WO2002019985A2 - Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure - Google Patents
Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure Download PDFInfo
- Publication number
- WO2002019985A2 WO2002019985A2 PCT/US2001/027551 US0127551W WO0219985A2 WO 2002019985 A2 WO2002019985 A2 WO 2002019985A2 US 0127551 W US0127551 W US 0127551W WO 0219985 A2 WO0219985 A2 WO 0219985A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- agent
- skin
- healing
- reservoir
- microprotrusions
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- 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
Definitions
- This invention relates to inhibiting a decrease in the transdermal flux of an agent by inhibiting pathway closure.
- this invention relates to a method for inhibiting a decrease in the transdermal flux of an agent that is being transdermally delivered or sampled over a prolonged period of time wherein the delivery or sampling involves disrupting at least the stratum corneum layer of the skin to form pathways through which the agent passes by co-delivering or co-sampling the agent with an amount of at least one anti-healing agent wherein the amount of the anti-healing agent is effective in inhibiting a decrease in the agent transdermal flux compared to when the delivery or sampling of the agent is done under substantially identical conditions except in the absence of the anti-healing agent(s).
- Electrotransport refers generally to the passage of a beneficial agent, e.g., a drug or drug precursor, through a body surface, such as skin, mucous membranes, nails, and the like where the agent is induced or enhanced by the application of an electrical potential.
- a beneficial agent e.g., a drug or drug precursor
- the electrotransport of agents through a body surface may be attained in various manners.
- One widely used electrotransport process, iontophoresis involves the electrically induced transport of charged ions.
- Electroosmosis another type of electrotransport process, involves the movement of a solvent with the agent through a membrane under the influence of an electric field.
- Electroporation still another type of electrotransport, involves the passage of an agent through pores formed by applying a high voltage electrical pulse(s) to a membrane. In many instances, more than one of these processes may be occurring simultaneously to a different extent. Accordingly, the term "electrotransport” is given herein its broadest possible interpretation, to include the electrically induced or enhanced transport of at least one charged or uncharged agent, or mixtures thereof, regardless of the specific mechanism or mechanisms by which the agent is actually being transported. Electrotransport delivery generally increases agent flux during transdermal delivery.
- Another method of increasing the agent flux involves pre- treating the skin with, or co-delivering with the beneficial agent, a skin permeation enhancer.
- a permeation enhancer substance when applied to a body surface through which the agent is delivered, enhances its flux therethrough such as by increasing the permselectivity and/or permeability of the body surface, creating hydrophilic pathways through the body surface, and/or reducing the degradation of the agent during transport.
- This methodology is typically used when the drug is delivered transdermally by passive diffusion.
- These devices use piercing elements of various shapes and sizes to pierce the outermost layer (i.e., the stratum corneum) of the skin.
- the piercing elements disclosed in these references generally extend perpendicularly from a thin, flat member, such as a pad or sheet.
- the piercing elements or microprotrusion in some of these devices are extremely small, some having dimensions (i.e., length and width) of only about 25 - 400 ⁇ m and a microprotrusion thickness of only about 5 - 50 ⁇ m. These tiny piercing/cutting elements make correspondingly small microslits/microcuts in the stratum corneum for enhanced transdermal agent delivery therethrough. [0006] It has now been discovered that in the case of human skin, the pathways created by the microslits/microcuts are quickly closed and sealed by the skin's natural healing processes. Although this process is not completely understood at this time, it is believed that it is closely related to wound healing. Wound healing is a complex phenomenon involving many biological processes.
- This invention is directed to a method for inhibiting a decrease in the transdermal flux of an agent which is being transdermally delivered or sampled over a prolonged period of time where the transdermal flux involves disrupting at least the stratum corneum layer of the skin.
- this invention is directed to a method for inhibiting a decrease in the transdermal flux of an agent being transdermally delivered or sampled over a prolonged period of time wherein the delivery involves disrupting (e.g., by puncturing) at least the stratum corneum layer of the skin to form a plurality of pathways through which the agent passes which method comprises co-delivering or co-sampling the agent with an amount of at least one anti-healing agent wherein said amount of said anti-healing agent is effective in inhibiting a decrease in said agent transdermal flux compared to delivering or sampling said agent under substantially identical conditions except in the absence of said anti-healing agent(s).
- this invention is directed to a method for transdermally delivering an agent over a prolonged period of time which method comprises:
- step (ii) placing a reservoir in agent transmitting relation with the micro- disruptions formed in step (i) said reservoir comprising the agent and an amount of at least one anti-healing agent wherein said amount of said anti-healing agent is effective in inhibiting the decrease in said agent transdermal flux compared to delivering said agent under substantially identical conditions except in the absence of said anti- healing agent(s).
- this invention is directed to a method for transdermally sampling an agent over a prolonged period of time which method comprises: (i) forming a plurality of micro-disruptions through the stratum corneum layer of the skin to form pathways through which the agent passes; and (ii) placing a reservoir in agent transmitting relation with the micro- disruptions formed in step (i) said reservoir comprising an amount of at least one anti-healing agent wherein said amount of said anti-healing agent is effective in inhibiting the decrease in said agent transdermal flux compared to sampling said agent under substantially identical conditions except in the absence of said anti-healing agent(s).
- At least the stratum corneum layer of the skin is pierced, cut or otherwise disrupted (e.g., by abrasives or tape stripping) and most preferably at least the stratum corneum layer of the skin is perforated with a skin perforating device having a plurality of microprotrusions which can penetrate the stratum corneum of the skin to form a plurality of pathways through which the agent and the anti-healing agent pass.
- the anti- healing agent(s) is delivered either before the agent is delivered or sampled; or before and during the transdermal flux of the agent; or during the transdermal flux of the agent; or during and after the transdermal flux of the agent.
- the anti-healing agent(s) is selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and osmotic agents in an amount effective to generate, in solution, an osmotic pressure greater than about 2000 kilopascals, preferably greater than about 3000 kilopascals at 20 e C or mixtures thereof.
- the anticoagulant is selected from the group consisting of heparin having a molecular weight from 3000 to 12,000 daltons, pentosan polysulfate, citric acid, citrate salts, EDTA, and dextrans having a molecular weight from 2000 to 10,000 daltons.
- the anti-inflammatory agent is selected from the group consisting of hydrocortisone sodium phosphate, betamethasone sodium phosphate, and triamcinolone sodium phosphate.
- the agent that inhibits the cellular migration is selected from the group consisting of laminin and related peptides.
- the osmotic agent is a biologically compatible salt such as sodium chloride or a neutral compound such as glucose, or a zwitterionic compound such as glycine having a sufficiently high concentration to generate, in solution, an osmotic pressure greater than about 2000 kilopascals, preferably greater than about 3000 kilopascals.
- a biologically compatible salt such as sodium chloride or a neutral compound such as glucose
- a zwitterionic compound such as glycine having a sufficiently high concentration to generate, in solution, an osmotic pressure greater than about 2000 kilopascals, preferably greater than about 3000 kilopascals.
- the agent that is transdermally delivered is a macromolecular agent selected from the group consisting of polypeptides, proteins, oligonucleotides, nucleic acids, and polysaccharides.
- the polypeptides and proteins are selected from the group selected from desmopressin, leutinizing releasing hormone (LHRH) and LHRH analogs (e.g., goserelin, leuprolide, buserelin, triptorelin), PTH, calcitonin, interferon- , interferon- ⁇ , interferon- ⁇ , follicle stimulating hormone (FSH), hGH, insulin, insulinotropin, and erythropoietin.
