CA1166961A - Dosage form for coadministering drug and percutaneous absorption enhancer - Google Patents
Dosage form for coadministering drug and percutaneous absorption enhancerInfo
- Publication number
- CA1166961A CA1166961A CA000395641A CA395641A CA1166961A CA 1166961 A CA1166961 A CA 1166961A CA 000395641 A CA000395641 A CA 000395641A CA 395641 A CA395641 A CA 395641A CA 1166961 A CA1166961 A CA 1166961A
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- CA
- Canada
- Prior art keywords
- drug
- enhancer
- skin
- rate
- dosage form
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
Abstract
DOSAGE FORM FOR COADMINISTERING DRUG AND
PERCUTANEOUS ABSORPTION ENHANCER
Abstract A dosage form that coadministers a drug and a percutaneous absorption enhancer to a defined area of the skin. The dosage form comprises a body that contains supplies of drug and enhancer and has a basal surface that contacts the area of skin and transmits the drug and enhancer to the area for absorption thereby. The drug is provided to the basal surface at a rate at least as great as the rate at which the skin is able to absorb the drug whereas the enhancer is via a rate controlling means at a substantially constant rate that increases the permeability of the treated area of skin to the drug to a level at which the drug is absorbed at a therapeutically effective rate. A preferred embodiment delivers estradiol and employs ethanol as an enhancer, the ethanol delivery rate being about 100-800 mcg/hr/cm2 of skin surface.
4:0130:3P1CMG
PERCUTANEOUS ABSORPTION ENHANCER
Abstract A dosage form that coadministers a drug and a percutaneous absorption enhancer to a defined area of the skin. The dosage form comprises a body that contains supplies of drug and enhancer and has a basal surface that contacts the area of skin and transmits the drug and enhancer to the area for absorption thereby. The drug is provided to the basal surface at a rate at least as great as the rate at which the skin is able to absorb the drug whereas the enhancer is via a rate controlling means at a substantially constant rate that increases the permeability of the treated area of skin to the drug to a level at which the drug is absorbed at a therapeutically effective rate. A preferred embodiment delivers estradiol and employs ethanol as an enhancer, the ethanol delivery rate being about 100-800 mcg/hr/cm2 of skin surface.
4:0130:3P1CMG
Description
~1~6~6~ ARC 742 DOSAGE FORM FOR COADMINISTERING DRUG AN~
PERCUTANEOUS ABSORPTION ENHANCER
Technical Field Ths invention is a dosage for administering drugs percutaneously. It is particularl~ useful for administering estradiol percutaneously.
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The practicality of administering a given drug percutane-ously on a continuous basis depends upon the concentration of drug in the blood that is required to provide the desired therapy, how permeable the skin i5 to the drug, and the amount of skin surface area that i~ available for administration.
The available skin surface area, while .theoretically not being limited, is for patient acceptance reasons typically confined to more than about 5 cm~ and less than about 100 cm2~ With available area fixed in this range, the matter narrows to whether sufficient drug will pass through that much area to provide~ the desired therapy. If it will, it is simple to e~fectively administer the drug percutaneously. If, however, the inherent permeability o~ the s~in to the drug is qo high or so low that too much or too little drug will pass through i `~ that area of skin, the rate~of administration of the drug to the skin, the rate of administration of the drug to the skin must be con~rolled or the permeability of the skin to the dru~
must be increased, as the case may be, to make percutaneous administration practical. The present invention invol~es a situation in which the permeability of the skin to the drug is increased.
.
~e
PERCUTANEOUS ABSORPTION ENHANCER
Technical Field Ths invention is a dosage for administering drugs percutaneously. It is particularl~ useful for administering estradiol percutaneously.
~ .
~ f~
The practicality of administering a given drug percutane-ously on a continuous basis depends upon the concentration of drug in the blood that is required to provide the desired therapy, how permeable the skin i5 to the drug, and the amount of skin surface area that i~ available for administration.
The available skin surface area, while .theoretically not being limited, is for patient acceptance reasons typically confined to more than about 5 cm~ and less than about 100 cm2~ With available area fixed in this range, the matter narrows to whether sufficient drug will pass through that much area to provide~ the desired therapy. If it will, it is simple to e~fectively administer the drug percutaneously. If, however, the inherent permeability o~ the s~in to the drug is qo high or so low that too much or too little drug will pass through i `~ that area of skin, the rate~of administration of the drug to the skin, the rate of administration of the drug to the skin must be con~rolled or the permeability of the skin to the dru~
must be increased, as the case may be, to make percutaneous administration practical. The present invention invol~es a situation in which the permeability of the skin to the drug is increased.
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-2 ARC 742 There is a great deal of literature concerning compounds that enhance the percutaneous abosrption of drugs. Typically a given amount of the enhancer is applied to the skin together with a given amount of the drug in a formulation that has no ability to control the rates at which the enhancer and drug are administered to the skin surface. In such instances more drug and more enhancer are present at the skin sur~ace than the skin can absorb. Thus both drug and enhancer pass through the skin at maximum rates which are likely to be in excess of that needed to provide the desired therapeutic result.
U.S. Patent No. 4031894 suggests pre- or coadministration of percutaneous absorption enhancers in connection with the controlled percutaneous administration of scopolamine. The enhancer is applied to eliminate the stratum corneum as a rate affecting barrier to scopolamine absorption. To do this the enhancer must elevate the skin permeability to a level at which scopolamine is capable of moving through the skin ~aster than it is being applied to the skin surface by the system described in the patent. Thus the scopolamine permeates through the skin surface. In this type of application the scopolamine administration rate ls said to be controlled by the system rather than by the skin. Correlatively, the enhancer ;~ administration rate (when coadministered with scopolamine) may be either system-controlled or skin-controlled, but in either case is of such magnitude as to make the scopolamine adminis-tration rate system-controlled.
U.S. Patent No. 3797494 describes bandages for admlnis-tering drugs percutaneously in which the drug may be mixed with a transport agent that enhances the penetration of the skin by the drug. The main components of these bandages are a backing layer, a drug reservoir layer, a microporous membrane layer, and a contact adhesive layer. The patent indicates that the rate oY drug administration is controlled by the rate at which drug diffuses from the reservoir through the micro-porous membrane. These bandages operate, therefore, in the
U.S. Patent No. 4031894 suggests pre- or coadministration of percutaneous absorption enhancers in connection with the controlled percutaneous administration of scopolamine. The enhancer is applied to eliminate the stratum corneum as a rate affecting barrier to scopolamine absorption. To do this the enhancer must elevate the skin permeability to a level at which scopolamine is capable of moving through the skin ~aster than it is being applied to the skin surface by the system described in the patent. Thus the scopolamine permeates through the skin surface. In this type of application the scopolamine administration rate ls said to be controlled by the system rather than by the skin. Correlatively, the enhancer ;~ administration rate (when coadministered with scopolamine) may be either system-controlled or skin-controlled, but in either case is of such magnitude as to make the scopolamine adminis-tration rate system-controlled.
U.S. Patent No. 3797494 describes bandages for admlnis-tering drugs percutaneously in which the drug may be mixed with a transport agent that enhances the penetration of the skin by the drug. The main components of these bandages are a backing layer, a drug reservoir layer, a microporous membrane layer, and a contact adhesive layer. The patent indicates that the rate oY drug administration is controlled by the rate at which drug diffuses from the reservoir through the micro-porous membrane. These bandages operate, therefore, in the
3; same manner as those described in U.S. Patent No. 4031894.
The drug administration rate is controlled by the bandage rather than by the rate at which drug is absorbed by the skin.
U.S. Patent No. 3053255 discloses a multilayer unit for administering drugs percutaneously that is composed of the following layers beginning with the one closest to the skin:
a fibrous carrier layer in which the drug is absorbed; an impervious separator layer; a reservoir layer in which a liquid transport agent that is a solvent for the drug is absorbed;
and an impervious cover layer. One or more wicks run between the reservoir layer and the carrier layer and serve as a conduit for the flow o~ transport agent from the ~ormer to the latter.
In operation the transport agent ~lows from the reservoir layer to the carrier layer via the wicks. The transport agent dissolves drug absorbed in the carrier layer as it passes therethrough and then, together with dissolved drug, is absorbed by the skin. The cross-sectional area of the wicks "must be ~uch that at least so much of the vehicle can flow therethrough (including the active agent dissolved therein) as will be absorbed by the skin from the active agent carrier". This quote indicates that the amounts of drug and transport agent presented to the skin are equal to or greater than the amounts that the skin can absorb.
Disclosure of Invention _ .
; 25 The invention is a unit dosage form and method that ; coadminister a drug and a percutaneous absorption enhancer to a predetermined a~ea of skin. The drug is administered to the skin at a rate at least as great as the rate at which the skin is capable of absorbing it while the percutaneous absorption enhancer is administered at a substantially constant rate that increases the permeability of the treated area of skin to the drug to a magnitude such that sufricient drug is absorbed to provide a therapeutically effective level of drug in the bloods~ream. Accordingly the rate of drug administration is controlled by the rate at which the skin absorbs the drug whereas the rate of percutaneous absorption enhancer ; ARC 742 administration is controlled by the rate at which the enhancer is released from the dosage form to the skin sur~ace. The rate of drug administration is, therefore, controlled indirectly by the controlled corelease of the enhancer since the latter affects the rate at which the skin will absorb the drug.
More specifically the dosage rorm comprises a body (a) having a basal surface (1) of area at least about equal to the area of skin to be treated, (ii) that is adapted to contact the area of skin over the time period, and (iii) via which the drug and enhancer are presented to the area of skin for absorption therby;
(b) containing a supply of the drug that communicates with the basal surface to provide drug at the basal surface over the time period such that over a substantial portion of the time period the amount of drug provided to the basal surface is in excess of that which the area of skin is able to absorb;
; (c) containing a suppy of the percutaneous absorption enhancer that communicates with the bas~al surface so as to provide the enhancer at the basal surface over said time period;
; and (d) including means for maintaining the rate at which the enharcer is provided at the basal surface substantially constant over a substantial portion of the time period, the rate being (i) below the maximum rate the area of skin is able to absorb, and ~ ii) sufficient to increase the per~eability of the area of skin to the drug such that the drug is absorbed thereby at a rate that provides a therapeutically effective level of the drug in the bloodstream of the patient.
Correlatively the method comprises (a) administering the drug to the area continuousl~
over the time period such that over a substantial portion of the time period the amount of drug administered is in excess of that which the area of skin is able to absorb; and (b) simultaneously and continuously coadministeri~g a percutaneous absorption enhancer to the area of skin at a rate that is substantially constant over a substantial portion of the time period, the rate being ~i) below the maximum rate the area of skin is able to absorb, and (ii) sufficient to increase the permeability of the area of skin to the drug such that the drug is absorbed thereby at a rate that provides a therapeutically effective level of the drug in the bloodstream of the patient.
As used herein the term "substantial portion of the time period" means at least about 60% of the time period, preferably at least about 90~ of the time period. Correlatively, the term "substantially constant" means a variation of less than about ~ 20%~ preferably less than about ~ 10%, over a substantial portion of the ti~e period.
The above described dosage form and method are especially useful for coadministering estradiol and ethanol percutaneously to treat conditions associated with natural estradiol deficiency, such as osteoporosis and headaches~ nausea, depression~ hot flashes, and other diseomforts that often occur during menopause.
~' Brief Desoription of the Drawin~
In the drawings, which are not to scale:
Fig. 1 is an enlarged sectional schematic view of a fir~t embodiment of the invention;
Fig. 2 is an enlarged sectional schematic view of a second embodiment of the invention;
Fig. 3 is an enlarged schematic sectional view of a third embodiment of the invention;
Fig. 4 is an enlarged sectional schematic view of a fourth embodiment of the invention;
Fig. 5 is a graph illustrating the rela~tionship between the drug flux through skin and the enhancer flux through skin that is typical for many drug-enhancer combinations;
Fig. 6 is a graph of estradiol ~luxes versus time for the bandage of Example 1 and for a gelled estradiol-ethanol mixture;
Fig. 7 is a graph of ethanol fluxes versus time for the bandage of Example 1 and for a gelled estradiol-ethanol mixture;
Fig. 8 is a graph showing the plasma estradiol concentra-tion resulting from estradiol administration via the invention and via a commercial ointment; and Fig. 9 is a graph of estradiol fluxes versus ethanol fluxes for the bandages of Example 2.
Modes for Carrying Out the Invention Fig. 1 illustrates a self-adhering skin patch 11 that is designed to be placed on unbroken skin 12. Patch 11 is a laminate that con3ists of four layers: a top backing layer 13; a drug-enhancer reservoir layer 14, a diffusion membrane layer 15, and a cQntact adhesive layer 16. Backing layer 13 define~ the top of the patch. It is made from a material or combination of materials that i5 substantially impermeable to the compenents of reservoir 14. It serves as a proteotive cover the for the patch, keeps the components of reservoir lamina 14 from escaping from the bandage, and ful~ills a structural support function. Examples of materials that may be u~ed to make layer 13 are high and low density polyethylene, polypropylene, polyvinylchloride, and polyethylene terephthalate.
2S In embodiment~ o~ the invention in which reservoir layer is fluid 9 the outer edge of the backing layer will overlay the edge of the reservoir layer and be saaled by adhesion or fusion to the dif~usion membrane layer. In such structures the reservoir layer is contained wholly between the backing layer and the membrane layer and does not have any exposed surfaces.
The backing and diffusion rnembrane layers will be inherently sealable to each other or will include sealing means, such as an additional layer or adhesi~e, in such embodiments.
