyl-2',6'-pipecoloxylidide and method of use
WO2011139714A2 (en) 2010-04-26 2011-11-10 Atyr Pharma, Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of cysteinyl-trna synthetase
CN103096911B (en) 2010-04-27 2018-05-29 Atyr 医药公司 Treatment relevant with the protein fragments of Isoleucyl-tRNA synthetase, diagnosis and the innovation of antibody compositions are found
CA2796965C (en) 2010-04-28 2019-04-16 Kimberly-Clark Worldwide, Inc. Method for increasing permeability of an epithelial barrier
WO2011135531A2 (en) 2010-04-28 2011-11-03 Kimberly-Clark Worldwide, Inc. MEDICAL DEVICES FOR DELIVERY OF siRNA
MX345837B (en) 2010-04-28 2017-02-16 Kimberly-Clark Worldwide Incorporated Device for delivery of rheumatoid arthritis medication.
JP5868953B2 (en) 2010-04-28 2016-02-24 キンバリー クラーク ワールドワイド インコーポレイテッド Injection mold microneedle array and manufacturing method thereof
JP6008837B2 (en) 2010-04-28 2016-10-19 エータイアー ファーマ, インコーポレイテッド Innovative discovery of therapeutic, diagnostic and antibody compositions related to protein fragments of alanyl tRNA synthetase
EP2563912B1 (en) 2010-04-29 2018-09-05 aTyr Pharma, Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of asparaginyl trna synthetases
CN103118693B (en) 2010-04-29 2017-05-03 Atyr 医药公司 Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of valyl tRNA synthetases
CA2797978C (en) 2010-05-03 2019-12-03 Atyr Pharma, Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of methionyl-trna synthetases
WO2011139986A2 (en) 2010-05-03 2011-11-10 Atyr Pharma, Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of arginyl-trna synthetases
US9034321B2 (en) 2010-05-03 2015-05-19 Atyr Pharma, Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of phenylalanyl-alpha-tRNA synthetases
ES2719595T3 (en) 2010-05-04 2019-07-11 Corium Int Inc Method and device for transdermal administration of parathyroid hormone using a microprojection matrix
CA2798139C (en) 2010-05-04 2019-09-24 Atyr Pharma, Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of p38 multi-trna synthetase complex
JP6396656B2 (en) 2010-05-14 2018-09-26 エータイアー ファーマ, インコーポレイテッド Innovative discovery of therapeutic, diagnostic and antibody compositions related to protein fragments of phenylalanyl βtRNA synthetase
JP6027965B2 (en) 2010-05-17 2016-11-16 エータイアー ファーマ, インコーポレイテッド Innovative discovery of therapeutic, diagnostic and antibody compositions related to protein fragments of leucyl-tRNA synthetase
EP2575856B1 (en) 2010-05-27 2017-08-16 aTyr Pharma, Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of glutaminyl-trna synthetases
US8962560B2 (en) 2010-06-01 2015-02-24 Atyr Pharma Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of Lysyl-tRNA synthetases
JP6116479B2 (en) 2010-07-12 2017-04-19 エータイアー ファーマ, インコーポレイテッド Innovative discovery of therapeutic, diagnostic and antibody compositions related to protein fragments of glycyl-tRNA synthetase
CN103108650A (en) 2010-08-25 2013-05-15 Atyr医药公司 Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of tyrosyl-trna synthetases
US8919385B2 (en) 2010-11-24 2014-12-30 Pall Corporation Manifold plates and fluid treatment arrangements including manifold plates
US20120208755A1 (en) 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
US8696637B2 (en) 2011-02-28 2014-04-15 Kimberly-Clark Worldwide Transdermal patch containing microneedles
US9585930B2 (en) 2011-03-20 2017-03-07 Trustees Of Boston University Therapeutic agent for emphysema and COPD
US8636696B2 (en) 2011-06-10 2014-01-28 Kimberly-Clark Worldwide, Inc. Transdermal device containing microneedles
US20140227293A1 (en) 2011-06-30 2014-08-14 Trustees Of Boston University Method for controlling tumor growth, angiogenesis and metastasis using immunoglobulin containing and proline rich receptor-1 (igpr-1)
EP2771059B1 (en) 2011-10-27 2019-07-17 Sorrento Therapeutics, Inc. Transdermal delivery of high viscosity bioactive agents
EP2884969A1 (en) * 2012-08-15 2015-06-24 Dow Corning Corporation Multi - layer transdermal drug delivery system
CA2896188C (en) 2012-12-21 2021-02-23 Corium International, Inc. Microarray for delivery of therapeutic agent and methods of use
US9861801B2 (en) 2013-02-28 2018-01-09 Kimberly-Clark Worldwide, Inc. Drug delivery device
BR112015020328B1 (en) 2013-02-28 2022-05-31 Sorrento Therapeutics, Inc Transdermal drug delivery device
AU2014249471B2 (en) 2013-03-12 2019-01-24 Corium Pharma Solutions, Inc. Microprojection applicators
CA2903763C (en) 2013-03-15 2021-11-16 Corium International, Inc. Microarray with polymer-free microstructures, methods of making, and methods of use
ES2939317T3 (en) 2013-03-15 2023-04-20 Corium Pharma Solutions Inc Multi-impact micro-spray applicators
JP2016512754A (en) 2013-03-15 2016-05-09 コリウム インターナショナル, インコーポレイテッド Microarray, method of use and manufacturing for delivery of therapeutic agents
MX2015012933A (en) 2013-03-15 2016-09-19 Corium Int Inc Microarray for delivery of therapeutic agent and methods of use.