- LHRH leutinizing releasing hormone
- FSH follicle stimulating hormone
- the oligonucleotide is selected from the group consisting of ISIS 2302, ISIS 15839 and other phosphorothiolated oligonucleotides and other methoxyethylphosphorothiolated oligonucleotides and the polysaccharide is selected from the group consisting of low molecular weight heparin having a molecular weight from 3000 to 12,000 daltons and pentosan polysulfate.
- the agent that is transdermally sampled is a body analyte.
- the body analyte is glucose.
- this invention is directed to a device for transdermally delivering an agent over a prolonged period of time which device comprises: (i) an element having a plurality of skin-piercing microprotrusions for forming a plurality of microcuts through the stratum corneum layer of the skin to form pathways through which the agent passes; and
- a reservoir comprising an agent and an amount of at least one anti- healing agent wherein said amount of said anti-healing agent is effective in inhibiting the decrease in said agent transdermal flux compared to delivering said agent under substantially identical conditions except in the absence of said anti-healing agent(s).
- this invention is directed to a device for transdermally sampling an agent over a prolonged period of time, which device comprises:
- this invention is directed to a kit transdermally delivering or sampling an agent over a prolonged period of time comprising: (i) a device with an array of microprotrusions for forming microcuts through the stratum corneum layer of the skin; and
- a reservoir comprising an amount of at least one anti-healing agent wherein said amount of said anti-healing agent is effective in inhibiting a decrease in an agent transdermal flux compared to when the agent is delivered or sampled under substantially identical conditions except in the absence of said anti-healing agent.
- the anti-healing agent(s) is selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and osmotic agents in an amount effective to generate, in solution, an osmotic pressure greater than about 2000 kilopascals, preferably greater than about 3000 kilopascals at 20 Q C or mixtures thereof.
- the anticoagulant is selected from the group consisting of heparin having a molecular weight from 3000 to 12,000 daltons, pentosan polysulfate, citric acid, citrate salts such as sodium citrate, EDTA, and dextrans having molecular weight from 2000 to 10,000 daltons.
- the anti-inflammatory agent is selected from the group consisting of hydrocortisone sodium phosphate, betamethasone sodium phosphate, and triamcinolone sodium phosphate.
- the agent that inhibits the cellular migration is selected from the group consisting of laminin and related peptides.
- the osmotic agent is a biologically compatible salt such as sodium chloride or a neutral compound such as glucose, or a zwitterionic compound such as glycine having a sufficiently high concentration to generate, in solution, an osmotic pressure greater than about 2000 kilopascals, preferably greater than about 3000 kilopascals.
- the agent that is transdermally delivered is a macromolecular agent selected from the group consisting of polypeptides, proteins, oligonucleotides, nucleic acids, and polysaccharides.
- the polypeptides and proteins are selected from the group selected from desmopressin, leutinizing releasing hormone (LHRH) and LHRH analogs (e.g., goserelin, leuprolide, buserelin, triptorelin), PTH, calcitonin, interferon- ⁇ , interferon- ⁇ , interferon- ⁇ , follicle stimulating hormone (FSH), hGH, insulin, insulinotropin, and erythropoietin.
- LHRH leutinizing releasing hormone
- FSH follicle stimulating hormone
- the oligonucleotide is selected from the group consisting of ISIS 2302, ISIS 15839 and other phosphorothiolated oligonucleotides and other methoxyethylphosphorothiolated oligonucleotides and the polysaccharide is selected from the group consisting of low molecular weight heparin having a molecular weight from 3000 to 12,000 daltons and pentosan polysulfate.
- the agent that is transdermally sampled is a body analyte.
- the body analyte is glucose.
- FIG. 1 is a graph of the effect of pathway closure inhibitors on passive transdermal pentosan polysulfate flux.
- FIG. 2 is a graph of the effect of pathway closure inhibitors on passive transdermal pentosan polysulfate delivery.
- FIG. 3 is a graph of the effect of pathway closure inhibitors on o passive transdermal pentosan polysulfate flux.
- FIG. 4 is a graph of the effect of pathway closure inhibitors on passive transdermal pentosan polysulfate delivery.
- FIG. 5 is a graph of the effect of pathway closure inhibitors on passive transdermal pentosan polysulfate delivery.
- FIG. 6 is a graph of the effect of pathway closure inhibitors on passive transdermal pentosan polysulfate delivery.
- FIG. 7 is a graph of the effect of pathway closure inhibitors on passive transdermal DNA delivery.
- FIG. 8 is a schematic side view of a device for transdermally o delivering or sampling an agent according to the present invention.
- transdermal flux means the rate of passage of any agent in and through the skin of an individual or the rate of passage of any analyte out through the skin of an individual.
- transdermal means the delivery or extraction of an o agent through the skin.
- pathway means passages formed in the stratum corneum of the skin by disrupting it which allow for enhanced transdemal flux of an agent.
- stratum corneum of the skin can be disrupted by methods well known in the art such as sanding, tape stripping, creating microcuts, and the like. Other methods are described in US Patents Nos. 6,022,316, 5,885,211 and 5,722,397 the disclosures of which are incorporated herein in their entirety.
- the passages are formed by disrupting of the skin with a device having a plurality of stratum corneum-piercing microprotrusions thereby creating microcuts in the stratum corneum
- the term "microprotrusion” as used herein refers to very tiny stratum corneum piercing elements typically having a length of less than 500 micrometers, and preferably less than 250 micrometer, which make a penetration in the stratum corneum.
- the microprotrusions preferably have a length of at least 50 micrometers.
- the microprotrusions may be formed in different shapes, such as needles, hollow needles, blades, pins, punches, and combinations thereof.
- microprotrusion array refers to a plurality of microprotrusions arranged in an array for piercing the stratum corneum.
- the microprotrusion array may be formed by etching a plurality of blades from a thin sheet and folding each of the blades out of the plane of the sheet to form the configuration shown in FIG. 8.
- the microprotrusion array may also be formed in other known manners, such as by connecting multiple strips having microprotrusions along an edge of each of the strips.
- the microprotrusion array may include hollow needles which inject a liquid formulation. Examples of microprotrusion arrays are described in U.S. Patent No.
- prolonged delivery means a period of delivery that lasts for at least half an hour, preferably between several hours to about 24 hours, more preferably between about 8 and 24 hours.
- co-delivering means the anti-healing agent(s) is administered transdermally before the agent is delivered; before and during transdermal flux of the agent; during transdermal flux of the agent; and/or during and after transdermal flux of the agent.
- co-sampling means the anti-healing agent(s) is administered transdermally before the agent is sampled by transdermal flux; before and during transdermal flux of the agent; during transdermal flux of the agent; and/or during and after transdermal flux of the agent.
- agent refers to an agent, drug, compound, composition of matter or mixture thereof which provides some pharmacological, often beneficial, effect. It is intended in its broadest interpretation as any pharmaceutically-acceptable substance which may be delivered to a living organism to produce a desired, usually beneficial, effect.
- this includes therapeutic agents in all of the major therapeutic fields including, but not limited to, anti-infectives such as antibiotics and antiviral agents; analgesics such as fentanyl, sufentanil, and buprenorphine, and analgesic combinations; anesthetics; anorexics; antiarthritics; antiasthmatic agents such as terbutaline; anticonvulsants; antidepressants; antidiabetics agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antimotion sickness preparations such as scopolamine and ondansetron; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics including gastrointestinal and urinary; anticholinergics; sympathomimetrics; xanthine derivatives; cardiovascular preparations including calcium channel blockers such as nifedipine; betaagonists such as do
- the invention is particularly useful in the controlled delivery of peptides, polypeptides, proteins, or other macromolecules difficult to deliver transdermally because of their size.