Reservoir layer 14 is immediately below backing 13. It contain~ supplies of both the percutaneous absorption enhancer and the drug. The amount of drug in the reservoir will depend ~6~
on the rate at which the drug is absorbed by the skin from the bandage and the intended duration of therapy. Correlatively, the amount of enhancer in the reservoir will depend upon the rate at which the enhancer is administered to the skin from the bandage to achieve the desired degree of drug permeability enhancement over the treatm0nt period. Reservoir layer 14 may include diluents, stabilizers, vehicles, gelling agents, and the like in addition to the drug and enhancer~
In the embodiment of the invention that coadministers estradiol and ethanol the principal components of lamina 14 are estradiol and ethanol. The estradiol is present either wholly in solution or in both dissolved and undissolved particulate form dispersed uniformly through a continuous ethanol phase. The continuous phase contains estradiol over the lifetime of the bandage and the minimum amount of estradiol in layer 14 wîll depend on its solubility in the continuous phase and the intended lifetime of the bandage. Typically about 0.2 to 12 mg estradiol will be contained in the reservoir layer. Similarly, the minimum amount of ethanol in layer 14 is that which is sufficient to provide a substantially constant ~lux of about 100 to 800 mcg/cm2/hr, preferably 100 to 400 mcg/cm2/hr, of ethanol to the area o~ skin being treated over a substantial portion of the intended lifetime of the bandage. The continunus ethanol phase may also contain one or more covehicles, such as water, along with ethanol to alter the solubility of eskradiol in the continuous phase. By reducing the solubility of estradiol in the lamina, the quantity of estradiol in the lamina may be reduoed signi~icantly. For instance by using water as a covehicle at a 40% by weight level, the quantity of estradiol may be reduced almost two orders o~
magnitude. Preferably the continuous phase is in the form of a gel that contains 50% to 75~, by weight water sa that it may be handled-sasily in manufacturing the bandage. Known gelling agents such as carboxypolymethylene, ethylene maleic anhydride, hydroxyethylcellulose, polyacrylamide, ethylhydroxyethylcellulose, hydroxypropylcellulose, and poly (methylvinylether-maleic ~ l ~ 6C9 ~ ARC 742 anhydride) may be included in the continuous phase to make it gel. The viscosity of these gels are such that the estradiol-ethanol layer should be wholly contained between the backing layer and-the diffusion membrane in the manner described above.
Diffusion membrane layer 15, the next layer of the laminate, may be made of a dense or microporous polymer ~ilm that has the requisite permeability to the drug and enhancer. It is the member of patch 11 that controls the rate at which the enhancer is administered to the skin. It does not, however, control the rate at which the drug is administered. In other words, it is a principal permeation barrier to the enhancer but not a significant permeation barrier to the drug. The respective fluxes of the drug and enhancer through layer 15 will depend upon the thickness of the layer and its diffusion coefficients relative to the drug and the enhancer. Diffusion coefricients may be determined by standard techniques.
Accordingly, films that will permit the required fluxes of drug and enhancer may be selected based on diffusion coef~
ficients and thickness. Preferably the membrane layer 15 is substantially impermeable to other com~onents of the reservoir layer. Examples of the types of polymer films that may be " used to make layer 15 are disclosed in U.S. Pats. Nos. 3797494 and ~031&94.
Contact adhe~ive lamina 16 is directly below diffusion membrane layer 15. It is the means by which bandage 11 is af~ixed to the area of skin to be treated. Its composition and thickne~s are such that it does not constitute a significant permeation barrier to the drug and the enhancer. In other words it should be substantially more permeable to the enhanoer than layer 15 and at least as permeable to the drug as layer 15. During the time interval between the manufacturer and the ; u~e of bandage 11, layer 16 may absorb enhancer and drug in amounts that will depend upon the composition and thickness of layer 16 and the length of that time interval. If that interval is quite long, layer 16 will absorb enhancer and drug until it is saturated therewith. The reléase of such absorbed enhancer from layer 16 once the bandage is applied to the skin may cause the release rate of enhancer from the bandage to exceed the desired steady~state rate for a short period of time. That condition will be transient and will not affect the function-ality of the bandage in providing controlled therapy. Contact adhesive compositions that may be used to make layer 16 are disclosed in U.S. Pats~ Nos. 3797494 and 4031894.
Prior to use, bandage 11 also includes a protective undercoating lamina (not shown). Just prior to use, the undercoating lamina is pulled away from lamina 16 and discarded.
It is made from materials that are substantially impermeable to the drug, the enhancer, and any other components of layer 16~ The same materials that are used to make backing layer 13 may be used to make the undercoating layer, provided they are made strippable such as by siliconizing.
Bandage 11 is applied to a relatively nohairy area of ~kin 12 that is substantially free of wrinkles, creases, or foldsO Various locations on the torso, such as the flank or shoulder, provide suitable sites for the bandage. As indicated above, once it is placed on the skin the bandage wilL begin coadministering drug and enhancer to the wearer, with the enhancer being released at a substantially constant rate (followin~ an initial transient surge) and drug being released at the rate at whlch the enhancer-treated skin is capable of absorbing it. The rate at which the treated skin is capable of absorbing the drug is a~ected by the enhancer flux through it. Therefore, although drug release is oontrolled principally by the skir., it is controlled indirectly via the enhancer flux.
In the embodiment that coadministers estradiol and ethanol the steady state release rate o~ ethanol from the bandage is about 100 to 800 mcg/cm2/hr, preferably about 100 to about 400 mcg/cm2/hr.
Such rates o~ ethanol release will permit percutaneous absorption of estradiol at a therapeutically effective rate. In t.his regard the steady state estradiol concentration in the plasma is incremented by about 15 to 40 pg/ml for every 1 mcg of estradiol administered per hour.
~ ~ ~ 6 ~9~ 1 ARC 742 -- 1 0~
Fig. 2 depicts another embodiment, generally designated 17, of the invention in which the drug and enhancer are stored in separate reservoirs. Embodiment 17 is a laminate composed of four layers: a backing layer 18, a percutaneous enhancer reservoir layer 19, a diffusion membrane layer 22, a drug reservoir-contact adhesive layer 23. Layer 18 is identical in structure and function to layer 13 of embodiment 11. Layer 19 contains the supply of percutaneous absorption enhancer. As lO .in embodiment 11, the amount of enhancer in layer 19 will depend on the rate of enhancer administration required to achieve the desired degree of drug permeability enhancement.
It may include diluent, stabilizers, vehicles, gelling agent, and other formulation aids in addition to the enhancer. Layer lS 22 is the component of bandage 17 that controls the release rate o~ enhancer to the skin. In this regard it is structurally compositionally, and ~unctionally similar to membrane 15 of embodiment 11. Since the drug does not pass through layer 22, layer 22 need not be permeable to the drug. Indeed it is preferred that it be substantially impermeable to the drug to 20 minimize upward migration of the drug from the drug reservoir ~; layer 23. Layer 23 contains the supply of drug admixed with a contact adhesive composition, with the amount of drug depending on the rate at which the drug is absorbed by the skin and the duration of therapy. The contact adhesive composition may be 25 the same material as is used to make layer 16 of embodiment 11. Alternatively, layer 23 may be separated into a distinct drug reservoir layer composed o~ the drug supply and a suitable matrix material and a distinct contact adhesive layer underlying the drug reservoir layer.
Embodiments such as bandage 17 in which the drug and enhancer supplies are separate may be advantageous or necessary in instances where formulation or storage o~ the drug and enhancer in contact with each other is impractical or undesirable or where separation of the drug and enhancer ~acilitate selection of the di~fusion membrane.
~ ARC 742 Fig. 3 illustrates another embodiment, generally designated 25, in which the supplies of drug and enhancer are separate.
Embodiment 25 is a laminate composed o~ two layers: a backing layer 26 and a heterogeneous microcapsule-containing basal layer 27. Backing layer 26 is structurally, compositionally, and functionally identical to layer 13 o~ embodiment 11.
Heterogeneous basal layer 27 is composed of a continuous matrix phase 28 in which enhancer-containing microcapsules 29 and drug 32 (represented by stippling in ~ig. 3) are dispersed.
Continuous matrix phase 28 is a solid, semi-solid or gel compo-sition that is permeable to the enhancer and the drug. It preferably adheres to skin. If it does not, an adhesive overlay will have to be used to keep embodiment 25 in contact with the skin. The contact adhesive compositions that are used to make the contact adhesive layers of embodiment 11 and 17 will usually be suitable for use as continuous matrix phase 28. Microcapsules 29 each consist o~ an inner core of percutaneous absorption enhancer encapsulated by a diffusion membrane. The diffusion membrane ~unctions as diffusion membranes 15 and 22 and may be made of the same materials and be selected based on the same criteria as membranes 15 and 22. Accordingly the dif~usion membrane of each microcapsule contr-ols the rate at which the enhancer from all the microcapsule controls the rate at which the enhancer is released there~rom. The combined release of 25 enhancer ~rom all the microcapsules in turn defines the rate of release of enhancer from embodiment 25. As in the case of the other embodiments the amount of enhancer contained in layer 27 in microoapsule form will depend upon the required enhancer release rate and duration of therapy. Microcapsules 29 may be made using conventional microcapsule ~orming techniques. Drug 32 is present in continuous phase 28 in dissolved or in both dissolved and undissolved forms. The amount of drug present in layer 27 i9 in exces3 o~ that required to provide a continuow~
source of drug at the skin surface. The particular amount present in a given in~tance will depend upon the rate at which the drug is absorbed by the skin from layer 27 and the duration 6~.
of therapy. The thickness and composition of continuous phase 28 should be such that the phase does not constitute a principal permeation barrler to either the enhancer or the drug.
Figure 4 shows another embodiment of the invention, gener-ally designated 33. The components of embodiment 33 are backing layer 34, a reservoir layer 35 that contains supplies of percutan-eous absorption enhancer and drug, a diffusion membrane layer 36, and a peripheral ring 37 of contact adhesive. Embodiment 33 is structurally~ functionally, and compositionally identical to embod-iment 11 except in the following respects. First, the contact adhesive component of embodiment 33 is in the form of a peripheral ring rather than a continuous basal layer. Neither drug nor enhan-cer passes through ring 37 and it, there~ore, need not to be ; permeable to those compositions. Secondly, in embodiment 33 the basal surface from which drug and enhancer is transferred to the skin is defined by diffusion membrane layer 36. Thirdly, the backing layer is not flat but instead forms a pocket or cavity in which the reservoir layer is held. Lastly, the outer ed~e of the backing layer is sealed to the peripheral ring of contact adhesive.
The embodiments of Figures 1-4 may be designed to admin-ister drug and enhancer at optimum rates to achieve the desired therapy. In order to determine the optimum rate for a given drug~
enhancer combination it is necessary to determine the relationship between the drug flux through the skin and the enhancer flux through the skin. Figure 5 shows a plo~ o~ enhancer flux versus drug flux that is typical for many combinations. Drug flux increas-es substantially linearly at enhancer fluxes between 0 and "a". At enhancer flux "a" the drug flux levels off at "y" and is not .increased by further increases in the enhancerflux above "a". An optimum design for embodiment involving drug-enhancer combinations having such a relationship will employ an enhancer flux slightly above "a': At thatenhancer flux, drug flux is at a maximum and is unaffected by minor perturbations in the enchancer flux.
- 12~ -6~
The following examples further illustrate the dosage form of the invention, its manufacture, and i-ts operation. These examples are not intended to limit the invention in any manner.
Unless indicated otherwise proportions are by weight.
Example 1 Bandages tha-t coadminister ethanol and estradiol were made as follows. A solution of estradiol in 95~ ethanol was prepared by mixing 0.0315 part 17-~- estradiol in 1.000 part 95~
ethanol. That mixture was gelled by adding 0.0210 part hydroxy-propyl-cellulose (mw 1000000, sold under the trademark Klucel) with mixing.
Next, a contact adhesive composition was made by mixing polyisobutene (mw 1200000), polyisobutene (mw 35000), and light mineral oil in a weight ratio of 1:1.25:2. A 50 micron thick layer of that contact adhesive was cast onto a 75 micron thick film of siliconized polyethylene terephthalate. The contact ; adhesive side of the resul-ting two-layer subassembly was laminated to a 50 micron-thick film of ethylene vinyl acetate (EVA~ copoly-mer (9% vinyl acetate). The resulting three-layer subassembly was cut into 15 cm x 11 cm pieces. Four 400 mg portions of the gelled estradiol-ethanol mixture were placed equally spaced on the EVA
~ copolymer side of each piece and a 63.5 micron thick backing ilm ; of aluminized polyethylene terephthalate with an EVA heat sealable coating was laid over the gels. The backing film was heat sealed to the EVA copolymer layer at the periphery o~ each piece at 130 C, 27 kg. Finished bandages were punched from laminate with a
The drug administration rate is controlled by the bandage rather than by the rate at which drug is absorbed by the skin.
U.S. Patent No. 3053255 discloses a multilayer unit for administering drugs percutaneously that is composed of the following layers beginning with the one closest to the skin:
a fibrous carrier layer in which the drug is absorbed; an impervious separator layer; a reservoir layer in which a liquid transport agent that is a solvent for the drug is absorbed;
and an impervious cover layer. One or more wicks run between the reservoir layer and the carrier layer and serve as a conduit for the flow o~ transport agent from the ~ormer to the latter.
In operation the transport agent ~lows from the reservoir layer to the carrier layer via the wicks. The transport agent dissolves drug absorbed in the carrier layer as it passes therethrough and then, together with dissolved drug, is absorbed by the skin. The cross-sectional area of the wicks "must be ~uch that at least so much of the vehicle can flow therethrough (including the active agent dissolved therein) as will be absorbed by the skin from the active agent carrier". This quote indicates that the amounts of drug and transport agent presented to the skin are equal to or greater than the amounts that the skin can absorb.
Disclosure of Invention _ .
; 25 The invention is a unit dosage form and method that ; coadminister a drug and a percutaneous absorption enhancer to a predetermined a~ea of skin. The drug is administered to the skin at a rate at least as great as the rate at which the skin is capable of absorbing it while the percutaneous absorption enhancer is administered at a substantially constant rate that increases the permeability of the treated area of skin to the drug to a magnitude such that sufricient drug is absorbed to provide a therapeutically effective level of drug in the bloods~ream. Accordingly the rate of drug administration is controlled by the rate at which the skin absorbs the drug whereas the rate of percutaneous absorption enhancer ; ARC 742 administration is controlled by the rate at which the enhancer is released from the dosage form to the skin sur~ace. The rate of drug administration is, therefore, controlled indirectly by the controlled corelease of the enhancer since the latter affects the rate at which the skin will absorb the drug.
More specifically the dosage rorm comprises a body (a) having a basal surface (1) of area at least about equal to the area of skin to be treated, (ii) that is adapted to contact the area of skin over the time period, and (iii) via which the drug and enhancer are presented to the area of skin for absorption therby;
(b) containing a supply of the drug that communicates with the basal surface to provide drug at the basal surface over the time period such that over a substantial portion of the time period the amount of drug provided to the basal surface is in excess of that which the area of skin is able to absorb;
; (c) containing a suppy of the percutaneous absorption enhancer that communicates with the bas~al surface so as to provide the enhancer at the basal surface over said time period;
; and (d) including means for maintaining the rate at which the enharcer is provided at the basal surface substantially constant over a substantial portion of the time period, the rate being (i) below the maximum rate the area of skin is able to absorb, and ~ ii) sufficient to increase the per~eability of the area of skin to the drug such that the drug is absorbed thereby at a rate that provides a therapeutically effective level of the drug in the bloodstream of the patient.