US20140272220A1 (en) * 2013-03-15 2014-09-18 Monosol Rx, Llc Reduction in stress cracking of films
TW201505677A (en) 2013-04-10 2015-02-16 Sanofi Sa Dispensing speed control mechanism and injection device
EP3036226B1 (en) 2013-08-22 2020-01-08 The General Hospital Corporation Inhibitors of human 12/15-lipoxygenase
JP2017519000A (en) 2014-06-12 2017-07-13 リガンド・ファーマシューティカルズ・インコーポレイテッド Glucagon antagonist
US10624843B2 (en) 2014-09-04 2020-04-21 Corium, Inc. Microstructure array, methods of making, and methods of use
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
WO2016123406A1 (en) 2015-01-28 2016-08-04 Chrono Therapeutics Inc. Drug delivery methods and systems
MX2017015504A (en) 2015-06-03 2018-05-15 Intarcia Therapeutics Inc Implant placement and removal systems.
WO2017004067A1 (en) 2015-06-29 2017-01-05 Corium International, Inc. Microarray for delivery of therapeutic agent, methods of use, and methods of making
IL258904B (en) 2015-11-05 2022-09-01 Massachusetts Gen Hospital Intrathecal delivery of nucleic acid sequences encoding abcd1 for treatment of adrenomyeloneuropathy
SG11201810102SA (en) 2016-05-16 2018-12-28 Intarcia Therapeutics Inc Glucagon-receptor selective polypeptides and methods of use thereof
USD840030S1 (en) 2016-06-02 2019-02-05 Intarcia Therapeutics, Inc. Implant placement guide
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
US10869842B1 (en) * 2016-09-07 2020-12-22 David P Summers Transdermal delivery of pharmaceutical agents
KR20190086460A (en) 2016-10-20 2019-07-22 더 유나이티드 스테이츠 오브 어메리카, 애즈 리프리젠티드 바이 더 세크러테리, 디파트먼트 오브 헬쓰 앤드 휴먼 서비씨즈 Methods for delivering neuroprotective polypeptides to the central nervous system
IL307966A (en) 2017-01-03 2023-12-01 Intarcia Therapeutics Inc Methods comprising continuous administration of a glp-1 receptor agonist and co-adminstration of a drug
JP2020503950A (en) 2017-01-06 2020-02-06 クロノ セラピューティクス インコーポレイテッドChrono Therapeutics Inc. Device and method for transdermal drug delivery
EP3592376A1 (en) 2017-03-08 2020-01-15 Intarcia Therapeutics, Inc Apparatus and methods for administration of a nauseogenic compound from a drug delivery device
WO2019232077A1 (en) 2018-05-29 2019-12-05 Chrono Therapeutics Inc. Drug delivery methods and systems
USD933219S1 (en) 2018-07-13 2021-10-12 Intarcia Therapeutics, Inc. Implant removal tool and assembly
WO2020077129A1 (en) 2018-10-11 2020-04-16 Intarcia Therapeutics, Inc. Human amylin analog polypeptides and methods of use
JP2022507660A (en) * 2018-11-16 2022-01-18 モーニングサイド ベンチャー インベストメンツ リミテッド Temperature-controlled transdermal drug delivery system
KR20220140711A (en) 2020-01-13 2022-10-18 듀렉트 코퍼레이션 Reduced Impurity Sustained Release Drug Delivery Systems and Related Methods
CN112472688A (en) * 2020-11-09 2021-03-12 黄家辉 Controlled release film and preparation method thereof

Family Cites Families (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3797494A (en) 1969-04-01 1974-03-19 Alza Corp Bandage for the administration of drug by controlled metering through microporous materials
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3788322A (en) * 1972-12-27 1974-01-29 Alza Corp Drug delivery device with means for maintaining device in environment of use
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US3987790A (en) 1975-10-01 1976-10-26 Alza Corporation Osmotically driven fluid dispenser
US4077407A (en) * 1975-11-24 1978-03-07 Alza Corporation Osmotic devices having composite walls
US4031894A (en) 1975-12-08 1977-06-28 Alza Corporation Bandage for transdermally administering scopolamine to prevent nausea
US4436741A (en) 1975-12-08 1984-03-13 Alza Corporation Method for administering scopolamine transdermally
US4111202A (en) 1976-11-22 1978-09-05 Alza Corporation Osmotic system for the controlled and delivery of agent over time
US4111203A (en) 1976-11-22 1978-09-05 Alza Corporation Osmotic system with means for improving delivery kinetics of system
US4203439A (en) 1976-11-22 1980-05-20 Alza Corporation Osmotic system with volume amplifier for increasing amount of agent delivered therefrom
US4201211A (en) 1977-07-12 1980-05-06 Alza Corporation Therapeutic system for administering clonidine transdermally