- macromolecular substances typically have a molecular weight of at least about 300 Daltons, and more typically, in the range of about 300 to 40,000 Daltons.
- agent may be incorporated into the agent formulation in the method of this invention, and that the use of the term "agent” in no way excludes the use of two or more such agents or drugs.
- the agents can be in various forms, such as free bases, acids, charged or uncharged molecules, components of molecular complexes or nonirritating, pharmacologically acceptable salts. Also, simple derivatives of the agents (such as ethers, esters, amides, etc) which are easily hydrolyzed by body pH, enzymes, etc, can be employed. The agents can be in solution, in suspension or a combination of both in the drug reservoir. Alternatively, the agent can be a particulate. [00058] The amount of agent employed in the delivery device will be that amount necessary to deliver a therapeutically effective amount of the agent to achieve the desired result. In practice, this will vary widely depending upon the particular agent, the site of delivery, the severity of the condition, and the desired therapeutic effect.
- agent refers to body analytes to be sampled.
- analyte means any chemical or biological material or compound suitable for passage through a biological membrane by the technology taught in this present invention, or by technology previously known in the art, of which an individual might want to know the concentration or activity inside the body.
- Glucose is a specific example of an analyte because it is a sugar suitable for passage through the skin, and individuals, for example those having diabetes, might want to know their blood glucose levels.
- Other examples of analytes include, but are not limited to, such compounds as sodium, potassium, bilirubin, urea, ammonia, calcium, lead, iron, lithium, salicylates, alcohol, licit substances, illicit drugs, and the like.
- therapeutic amount or rate refer to the amount or rate of the agent needed to effect the desired pharmacological, often beneficial, result.
- passive transdermal delivery is used herein to describe the passage of an agent through a body surface, eg, skin by passive diffusion.
- passive delivery devices have a drug reservoir which contains a high concentration of a drug. The device is placed in contact with a body surface for an extended period of time, and is allowed to diffuse from the reservoir and into the body of the patient, which has a much lower concentration of drug.
- the primary driving force for passive drug delivery is the concentration gradient of the drug across the skin. In this type of delivery, the drug reaches the bloodstream by diffusion through the dermal layers of the body.
- the preferred agents for passive delivery are hydrophobic non-ionic agents, given that the drug must diffuse through the lipid layers of the skin.
- electrotransport is used herein to describe the passage of a substance, eg, a drug or prodrug, through a body surface or membrane, such as the skin, mucous membranes, or nails, induced at least partially by the application of an electric field across the body surface (eg, skin).
- a widely used electrotransport process, iontophoresis involves the electrically induced transport of therapeutic agents in the form of charged ions, lonizable therapeutic agents, eg, in the form of a salt which when dissolved forms charged agent ions, are preferred for iontophoretic delivery because the charged agent ions move by electromigration within the applied electric field.
- Electroosmosis another type of electrotransport process, involves the movement of a liquid, which liquid contains a charged and/or uncharged therapeutic agent dissolved therein, through a biological membrane (e.g., skin) under the influence of an electric field.
- a biological membrane e.g., skin
- electroporation Another type of electrotransport, electroporation, involves the formation of transiently-existing pores in a living biological membrane by applying high voltage pulses thereto and delivery of a therapeutic agent therethrough.
- more than one of these processes may be occurring simultaneously to some extent.
- electrotransport is used herein in its broadest possible interpretation to include the electrically induced or enhanced transport of at least one agent, which may be charged, ie, in the form of ions, or uncharged, or of mixtures thereof, regardless of the specific mechanisms by which the agent is actually transported.
- anti-healing agent means an agent which alone or in combination acts to prevent or diminish skin's natural healing processes thereby preventing the closure of the pathways formed by disruptions such as microslits/microcuts in the stratum corneum of the skin.
- suitable anti-healing agents include, but are not limited to:
- osmotic agents which include neutral compounds such as glucose, salts such as sodium chloride, and zwitterionic compounds such as amino acids.
- the formulation (as is or reconstituted from a dry formulation) should have an osmotic pressure greater than about 2000 kPa and more preferably about 3000 kPa at 20° C.
- Neutral compounds include:
- organic solvents such as dimethylsulfoxide.
- acids in the neutral state such as boric acid, and the like.
- ether alcohols and polymers of ethylene oxide comprising at least one alcohol group and having a molecular weight ranging from 92 to 500.
- Compounds in this group include ethoxydiglycol, diethylene glycol, dipropylene glycol, triethylene glycol, PEG-4, PEG-6, PEG-8 and PEG-9, and the like;
- aliphatic alcohols comprising two alcohol groups such as propylene glycol and butane diol, and the like;
- aliphatic alcohols comprising three alcohol groups such as glycerol, and 1 ,2,6-hexanetriol, and the like;
- g pentahydric alcohols such as adonitol, xylitol and arabitol, and the like;
- hexahydric alcohols such as sorbitol, mannitol, galactitol, and the like;
- aliphatic compounds comprising one ketonic or aldehyde group and at least two alcohol groups.
- Compounds in this group include deoxyribose, ribulose, xylulose, psicose, sorbose, and the like, (j) cyclic polyols such as inositol, and the like; (k) monosaccharides such as apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, quinovose, rhamnose, allose, altrose, fructose, galactose, glucose, gulose, hamamelose, idose, mannose, tagatose, and the like; (I) disaccharides such as sucrose, trehalose, primeverose, vicianose, rutinose, scillabiose, cellobiose, gentiobiose, lactose, lactulose, maltose, melibios
- These salts include: sodium chloride, the salt forms of acetic acid, propionic acid, glycolic acid, pyruvic acid, hydracrylic acid, lactic acid, pivalic acid, beta-hydroxybutyric acid, glyceric acid, sorbic acid, mandelic acid, atrolactic acid, tropic acid, quinic acid, glucuronic acid, gluconic acid, gulonic acid, glucoheptonic acid, benzilic acid, ammonia, monoethanolamine, diethanolamine, aminomethylpropanediol, tromethamine, triethanolamine, galactosamine and glucosamine.
- These salts include: the salt forms of phosphoric acid, malonic acid, fumaric acid, maleic acid, succinic acid, tartronic acid, oxaloacetic acid, malic acid, alpha-ketoglutaric acid, citramalic acid, and tartaric acid.
- These salts include: the salt forms of aconitic acid, citric acid and isocitric acid.
- i is about 1 and the concentration at about 2000 kPa is about 0.8 M; at about 3000 kPa it is about 1.2 M.
- Zwitterionic coumpounds include: amino acids such as glycine, alanine, proline, threonine and valine, diamino acids such as glycylglycine, buffers such as 4-morpholinepropane sulfonic acid (MOPS), (2- ⁇ [tris(hydroxymethyl) methyl]amino ⁇ -1 -ethane sulfonic acid (TES), 4-(2- hydroxyethyl)-1-piperazineethane sulfonic acid (HEPES), ⁇ -hydroxy-4-(2- hydroxyethyl)-1-piperazinepropane sulfonic acid monohydrate (HEPPSO), tricine, bicine, CHES and CAPS and the like.