Correlatively the method comprises (a) administering the drug to the area continuousl~
over the time period such that over a substantial portion of the time period the amount of drug administered is in excess of that which the area of skin is able to absorb; and (b) simultaneously and continuously coadministeri~g a percutaneous absorption enhancer to the area of skin at a rate that is substantially constant over a substantial portion of the time period, the rate being ~i) below the maximum rate the area of skin is able to absorb, and (ii) sufficient to increase the permeability of the area of skin to the drug such that the drug is absorbed thereby at a rate that provides a therapeutically effective level of the drug in the bloodstream of the patient.
As used herein the term "substantial portion of the time period" means at least about 60% of the time period, preferably at least about 90~ of the time period. Correlatively, the term "substantially constant" means a variation of less than about ~ 20%~ preferably less than about ~ 10%, over a substantial portion of the ti~e period.
The above described dosage form and method are especially useful for coadministering estradiol and ethanol percutaneously to treat conditions associated with natural estradiol deficiency, such as osteoporosis and headaches~ nausea, depression~ hot flashes, and other diseomforts that often occur during menopause.
~' Brief Desoription of the Drawin~
In the drawings, which are not to scale:
Fig. 1 is an enlarged sectional schematic view of a fir~t embodiment of the invention;
Fig. 2 is an enlarged sectional schematic view of a second embodiment of the invention;
Fig. 3 is an enlarged schematic sectional view of a third embodiment of the invention;
Fig. 4 is an enlarged sectional schematic view of a fourth embodiment of the invention;
Fig. 5 is a graph illustrating the rela~tionship between the drug flux through skin and the enhancer flux through skin that is typical for many drug-enhancer combinations;
Fig. 6 is a graph of estradiol ~luxes versus time for the bandage of Example 1 and for a gelled estradiol-ethanol mixture;
Fig. 7 is a graph of ethanol fluxes versus time for the bandage of Example 1 and for a gelled estradiol-ethanol mixture;
Fig. 8 is a graph showing the plasma estradiol concentra-tion resulting from estradiol administration via the invention and via a commercial ointment; and Fig. 9 is a graph of estradiol fluxes versus ethanol fluxes for the bandages of Example 2.
Modes for Carrying Out the Invention Fig. 1 illustrates a self-adhering skin patch 11 that is designed to be placed on unbroken skin 12. Patch 11 is a laminate that con3ists of four layers: a top backing layer 13; a drug-enhancer reservoir layer 14, a diffusion membrane layer 15, and a cQntact adhesive layer 16. Backing layer 13 define~ the top of the patch. It is made from a material or combination of materials that i5 substantially impermeable to the compenents of reservoir 14. It serves as a proteotive cover the for the patch, keeps the components of reservoir lamina 14 from escaping from the bandage, and ful~ills a structural support function. Examples of materials that may be u~ed to make layer 13 are high and low density polyethylene, polypropylene, polyvinylchloride, and polyethylene terephthalate.
2S In embodiment~ o~ the invention in which reservoir layer is fluid 9 the outer edge of the backing layer will overlay the edge of the reservoir layer and be saaled by adhesion or fusion to the dif~usion membrane layer. In such structures the reservoir layer is contained wholly between the backing layer and the membrane layer and does not have any exposed surfaces.
The backing and diffusion rnembrane layers will be inherently sealable to each other or will include sealing means, such as an additional layer or adhesi~e, in such embodiments.
Reservoir layer 14 is immediately below backing 13. It contain~ supplies of both the percutaneous absorption enhancer and the drug. The amount of drug in the reservoir will depend ~6~
on the rate at which the drug is absorbed by the skin from the bandage and the intended duration of therapy. Correlatively, the amount of enhancer in the reservoir will depend upon the rate at which the enhancer is administered to the skin from the bandage to achieve the desired degree of drug permeability enhancement over the treatm0nt period. Reservoir layer 14 may include diluents, stabilizers, vehicles, gelling agents, and the like in addition to the drug and enhancer~
In the embodiment of the invention that coadministers estradiol and ethanol the principal components of lamina 14 are estradiol and ethanol. The estradiol is present either wholly in solution or in both dissolved and undissolved particulate form dispersed uniformly through a continuous ethanol phase. The continuous phase contains estradiol over the lifetime of the bandage and the minimum amount of estradiol in layer 14 wîll depend on its solubility in the continuous phase and the intended lifetime of the bandage. Typically about 0.2 to 12 mg estradiol will be contained in the reservoir layer. Similarly, the minimum amount of ethanol in layer 14 is that which is sufficient to provide a substantially constant ~lux of about 100 to 800 mcg/cm2/hr, preferably 100 to 400 mcg/cm2/hr, of ethanol to the area o~ skin being treated over a substantial portion of the intended lifetime of the bandage. The continunus ethanol phase may also contain one or more covehicles, such as water, along with ethanol to alter the solubility of eskradiol in the continuous phase. By reducing the solubility of estradiol in the lamina, the quantity of estradiol in the lamina may be reduoed signi~icantly. For instance by using water as a covehicle at a 40% by weight level, the quantity of estradiol may be reduced almost two orders o~
magnitude. Preferably the continuous phase is in the form of a gel that contains 50% to 75~, by weight water sa that it may be handled-sasily in manufacturing the bandage. Known gelling agents such as carboxypolymethylene, ethylene maleic anhydride, hydroxyethylcellulose, polyacrylamide, ethylhydroxyethylcellulose, hydroxypropylcellulose, and poly (methylvinylether-maleic ~ l ~ 6C9 ~ ARC 742 anhydride) may be included in the continuous phase to make it gel. The viscosity of these gels are such that the estradiol-ethanol layer should be wholly contained between the backing layer and-the diffusion membrane in the manner described above.
Diffusion membrane layer 15, the next layer of the laminate, may be made of a dense or microporous polymer ~ilm that has the requisite permeability to the drug and enhancer. It is the member of patch 11 that controls the rate at which the enhancer is administered to the skin. It does not, however, control the rate at which the drug is administered. In other words, it is a principal permeation barrier to the enhancer but not a significant permeation barrier to the drug. The respective fluxes of the drug and enhancer through layer 15 will depend upon the thickness of the layer and its diffusion coefficients relative to the drug and the enhancer. Diffusion coefricients may be determined by standard techniques.
Accordingly, films that will permit the required fluxes of drug and enhancer may be selected based on diffusion coef~
ficients and thickness. Preferably the membrane layer 15 is substantially impermeable to other com~onents of the reservoir layer. Examples of the types of polymer films that may be " used to make layer 15 are disclosed in U.S. Pats. Nos. 3797494 and ~031&94.
Contact adhe~ive lamina 16 is directly below diffusion membrane layer 15. It is the means by which bandage 11 is af~ixed to the area of skin to be treated. Its composition and thickne~s are such that it does not constitute a significant permeation barrier to the drug and the enhancer. In other words it should be substantially more permeable to the enhanoer than layer 15 and at least as permeable to the drug as layer 15. During the time interval between the manufacturer and the ; u~e of bandage 11, layer 16 may absorb enhancer and drug in amounts that will depend upon the composition and thickness of layer 16 and the length of that time interval. If that interval is quite long, layer 16 will absorb enhancer and drug until it is saturated therewith. The reléase of such absorbed enhancer from layer 16 once the bandage is applied to the skin may cause the release rate of enhancer from the bandage to exceed the desired steady~state rate for a short period of time. That condition will be transient and will not affect the function-ality of the bandage in providing controlled therapy. Contact adhesive compositions that may be used to make layer 16 are disclosed in U.S. Pats~ Nos. 3797494 and 4031894.
Prior to use, bandage 11 also includes a protective undercoating lamina (not shown). Just prior to use, the undercoating lamina is pulled away from lamina 16 and discarded.
It is made from materials that are substantially impermeable to the drug, the enhancer, and any other components of layer 16~ The same materials that are used to make backing layer 13 may be used to make the undercoating layer, provided they are made strippable such as by siliconizing.
Bandage 11 is applied to a relatively nohairy area of ~kin 12 that is substantially free of wrinkles, creases, or foldsO Various locations on the torso, such as the flank or shoulder, provide suitable sites for the bandage. As indicated above, once it is placed on the skin the bandage wilL begin coadministering drug and enhancer to the wearer, with the enhancer being released at a substantially constant rate (followin~ an initial transient surge) and drug being released at the rate at whlch the enhancer-treated skin is capable of absorbing it. The rate at which the treated skin is capable of absorbing the drug is a~ected by the enhancer flux through it. Therefore, although drug release is oontrolled principally by the skir., it is controlled indirectly via the enhancer flux.
In the embodiment that coadministers estradiol and ethanol the steady state release rate o~ ethanol from the bandage is about 100 to 800 mcg/cm2/hr, preferably about 100 to about 400 mcg/cm2/hr.
Such rates o~ ethanol release will permit percutaneous absorption of estradiol at a therapeutically effective rate. In t.his regard the steady state estradiol concentration in the plasma is incremented by about 15 to 40 pg/ml for every 1 mcg of estradiol administered per hour.
~ ~ ~ 6 ~9~ 1 ARC 742 -- 1 0~
Fig. 2 depicts another embodiment, generally designated 17, of the invention in which the drug and enhancer are stored in separate reservoirs. Embodiment 17 is a laminate composed of four layers: a backing layer 18, a percutaneous enhancer reservoir layer 19, a diffusion membrane layer 22, a drug reservoir-contact adhesive layer 23. Layer 18 is identical in structure and function to layer 13 of embodiment 11. Layer 19 contains the supply of percutaneous absorption enhancer. As lO .in embodiment 11, the amount of enhancer in layer 19 will depend on the rate of enhancer administration required to achieve the desired degree of drug permeability enhancement.
It may include diluent, stabilizers, vehicles, gelling agent, and other formulation aids in addition to the enhancer. Layer lS 22 is the component of bandage 17 that controls the release rate o~ enhancer to the skin. In this regard it is structurally compositionally, and ~unctionally similar to membrane 15 of embodiment 11. Since the drug does not pass through layer 22, layer 22 need not be permeable to the drug. Indeed it is preferred that it be substantially impermeable to the drug to 20 minimize upward migration of the drug from the drug reservoir ~; layer 23. Layer 23 contains the supply of drug admixed with a contact adhesive composition, with the amount of drug depending on the rate at which the drug is absorbed by the skin and the duration of therapy. The contact adhesive composition may be 25 the same material as is used to make layer 16 of embodiment 11. Alternatively, layer 23 may be separated into a distinct drug reservoir layer composed o~ the drug supply and a suitable matrix material and a distinct contact adhesive layer underlying the drug reservoir layer.
Embodiments such as bandage 17 in which the drug and enhancer supplies are separate may be advantageous or necessary in instances where formulation or storage o~ the drug and enhancer in contact with each other is impractical or undesirable or where separation of the drug and enhancer ~acilitate selection of the di~fusion membrane.
~ ARC 742 Fig. 3 illustrates another embodiment, generally designated 25, in which the supplies of drug and enhancer are separate.
Embodiment 25 is a laminate composed o~ two layers: a backing layer 26 and a heterogeneous microcapsule-containing basal layer 27. Backing layer 26 is structurally, compositionally, and functionally identical to layer 13 o~ embodiment 11.
Heterogeneous basal layer 27 is composed of a continuous matrix phase 28 in which enhancer-containing microcapsules 29 and drug 32 (represented by stippling in ~ig. 3) are dispersed.
Continuous matrix phase 28 is a solid, semi-solid or gel compo-sition that is permeable to the enhancer and the drug. It preferably adheres to skin. If it does not, an adhesive overlay will have to be used to keep embodiment 25 in contact with the skin. The contact adhesive compositions that are used to make the contact adhesive layers of embodiment 11 and 17 will usually be suitable for use as continuous matrix phase 28. Microcapsules 29 each consist o~ an inner core of percutaneous absorption enhancer encapsulated by a diffusion membrane. The diffusion membrane ~unctions as diffusion membranes 15 and 22 and may be made of the same materials and be selected based on the same criteria as membranes 15 and 22. Accordingly the dif~usion membrane of each microcapsule contr-ols the rate at which the enhancer from all the microcapsule controls the rate at which the enhancer is released there~rom. The combined release of 25 enhancer ~rom all the microcapsules in turn defines the rate of release of enhancer from embodiment 25. As in the case of the other embodiments the amount of enhancer contained in layer 27 in microoapsule form will depend upon the required enhancer release rate and duration of therapy. Microcapsules 29 may be made using conventional microcapsule ~orming techniques. Drug 32 is present in continuous phase 28 in dissolved or in both dissolved and undissolved forms. The amount of drug present in layer 27 i9 in exces3 o~ that required to provide a continuow~
source of drug at the skin surface. The particular amount present in a given in~tance will depend upon the rate at which the drug is absorbed by the skin from layer 27 and the duration 6~.
of therapy. The thickness and composition of continuous phase 28 should be such that the phase does not constitute a principal permeation barrler to either the enhancer or the drug.
Figure 4 shows another embodiment of the invention, gener-ally designated 33. The components of embodiment 33 are backing layer 34, a reservoir layer 35 that contains supplies of percutan-eous absorption enhancer and drug, a diffusion membrane layer 36, and a peripheral ring 37 of contact adhesive. Embodiment 33 is structurally~ functionally, and compositionally identical to embod-iment 11 except in the following respects. First, the contact adhesive component of embodiment 33 is in the form of a peripheral ring rather than a continuous basal layer. Neither drug nor enhan-cer passes through ring 37 and it, there~ore, need not to be ; permeable to those compositions. Secondly, in embodiment 33 the basal surface from which drug and enhancer is transferred to the skin is defined by diffusion membrane layer 36. Thirdly, the backing layer is not flat but instead forms a pocket or cavity in which the reservoir layer is held. Lastly, the outer ed~e of the backing layer is sealed to the peripheral ring of contact adhesive.
The embodiments of Figures 1-4 may be designed to admin-ister drug and enhancer at optimum rates to achieve the desired therapy. In order to determine the optimum rate for a given drug~
enhancer combination it is necessary to determine the relationship between the drug flux through the skin and the enhancer flux through the skin. Figure 5 shows a plo~ o~ enhancer flux versus drug flux that is typical for many combinations. Drug flux increas-es substantially linearly at enhancer fluxes between 0 and "a". At enhancer flux "a" the drug flux levels off at "y" and is not .increased by further increases in the enhancerflux above "a". An optimum design for embodiment involving drug-enhancer combinations having such a relationship will employ an enhancer flux slightly above "a': At thatenhancer flux, drug flux is at a maximum and is unaffected by minor perturbations in the enchancer flux.
- 12~ -6~
The following examples further illustrate the dosage form of the invention, its manufacture, and i-ts operation. These examples are not intended to limit the invention in any manner.
Unless indicated otherwise proportions are by weight.