US4327725A (en) 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US4379454A (en) 1981-02-17 1983-04-12 Alza Corporation Dosage for coadministering drug and percutaneous absorption enhancer
US4725272A (en) 1981-06-29 1988-02-16 Alza Corporation Novel bandage for administering beneficial drug
US4661105A (en) 1981-06-29 1987-04-28 Alza Corporation Medical bandage for administering vasodilator drug
US5310559A (en) 1982-09-01 1994-05-10 Hercon Laboratories Corporation Device for controlled release and delivery to mammalian tissue of pharmacologically active agents incorporating a rate controlling member which comprises an alkylene-alkyl acrylate copolymer
US4612008A (en) 1983-05-11 1986-09-16 Alza Corporation Osmotic device with dual thermodynamic activity
US4588580B2 (en) * 1984-07-23 1999-02-16 Alaz Corp Transdermal administration of fentanyl and device therefor
US4615699A (en) 1985-05-03 1986-10-07 Alza Corporation Transdermal delivery system for delivering nitroglycerin at high transdermal fluxes
US4681584A (en) 1985-05-03 1987-07-21 Alza Corporation Transdermal delivery system for delivering nitroglycerin at high transdermal fluxes
US4698062A (en) 1985-10-30 1987-10-06 Alza Corporation Medical device for pulsatile transdermal delivery of biologically active agents
US4865845A (en) 1986-03-21 1989-09-12 Alza Corporation Release rate adjustment of osmotic or diffusional delivery devices
US4908027A (en) 1986-09-12 1990-03-13 Alza Corporation Subsaturated transdermal therapeutic system having improved release characteristics
US5344656A (en) 1986-09-12 1994-09-06 Alza Corporation Subsaturated transdermal therapeutic system having improved release characteristics
US4832953A (en) 1987-08-13 1989-05-23 Alza Corporation Method for preventing the formation of a crystalline hydrate in a dispersion of a liquid in a monaqueous matrix
US5024842A (en) * 1988-04-28 1991-06-18 Alza Corporation Annealed coats
US4931285A (en) 1988-04-28 1990-06-05 Alza Corporation Aqueous based pharmaceutical coating composition for dosage forms
US5160743A (en) 1988-04-28 1992-11-03 Alza Corporation Annealed composition for pharmaceutically acceptable drug
US5364630A (en) 1988-06-14 1994-11-15 Alza Corporation Subsaturated nicotine transdermal therapeutic system
US5004610A (en) 1988-06-14 1991-04-02 Alza Corporation Subsaturated nicotine transdermal therapeutic system
US5110596A (en) 1988-12-13 1992-05-05 Alza Corporation Delivery system comprising means for delivering agent to livestock
US5034229A (en) 1988-12-13 1991-07-23 Alza Corporation Dispenser for increasing feed conversion of hog
US5059423A (en) 1988-12-13 1991-10-22 Alza Corporation Delivery system comprising biocompatible beneficial agent formulation
US5057318A (en) 1988-12-13 1991-10-15 Alza Corporation Delivery system for beneficial agent over a broad range of rates
US5112614A (en) 1989-09-14 1992-05-12 Alza Corporation Implantable delivery dispenser
US5324280A (en) * 1990-04-02 1994-06-28 Alza Corporation Osmotic dosage system for delivering a formulation comprising liquid carrier and drug
US5234693A (en) 1990-07-11 1993-08-10 Alza Corporation Delivery device with a protective sleeve
US5234692A (en) 1990-07-11 1993-08-10 Alza Corporation Delivery device with a protective sleeve
AU651654B2 (en) * 1992-01-14 1994-07-28 Endo Pharmaceuticals Solutions Inc. Manufacture of water-swellable hydrophilic articles and drug delivery devices
US5137727A (en) 1991-06-12 1992-08-11 Alza Corporation Delivery device providing beneficial agent stability
WO1997020550A2 (en) * 1995-12-01 1997-06-12 Alza Corporation Improved method for preventing crystal formation in a dispersion of a liquid in a matrix
DK1238657T3 (en) * 1996-02-02 2005-01-17 Alza Corp Sustained release of an active agent using an implantable system
JP4215188B2 (en) * 1997-12-22 2009-01-28 インターシア セラピューティクス,インコーポレイティド Rate-regulating membranes for devices that regulate drug delivery

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US6375978B1 (en) 2002-04-23
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ATE223208T1 (en) 2002-09-15
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HK1029923A1 (en) 2001-04-20
US20020034535A1 (en) 2002-03-21

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