- MOPS 4-morpholinepropane sulfonic acid
- TES (2- ⁇ [tris(hydroxymethyl) methyl]amino ⁇ -1 -ethane sulfonic acid
- HPES 4-(2- hydroxyethyl)-1
- Anticoagulants such as citric acid, citrate salts (e.g. sodium citrate), dextran sulfate sodium, EDTA, pentosan polysulfate, oligonucleotides, aspirin, low molecular weight heparin, and lyapolate sodium.
- anti-inflammatory agents such as betamethasone 21 -phosphate disodium salt, triamcinolone acetonide 21-disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21 -phosphate disodium salt, methylprednisolone 21 -phosphate disodium salt, methylprednisolone 21- succinate sodium salt, paramethasone disodium phosphate, prednisolone 21-succinate sodium salt, prednisolone 21- -sulfobenzoate sodium salt, prednisolone 21 -diethylaminoacetate hydrochloride, prednisolone sodium phosphate, prednylidene 21 -diethylaminoacetate hydrochloride, triamcinolone acetonide 21-disodium phosphate; the salt form of NSAIDs such as aspirin and other salicylates, bromfenac, diclofenac, diflun
- agents that effect cellular migration such as laminin and related peptides and fibronectin related peptides.
- the range of concentration for anticoagulant agents, anti- inflammatory agents, and agents that inhibit cellular migration is between 0.1 and 10% in the formulation.
- the major barrier properties of the skin reside with the outermost layer of the skin, i.e., the stratum corneum.
- the inner division, i.e., the backing layers, of the epidermis generally comprises three layers commonly identified as stratum granulosum, stratum malpighii, and stratum germinativum. There is essentially little or no resistance to transport or to absorption of an agent through these layers.
- the microprotrusions used to create pathways in the body surface in accordance with the present invention need only penetrate through the stratum corneum in order for the agent to be transdermally delivered or sampled with little or no resistance through the skin.
- the pathways created by the microslits/microcuts are quickly closed and sealed by the skin's natural healing processes. Accordingly, the enhancement in transdermal agent flux provided by these pathways is completely eliminated within several hours of making the pathways.
- the present invention inhibits the decrease in the transdermal flux of an agent due to the pathway closure after the pathways have been made.
- the skin is treated with a microprotusion array device to form small cuts, slits, or holes called pathways in the outermost layer of the body surface to a limited depth.
- the microprotrusions may be formed in different shapes, such as needles, hollow needles, pins, punches, and combinations thereof.
- FIG. 8 illustrates a transdermal delivery or sampling patch 10 including a plurality of microprotrusions 12, a reservoir 14, an adhesive backing layer 16, and an impermeable backing layer 18.
- a reservoir 14 may be provided by a discreet layer on the skin proximal or skin distal side of the base sheet which supports the microprotrusions 12.
- the reservoir 14 may be provided by coatings on the microprotrusions, and/or the reservoir may be provided by coatings on the other parts of the patch 10.
- the present invention has been described as including an agent and an anti-healing agent, it should be understood that the agent and the anti-healing agent may be provided in the same reservoir or different reservoirs in the device. [00076]
- the device of the present invention can be used in connection with agent delivery, agent sampling, or both.
- the device of the present invention is used in connection with transdermal drug delivery, transdermal analyte sampling, or both.
- Transdermal delivery devices for use with the present invention include, but are not limited to, passive devices, electrotransport devices, osmotic devices, and pressure-driven devices.
- Transdermal sampling devices for use with the present invention include, but are not limited to, passive devices, reverse electrotransport devices, negative pressure driven devices, and osmotic devices.
- the transdermal devices of the present invention may be used in combination with other methods of increasing agent flux, such as skin permeation enhancers.
- Example 1 Decrease in drug flux has been studied with three model drugs presenting different charge characteristics: pentosan polysulfate (PPS), a highly negatively charged compound, DECAD, a synthetic model decapeptide bearing two positive charges at pH 5.5, and inulin, a neutral polysaccharide. These compounds do not penetrate the skin significantly without the use of penetration enhancers or physical disruption of the skin barrier.
- PPS pentosan polysulfate
- DECAD highly negatively charged compound
- inulin a synthetic model decapeptide bearing two positive charges at pH 5.5
- inulin a neutral polysaccharide
- microprotrusion array is then removed from the skin and then some form of agent delivery device or agent reservoir is placed over the pathways in order to effect agent delivery or sampling.
- Pretreatment was used instead of integrated system because pathway closure appears to occur more rapidly and more reproducibly following pretreatment than when the microprotrusions are left in the skin during drug delivery.
- concentration of PPS was below the concentration required for anticoagulant effect. All drugs were dissolved in water and solutions were gelled with 2% hydroxyethylcellulose. Concentration of PPS, DECAD and inulin were 0.1 mg/mL, 13 mg/mL and 2.5 mg/mL, respectively. PPS and DECAD were radiolabeled with tritium. Insulin was radiolabeled with 14 C.
- HGPs hairless guinea pigs
- the system applied comprised a foam double adhesive ring (diameter 3.8 cm, thickness 0.16 cm) with a 2 cm 2 reservoir in the middle containing a microprotrusion array having an area of 2 cm 2 and comprised of a stainless steel sheet having a thickness of 0.025 mm, trapezoidally shaped blades bent at an angle of approximately 90° to the plane of the sheet, the microprotrusions had a length of 545 micrometer, and a microprotrusion density of 72 microprotrusions /cm 2 .
- the stretching tension was released.
- the adhesive ring was left adhered on the skin and the microprotrusion array was removed.
- the drug formulation (350 ⁇ L) was dispensed into the drug compartment and a backing membrane was applied to the adhesive outer surface of the ring to seal the system.
- a total of six HGPs were treated with the same drug formulation. At 1 hour and 24 hours after application, the systems from 3 HGPs from each group were removed and residual drug washed from the skin.
- the amount of drug that had penetrated during these time intervals was determined by measuring urinary excretion of radioactivity for two days following removal of the patch and corrected from the percentage excreted following iv injection (previous studies had shown that for 3 H-PPS, 3 H DECAD, and 14 C inulin, percentage excreted over two days following injection were 32%, 65% and 94%, respectively).
- the results (Table I) show that between 1 hour and 24 hour, flux decreased by at least one order of magnitude for all drugs indicating that pathways formed by piercing of the skin by the microprotrusions had at least partially closed.
- the system applied comprised a foam double adhesive ring (diameter 3.8 cm, thickness 0.16 cm) with a 2 cm 2 reservoir in the middle containing a microprotrusion array having an area of 2 cm 2 and comprised of a stainless steel sheet having a thickness of 0.025 mm, trapezoidally shaped blades bent at an angle of approximately 90° to the plane of the sheet.
- the microprotrusions had a length of 545 micrometer, and a microprotrusion density of 72 microprotrusions/cm 2 . Following application, the stretching tension was released. The adhesive ring was left adhered on the skin and the microprotrusion array was removed.
- a formulation (350 ⁇ L) containing the tested compound in water and optionally a gelling agent (hydroxyethylcellulose (HEC) at 2% or silica gel at 50%) was dispensed into the drug reservoir and a backing membrane was applied to the adhesive outer surface of the ring to seal the system.
- the guinea pig received a second system containing a different formulation on the opposite site. Twenty four hours after application, three systems from each group were removed and residual formulation washed from the skin. The skin was stained with a 1% methylene blue solution. Excess dye was thoroughly removed with 70% isopropyl alcohol pads and a picture of the site was taken.