Example 1 Bandages tha-t coadminister ethanol and estradiol were made as follows. A solution of estradiol in 95~ ethanol was prepared by mixing 0.0315 part 17-~- estradiol in 1.000 part 95~
ethanol. That mixture was gelled by adding 0.0210 part hydroxy-propyl-cellulose (mw 1000000, sold under the trademark Klucel) with mixing.
Next, a contact adhesive composition was made by mixing polyisobutene (mw 1200000), polyisobutene (mw 35000), and light mineral oil in a weight ratio of 1:1.25:2. A 50 micron thick layer of that contact adhesive was cast onto a 75 micron thick film of siliconized polyethylene terephthalate. The contact ; adhesive side of the resul-ting two-layer subassembly was laminated to a 50 micron-thick film of ethylene vinyl acetate (EVA~ copoly-mer (9% vinyl acetate). The resulting three-layer subassembly was cut into 15 cm x 11 cm pieces. Four 400 mg portions of the gelled estradiol-ethanol mixture were placed equally spaced on the EVA
~ copolymer side of each piece and a 63.5 micron thick backing ilm ; of aluminized polyethylene terephthalate with an EVA heat sealable coating was laid over the gels. The backing film was heat sealed to the EVA copolymer layer at the periphery o~ each piece at 130 C, 27 kg. Finished bandages were punched from laminate with a
4 cm diameter punch.
In vitro tests were carried out to determine the flu~ of estradiol and ethanol from the above described bandages using the basic techniques described by Chandrasekaran, et al, Am~ Inst.
;~ Chem. Eng. J., 22, 828 (1976). Estradiol concentra-tion in the receptor liquid was assayed chromatographically. For comparison the same tests were carried out by applying a 2 ml layer of the above described gelled estradiol-ethanol mixture on the stratum corneum side o~ the skin mounted in the ,i .
_ 1 ~
diffusional cellsA Figs. 6 and 7 are plots of the results of those tests, with Fig. 6 showing the estradiol fluxes and Fig. 7 showing the ethanol fluxes. As shown the estradiol flux from the gelled estradol ethanol mixture was nonlinear despite a very high, substantially constant ethanol flux. In contrast both the estradiol and ethanol fluxes were substantially constant from the bandages.
In vivo tests were carried out by applying two of the above described bandages to the flank skin of 4 postmenopausal subjects. The results were compared with those reported by Strecker, et al., Maturitas, 1:183-190 (1979). These reported tests were carried out by applying Oestrogel ointment as pre-scribed to the abdominal skin (a portion containing 3000 mcg estradiol was rubbed onto a 400 cm2 area of skin). In t~e tests on the invention bandage~ plasma samples were taken from the subjects at regular time interva~s and analyzed by radio-immunoassay for estradiol content. Fig. 8 is a plot of the results of those analyses together with the reported values for the ointment. As shown, estradiol administration via the bandages caused the concentration of estradiol in the plasma to rise rapidly to about 70 pg/ml and hold at that level. In contra t estradiol administration via the ointment caused the concentration of estradiol in the plasma to rise rapidly to about 80 pg~ml and then continuously drop off over the suc-ceeding 20 hr to about 25 pg/ml.
. ~
The dependence of estradiol flux on ethanol flux in thebandage was illustrated by the following tests.
Four bandages were made as in Example 1 except that the ethanol concentration was varied to vary the ethanol flux.
In vitro ethanol and estradiol fluxes from these bandages were __ determined by the procedure of Example 1. These determinations are plotted Ln Fig. 9. As shown9 estradiol flux is directly proportional to ethanol flux over the indicated ethanol flux range.
3~
Example 3 This example illustrates the use of water as a covehicle with ethanol in the reservoir. Three sets of bandages were made as in Example 1 except that a 12% rather than a 9% vinyl acetate EVA film was u~ed and 95% ethanol was replaced with ca 75:25, 60:40, and 50:50 w/w ethanol-water mixes. Estradiol content per bandage was 8.5 mg, 3.6 mg, and 1.3 mg, respectively.
In vitro tests were carried out as in Example 1 and the ethanol and estradiol Yluxes were comparable to those of the bandages of Example 1.
As described and shown above, the embodiments of the invention may be used to conveniently elevate the concentration of estradiol in the pla~ma to constant levels. In this regard, lS it i9 believed that total plasma estradiol levels in the range of about 25 to 60 pg/ml are mo~t advantageous for treating conditions associ~ted with menopause and that levels in the range of about 25 to 40 pg/ml will be most advantageous for treating postmenopausal conditions associated with the natural decrease in estradiol after the ovaries cease ~unctioningO
Thus, to treat a given patient one ~ir~.t determines the extent to which the concentration must be elevated to reach the above treatment levels. One then administers a bandage having an effective surface area that will provide the estradiol flux that will achieve the required degree of elevation. Based on the estradiol ~lux per.unit area of skin treated and the elevation of eskradiol in the plasma per 1 mcg estradiol administered per hour that are described above, it is apparent that the surface area of skin treated will typically be in the range of 5 to 20 cm2.
~
Ban~ages that coadminister ethanol and estradiol were made as follows. A solution of estradiol i~ 95~ ethanol was - prepared by mixing 2 g of estradiol in 100 ml in 95% ethanol.
A gelled solution of esthanol was prepared by mixing 215.5 g of 95% ethanol with 353.5 g of water and adding 0.5 g hydroxy-^ ~
~16:Çii96~
propylcellulose (mw 1,000,000 sold under the trademark Klucel) while mixing.
Next, a contact adhesive composition was made by mixing polyiso-butene (mw 1200000), polyisobutene (mw 35000), and light mineral oil in a weight ratio of 1:1.25:2. A 50 micron thick layer of that adhesvie was cast onto a 7S micron film of siliconi~ed polyethylene terephthalate. The contact adhesive side of the resulting two-:Layer subassembly was laA,.inated to a 38 - micron-thick film oE ethylene-vinyl acetate (EVA) copolymer~l2% vinyl acetate).
The resulting three-layer subaasembly was cut into 8 cm x 5 cm pieces. A 580 mg portion of the gelled ethanol mixture and a 20 mg portion of the estradiol solution in ethanol were placed equally spaced on the EVA copolymer side of each piece and 45.7 micron thick backing film of polyethylene terephthalate with an EVA heat sealable coating was laid over the gels. The backing film was heat sealed to the EVA copolymer layer at the periphery of each piece at 150 C, 23 kg. Finished bandages were punched from laminate with a 4 cm diameter cir-cular punch.
Modifications of the above described invention that are within the skill of those working in the pharmaceutical, chemical, and/or medical arts are intended to be within the scope of the following claims.
~:
.
~, ., - 16 -. _ , , . i, ".
In vitro tests were carried out to determine the flu~ of estradiol and ethanol from the above described bandages using the basic techniques described by Chandrasekaran, et al, Am~ Inst.
;~ Chem. Eng. J., 22, 828 (1976). Estradiol concentra-tion in the receptor liquid was assayed chromatographically. For comparison the same tests were carried out by applying a 2 ml layer of the above described gelled estradiol-ethanol mixture on the stratum corneum side o~ the skin mounted in the ,i .
_ 1 ~
diffusional cellsA Figs. 6 and 7 are plots of the results of those tests, with Fig. 6 showing the estradiol fluxes and Fig. 7 showing the ethanol fluxes. As shown the estradiol flux from the gelled estradol ethanol mixture was nonlinear despite a very high, substantially constant ethanol flux. In contrast both the estradiol and ethanol fluxes were substantially constant from the bandages.
In vivo tests were carried out by applying two of the above described bandages to the flank skin of 4 postmenopausal subjects. The results were compared with those reported by Strecker, et al., Maturitas, 1:183-190 (1979). These reported tests were carried out by applying Oestrogel ointment as pre-scribed to the abdominal skin (a portion containing 3000 mcg estradiol was rubbed onto a 400 cm2 area of skin). In t~e tests on the invention bandage~ plasma samples were taken from the subjects at regular time interva~s and analyzed by radio-immunoassay for estradiol content. Fig. 8 is a plot of the results of those analyses together with the reported values for the ointment. As shown, estradiol administration via the bandages caused the concentration of estradiol in the plasma to rise rapidly to about 70 pg/ml and hold at that level. In contra t estradiol administration via the ointment caused the concentration of estradiol in the plasma to rise rapidly to about 80 pg~ml and then continuously drop off over the suc-ceeding 20 hr to about 25 pg/ml.
. ~
The dependence of estradiol flux on ethanol flux in thebandage was illustrated by the following tests.
Four bandages were made as in Example 1 except that the ethanol concentration was varied to vary the ethanol flux.
In vitro ethanol and estradiol fluxes from these bandages were __ determined by the procedure of Example 1. These determinations are plotted Ln Fig. 9. As shown9 estradiol flux is directly proportional to ethanol flux over the indicated ethanol flux range.
3~
Example 3 This example illustrates the use of water as a covehicle with ethanol in the reservoir. Three sets of bandages were made as in Example 1 except that a 12% rather than a 9% vinyl acetate EVA film was u~ed and 95% ethanol was replaced with ca 75:25, 60:40, and 50:50 w/w ethanol-water mixes. Estradiol content per bandage was 8.5 mg, 3.6 mg, and 1.3 mg, respectively.
In vitro tests were carried out as in Example 1 and the ethanol and estradiol Yluxes were comparable to those of the bandages of Example 1.
As described and shown above, the embodiments of the invention may be used to conveniently elevate the concentration of estradiol in the pla~ma to constant levels. In this regard, lS it i9 believed that total plasma estradiol levels in the range of about 25 to 60 pg/ml are mo~t advantageous for treating conditions associ~ted with menopause and that levels in the range of about 25 to 40 pg/ml will be most advantageous for treating postmenopausal conditions associated with the natural decrease in estradiol after the ovaries cease ~unctioningO
Thus, to treat a given patient one ~ir~.t determines the extent to which the concentration must be elevated to reach the above treatment levels. One then administers a bandage having an effective surface area that will provide the estradiol flux that will achieve the required degree of elevation. Based on the estradiol ~lux per.unit area of skin treated and the elevation of eskradiol in the plasma per 1 mcg estradiol administered per hour that are described above, it is apparent that the surface area of skin treated will typically be in the range of 5 to 20 cm2.
~
Ban~ages that coadminister ethanol and estradiol were made as follows. A solution of estradiol i~ 95~ ethanol was - prepared by mixing 2 g of estradiol in 100 ml in 95% ethanol.
A gelled solution of esthanol was prepared by mixing 215.5 g of 95% ethanol with 353.5 g of water and adding 0.5 g hydroxy-^ ~
~16:Çii96~
propylcellulose (mw 1,000,000 sold under the trademark Klucel) while mixing.
Next, a contact adhesive composition was made by mixing polyiso-butene (mw 1200000), polyisobutene (mw 35000), and light mineral oil in a weight ratio of 1:1.25:2. A 50 micron thick layer of that adhesvie was cast onto a 7S micron film of siliconi~ed polyethylene terephthalate. The contact adhesive side of the resulting two-:Layer subassembly was laA,.inated to a 38 - micron-thick film oE ethylene-vinyl acetate (EVA) copolymer~l2% vinyl acetate).
The resulting three-layer subaasembly was cut into 8 cm x 5 cm pieces. A 580 mg portion of the gelled ethanol mixture and a 20 mg portion of the estradiol solution in ethanol were placed equally spaced on the EVA copolymer side of each piece and 45.7 micron thick backing film of polyethylene terephthalate with an EVA heat sealable coating was laid over the gels. The backing film was heat sealed to the EVA copolymer layer at the periphery of each piece at 150 C, 23 kg. Finished bandages were punched from laminate with a 4 cm diameter cir-cular punch.
Modifications of the above described invention that are within the skill of those working in the pharmaceutical, chemical, and/or medical arts are intended to be within the scope of the following claims.
~:
.
~, ., - 16 -. _ , , . i, ".
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A unit dosage form for coadministering a drug and a percutaneous ab-sorption enhancer to a predetermined area of unbroken skin for a pred termined time period, the dosage form comprising a body (a) having a basal surface (i) of area at least about equal to said predetermined area of skin, (ii) that is adapted to contact said area of skin over the time period, and (iii) via which the drug and enhancer are presented to the area of skin for absorption thereby;
(b) containing a supply of the drug that communicates with the basal sur-face to provide drug at the basal surface over the time period such that over a substantial portion of the time period the amount of drug provided is in excess of that which the area of skin is able to absorb;
(c) containing a supply of the percutaneous absorption enhancer that com-municates with the basal surface over said time period; and (d) including enhancer delivery rate controlling means for maintaining the rate at which the enhancer is provided at the basal surface substantially con-stant over a substantial portion of the time period, said dosage form being characterized by said enhancer delivery rate being (i) below the maximum rate the area of skin is able to absorb, and (ii) sufficient to increase the permeability of the area of skin to the drug such that the drug is absorbed thereby at a rate that provides a thera-peutically effective level of the drug in the bloodstream of the patient.
(b) containing a supply of the drug that communicates with the basal sur-face to provide drug at the basal surface over the time period such that over a substantial portion of the time period the amount of drug provided is in excess of that which the area of skin is able to absorb;
(c) containing a supply of the percutaneous absorption enhancer that com-municates with the basal surface over said time period; and (d) including enhancer delivery rate controlling means for maintaining the rate at which the enhancer is provided at the basal surface substantially con-stant over a substantial portion of the time period, said dosage form being characterized by said enhancer delivery rate being (i) below the maximum rate the area of skin is able to absorb, and (ii) sufficient to increase the permeability of the area of skin to the drug such that the drug is absorbed thereby at a rate that provides a thera-peutically effective level of the drug in the bloodstream of the patient.
2. The unit dosage form of claim 1 further characterized by said basal surface having thereon a contact adhesive permeable to said drug and enhancer to attach said dosage to the skin.
3. The unit dosage form of claim 1 further characterized by the supply of drug and the supply of enhancer being admixed and contained in a common reservoir.
4. The unit dosage form of claim 1 further characterized by the supply of drug and the supply of enhancer being maintained in separate reservoirs.
5. The unit dosage form of claim 1 further characterized by said enhance delivery rate controlling means being a diffusion membrane positioned between the supply of enhancer and the basal surface and through which the enhancer must permeate to reach the basal surface.
6. The unit dosage form of claim 5 further characterized by said enhancer delivery rate controlling means being a diffusion membrane positioned between the supply of enhancer and the basal surface and through which the enhancer must permeate to reach the basal surface.
7. The unit dosage form of claim 1, 2 or 5 further characterized by the rate at which the enhancer is provided at the basal surface being above that rate at which the rate of absorption of the drug by the area of skin ceases to increase significantly as the rate at which the enhancer is provided is increased.
8. The dosage form of claim 6 further characterized by said supply of drug and enhancer comprising estradiol dispersed in gelled ethanol and said rate of enhancer delivery being in the range of 100 - 800 mcg/hr/cm2 of said predetermined area of skin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000445581A CA1183085A (en) | 1981-02-17 | 1984-01-18 | Percutaneous absorption enhancer dispenser |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/235,068 US4379454A (en) | 1981-02-17 | 1981-02-17 | Dosage for coadministering drug and percutaneous absorption enhancer |
| US235,068 | 1981-02-17 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000445581A Division CA1183085A (en) | 1981-02-17 | 1984-01-18 | Percutaneous absorption enhancer dispenser |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1166961A true CA1166961A (en) | 1984-05-08 |
Family
ID=22883968
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000395641A Expired CA1166961A (en) | 1981-02-17 | 1982-02-05 | Dosage form for coadministering drug and percutaneous absorption enhancer |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4379454A (en) |
| JP (1) | JPS57154122A (en) |
| AU (2) | AU547007B2 (en) |
| CA (1) | CA1166961A (en) |
| CH (1) | CH657055A5 (en) |
| CY (1) | CY1400A (en) |
| DE (1) | DE3205258A1 (en) |
| FR (1) | FR2499859B1 (en) |
| GB (1) | GB2093694B (en) |
| HK (1) | HK90687A (en) |
| IE (1) | IE52930B1 (en) |
| IT (1) | IT1218310B (en) |
| MX (2) | MX161285A (en) |
| MY (1) | MY8700746A (en) |
| SE (1) | SE452407B (en) |
| SG (1) | SG68387G (en) |
Families Citing this family (337)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2105990B (en) * | 1981-08-27 | 1985-06-19 | Nitto Electric Ind Co | Adhesive skin patches |
| US4460370A (en) * | 1981-10-29 | 1984-07-17 | Almedco, Inc. | Trans-dermal medication application cell |
| DE3204582A1 (en) * | 1982-02-10 | 1983-08-25 | Hassia Verpackung Gmbh, 6479 Ranstadt | Method of continuously producing plaster packs for transdermal administration of medicaments |
| DE3347277A1 (en) * | 1983-12-28 | 1985-07-11 | Bayer Ag, 5090 Leverkusen | ACTIVE SUBSTANCE DELIVERY SYSTEMS |
| US4573996A (en) * | 1984-01-03 | 1986-03-04 | Jonergin, Inc. | Device for the administration of an active agent to the skin or mucosa |
| EP0156080B2 (en) * | 1984-03-05 | 1993-10-20 | Nitto Denko Corporation | Percutaneous absorption type adhesive pharmaceutical preparation |
| US4725439A (en) * | 1984-06-29 | 1988-02-16 | Alza Corporation | Transdermal drug delivery device |
| US4704282A (en) * | 1984-06-29 | 1987-11-03 | Alza Corporation | Transdermal therapeutic system having improved delivery characteristics |
| DE3424837C1 (en) * | 1984-07-03 | 1986-01-16 | Hassia-Verpackung Karl Klein Gmbh, 1000 Berlin | Depot plaster |
| US4588580B2 (en) * | 1984-07-23 | 1999-02-16 | Alaz Corp | Transdermal administration of fentanyl and device therefor |
| US4649075A (en) * | 1984-08-09 | 1987-03-10 | Leonora Jost | Transdermal and transmucosal vortexed foam devices and the method of making |
| ES8608895A1 (en) * | 1984-08-17 | 1986-07-16 | Allpack Ind Lohnverpackung | Therapeutical adhesive plaster and process for its manufacture. |
| US4927687A (en) * | 1984-10-01 | 1990-05-22 | Biotek, Inc. | Sustained release transdermal drug delivery composition |
| US4568343A (en) * | 1984-10-09 | 1986-02-04 | Alza Corporation | Skin permeation enhancer compositions |
| AU592322B2 (en) * | 1984-10-11 | 1990-01-11 | Key Pharmaceuticals, Inc. | Physiological means of enhancing transdermal delivery of drugs |
| US4883669A (en) * | 1985-02-25 | 1989-11-28 | Rutgers, The State University Of New Jersey | Transdermal absorption dosage unit for estradiol and other estrogenic steroids and process for administration |
| US4904475A (en) * | 1985-05-03 | 1990-02-27 | Alza Corporation | Transdermal delivery of drugs from an aqueous reservoir |
| US4645502A (en) * | 1985-05-03 | 1987-02-24 | Alza Corporation | Transdermal delivery of highly ionized fat insoluble drugs |
| GB8512358D0 (en) * | 1985-05-16 | 1985-06-19 | Euro Celtique Sa | Transdermal delivery system |
| US4690683A (en) * | 1985-07-02 | 1987-09-01 | Rutgers, The State University Of New Jersey | Transdermal varapamil delivery device |
| US4698062A (en) * | 1985-10-30 | 1987-10-06 | Alza Corporation | Medical device for pulsatile transdermal delivery of biologically active agents |
| EP0252076A1 (en) * | 1985-12-12 | 1988-01-13 | Flexcon Company, Inc. | Transdermal methods and adhesives |
| US4710191A (en) * | 1985-12-16 | 1987-12-01 | Jonergin, Inc. | Therapeutic device for the administration of medicaments |
| US4666441A (en) * | 1985-12-17 | 1987-05-19 | Ciba-Geigy Corporation | Multicompartmentalized transdermal patches |
| ATE64539T1 (en) * | 1986-02-14 | 1991-07-15 | Ciba Geigy Ag | DERMAL AND TRANSDERMAL THERAPEUTIC SYSTEMS WITH A PATTERNAL ADHESIVE LAYER AND PROCESS FOR PRODUCTION THEREOF. |
| US5560922A (en) * | 1986-05-30 | 1996-10-01 | Rutgers, The State University Of New Jersey | Transdermal absorption dosage unit using a polyacrylate adhesive polymer and process |
| DE3775830D1 (en) * | 1986-06-13 | 1992-02-20 | Alza Corp | ACTIVATING A TRANSDERMAL DRUG DELIVERY SYSTEM THROUGH MOISTURE. |
| US4755180A (en) * | 1986-06-16 | 1988-07-05 | Alza Corporation | Dosage form comprising solubility regulating member |
| USRE37934E1 (en) | 1986-08-28 | 2002-12-10 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system |
| DE3629304A1 (en) * | 1986-08-28 | 1988-03-24 | Lohmann Gmbh & Co Kg | TRANSDERMAL THERAPEUTIC SYSTEM, ITS USE AND METHOD FOR THE PRODUCTION THEREOF |
| US6139868A (en) * | 1986-08-28 | 2000-10-31 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
| US6117448A (en) * | 1986-08-28 | 2000-09-12 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
| US6126963A (en) * | 1986-08-28 | 2000-10-03 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
| US5820876A (en) * | 1986-08-28 | 1998-10-13 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system |
| US6110488A (en) * | 1986-08-28 | 2000-08-29 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
| US4938759A (en) * | 1986-09-02 | 1990-07-03 | Alza Corporation | Transdermal delivery device having a rate controlling adhesive |
| 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 |
| US5422118A (en) * | 1986-11-07 | 1995-06-06 | Pure Pac, Inc. | Transdermal administration of amines with minimal irritation and high transdermal flux rate |
| US4863970A (en) * | 1986-11-14 | 1989-09-05 | Theratech, Inc. | Penetration enhancement with binary system of oleic acid, oleins, and oleyl alcohol with lower alcohols |
| AU607172B2 (en) * | 1986-12-22 | 1991-02-28 | Cygnus, Inc. | Diffusion matrix for transdermal drug administration |
| US4906463A (en) * | 1986-12-22 | 1990-03-06 | Cygnus Research Corporation | Transdermal drug-delivery composition |
| AU601528B2 (en) * | 1986-12-22 | 1990-09-13 | Ortho-Mcneil Pharmaceutical, Inc. | Resilient transdermal drug-delivery device and compositions and devices employing fatty acid esters/ethers of alkanediols and percutaneous absorption enhancers |
| US5006342A (en) * | 1986-12-22 | 1991-04-09 | Cygnus Corporation | Resilient transdermal drug delivery device |
| US5322695A (en) * | 1987-01-09 | 1994-06-21 | Hercon Laboratories Corporation | Moisture-vapor-permeable dressing |
| US4865848A (en) * | 1987-02-26 | 1989-09-12 | Alza Corporation | Skin permeation enhancer compositions using sucrose esters |
| US4788062A (en) * | 1987-02-26 | 1988-11-29 | Alza Corporation | Transdermal administration of progesterone, estradiol esters, and mixtures thereof |
| US4816258A (en) * | 1987-02-26 | 1989-03-28 | Alza Corporation | Transdermal contraceptive formulations |
| US4940586A (en) * | 1987-02-26 | 1990-07-10 | Alza Corporation | Skin permeation enhancer compositions using sucrose esters |
| US4746515A (en) * | 1987-02-26 | 1988-05-24 | Alza Corporation | Skin permeation enhancer compositions using glycerol monolaurate |
| US5071656A (en) * | 1987-03-05 | 1991-12-10 | Alza Corporation | Delayed onset transdermal delivery device |
| US5049387A (en) * | 1987-03-09 | 1991-09-17 | Alza Corporation | Inducing skin tolerance to a sensitizing drug |
| US5077054A (en) * | 1987-03-09 | 1991-12-31 | Alza Corporation | Prevention of contact allergy by coadministration of a corticosteroid with a sensitizing drug |
| US5000956A (en) * | 1987-03-09 | 1991-03-19 | Alza Corporation | Prevention of contact allergy by coadministration of a corticosteroid with a sensitizing drug |
| US5171576A (en) * | 1987-03-09 | 1992-12-15 | Alza Corporation | Prevention of contact allergy by coadministration of a corticosteroid with a sensitizing drug |
| US5118509A (en) * | 1987-03-09 | 1992-06-02 | Alza Corporation | Inducing skin tolerance to a sensitizing drug |
| CH674618A5 (en) * | 1987-04-02 | 1990-06-29 | Ciba Geigy Ag | |
| US5045553A (en) * | 1987-06-24 | 1991-09-03 | Fujisawa Pharmaceutical Company, Ltd. | Pharmaceutical composition for percutaneous drug absorption and percutaneous drug absorption promoter |
| US4804541A (en) * | 1987-08-11 | 1989-02-14 | Moleculon, Inc. | Transdermal administration using benzyl alcohol |
| US4764379A (en) * | 1987-08-24 | 1988-08-16 | Alza Corporation | Transdermal drug delivery device with dual permeation enhancers |
| US4820720A (en) * | 1987-08-24 | 1989-04-11 | Alza Corporation | Transdermal drug composition with dual permeation enhancers |
| US4917895A (en) * | 1987-11-02 | 1990-04-17 | Alza Corporation | Transdermal drug delivery device |
| US4837027A (en) * | 1987-11-09 | 1989-06-06 | Alza Corporation | Transdermal drug delivery device |
| US4781924A (en) | 1987-11-09 | 1988-11-01 | Alza Corporation | Transdermal drug delivery device |
| US4863738A (en) * | 1987-11-23 | 1989-09-05 | Alza Corporation | Skin permeation enhancer compositions using glycerol monooleate |
| FR2623718B1 (en) * | 1987-11-27 | 1994-04-15 | Fabre Medicament Pierre | TRANSDERMAL THERAPEUTIC DEVICE AND ITS PREPARATION METHOD |
| US5068226A (en) * | 1987-12-07 | 1991-11-26 | Cyclex, Inc. | Pharmaceutical preparations containing cyclodextrins and their use in iontophoretic therapies |
| US4979946A (en) * | 1987-12-14 | 1990-12-25 | The Kendall Company | Environmental absorbent dressing |
| US5925372A (en) * | 1987-12-16 | 1999-07-20 | Novartis Corporation | Mixed solvent mutually enhanced transdermal therapeutic system |
| US5064654A (en) * | 1989-01-11 | 1991-11-12 | Ciba-Geigy Corporation | Mixed solvent mutually enhanced transdermal therapeutic system |
| US4906475A (en) * | 1988-02-16 | 1990-03-06 | Paco Pharmaceutical Services | Estradiol transdermal delivery system |
| US5223261A (en) * | 1988-02-26 | 1993-06-29 | Riker Laboratories, Inc. | Transdermal estradiol delivery system |
| US4885154A (en) * | 1988-03-01 | 1989-12-05 | Alza Corporation | Method for reducing sensitization or irritation in transdermal drug delivery and means therefor |
| US5300291A (en) * | 1988-03-04 | 1994-04-05 | Noven Pharmaceuticals, Inc. | Method and device for the release of drugs to the skin |
| US5719197A (en) * | 1988-03-04 | 1998-02-17 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
| US5641504A (en) * | 1988-06-09 | 1997-06-24 | Alza Corporation | Skin permeation enhancer compositions using glycerol monolinoleate |
| US5378730A (en) * | 1988-06-09 | 1995-01-03 | Alza Corporation | Permeation enhancer comprising ethanol and monoglycerides |
| US5004610A (en) * | 1988-06-14 | 1991-04-02 | Alza Corporation | Subsaturated nicotine transdermal therapeutic system |
| PT90820B (en) * | 1988-06-14 | 1995-05-31 | Alza Corp | SUB-SATURATED TRANSDERMIC LIBRARIAN DEVICE |
| US5181914A (en) * | 1988-08-22 | 1993-01-26 | Zook Gerald P | Medicating device for nails and adjacent tissue |
| DE68920109T2 (en) * | 1988-10-11 | 1995-05-11 | Shire Holdings Ltd | Drug preparation for percutaneous absorption. |
| US5026556A (en) * | 1988-11-10 | 1991-06-25 | Norwich Eaton Pharmaceuticals, Inc. | Compositions for the transdermal delivery of pharmaceutical actives |
| CA2004203A1 (en) * | 1988-12-01 | 1990-06-01 | Sharad K. Govil | Compositions for transdermal delivery of estradiol |
| US5241925A (en) * | 1988-12-27 | 1993-09-07 | Dermamed | Apparatus and techniques for administering veterinary medicaments |