- the most effective agents were the polyol 1 ,2,6-hexanetriol, glucuronic acid, the polymer of ethylene oxide diethylene glycol, the pentahydric alcohol adonitol, the hexahydric alcohol sorbitol, the polyol-amine tromethamine, and the monosaccharide glucose.
- citric acid, EDTA, as well as dextran 5000 were the most effective agents in preventing pathway closure.
- the antiinflammatory agents betamethasone disodium phosphate as well as ketoprofen sodium salt presented a significant effect.
- the keratolytic agent salicylic acid also had an effect on pathway closure. Low pH also inhibited pathway closure.
- Surfactants (anionic, cationic and nonionic), at non-irritating concentrations, had no effect. Inert agents failed to prevent pathway closure. Sites exposed to glycerol and citric acid were also stained with India ink to confirm that the pathways were open for larger sized compounds.
- Example 3 Pentosan polysulfate (PPS), a highly negatively charged compound, does not penetrate the skin significantly without the use of penetration enhancers or physical disruption of the skin barrier.
- PPS was delivered by passive diffusion through pathways in the skin created by a microprotrusion array.
- the concentration of PPS was below the concentration required for inhibition of pathway collapse (see Table II). Therefore, at the concentration used in this experiment, PPS behaved like a drug lacking any activity on pathway closure.
- the purpose of the experiment was to show that inhibitors of pathway collapse identified in Example 2 also improved drug flux through the skin in vivo.
- the skin of one flank was manually stretched bilaterally at the time of the application of the system.
- Microprotrusion array application was performed with an impact applicator.
- the system applied comprised a foam double adhesive ring (diameter 3.8 cm, thickness 0.16 cm) with a drug containing hydrogel having a skin contact area of 2 cm 2 in the middle containing a microprotrusion array having an area of 2 cm 2 and comprised of a stainless steel sheet having a thickness of 0.025 mm, trapezoidally shaped blades bent at an angle of approximately 90° to the plane of the sheet, the microprotrusion had a length of 545 ⁇ m, and a microprotrusion density of 72 microprotrusion/cm 2 . Following application, the stretching tension was released. The adhesive ring was left adhered on the skin and the microprotrusion array was removed.
- a hydrogel containing 3 H- PPS in water (PPS concentration of 0.1 mg/mL, 2% HEC, 350 ⁇ L) was dispensed into the drug compartment and a plastic cover was applied to the adhesive outer surface of the ring to seal the system. Additional groups of HGPs were treated in the same way, except that the formulation contained 3% citric acid trisodium salt or 50% 1 ,2,6-hexanetriol. At 1 and 24 h after application, 3 systems from each group were removed and residual drug washed from the skin.
- the amount of drug penetrated during these time intervals was determined by measuring urinary excretion of tritium (previous studies had shown that in HGPs, 32% of the tritium derived from 3 H-PPS injected intravenously is excreted in urine).
- the results, as shown in FIG.1 show that between 1 hour and 24 hours, flux decreased by about 12 fold, demonstrating pathway closure.
- Citric acid and 1 ,2,6-hexanetriol inhibited this decrease in flux. Flux in the presence of 1 ,2,6-hexanetriol was decreased by less than 2 fold between 1 and 24 h. Total amount transported was increased about 4 and 7 folds in the presence of citric acid and 1 ,2,6- hexanetriol, respectively, as compared to controls as shown in FIG. 2.
- the additive used did not modify the 45 min PPS flux, indication that they did not present permeation enhancing properties and that pathways had not significantly closed during this period.
- citric acid and 1 ,2,6-hexanetriol inhibited significantly the decrease in flux. Flux in the presence of the mixture of citric acid trisodium salt and 1 ,2,6-hexanetriol resulted in a complete inhibition of the decrease in PPS flux observed between 45 min and 24 h. Total amounts of PPS transported are shown in FIG. 4.
- the effect observed in the presence of 3% citric acid trisodium salt and 50% 1 ,2,6- hexanetriol is greater than additive. This is probably the indication that these two agents are effective on different wound healing mechanisms (citric acid is probably preventing clot formation while 1 ,2,6-hexanetriol is probably preventing another regeneration process such as keratinocyte migration).
- Example 5 An additional experiment was performed with PPS. Conditions were identical to that described in Example 4. Gluconic acid sodium salt, glucuronic acid sodium salt and glucose were evaluated at 0.6 M concentration with or without 3% citric acid. Similarly to the precedent example, as shown in FIG. 5, results show that between 1 hour and 24 hours, flux decreased dramatically, demonstrating pathways closure. At 24 hours, all compounds and combinations significantly increased PPS flux. Total amounts of PPS transported are shown in FIG. 6. These results support the conclusions presented in Example 4 and demonstrate that lower concentrations of anti-healing agents are still very effective at inhibiting microprotrusion pathway closure.
- Example 6 [00087] Feasibility studies were conducted in hairless guinea pigs
- HGPs to determine whether passive intracutaneous delivery of a plasmid DNA vaccine (pCMV-AYW-HBs-Mkan), which encodes for hepatitis B surface antigen [HBsAg]), could be achieved using Macroflux.
- pCMV-AYW-HBs-Mkan which encodes for hepatitis B surface antigen [HBsAg]
- Macroflux hepatitis B surface antigen
- Each configuration has a total surface area of 2 cm 2 and an active total blade surface area of 1 cm 2 .
- a microprotrusion array of the selected type was adhered to the adhesive foam and covered the bottom of the reservoir (after application, the microprotrusion array is in contact with the skin). Following application, the stretching tension was released and the microprotrusion array was left in situ.
- a liquid formulation (90 ⁇ L) containing 3.5 mg/mL of the plasmid DNA vaccine in buffer (TRIS 5 mM pH 7.6) was dispensed into the drug reservoir and a backing membrane was applied to the adhesive outer surface of the ring to seal the system. Additional HGPs were treated in the same way, except that the formulation contained either 1 % Tween 80 or 3% citric acid trisodium salt in addition to the plasmid DNA and the Tris buffer.
- Example 7 [00090] Examples 2-6 demonstrate that drugs of interest can have their flux enhanced by co-delivery of pathway closure inhibitors. In particular, it was shown that compounds presenting anticoagulants properties are effective in preventing pathway collapse. If these compounds can prevent pathway collapse and therefore prolong the delivery of drug molecules, it is obvious that if they are delivered at concentrations high enough to exert locally their anticoagulant activity, they will prolong their own delivery. Delivery experiments with drugs presenting anticoagulant properties have been performed in the HGP with PPS and the phosphorothiolated oligonucleotide ISIS 2302.
- PPS is a drug used in the management of inflammatory conditions such as interstitial cystitis
- the phosphorothiolated oligonucleotide ISIS 2302 is an antisense drug to the mRNA coding for the ICAM1 molecule and presenting antiinflammatory properties. Both molecules are highly negatively charged compound and do not penetrate the skin significantly without the use of penetration enhancers or physical disruption of the skin barrier.
- a total dose of 1.9 ⁇ 0.1 mg was delivered in 4 hours by electrotransport with a current of 100 ⁇ A/cm 2 and a microprotrusion array having an area of 2 cm 2 and comprised of a stainless steel sheet having a thickness of 0.025 mm, trapezoidally shaped blades bent at an angle of approximately 90 Q to the plane of the sheet, the microprotrusions had a length of 480 ⁇ m, and a microprotrusion density of 241 microprotrusion/cm 2 .
- the phosphorothiolated oligonucleotide ISIS 2302 was delivered for 24 hours using a microprotrusion array with an area of 2 cm 2 , microprotrusion lengths of 480 ⁇ m and 241 microprotrusions/cm 2 .
- the effect of drug concentration, microprotrusion array pretreatment versus integrated treatment and delivery passive versus electrotransport were evaluated. Results, summarized in Table III, demonstrate that this compound can be effectively delivered through the skin for extended periods of time, probably as a result of its anticoagulant properties.
- Drugs of interest that could be delivered at therapeutic levels using the microprotrusion technology during extended periods of time (i.e. 24 hours) and without the help of adjuvant that prevent pathway collapse include all compounds presenting anticoagulants properties during local delivery and having a molecular weight greater than about 2000. These compounds include pentosan polysulfate, oligonucleotides, low molecular weight heparin, hirudin and hirudin analogs such as hirulog.
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK01968531T DK1335711T3 (en) | 2000-09-08 | 2001-09-06 | Transdermal device |
DE60129585T DE60129585T2 (en) | 2000-09-08 | 2001-09-06 | TRANSDERMALE DEVICE |
CA002422200A CA2422200A1 (en) | 2000-09-08 | 2001-09-06 | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure |
AU8877401A AU8877401A (en) | 2000-09-08 | 2001-09-06 | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure |
NZ524646A NZ524646A (en) | 2000-09-08 | 2001-09-06 | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure |
MXPA03002122A MXPA03002122A (en) | 2000-09-08 | 2001-09-06 | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure. |
EEP200300095A EE200300095A (en) | 2000-09-08 | 2001-09-06 | Methods of Inhibiting Decrease in Drug Transdermal Transportation by Inhibiting Canal Closure |
EP01968531A EP1335711B1 (en) | 2000-09-08 | 2001-09-06 | Transdermal device |
IL15481101A IL154811A0 (en) | 2000-09-08 | 2001-09-06 | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure |
JP2002524470A JP5507030B2 (en) | 2000-09-08 | 2001-09-06 | Methods for suppressing reduction in transdermal drug flow by inhibiting pathway closure |
KR1020037003472A KR100764699B1 (en) | 2000-09-08 | 2001-09-06 | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure |
AU2001288774A AU2001288774B2 (en) | 2000-09-08 | 2001-09-06 | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure |
BR0113749-2A BR0113749A (en) | 2000-09-08 | 2001-09-06 | Methods to inhibit decrease in transdermal drug flow by inhibiting pathway closure |
NO20031071A NO20031071L (en) | 2000-09-08 | 2003-03-07 | Method of Inhibiting Decrease in Transdermal Drug Flow Through Inhibition by Closing the Reaction Pathway |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US23116000P | 2000-09-08 | 2000-09-08 | |
US60/231,160 | 2000-09-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002019985A2 true WO2002019985A2 (en) | 2002-03-14 |
WO2002019985A3 WO2002019985A3 (en) | 2002-09-06 |
Family
ID=22867983
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/027551 WO2002019985A2 (en) | 2000-09-08 | 2001-09-06 | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure |
Country Status (24)
Country | Link |
---|---|
US (1) | US7438926B2 (en) |
EP (1) | EP1335711B1 (en) |
JP (2) | JP5507030B2 (en) |
KR (1) | KR100764699B1 (en) |
CN (1) | CN100421653C (en) |
AT (1) | ATE367805T1 (en) |
AU (2) | AU2001288774B2 (en) |
BR (1) | BR0113749A (en) |
CA (1) | CA2422200A1 (en) |
CZ (1) | CZ2003687A3 (en) |
DE (1) | DE60129585T2 (en) |
DK (1) | DK1335711T3 (en) |
EE (1) | EE200300095A (en) |
ES (1) | ES2290166T3 (en) |
IL (1) | IL154811A0 (en) |
MA (1) | MA25958A1 (en) |
MX (1) | MXPA03002122A (en) |
NO (1) | NO20031071L (en) |
NZ (1) | NZ524646A (en) |
PL (1) | PL365603A1 (en) |
PT (1) | PT1335711E (en) |
RU (1) | RU2272618C2 (en) |
WO (1) | WO2002019985A2 (en) |
ZA (1) | ZA200302700B (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006020841A2 (en) * | 2004-08-11 | 2006-02-23 | Alza Corporation | Apparatus and method for transdermal delivery of natriuretic peptides |
EP1682012A2 (en) * | 2003-11-13 | 2006-07-26 | ALZA Corporation | Composition and apparatus for transdermal delivery |
EP1734993A2 (en) | 2004-04-01 | 2006-12-27 | Alza Corporation | Apparatus and method for transdermal delivery of influenza vaccine |
JP2007527392A (en) * | 2003-06-30 | 2007-09-27 | アルザ・コーポレーシヨン | Formulations for coated microprojections containing non-volatile counterions |
EP2818159A1 (en) * | 2013-06-25 | 2014-12-31 | LTS LOHMANN Therapie-Systeme AG | Device having transdermal therapeutic system, positioning and penetration aid |
US9987361B1 (en) * | 2014-12-29 | 2018-06-05 | Noven Pharmaceuticals, Inc. | Compositions and method for sustained drug delivery by active transdermal technology |
WO2019092257A1 (en) | 2017-11-10 | 2019-05-16 | Lts Lohmann Therapie-Systeme Ag | Microneedle system for applying a hepatitis vaccine |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2422200A1 (en) * | 2000-09-08 | 2002-03-14 | Alza Corporation | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure |
EP2085109A3 (en) * | 2000-10-26 | 2009-09-02 | Alza Corporation | Transdermal drug delivery devices having coated microprotrusions |
US6908453B2 (en) * | 2002-01-15 | 2005-06-21 | 3M Innovative Properties Company | Microneedle devices and methods of manufacture |
PE20050288A1 (en) * | 2003-07-02 | 2005-04-29 | Alza Corp | METHOD AND IMMUNIZATION PATCH BY MICROPROJECTION DISPOSAL |
AU2004268616B2 (en) | 2003-08-25 | 2010-10-07 | 3M Innovative Properties Company | Delivery of immune response modifier compounds |
CN101415443A (en) * | 2003-10-23 | 2009-04-22 | 阿尔扎公司 | Compositions of stabilized DNA for coating microprojctions |
AU2004285484A1 (en) * | 2003-10-24 | 2005-05-12 | Alza Corporation | Pretreatment method and system for enhancing transdermal drug delivery |
CN101120101A (en) * | 2004-04-13 | 2008-02-06 | 阿尔扎公司 | Apparatus and method for transdermal delivery of multiple vaccines |
BRPI0509901A (en) * | 2004-04-13 | 2007-08-07 | Alza Corp | apparatus and method for transdermal delivery of fentanyl-based agents |
WO2006055799A1 (en) * | 2004-11-18 | 2006-05-26 | 3M Innovative Properties Company | Masking method for coating a microneedle array |
US8057842B2 (en) | 2004-11-18 | 2011-11-15 | 3M Innovative Properties Company | Method of contact coating a microneedle array |
CA2587387C (en) | 2004-11-18 | 2013-06-25 | 3M Innovative Properties Company | Method of contact coating a microneedle array |
CN101160117A (en) * | 2005-02-16 | 2008-04-09 | 阿尔扎公司 | Apparatus and method for transdermal delivery of epoetin-based agents |
US20060253078A1 (en) * | 2005-04-25 | 2006-11-09 | Wu Jeffrey M | Method of treating skin disorders with stratum corneum piercing device |
US20070270738A1 (en) * | 2005-04-25 | 2007-11-22 | Wu Jeffrey M | Method of treating ACNE with stratum corneum piercing patch |
EP1904158B1 (en) | 2005-06-24 | 2013-07-24 | 3M Innovative Properties Company | Collapsible patch with microneedle array |
US20070078414A1 (en) * | 2005-08-05 | 2007-04-05 | Mcallister Devin V | Methods and devices for delivering agents across biological barriers |
US8900180B2 (en) * | 2005-11-18 | 2014-12-02 | 3M Innovative Properties Company | Coatable compositions, coatings derived therefrom and microarrays having such coatings |
EP2018835B1 (en) * | 2007-07-09 | 2014-03-05 | Augustinus Bader | Agent-eluting plaster |
US8617487B2 (en) | 2009-03-25 | 2013-12-31 | Venture Lending & Leasing Vi, Inc. | Saliva sample collection systems |
JPWO2011010456A1 (en) * | 2009-07-24 | 2012-12-27 | 株式会社ネクスト21 | NSAIDs-containing external preparation and method for producing the external preparation |
US20190231925A1 (en) * | 2018-01-31 | 2019-08-01 | Changchun Ja Biotech. Co., Ltd. | Heparin sodium supported hydrogel sustained-release paster |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996017648A1 (en) * | 1994-12-09 | 1996-06-13 | Novartis Ag | Transdermal system |
WO1997048440A1 (en) * | 1996-06-18 | 1997-12-24 | Alza Corporation | Device for enhancing transdermal agent delivery or sampling |
WO2000074763A2 (en) * | 1999-06-04 | 2000-12-14 | Georgia Tech Research Corporation | Devices and methods for enhanced microneedle penetration of biological barriers |
WO2001041864A1 (en) * | 1999-12-10 | 2001-06-14 | Alza Corporation | Skin treatment apparatus for sustained transdermal drug delivery |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE25637E (en) | 1964-09-08 | Means for vaccinating | ||
US3964482A (en) | 1971-05-17 | 1976-06-22 | Alza Corporation | Drug delivery device |
BE795384A (en) | 1972-02-14 | 1973-08-13 | Ici Ltd | DRESSINGS |
EP0429842B1 (en) | 1989-10-27 | 1996-08-28 | Korea Research Institute Of Chemical Technology | Device for the transdermal administration of protein or peptide drug |
US5279544A (en) | 1990-12-13 | 1994-01-18 | Sil Medics Ltd. | Transdermal or interdermal drug delivery devices |
IL109037A (en) * | 1993-03-19 | 1999-01-26 | Cellegy Pharma Inc | Compositions for inducing phase separation of epithelial lipid bilayers and preparation of said compositions |
US5885211A (en) | 1993-11-15 | 1999-03-23 | Spectrix, Inc. | Microporation of human skin for monitoring the concentration of an analyte |
US5458140A (en) | 1993-11-15 | 1995-10-17 | Non-Invasive Monitoring Company (Nimco) | Enhancement of transdermal monitoring applications with ultrasound and chemical enhancers |
WO1996037256A1 (en) | 1995-05-22 | 1996-11-28 | Silicon Microdevices, Inc. | Micromechanical patch for enhancing the delivery of compounds through the skin |
AU5740496A (en) | 1995-05-22 | 1996-12-11 | General Hospital Corporation, The | Micromechanical device and method for enhancing delivery of compounds through the skin |
DE19525607A1 (en) | 1995-07-14 | 1997-01-16 | Boehringer Ingelheim Kg | Transcorneal drug delivery system |
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 |
DE19541260A1 (en) * | 1995-11-06 | 1997-05-07 | Lohmann Therapie Syst Lts | Therapeutic preparation for transdermal application of active ingredients through the skin |
DE69722414T2 (en) | 1996-07-03 | 2004-05-19 | Altea Therapeutics Corp. | MULTIPLE MECHANICAL MICROPERFORATION OF SKIN OR MUCOSA |
ATE231015T1 (en) | 1996-09-17 | 2003-02-15 | Deka Products Lp | SYSTEM FOR DELIVERY OF MEDICATION THROUGH TRANSPORT |
KR100453132B1 (en) | 1996-12-20 | 2004-10-15 | 앨자 코포레이션 | Device and method for enhancing transdermal agent flux |
DE19654391A1 (en) | 1996-12-27 | 1998-07-02 | Basf Ag | Catalyst for the selective production of propylene from propane |
DK1314400T3 (en) * | 1996-12-31 | 2007-10-15 | Altea Therapeutics Corp | Microporation of tissues for delivery of bioactive agents |
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 |
WO1999029365A1 (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 |
US6022316A (en) | 1998-03-06 | 2000-02-08 | Spectrx, Inc. | Apparatus and method for electroporation of microporated tissue for enhancing flux rates for monitoring and delivery applications |
AU767122B2 (en) | 1998-06-10 | 2003-10-30 | Georgia Tech Research Corporation | Microneedle devices and methods of manufacture and use thereof |
AU771818B2 (en) * | 1999-05-17 | 2004-04-01 | Stephen T Flock | Remote and local controlled delivery of pharmaceutical compounds using electromagnetic energy |
DE60024312T2 (en) * | 1999-12-10 | 2006-08-17 | Alza Corp., Mountain View | Transdermal drug delivery of macromolecular agents and device therefor |
CA2422200A1 (en) * | 2000-09-08 | 2002-03-14 | Alza Corporation | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure |
EP2085109A3 (en) * | 2000-10-26 | 2009-09-02 | Alza Corporation | Transdermal drug delivery devices having coated microprotrusions |
CA2516547A1 (en) * | 2002-09-30 | 2004-04-15 | Alza Corporation | Drug delivery device having coated microprojections incorporating vasoconstrictors |
-
2001
- 2001-09-06 CA CA002422200A patent/CA2422200A1/en not_active Abandoned
- 2001-09-06 MX MXPA03002122A patent/MXPA03002122A/en active IP Right Grant
- 2001-09-06 CZ CZ2003687A patent/CZ2003687A3/en unknown
- 2001-09-06 EP EP01968531A patent/EP1335711B1/en not_active Expired - Lifetime
- 2001-09-06 PL PL01365603A patent/PL365603A1/en not_active Application Discontinuation
- 2001-09-06 DK DK01968531T patent/DK1335711T3/en active
- 2001-09-06 JP JP2002524470A patent/JP5507030B2/en not_active Expired - Fee Related
- 2001-09-06 EE EEP200300095A patent/EE200300095A/en unknown
- 2001-09-06 AU AU2001288774A patent/AU2001288774B2/en not_active Ceased
- 2001-09-06 PT PT01968531T patent/PT1335711E/en unknown
- 2001-09-06 NZ NZ524646A patent/NZ524646A/en unknown
- 2001-09-06 BR BR0113749-2A patent/BR0113749A/en not_active IP Right Cessation
- 2001-09-06 CN CNB018185835A patent/CN100421653C/en not_active Expired - Fee Related
- 2001-09-06 AU AU8877401A patent/AU8877401A/en active Pending
- 2001-09-06 WO PCT/US2001/027551 patent/WO2002019985A2/en active IP Right Grant
- 2001-09-06 IL IL15481101A patent/IL154811A0/en unknown
- 2001-09-06 AT AT01968531T patent/ATE367805T1/en not_active IP Right Cessation
- 2001-09-06 KR KR1020037003472A patent/KR100764699B1/en not_active IP Right Cessation
- 2001-09-06 ES ES01968531T patent/ES2290166T3/en not_active Expired - Lifetime
- 2001-09-06 DE DE60129585T patent/DE60129585T2/en not_active Expired - Lifetime
- 2001-09-06 RU RU2003109743/15A patent/RU2272618C2/en not_active IP Right Cessation
- 2001-09-08 US US09/950,436 patent/US7438926B2/en not_active Expired - Fee Related
-
2003
- 2003-03-07 NO NO20031071A patent/NO20031071L/en not_active Application Discontinuation
- 2003-04-07 MA MA27093A patent/MA25958A1/en unknown
- 2003-04-07 ZA ZA200302700A patent/ZA200302700B/en unknown
-
2013
- 2013-07-09 JP JP2013143738A patent/JP2013256500A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996017648A1 (en) * | 1994-12-09 | 1996-06-13 | Novartis Ag | Transdermal system |
WO1997048440A1 (en) * | 1996-06-18 | 1997-12-24 | Alza Corporation | Device for enhancing transdermal agent delivery or sampling |
WO2000074763A2 (en) * | 1999-06-04 | 2000-12-14 | Georgia Tech Research Corporation | Devices and methods for enhanced microneedle penetration of biological barriers |
WO2001041864A1 (en) * | 1999-12-10 | 2001-06-14 | Alza Corporation | Skin treatment apparatus for sustained transdermal drug delivery |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007527392A (en) * | 2003-06-30 | 2007-09-27 | アルザ・コーポレーシヨン | Formulations for coated microprojections containing non-volatile counterions |
US8920817B2 (en) | 2003-06-30 | 2014-12-30 | Alza Corporation | Formulations for coated microprojections containing non-volatile counterions |
EP1682012A4 (en) * | 2003-11-13 | 2008-09-24 | Alza Corp | Composition and apparatus for transdermal delivery |
JP2007511508A (en) * | 2003-11-13 | 2007-05-10 | アルザ・コーポレーシヨン | Compositions and devices for transdermal delivery |
EP1682012A2 (en) * | 2003-11-13 | 2006-07-26 | ALZA Corporation | Composition and apparatus for transdermal delivery |
EP1734993A2 (en) | 2004-04-01 | 2006-12-27 | Alza Corporation | Apparatus and method for transdermal delivery of influenza vaccine |
EP1734993A4 (en) * | 2004-04-01 | 2009-10-21 | Alza Corp | Apparatus and method for transdermal delivery of influenza vaccine |
WO2006020841A3 (en) * | 2004-08-11 | 2007-08-16 | Alza Corp | Apparatus and method for transdermal delivery of natriuretic peptides |
WO2006020841A2 (en) * | 2004-08-11 | 2006-02-23 | Alza Corporation | Apparatus and method for transdermal delivery of natriuretic peptides |
EP2818159A1 (en) * | 2013-06-25 | 2014-12-31 | LTS LOHMANN Therapie-Systeme AG | Device having transdermal therapeutic system, positioning and penetration aid |
WO2014207033A1 (en) * | 2013-06-25 | 2014-12-31 | Lts Lohmann Therapie-Systeme Ag | Device with transdermal therapeutic system and positioning and penetration aid |
US9987361B1 (en) * | 2014-12-29 | 2018-06-05 | Noven Pharmaceuticals, Inc. | Compositions and method for sustained drug delivery by active transdermal technology |
WO2019092257A1 (en) | 2017-11-10 | 2019-05-16 | Lts Lohmann Therapie-Systeme Ag | Microneedle system for applying a hepatitis vaccine |
DE102017126501A1 (en) | 2017-11-10 | 2019-05-16 | Lts Lohmann Therapie-Systeme Ag | Micro needle system for the application of a hepatitis vaccine |
Also Published As
Publication number | Publication date |
---|---|
IL154811A0 (en) | 2003-10-31 |
EP1335711B1 (en) | 2007-07-25 |
PT1335711E (en) | 2007-09-05 |
NZ524646A (en) | 2004-10-29 |
CZ2003687A3 (en) | 2004-01-14 |
DK1335711T3 (en) | 2007-11-26 |
AU8877401A (en) | 2002-03-22 |
CN100421653C (en) | 2008-10-01 |
JP2004508319A (en) | 2004-03-18 |
JP2013256500A (en) | 2013-12-26 |
CA2422200A1 (en) | 2002-03-14 |
EE200300095A (en) | 2005-02-15 |
ES2290166T3 (en) | 2008-02-16 |
US7438926B2 (en) | 2008-10-21 |
EP1335711A2 (en) | 2003-08-20 |
PL365603A1 (en) | 2005-01-10 |
ATE367805T1 (en) | 2007-08-15 |
CN1473037A (en) | 2004-02-04 |
AU2001288774B2 (en) | 2006-06-29 |
KR100764699B1 (en) | 2007-10-08 |
WO2002019985A3 (en) | 2002-09-06 |
NO20031071L (en) | 2003-05-06 |
US20020102292A1 (en) | 2002-08-01 |
MA25958A1 (en) | 2003-12-31 |
RU2272618C2 (en) | 2006-03-27 |
DE60129585D1 (en) | 2007-09-06 |
NO20031071D0 (en) | 2003-03-07 |
JP5507030B2 (en) | 2014-05-28 |
MXPA03002122A (en) | 2004-09-10 |
DE60129585T2 (en) | 2008-04-17 |
ZA200302700B (en) | 2004-08-13 |
BR0113749A (en) | 2004-06-22 |
KR20030074595A (en) | 2003-09-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7438926B2 (en) | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure | |
AU2001288774A1 (en) | Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure | |
US20050089554A1 (en) | Apparatus and method for enhancing transdermal drug delivery | |
US7579013B2 (en) | Formulations for coated microprojections containing non-volatile counterions | |
US20050106226A1 (en) | Pretreatment method and system for enhancing transdermal drug delivery | |
US20050123507A1 (en) | Formulations for coated microprojections having controlled solubility | |
EP1737434A2 (en) | Apparatus and method for transdermal delivery of fentanyl-based agents | |
MXPA06004531A (en) | Apparatus and method for enhancing transdermal drug delivery | |
MXPA06004476A (en) | Pretreatment method and system for enhancing transdermal drug delivery |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 154811 Country of ref document: IL Ref document number: PV2003-687 Country of ref document: CZ Ref document number: 2001288774 Country of ref document: AU Ref document number: 2422200 Country of ref document: CA Ref document number: 289/KOLNP/2003 Country of ref document: IN Ref document number: 1200300231 Country of ref document: VN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020037003472 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2003/002122 Country of ref document: MX Ref document number: 524646 Country of ref document: NZ Ref document number: 2002524470 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2001968531 Country of ref document: EP Ref document number: 2003/02700 Country of ref document: ZA Ref document number: 200302700 Country of ref document: ZA |
|
ENP | Entry into the national phase |
Ref document number: 2003109743 Country of ref document: RU Kind code of ref document: A Ref country code: RU Ref document number: RU A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 018185835 Country of ref document: CN |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 2001968531 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1020037003472 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: PV2003-687 Country of ref document: CZ |
|
WWP | Wipo information: published in national office |
Ref document number: 524646 Country of ref document: NZ |
|
WWG | Wipo information: grant in national office |
Ref document number: 524646 Country of ref document: NZ |
|
WWG | Wipo information: grant in national office |
Ref document number: 2001968531 Country of ref document: EP |