| US5332577A (en) * | 1988-12-27 | 1994-07-26 | Dermamed | Transdermal administration to humans and animals |
| US5223262A (en) * | 1989-02-23 | 1993-06-29 | University Of Utah | Transdermal delivery system utilizing one way membranes |
| US4973468A (en) * | 1989-03-22 | 1990-11-27 | Cygnus Research Corporation | Skin permeation enhancer compositions |
| US5059426A (en) * | 1989-03-22 | 1991-10-22 | Cygnus Therapeutic Systems | Skin permeation enhancer compositions, and methods and transdermal systems associated therewith |
| US5053227A (en) * | 1989-03-22 | 1991-10-01 | Cygnus Therapeutic Systems | Skin permeation enhancer compositions, and methods and transdermal systems associated therewith |
| US5788983A (en) * | 1989-04-03 | 1998-08-04 | Rutgers, The State University Of New Jersey | Transdermal controlled delivery of pharmaceuticals at variable dosage rates and processes |
| KR920700014A (en) * | 1989-06-02 | 1992-02-19 | 테오도르 에이취. 스탠리 | Non-Invasive Blood Glucose Testing Apparatus and Method |
| US5139023A (en) * | 1989-06-02 | 1992-08-18 | Theratech Inc. | Apparatus and method for noninvasive blood glucose monitoring |
| US5232703A (en) * | 1989-07-21 | 1993-08-03 | Izhak Blank | Estradiol compositions and methods for topical application |
| DE69007886T2 (en) * | 1989-07-21 | 1994-11-17 | Izhak Blank | Oestradiol containing agents and methods for topical use. |
| US4956171A (en) * | 1989-07-21 | 1990-09-11 | Paco Pharmaceutical Services, Inc. | Transdermal drug delivery using a dual permeation enhancer and method of performing the same |
| US5252334A (en) * | 1989-09-08 | 1993-10-12 | Cygnus Therapeutic Systems | Solid matrix system for transdermal drug delivery |
| US5324521A (en) * | 1989-12-18 | 1994-06-28 | Dermamed | Systems for transdermal administration of medicaments |
| ES2097145T3 (en) | 1990-03-28 | 1997-04-01 | Noven Pharma | METHOD AND DEVICE FOR THE RELEASE OF DRUGS IN THE SKIN. |
| US5508038A (en) * | 1990-04-16 | 1996-04-16 | Alza Corporation | Polyisobutylene adhesives for transdermal devices |
| DK0600873T3 (en) * | 1990-06-01 | 1997-05-20 | Population Council Inc | Therapeutically effective topical application of ST1435 |
| US5071704A (en) * | 1990-06-13 | 1991-12-10 | Fischel Ghodsian Fariba | Device for controlled release of vapors and scents |
| US5455043A (en) * | 1990-06-13 | 1995-10-03 | Fischel-Ghodsian; Fariba | Device for controlled release of vaporous medications through nasal route |
| US5160741A (en) * | 1990-07-06 | 1992-11-03 | Alza Corporation | Reduction or prevention of skin irritation by drugs |
| US5130139A (en) * | 1990-07-06 | 1992-07-14 | Alza Corporation | Reduction or prevention of skin irritation by drugs |
| US5120545A (en) * | 1990-08-03 | 1992-06-09 | Alza Corporation | Reduction or prevention of sensitization to drugs |
| US5149539A (en) * | 1990-08-03 | 1992-09-22 | Alza Corporation | Reduction or prevention of sensitization to drugs |
| MX9101787A (en) * | 1990-10-29 | 1992-06-05 | Alza Corp | TRANSDERMAL CONTRACEPTIVE FORMULATIONS, METHODS AND DEVICES |
| US5198223A (en) * | 1990-10-29 | 1993-03-30 | Alza Corporation | Transdermal formulations, methods and devices |
| US5512292A (en) * | 1990-10-29 | 1996-04-30 | Alza Corporation | Transdermal contraceptive formulations methods and devices |
| US5314694A (en) * | 1990-10-29 | 1994-05-24 | Alza Corporation | Transdermal formulations, methods and devices |
| US5320850A (en) * | 1990-10-29 | 1994-06-14 | Alza Corporation | Transdermal delivery of the gestogen ST-1435 and devices therefor |
| DE4115849A1 (en) * | 1991-05-15 | 1992-11-19 | Lohmann Therapie Syst Lts | PENETRATION PROMOTING SUBSTANCE |
| US5402777A (en) * | 1991-06-28 | 1995-04-04 | Alza Corporation | Methods and devices for facilitated non-invasive oxygen monitoring |
| CN1042699C (en) * | 1991-07-10 | 1999-03-31 | 生达化学制药股份有限公司 | Female hormone plaster |
| US5203768A (en) * | 1991-07-24 | 1993-04-20 | Alza Corporation | Transdermal delivery device |
| US5464387A (en) * | 1991-07-24 | 1995-11-07 | Alza Corporation | Transdermal delivery device |
| US5189986A (en) * | 1991-09-23 | 1993-03-02 | Alza Corporation | Veterinary transdermal active agent delivery device |
| US5518734A (en) * | 1991-09-25 | 1996-05-21 | Beta Pharmaceuticals Co. | Transdermal delivery system for estradiol and process for manufacturing said device |
| US5705185A (en) * | 1991-09-25 | 1998-01-06 | Beta Pharmaceuticals Co. | Transdermal delivery of estradiol and process for manufacturing said device |
| US5352456A (en) * | 1991-10-10 | 1994-10-04 | Cygnus Therapeutic Systems | Device for administering drug transdermally which provides an initial pulse of drug |
| JPH07503232A (en) * | 1991-10-18 | 1995-04-06 | アルザ・コーポレーション | Controlled transdermal administration of melatonin |
| US5229130A (en) * | 1991-12-20 | 1993-07-20 | Cygnus Therapeutics Systems | Vegetable oil-based skin permeation enhancer compositions, and associated methods and systems |
| US5900250A (en) * | 1992-05-13 | 1999-05-04 | Alza Corporation | Monoglyceride/lactate ester permeation enhancer for oxybutnin |
| WO1993023025A1 (en) * | 1992-05-13 | 1993-11-25 | Alza Corporation | Transdermal administration of oxybutynin |
| DE4336557C2 (en) * | 1993-05-06 | 1997-07-17 | Lohmann Therapie Syst Lts | Estradiol-containing transdermal therapeutic system, process for its preparation and its use |
| US5330452A (en) * | 1993-06-01 | 1994-07-19 | Zook Gerald P | Topical medicating device |
| US5451407A (en) * | 1993-06-21 | 1995-09-19 | Alza Corporation | Reduction or prevention of skin irritation or sensitization during transdermal administration of a irritating or sensitizing drug |
| JPH08512054A (en) * | 1993-06-25 | 1996-12-17 | アルザ・コーポレーション | Inclusion of poly-N-vinylamide in transdermal system |
| US5415866A (en) * | 1993-07-12 | 1995-05-16 | Zook; Gerald P. | Topical drug delivery system |
| US5691377A (en) * | 1993-07-30 | 1997-11-25 | University Of Maryland Eastern Shore And University Of Maryland College Park | Use of N-methyl-aspartic acid for enhancing growth and altering body composition |
| DE4332094C2 (en) * | 1993-09-22 | 1995-09-07 | Lohmann Therapie Syst Lts | Active substance plaster which can be produced without solvent and process for its preparation |
| KR960011044B1 (en) * | 1993-09-27 | 1996-08-16 | 재단법인 한국화학연구소 | High membrane with excellent alkanol permeability |
| KR960704579A (en) * | 1993-09-29 | 1996-10-09 | 에드워드 엘. 만델 | Monoglyceride / lactate Ester Permeation Enhancer for Oxybutynin |
| US5962011A (en) * | 1993-12-06 | 1999-10-05 | Schering-Plough Healthcare Products, Inc. | Device for delivery of dermatological ingredients |
| US5641507A (en) * | 1993-12-06 | 1997-06-24 | Devillez; Richard L. | Delivery system for dermatological and cosmetic ingredients |
| US5466465A (en) * | 1993-12-30 | 1995-11-14 | Harrogate Holdings, Limited | Transdermal drug delivery system |
| DE4400770C1 (en) * | 1994-01-13 | 1995-02-02 | Lohmann Therapie Syst Lts | Plaster containing an active substance for delivery of oestradiol with at least one penetration enhancer, method of producing it and its use |
| US5635203A (en) * | 1994-09-29 | 1997-06-03 | Alza Corporation | Transdermal device having decreased delamination |
| US5505958A (en) * | 1994-10-31 | 1996-04-09 | Algos Pharmaceutical Corporation | Transdermal drug delivery device and method for its manufacture |
| CA2208132A1 (en) * | 1994-12-21 | 1996-06-27 | Theratech, Inc. | Transdermal delivery system with adhesive overlay and peel seal disc |
| DE19500662C2 (en) * | 1995-01-12 | 2001-04-26 | Lohmann Therapie Syst Lts | Plaster containing estradiol and its use |
| US5882676A (en) * | 1995-05-26 | 1999-03-16 | Alza Corporation | Skin permeation enhancer compositions using acyl lactylates |
| US5785991A (en) * | 1995-06-07 | 1998-07-28 | Alza Corporation | Skin permeation enhancer compositions comprising glycerol monolaurate and lauryl acetate |
| US6572879B1 (en) * | 1995-06-07 | 2003-06-03 | Alza Corporation | Formulations for transdermal delivery of pergolide |
| US5840327A (en) * | 1995-08-21 | 1998-11-24 | Alza Corporation | Transdermal drug delivery device having enhanced adhesion |
| US5902603A (en) * | 1995-09-14 | 1999-05-11 | Cygnus, Inc. | Polyurethane hydrogel drug reservoirs for use in transdermal drug delivery systems, and associated methods of manufacture and use |
| US5891461A (en) * | 1995-09-14 | 1999-04-06 | Cygnus, Inc. | Transdermal administration of olanzapine |
| US6238700B1 (en) | 1995-12-01 | 2001-05-29 | Alza Corporation | Method for preventing crystal formation in a dispersion of a liquid in a matrix |
| DE69616370T2 (en) | 1995-12-01 | 2002-07-11 | Alza Corp | IMPROVED METHOD FOR PREVENTING CRYSTALIZATION IN A DISPERSION OF A LIQUID IN A MATRIX |
| US5733571A (en) * | 1995-12-08 | 1998-03-31 | Euro-Celtique, S.A. | Transdermal patch for comparative evaluations |
| US5730721A (en) * | 1996-01-25 | 1998-03-24 | Vesture Corporation | Medical applicator and method |
| US6007837A (en) * | 1996-07-03 | 1999-12-28 | Alza Corporation | Drug delivery devices and process of manufacture |
| US6512010B1 (en) | 1996-07-15 | 2003-01-28 | Alza Corporation | Formulations for the administration of fluoxetine |
| EP0934078B1 (en) * | 1996-10-24 | 2002-12-18 | Alza Corporation | Permeation enhancers for transdermal drug delivery compositions, devices, and methods |
| US6019988A (en) * | 1996-11-18 | 2000-02-01 | Bristol-Myers Squibb Company | Methods and compositions for enhancing skin permeation of drugs using permeation enhancers, when drugs and/or permeation enhancers are unstable in combination during long-term storage |
| DE19701949A1 (en) * | 1997-01-13 | 1998-07-16 | Jenapharm Gmbh | Transdermal therapeutic system |
| DE19700913C2 (en) * | 1997-01-14 | 2001-01-04 | Lohmann Therapie Syst Lts | Transdermal therapeutic system for the delivery of hormones |
| US6203817B1 (en) | 1997-02-19 | 2001-03-20 | Alza Corporation | Reduction of skin reactions caused by transdermal drug delivery |
| US5968547A (en) | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
| GB9711032D0 (en) * | 1997-05-30 | 1997-07-23 | Johnson Matthey Plc | Compound as a stimulant for the central nervous system |
| US6174545B1 (en) | 1997-07-01 | 2001-01-16 | Alza Corporation | Drug delivery devices and process of manufacture |
| US6420622B1 (en) * | 1997-08-01 | 2002-07-16 | 3M Innovative Properties Company | Medical article having fluid control film |
| US6660295B2 (en) | 1997-09-30 | 2003-12-09 | Alza Corporation | Transdermal drug delivery device package with improved drug stability |
| US6918901B1 (en) | 1997-12-10 | 2005-07-19 | Felix Theeuwes | Device and method for enhancing transdermal agent flux |
| WO1999029364A1 (en) * | 1997-12-11 | 1999-06-17 | Alza Corporation | Device for enhancing transdermal agent flux |
| WO1999029298A2 (en) | 1997-12-11 | 1999-06-17 | Alza Corporation | Device for enhancing transdermal agent flux |
| EP1911488A3 (en) | 1997-12-11 | 2008-12-03 | Alza Corporation | Device for enhancing transdermal agent flux |
| WO1999029365A1 (en) * | 1997-12-11 | 1999-06-17 | Alza Corporation | Device for enhancing transdermal agent flux |
| DK1041975T3 (en) | 1997-12-22 | 2002-11-04 | Alza Corp | Speed-controlling membranes for controlled drug delivery devices |
| US6267984B1 (en) | 1997-12-22 | 2001-07-31 | Alza Corporation | Skin permeation enhancer compositions comprising a monoglyceride and ethyl palmitate |
| US6269820B1 (en) | 1998-02-26 | 2001-08-07 | Xomed Surgical Products, Inc. | Method of controlling post-operative leakage associated with tumescent liposuction |
| US6699497B1 (en) | 1998-07-24 | 2004-03-02 | Alza Corporation | Formulations for the transdermal administration of fenoldopam |
| DE19834007C1 (en) | 1998-07-29 | 2000-02-24 | Lohmann Therapie Syst Lts | Estradiol-containing patch for the transdermal application of hormones and its use |
| US6348210B1 (en) | 1998-11-13 | 2002-02-19 | Alza Corporation | Methods for transdermal drug administration |
| JP4864204B2 (en) * | 1998-12-18 | 2012-02-01 | アルザ・コーポレーション | Transparent transdermal nicotine delivery device |
| US20070196490A1 (en) * | 1999-01-22 | 2007-08-23 | Powderject Research Limited | Method of enhancing needleless transdermal powered drug delivery |
| EP2305324B1 (en) * | 1999-03-25 | 2014-09-17 | Metabolix, Inc. | Medical devices and applications of polyhydroxyalkanoate polymers |
| ES2244422T3 (en) * | 1999-04-01 | 2005-12-16 | Alza Corporation | DEVICES FOR THE TRANSDERMAL ADMINISTRATION OF PHARMACOS THAT INCLUDE A POLYURETHANE DEPOSIT FOR PHARMACOS. |
| US6544541B1 (en) | 1999-06-02 | 2003-04-08 | Cardiovascular Solutions, Inc. | Devices and compounds for treating arterial restenosis |
| AU780953B2 (en) | 1999-08-30 | 2005-04-28 | Tepha, Inc. | Flushable disposable polymeric products |
| DE60024312T2 (en) | 1999-12-10 | 2006-08-17 | Alza Corp., Mountain View | Transdermal drug delivery of macromolecular agents and device therefor |
| JP4653893B2 (en) * | 2000-01-27 | 2011-03-16 | 純一 須藤 | Bilayer type transdermal preparation |
| US7179483B2 (en) * | 2000-04-26 | 2007-02-20 | Watson Pharmaceuticals, Inc. | Compositions and methods for transdermal oxybutynin therapy |
| FR2814074B1 (en) * | 2000-09-15 | 2003-03-07 | Theramex | NOVEL TOPICAL ESTRO-PROGESTIVE COMPOSITIONS WITH SYSTEMIC EFFECT |
| US20020119187A1 (en) * | 2000-09-29 | 2002-08-29 | Cantor Adam S. | Composition for the transdermal delivery of fentanyl |
| US8329734B2 (en) * | 2009-07-27 | 2012-12-11 | Afgin Pharma Llc | Topical therapy for migraine |
| ATE404193T1 (en) * | 2001-06-05 | 2008-08-15 | Ronald Aung-Din | TOPICAL MIGRAINE THERAPY |
| US20090162342A1 (en) * | 2001-06-07 | 2009-06-25 | Sanomune Inc. | Therapeutic uses of glandular kallikrein |
| US20040033253A1 (en) * | 2002-02-19 | 2004-02-19 | Ihor Shevchuk | Acyl opioid antagonists |
| US20040033255A1 (en) | 2002-06-10 | 2004-02-19 | Baker Carl J. | Transdermal delivery device disposal system |
| US7099713B2 (en) | 2002-06-28 | 2006-08-29 | Battelle Memorial Institute | Skin conduction and transport systems |
| US8450302B2 (en) * | 2002-08-02 | 2013-05-28 | Ab Science | 2-(3-aminoaryl) amino-4-aryl-thiazoles and their use as c-kit inhibitors |
| DE60316810T2 (en) | 2002-08-02 | 2008-07-17 | Ab Science | 2- (3-AMINOARYL) AMINO-4-ARYL-THIAZOLE AND THEIR USE AS C-KIT INHIBITORS |
| DE60326354D1 (en) * | 2002-08-20 | 2009-04-09 | Euro Celtique Sa | TRANSDERMAL DOSAGE FORM CONTAINING AN ACTIVE SUBSTANCE AND AN ANTAGONIST IN FREE BASE AND SALT FORM |
| US20040086579A1 (en) * | 2002-11-05 | 2004-05-06 | Higgins James W. | Dietary supplement comprising parthenolide |
| US7192614B2 (en) | 2002-11-05 | 2007-03-20 | Gelstat Corporation | Compositions and methods of treatment to alleviate or prevent migrainous headaches and their associated symptoms |
| US6866856B2 (en) * | 2002-12-31 | 2005-03-15 | Avon Products, Inc. | Compositions and delivery methods for the treatment of wrinkles, fine lines and hyperhidrosis |
| US7060303B2 (en) * | 2002-12-31 | 2006-06-13 | Avon Products, Inc. | Use of purslane to treat facial wrinkles |
| US20040191301A1 (en) * | 2003-03-27 | 2004-09-30 | Van Duren Albert Philip | Transdermal device having a phase change material |
| ES2496102T3 (en) * | 2003-03-28 | 2014-09-18 | Sigmoid Pharma Limited | Solid oral dosage form containing seamless microcapsules |
| US20040258742A1 (en) * | 2003-04-11 | 2004-12-23 | Van Osdol William Woodson | Transdermal administration of N-(2,5-disubstituted phenyl)-N'-(3-substituted phenyl)-N'-methyl guanidines |
| DK1638615T3 (en) | 2003-05-08 | 2015-01-12 | Tepha Inc | MEDICAL POLYHYDROXYALKANOATE TEXTILES AND FIBERS |
| US20040247705A1 (en) * | 2003-06-06 | 2004-12-09 | Roberts Stephen C. | Transdermal compositions and methods of treatment to alleviate or prevent migrainous headaches and their associated symptoms |
| US20040247706A1 (en) * | 2003-06-06 | 2004-12-09 | Roberts Stephen C. | Transdermal dietary supplement comprising parthenolide |
| US20060200100A1 (en) * | 2003-06-18 | 2006-09-07 | Rosati Coni F | Method and apparatus for supplying gas to an area |
| US20070065463A1 (en) * | 2003-06-20 | 2007-03-22 | Ronald Aung-Din | Topical therapy for the treatment of migranes, muscle sprains, muscle spasms, spasticity and related conditions |
| JP2007528853A (en) * | 2003-07-08 | 2007-10-18 | テファ， インコーポレイテッド | Poly-4-hydroxybutyrate matrix for sustained release drug delivery |
| WO2005011644A1 (en) | 2003-07-28 | 2005-02-10 | Alza Corporation | Transdermal warfarin-containing delivery system |
| US20080020028A1 (en) * | 2003-08-20 | 2008-01-24 | Euro-Celtique S.A. | Transdermal dosage form comprising an active agent and a salt and a free-base form of an adverse agent |
| US20060287659A1 (en) * | 2003-08-22 | 2006-12-21 | Tepha, Inc. | Polyhydroxyalkanoate nerve regeneration devices |
| BRPI0415467A (en) * | 2003-10-23 | 2006-12-19 | Ab Science | 2-aminoaryloxazole compounds for the treatment of disease |
| ATE448828T1 (en) * | 2003-10-27 | 2009-12-15 | Univ Basel | TRANSDERMAL DRUG DELIVERY SYSTEM |
| US7504385B2 (en) * | 2003-12-17 | 2009-03-17 | Avon Products, Inc. | si-RNA-mediated gene silencing technology to inhibit tyrosinase and reduce pigmentation |
| US7105263B2 (en) * | 2003-12-30 | 2006-09-12 | Samsung Electronics Company | Dry toner comprising encapsulated pigment, methods and uses |
| US20050232983A1 (en) * | 2004-04-14 | 2005-10-20 | Indevus Pharmaceuticals, Inc. | Transdermal patch |
| US20060008432A1 (en) * | 2004-07-07 | 2006-01-12 | Sebastiano Scarampi | Gilsonite derived pharmaceutical delivery compositions and methods: nail applications |
| EP2221069B1 (en) * | 2004-08-03 | 2012-05-09 | Tepha, Inc. | Non-curling polyhydroxyalkanoate sutures |
| US8252321B2 (en) | 2004-09-13 | 2012-08-28 | Chrono Therapeutics, Inc. | Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like |
| CA2580329C (en) | 2004-09-13 | 2015-01-06 | Chrono Therapeutics Inc. | Biosynchronous transdermal drug delivery |
| WO2006035418A2 (en) * | 2004-09-27 | 2006-04-06 | Sigmoid Biotechnologies Limited | Microcapsules comprising a methylxanthine and a corticosteroid |
| US20060127463A1 (en) * | 2004-12-15 | 2006-06-15 | Nugara Peter N | Composite structure including a low vinyl acetate layer |
| CN101080220A (en) * | 2004-12-17 | 2007-11-28 | 阿尔扎公司 | Temperature modulation of transdermal drug delivery |
| US7618662B2 (en) * | 2004-12-22 | 2009-11-17 | Avon Products, Inc | Use of natural plant extracts in cosmetic compositions |
| US7351745B2 (en) | 2004-12-22 | 2008-04-01 | Avon Products, Inc | Compositions and methods of their use for improving the condition and appearance of skin |
| US7514092B2 (en) | 2004-12-22 | 2009-04-07 | Avon Products, Inc. | Compositions and methods of their use for improving the condition and appearance of skin |
| US7410658B2 (en) * | 2004-12-22 | 2008-08-12 | Avon Products, Inc. | Use of Alisma orientale in cosmetics and compositions thereof |
| DE102004062614B4 (en) * | 2004-12-24 | 2011-12-29 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system with activatable supersaturation and controlled permeation promotion and process for its preparation |
| ES2362221T3 (en) * | 2005-01-28 | 2011-06-29 | Tepha, Inc. | EMBOLIZATION WITH POLI-4-HYDROXIBUTIRATE PARTICLES. |
| US20060188558A1 (en) * | 2005-02-18 | 2006-08-24 | Mylan Technologies, Inc. | Transdermal systems having control delivery system |
| MX2007012392A (en) | 2005-04-04 | 2007-12-05 | Ab Science | Substituted oxazole derivatives and their use as tyrosine kinase inhibitors. |
| DE602006016441D1 (en) * | 2005-05-13 | 2010-10-07 | Alza Corp | MULTILAYER DRUG DISPOSAL SYSTEM WITH BARRIER AGAINST RESERVOIR MATERIAL FLOW |
| US8372040B2 (en) | 2005-05-24 | 2013-02-12 | Chrono Therapeutics, Inc. | Portable drug delivery device including a detachable and replaceable administration or dosing element |
| US9056061B2 (en) * | 2005-09-23 | 2015-06-16 | Alza Corporation | Transdermal nicotine salt delivery system |
| EP1937226A2 (en) * | 2005-09-23 | 2008-07-02 | Alza Corporation | Transdermal galantamine delivery system |
| WO2007035942A2 (en) * | 2005-09-23 | 2007-03-29 | Alza Corporation | Transdermal risperidone delivery system |
| WO2007035939A2 (en) | 2005-09-23 | 2007-03-29 | Alza Corporation | High enhancer-loading polyacrylate formulation for transdermal applications |
| US8518926B2 (en) * | 2006-04-10 | 2013-08-27 | Knopp Neurosciences, Inc. | Compositions and methods of using (R)-pramipexole |
| WO2007121188A2 (en) * | 2006-04-10 | 2007-10-25 | Knopp Neurosciences, Inc. | Compositions and methods of using r(+) pramipexole |
| ATE537826T1 (en) | 2006-05-16 | 2012-01-15 | Knopp Neurosciences Inc | COMPOSITIONS OF R(+)- AND S(-)-PRAMIPEXOLE AND METHOD FOR THEIR USE |
| US20070278289A1 (en) * | 2006-05-31 | 2007-12-06 | Toshiba Tec Kabushiki Kaisha | Payment adjusting apparatus and program therefor |
| US7833284B2 (en) * | 2006-06-28 | 2010-11-16 | The Cleveland Clinic Foundation | Anti-adhesion membrane |
| EP2486938B1 (en) | 2006-09-26 | 2018-05-09 | Infectious Disease Research Institute | Vaccine composition containing synthetic adjuvant |
| US20090181078A1 (en) | 2006-09-26 | 2009-07-16 | Infectious Disease Research Institute | Vaccine composition containing synthetic adjuvant |
| US7943683B2 (en) * | 2006-12-01 | 2011-05-17 | Tepha, Inc. | Medical devices containing oriented films of poly-4-hydroxybutyrate and copolymers |
| US8524695B2 (en) * | 2006-12-14 | 2013-09-03 | Knopp Neurosciences, Inc. | Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same |
| US7642062B2 (en) | 2006-12-29 | 2010-01-05 | Avon Products Inc. | Compositions and methods of their use for improving the condition and appearance of skin |
| US20100143270A1 (en) * | 2007-02-21 | 2010-06-10 | University Of Louisville Research Foubdation | Therapeutic cotinine compositions |
| US8519148B2 (en) * | 2007-03-14 | 2013-08-27 | Knopp Neurosciences, Inc. | Synthesis of chirally purified substituted benzothiazole diamines |
| US8940326B2 (en) | 2007-03-19 | 2015-01-27 | Vita Sciences Llc | Transdermal patch and method for delivery of vitamin B12 |
| EP2066309B1 (en) | 2007-04-04 | 2012-08-29 | Sigmoid Pharma Limited | An oral pharmaceutical composition |
| EP2586428B1 (en) * | 2007-04-26 | 2023-11-08 | Sublimity Therapeutics Limited | Manufacture of multiple minicapsules |
| JP2010526053A (en) * | 2007-05-01 | 2010-07-29 | シグモイド・ファーマ・リミテッド | Nimodipine pharmaceutical composition |
| PL2173330T3 (en) * | 2007-07-04 | 2012-08-31 | Luye Pharma Ag | Reservoir system comprising a closed membrane |
| US20090304776A1 (en) * | 2008-06-06 | 2009-12-10 | Totada Shantha | Transmucosal delivery of therapeutic agents and methods of use thereof |
| US7883487B2 (en) * | 2008-06-16 | 2011-02-08 | Shantha Totada R | Transdermal local anesthetic patch with injection port |
| WO2010005507A1 (en) | 2008-06-30 | 2010-01-14 | Afgin Pharma, Llc | Topical regional neuro-affective therapy |
| US20110190356A1 (en) * | 2008-08-19 | 2011-08-04 | Knopp Neurosciences Inc. | Compositions and Methods of Using (R)- Pramipexole |
| US8715715B2 (en) | 2008-11-03 | 2014-05-06 | Nal Pharmaceuticals Ltd. | Dosage form for insertion into the mouth |
| US20100209484A1 (en) * | 2009-02-13 | 2010-08-19 | Hoo-Kyun Choi | Transdermal Triptan Delivery System |
| SI2432455T1 (en) | 2009-05-18 | 2015-04-30 | Sigmoid Pharma Limited | Composition comprising oil drops |
| TWI494125B (en) | 2009-06-05 | 2015-08-01 | Infectious Disease Res Inst | Synthetic glucopyranosyl lipid adjuvants |
| CN102802418A (en) * | 2009-06-19 | 2012-11-28 | 诺普神经科学股份有限公司 | Compositions and methods for treating amyotrophic lateral sclerosis |
| EP2464341B1 (en) | 2009-08-12 | 2022-07-06 | Sublimity Therapeutics Limited | Immunomodulatory compositions comprising a polymer matrix and an oil phase |
| US8962665B2 (en) | 2010-01-12 | 2015-02-24 | Ab Science | Thiazole and oxazole kinase inhibitors |
| TW201202232A (en) | 2010-01-28 | 2012-01-16 | Ab Science | Treatment of GIST with masitinib |
| JP5871907B2 (en) | 2010-04-28 | 2016-03-01 | 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 | Nanopatterned medical device with enhanced cell-cell interaction |
| RU2585138C2 (en) | 2010-04-28 | 2016-05-27 | Кимберли-Кларк Ворлдвайд, Инк. | Medical devices for delivery of sirna |
| EP2563450B1 (en) | 2010-04-28 | 2017-07-26 | Kimberly-Clark Worldwide, Inc. | Device for delivery of rheumatoid arthritis medication |
| MX2012012567A (en) | 2010-04-28 | 2012-11-21 | Kimberly Clark Co | Method for increasing permeability of an epithelial barrier. |
| WO2011143657A1 (en) | 2010-05-14 | 2011-11-17 | Dana-Farber Cancer Institute, Inc. | Male contraceptive compositions and methods of use |
| GB201020032D0 (en) | 2010-11-25 | 2011-01-12 | Sigmoid Pharma Ltd | Composition |
| JP6527305B2 (en) | 2011-01-10 | 2019-06-05 | インヴィオン， インコーポレイテッド | Use of beta-adrenergic inverse agonists for smoking cessation |
| US8696637B2 (en) | 2011-02-28 | 2014-04-15 | Kimberly-Clark Worldwide | Transdermal patch containing microneedles |
| JP6050763B2 (en) | 2011-03-03 | 2016-12-21 | デノバメド インク． | Antibacterial compounds / adjuvant compounds and methods |
| JP6054942B2 (en) | 2011-04-08 | 2016-12-27 | イミューン デザイン コーポレイション | Immunogenic compositions and methods of using the compositions to elicit humoral and cellular immune responses |
| WO2013006643A1 (en) | 2011-07-06 | 2013-01-10 | The Parkinson's Institute | Compositions and methods for treatment of symptoms in parkinson's disease patients |
| EP2736904B1 (en) | 2011-07-27 | 2016-03-16 | AB Science | Oxazole and thiazole derivatives as selective protein kinase inhibitors (c-kit) |
| BR112014009713A2 (en) | 2011-10-27 | 2017-04-18 | Kimberly Clark Co | transdermal administration of high viscosity bioactive agents |
| US9512096B2 (en) | 2011-12-22 | 2016-12-06 | Knopp Biosciences, LLP | Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds |
| US11510875B2 (en) | 2012-02-07 | 2022-11-29 | Access To Advanced Health Institute | Adjuvant formulations comprising TLR4 agonists and methods of using the same |
| BR112014028476A2 (en) | 2012-05-16 | 2017-08-01 | Immune Design Corp | immunogenic fragment of a polypeptide, isolated polynucleotide, immunogenic pharmaceutical composition, methods for treating an infection, for generating an immune response in a subject, and for immunizing a subject |
| WO2013173923A1 (en) | 2012-05-25 | 2013-11-28 | Diamedica, Inc. | Formulations of human tissue kallikrein-1 for parenteral delivery and related methods |
| LT2854841T (en) | 2012-06-04 | 2017-06-12 | Diamedica Inc. | Human tissue kallikrein 1 glycosylation isoforms |
| GB201212010D0 (en) | 2012-07-05 | 2012-08-22 | Sigmoid Pharma Ltd | Formulations |
| EP3712142B1 (en) | 2013-01-11 | 2022-07-06 | Corsair Pharma, Inc. | Prodrugs of treprostinil |
| US9505737B2 (en) | 2013-01-11 | 2016-11-29 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| WO2014113541A1 (en) | 2013-01-16 | 2014-07-24 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Attenuated chlamydia vaccine |
| US10105487B2 (en) | 2013-01-24 | 2018-10-23 | Chrono Therapeutics Inc. | Optimized bio-synchronous bioactive agent delivery system |
| US9662313B2 (en) | 2013-02-28 | 2017-05-30 | Knopp Biosciences Llc | Compositions and methods for treating amyotrophic lateral sclerosis in responders |
| CN105377292A (en) | 2013-04-07 | 2016-03-02 | 博德研究所 | Compositions and methods for personalized neoplasia vaccines |
| EA032326B1 (en) | 2013-04-18 | 2019-05-31 | Иммьюн Дизайн Корп. | Gla monotherapy for use in cancer treatment |
| US9682068B2 (en) | 2013-05-20 | 2017-06-20 | Mylan Inc. | Transdermal therapeutic system for extended dosing of pramipexole in treating neurological disorders |
| US9463198B2 (en) | 2013-06-04 | 2016-10-11 | Infectious Disease Research Institute | Compositions and methods for reducing or preventing metastasis |
| LT3019167T (en) | 2013-07-12 | 2021-03-25 | Knopp Biosciences Llc | Treating elevated levels of eosinophils and/or basophils |
| US9468630B2 (en) | 2013-07-12 | 2016-10-18 | Knopp Biosciences Llc | Compositions and methods for treating conditions related to increased eosinophils |
| WO2015023786A1 (en) | 2013-08-13 | 2015-02-19 | Knopp Biosciences Llc | Compositions and methods for treating plasma cell disorders and b-cell prolymphocytic disorders |
| PL3033081T3 (en) | 2013-08-13 | 2021-08-30 | Knopp Biosciences Llc | Compositions and methods for treating chronic urticaria |
| GB201319791D0 (en) | 2013-11-08 | 2013-12-25 | Sigmoid Pharma Ltd | Formulations |
| US20160287549A1 (en) | 2013-11-22 | 2016-10-06 | Genzyme Corporation | Novel methods for treating neurodegenerative diseases |
| US10801070B2 (en) | 2013-11-25 | 2020-10-13 | The Broad Institute, Inc. | Compositions and methods for diagnosing, evaluating and treating cancer |
| US11725237B2 (en) | 2013-12-05 | 2023-08-15 | The Broad Institute Inc. | Polymorphic gene typing and somatic change detection using sequencing data |
| CN106456724A (en) | 2013-12-20 | 2017-02-22 | 博德研究所 | Combination therapy with neoantigen vaccine |
| AU2015209575A1 (en) | 2014-01-21 | 2016-07-21 | Immune Design Corp. | Compositions for use in the treatment of allergic conditions |
| CN111620830A (en) | 2014-03-14 | 2020-09-04 | 北卡罗来纳大学教堂山分校 | Small molecules for inhibiting male fertility |
| EP3122744B1 (en) | 2014-03-24 | 2018-11-07 | AB Science | Diazaspiroalkaneone-substituted oxazole derivatives as spleen tyrosine kinase inhibitors |
| JP6561109B2 (en) | 2014-07-16 | 2019-08-14 | コルセア ファーマ インコーポレイテッド | Treprostinil derivative compound and method of using the same |
| US10500303B2 (en) | 2014-08-15 | 2019-12-10 | Tepha, Inc. | Self-retaining sutures of poly-4-hydroxybutyrate and copolymers thereof |
| CA2966801A1 (en) | 2014-11-07 | 2016-05-12 | Sigmoid Pharma Limited | Compositions comprising cyclosporin |
| EP3230500A1 (en) | 2014-12-11 | 2017-10-18 | Tepha, Inc. | Methods of orienting multifilament yarn and monofilaments of poly-4-hydroxybutyrate and copolymers thereof |
| US10626521B2 (en) | 2014-12-11 | 2020-04-21 | Tepha, Inc. | Methods of manufacturing mesh sutures from poly-4-hydroxybutyrate and copolymers thereof |
| EP3234193B1 (en) | 2014-12-19 | 2020-07-15 | Massachusetts Institute of Technology | Molecular biomarkers for cancer immunotherapy |
| WO2016100977A1 (en) | 2014-12-19 | 2016-06-23 | The Broad Institute Inc. | Methods for profiling the t-cel- receptor repertoire |
| AU2016211330A1 (en) | 2015-01-28 | 2017-08-03 | Chrono Therapeutics Inc. | Drug delivery methods and systems |
| EP3053920B1 (en) | 2015-02-05 | 2020-04-08 | AB Science | Compounds with anti-tumoral activity |
| US10716766B2 (en) | 2015-03-02 | 2020-07-21 | Afgin Pharma, Llc | Topical regional neuro-affective therapy with cannabinoids |
| US10383816B2 (en) | 2015-03-02 | 2019-08-20 | Afgin Pharma, Llc | Topical regional neuro-affective therapy with cannabinoid combination products |
| JP2018511127A (en) | 2015-03-12 | 2018-04-19 | 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． | Craving input and support system |
| CR20230191A (en) | 2015-05-20 | 2023-07-06 | Dana Farber Cancer Inst Inc | SHARED NEOANTIGENS (Div. exp 2017-584) |
| US9394227B1 (en) | 2015-06-17 | 2016-07-19 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US9643911B2 (en) | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| EP3144307A1 (en) | 2015-09-18 | 2017-03-22 | AB Science | Novel oxazole derivatives that inhibit syk |
| US20190346442A1 (en) | 2016-04-18 | 2019-11-14 | The Broad Institute, Inc. | Improved hla epitope prediction |
| MX2018013640A (en) | 2016-05-16 | 2019-08-01 | Infectious Disease Res Inst | Pegylated liposomes and methods of use. |
| CN109310773B (en) | 2016-05-16 | 2022-04-26 | 传染病研究所 | Formulations containing TLR agonists and methods of use |
| AU2017273650B2 (en) | 2016-06-01 | 2022-08-18 | Access To Advanced Health Institute | Nanoalum particles containing a sizing agent |
| US20180049994A1 (en) | 2016-08-16 | 2018-02-22 | Afgin Pharma, Llc | Topical regional neuro-affective therapy with caryophyllene |
| JP2020500882A (en) | 2016-12-05 | 2020-01-16 | コルセア ファーマ インコーポレイテッド | Dermal and transdermal administration methods of treprostinil and its salts |
| 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 |
| EP3574116A1 (en) | 2017-01-24 | 2019-12-04 | The Broad Institute, Inc. | Compositions and methods for detecting a mutant variant of a polynucleotide |
| JP2020510023A (en) | 2017-03-09 | 2020-04-02 | ダイアメディカ， インコーポレイテッド | Tissue kallikrein 1 dosage form |
| CA3066915A1 (en) | 2017-06-11 | 2018-12-20 | Molecular Express, Inc. | Methods and compositions for substance use disorder vaccine formulations and uses thereof |
| EP3762376B1 (en) | 2018-03-05 | 2023-03-01 | Denovamed Inc. | Diphenyl substituted thiophene-2-amide derivatives and pharmaceutical compositions thereof useful as antimicrobial |
| AU2019279884A1 (en) | 2018-05-29 | 2020-12-10 | Morningside Venture Investments Limited | Drug delivery methods and systems |
| WO2020072700A1 (en) | 2018-10-02 | 2020-04-09 | Dana-Farber Cancer Institute, Inc. | Hla single allele lines |
| US20220062394A1 (en) | 2018-12-17 | 2022-03-03 | The Broad Institute, Inc. | Methods for identifying neoantigens |
| CN117120087A (en) | 2020-12-23 | 2023-11-24 | 高级健康研究所 | Solanesol vaccine adjuvant and its preparation method |
| NL2035417A (en) | 2022-07-19 | 2024-01-26 | Coty Inc | Cosmetic composition |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL107185C (en) * | 1957-12-19 | |||
| US3797494A (en) * | 1969-04-01 | 1974-03-19 | Alza Corp | Bandage for the administration of drug by controlled metering through microporous materials |
| US3731683A (en) * | 1971-06-04 | 1973-05-08 | Alza Corp | Bandage for the controlled metering of topical drugs to the skin |
| CA1076480A (en) * | 1975-04-28 | 1980-04-29 | John S. Kent | Inert core implant pellet |
| US4031894A (en) * | 1975-12-08 | 1977-06-28 | Alza Corporation | Bandage for transdermally administering scopolamine to prevent nausea |
| US4060084A (en) * | 1976-09-07 | 1977-11-29 | Alza Corporation | Method and therapeutic system for providing chemotherapy transdermally |
| US4230105A (en) * | 1978-11-13 | 1980-10-28 | Merck & Co., Inc. | Transdermal delivery of drugs |
| US4291014A (en) * | 1979-01-11 | 1981-09-22 | Key Pharmaceuticals, Inc. | Polymeric diffusion matrix containing estradiol diacetate |
| US4286592A (en) * | 1980-02-04 | 1981-09-01 | Alza Corporation | Therapeutic system for administering drugs to the skin |
-
1981
- 1981-02-17 US US06/235,068 patent/US4379454A/en not_active Expired - Lifetime
-
1982
- 1982-01-15 AU AU79545/82A patent/AU547007B2/en not_active Ceased
- 1982-01-18 GB GB8201314A patent/GB2093694B/en not_active Expired
- 1982-01-18 CY CY140082A patent/CY1400A/en unknown
- 1982-02-05 CA CA000395641A patent/CA1166961A/en not_active Expired
- 1982-02-10 IE IE296/82A patent/IE52930B1/en not_active IP Right Cessation
- 1982-02-12 CH CH903/82A patent/CH657055A5/en not_active IP Right Cessation
- 1982-02-15 FR FR8202409A patent/FR2499859B1/en not_active Expired
- 1982-02-15 SE SE8200892A patent/SE452407B/en not_active IP Right Cessation
- 1982-02-15 DE DE19823205258 patent/DE3205258A1/en active Granted
- 1982-02-16 JP JP57023504A patent/JPS57154122A/en active Granted
- 1982-02-16 IT IT67175/82A patent/IT1218310B/en active Protection Beyond IP Right Term
- 1982-02-17 MX MX191442A patent/MX161285A/en unknown
- 1982-02-17 MX MX198185A patent/MX166954B/en unknown
-
1985
- 1985-07-15 AU AU45020/85A patent/AU565178B2/en not_active Expired
-
1987
- 1987-08-20 SG SG683/87A patent/SG68387G/en unknown
- 1987-12-03 HK HK906/87A patent/HK90687A/en not_active IP Right Cessation
- 1987-12-30 MY MY746/87A patent/MY8700746A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU4502085A (en) | 1985-10-31 |
| CY1400A (en) | 1987-12-18 |
| IE52930B1 (en) | 1988-04-13 |
| IT1218310B (en) | 1990-04-12 |
| DE3205258C2 (en) | 1991-02-28 |
| HK90687A (en) | 1987-12-11 |
| AU565178B2 (en) | 1987-09-10 |
| GB2093694A (en) | 1982-09-08 |
| SE452407B (en) | 1987-11-30 |
| AU7954582A (en) | 1982-08-26 |
| MY8700746A (en) | 1987-12-31 |
| DE3205258A1 (en) | 1982-09-16 |
| JPS57154122A (en) | 1982-09-22 |
| JPH044295B2 (en) | 1992-01-27 |
| US4379454A (en) | 1983-04-12 |
| SG68387G (en) | 1988-02-19 |
| CH657055A5 (en) | 1986-08-15 |
| MX161285A (en) | 1990-08-29 |
| IE820296L (en) | 1982-08-17 |
| GB2093694B (en) | 1985-03-27 |
| FR2499859B1 (en) | 1986-02-14 |
| IT8267175A0 (en) | 1982-02-16 |
| FR2499859A1 (en) | 1982-08-20 |
| SE8200892L (en) | 1982-08-18 |
| AU547007B2 (en) | 1985-10-03 |
| MX166954B (en) | 1993-02-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |