WO1989011872A1 - Permeation enhancer comprising ethanol and glycerol monooleate - Google Patents
Permeation enhancer comprising ethanol and glycerol monooleate Download PDFInfo
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- WO1989011872A1 WO1989011872A1 PCT/US1989/002506 US8902506W WO8911872A1 WO 1989011872 A1 WO1989011872 A1 WO 1989011872A1 US 8902506 W US8902506 W US 8902506W WO 8911872 A1 WO8911872 A1 WO 8911872A1
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- Prior art keywords
- ethanol
- drug
- skin
- gmo
- rate
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Definitions
- This invention relates to the transdermal delivery of drugs and other biologically active agents. More particularly, this invention relates to novel methods and compositions for enhancing the percutaneous absorption of drugs when incorporated in transdermal drug delivery systems. Still more particularly, but without limitation thereto, this invention relates to the transdermal delivery of drugs utilizing a mixture of glycerol monooleate (GMO) and ethanol .
- GMO glycerol monooleate
- transdermal route of parenteral delivery of drugs provides many advantages over other administrative routes and transdermal systems for delivering a wide variety of drugs or other beneficial agents are described in U.S. Patent Numbers 3,598,122; 3,598,123; 4,379,454; 4,286,592; 4,314,557 and 4,568,343, for example, all of which are incorporated herein by reference.
- drugs which would appear to be ideal candidates for transdermal delivery are found to have such low permeability through intact skin that they can not be delivered at therapeutically effective rates from reasonably sized systems.
- a permeation enhancer should have the ability to enhance the permeability of the skin for at least one and preferably a significant number of drugs. More importantly, it should be able to enhance the skin permeability such that the drug delivery rate from a reasonably sized system (preferably 5-50 cm 2 ), is at therapeutic levels. Additionally, the enhancer, when applied to the skin surface should be non-toxic, non-irritating on prolonged exposure and under occlusion, and non-sensitizing on repeated exposure. Preferably it should be odorless and capable of delivering drugs without producing burning or tingling sensations.
- the present invention greatly increases drug permeability through the skin, and also reduces the lag time between application of the drug to the skin and attainment of the desired therapeutic effect.
- FIG. 1 is a cross-sectional view of one embodiment of the transdermal drug delivery system according to this invention, ut l zing a rate controlling membrane;
- FIG. 2 is a cross-sectional view of another embodiment of the transdermal drug delivery system of this invention.
- FIG. 3 is a cross-sectional view of still another embodiment of the transdermal drug delivery system according to this invention, utilizing a rate controlling membrane;
- FIG. 4 is a cross-sectional view of yet another embodiment of the transdermal drug delivery system of this invention.
- FIG. 5 is a cross-sectional view of another embodiment of the transdermal drug delivery system according to this invention, utilizing an adhesive overlay.
- FIG. 6 is a bar chart showing transdermal flux across cadaver skin at 35#C, of hydrocortisone vs. permeation enhancer used;
- FIG. 7 is a three component phase diagram showing the soluble and insoluble ranges for ethanol/glycerol monooleate/water mixtures at room temperature (22#C) and at 35#C;
- FIGS. 8 and 9 are plots showing the increased skin permeability obtained from certain embodiments of this invention.
- This invention codelivers GMO and ethanol to aid in delivery of drugs across the skin. While both GMO and ethanol are known permeation enhancers, their combined effect according to this invention has been shown to produce dramatic increases (in the order of 10-20 times or even higher) in the permeation of drugs when compared to the use of either ethanol or GMO alone. Improved enhancement of permeation according to this invention can be obtained over a relatively wide range of ethanol/GMO weight ratios. This invention contemplates ethanol/GMO weight ratios in the range of about 5/95 to 97/3 and preferably in the range of 80/20 to 40/60. This invention finds particular usefulness in enhancing permeability across skin.
- ethanol, GMO and the drug to be delivered are placed in drug, ethanol and GMO transmitting relationship to the appropriate body surface, preferably in a pharmaceutically acceptable carrier therefor, and maintained in place for the desired period of time.
- the drug, ethanol, and GMO are typically dispersed within a physiologically compatible matrix or carrier as more fully described below which may be applied directly to the body as an ointment, gel, cream, suppository or sublingual or buccal tablet for example.
- ethanol and GMO are dispersed in a liquid vehicle for topical application to the skin, greater enhancement of drug flux has been observed when the concentration of ethanol, GMO and the vehicle are selected such that a single liquid phase exists for these components.
- concentration of ethanol, GMO and the vehicle are selected such that a single liquid phase exists for these components.
- ointment, lotion, cream or gel appl ed directly to the skin it is preferable to occlude the site of administration to prevent evaporation of the ethanol and other volatile components such as water.
- compositions can also contain other permeation enhancers such as sucrose monococoate, stablizers such as salicylic acid, dyes, diluents, pigments, stabilizers, vehicles, inert filters, excipients, gelling agents and other components of topical compositions as known to the art.
- permeation enhancers such as sucrose monococoate
- stablizers such as salicylic acid, dyes, diluents, pigments, stabilizers, vehicles, inert filters, excipients, gelling agents and other components of topical compositions as known to the art.
- the drugs and permeation enhancers would be administered from a transdermal delivery device as more fully described below.
- the device administering an excess of drug to the skin and at least one of the ethanol or GMO is coadministered at a controlled, preferably substantially constant rate.
- the rate of drug administration is determined by the rate of administration of the enhancer whose rate is intentionally controlled.
- the dosage form could comprise a body: (a) having a basal surface.
- the supply of drug is 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 treated skin is able to absorb, and the rate at which one of the GMO or ethanol is provided is substantially constant over a substantial portion of the time period, the rate being:
- the method of this invention comprises:
- 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.
- the term “substantially constant” means a variation of less than about +20%, preferably less than about ⁇ 10%, over a substantial portion of the time period.
- drug and “agent” are used interchangeably and are intended to have their broadest interpretation as to any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial, effect.
- this includes therapeutic agents in all of the major therapeutic areas, including, but not limited to, anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, anti depressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, anti igraine preparations, antimotion sickness preparations, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, including gastrointestinal and urinary, anticholinergics, sympathomimetrics, xanthine derivatives, cardiovascular preparations including calcium channel blockers, beta-blockers, antiarrythmics, antihypertensives, diuretics, vasodilators, including general, coronary, peripheral and cerebral, central nervous system stimulants, cough and cold preparations, decongestants,
- Representative drugs include, by way of example and not for purposes of limitation, scopolamine, isosorbide dinitrate, nitroglycerin, estradiol, clonidine, cortisone, theophylline, phenyl ⁇ phrine, terbutaline, ephedrine, narcodine, quinidine, estradiol diacetate, progesterone, pilocarpine, furosemide, tetracycline, insulin, chlorpheniramine, sulfathiazides, propranolol, testosterone, norgestrel, morphinone, morphine, dihydrocodeine, dihydromorphine, oxycodone, hydrocodone, codeine, norcodeine, hydromorphine, normorphine, norlevorphanol, dihydrothebaine, ouabain, bromocryptine, haloperidol, guanabenz, salbutamol, oxprenolol, dibucaine
- FIG. 1 illustrates a transdermal drug delivery device 10.
- Device 10 is a multilaminate system comprised of five layers: a top impermeable backing layer 12, a permeation enhancer reservoir layer 14, a permeation er.hancer rate controlling membrane 16, a drug reservoir 18, an adhesive layer 20 and a strippable release liner 22.
- the reservoirs 14 may be comprised of a gel or polymeric matrix or other carrier having the permeation enhancer or drug to be delivered, dispersed throughout.
- Device 10 is held in place by means of an in-line pharmaceutically acceptable contact adhesive 20.
- An additional loading of the drug, GMO and/or ethanol may also be incorporated into the adhesive layer 20.
- the composition and thickness of the adhesive layer are preferably selected such that it does not constitute a significant permeation barrier to the drug, GMO or ethanol.
- adhesive layer 20 with the other layers will equilibrate and will contain GMO, ethanol and drug in amounts that will depend upon the composition and thickness of layer 20 and the length of the time interval.
- Contact adhesive compositions that are suitable for use as layer 20 are disclosed in U.S. Pat. Nos. 3,797,494 and 4,031,894.
- a strippable release liner 22, adapted to be removed prior to application, would normally be included in the packaged product.
- Layer 14 may comprise a continuous GMO/ethanol phase, which may also contain one or more covehicles, such as water.
- the continuous phase is in the form of a gel that can contain 5% to 75% by weight water.
- gelling agents such as carboxypolymethylene, ethylene maleic anhydride, hydroxyethylcellulose, polyacrylamide, ethylhydroxyethylcellulose, hydroxypropylcellulose, and-- poly(methylvinylether-maleic anhydride) may also be included in the continuous phase to make it gel.
- Layer 14 may also include diluents, stabilizers, vehicles, gelling agents, and the like.
- the rate controlling membrane 16 may be fabricated from permeable, semipermeable or microporous materials which are known in the art to control the rate of agents into and out of delivery devices. Suitable materials include polyvinylacetate and ethylene vinyl acetate polymers.
- the size of the device of this invention can vary from less than 1 cm 2 to greater than 200 cm 2 .
- a typical device however, will have a size within the range of about 5-50 CM 2 .
- Suitable anhydrous materials include, without limitation, natural and synthetic rubbers or other polymeric materials, thickened mineral oil, or petroleum jelly.
- a preferred embodiment according to this invention is fabricated from an ethylene/vinyl acetate (EVA) copolymer of the type described in U.S. Patent Number 4,144,317, preferably those having a vinyl acetate content in the range of about 28 to 60 weight percent. Particularly good results have been obtained using an EVA copolymer of 40 weight percent vinyl acetate content (EVA 40).
- the drug reservoir 18 will contain the drug with an equilibrium concentration of the GMO and ethanol.
- the amount of drug in the reservoir will depend upon the rate at which the drug is absorbed by the skin from the system and the intended duration of therapy.
- the reservoir 18 may also include dyes, diluents, pigments, stabilizers, vehicles, inert fillers, excipients, gelling agents, and conventional components of pharmaceutical products or transdermal therapeutic systems as are known in the art.
- Certain drugs are highly soluble in the permeation enhancers.
- the permeation enhancer reservoir layer 14 would be initially saturated with drug to insure that the drug contained within matrix 18 will diffuse towards the skin rather than into the permeation enhancer reservoir.
- the loading of the drug which is ultimately to be delivered will usually be contained within the drug reservoir 18 in excess of saturation.
- Embodiments such as device 10 in which the drug and enhancer supplies are separate may be advantageous or necessary in instances where formulation or storage of the drug and enhancers in contact with each other is impractical or undesirable or where separation of the drug and enhancers facilitate selection of the rate controlling membrane.
- the initial loading of ethanol and GMO in device 10 will depend upon the rates at which the enhancers are administered to the skin from the system to achieve the desired degree of drug permeability enhancement over the treatment period.
- the backing member 12 serves the purpose of both preventing passage of the drug and permeation enhancers through the surface of the gel layer distant from the skin, and also of providing support for the system, where needed.
- the backing layer can be flexible or nonflexible and suitable materials include, without limitation, cellophane, cellulose acetate, ethyl cellulose, plasticized vinyl acetate-vinyl chloride copolymers, polyethylene terephthalate, nylon, high and low density polyethylene, polypropylene, metalized polyester films, polyvinylidene chloride, coated flexible fibrous backings such as paper and cloth and aluminum foil.
- Such backings can be in the form of precast films or fabrics which are bonded to the reservoir by heat, adhesives or otherwise or they can be coated onto the reservoir itself.
- the preferred embodiment utilizes a heat sealable backing membrane, such that the device is sealed around its periphery to prevent evaporation of the ethanol. The heat seal is shown schematically in FIG. 1, by line 24.
- device 10 is applied to a relatively nonhairy area of the skin that is preferably substantially free of wrinkles, creases or folds.
- Various locations on the torso, such as the flank or shoulder, provide suitable sites for the transdermal system.
- the device Once the device is placed on the skin, it will begin coadministering drug, ethanol and glycerol monooleate, to the wearer.
- FIG. 2 A second embodiment of the invention is shown in FIG. 2.
- the transdermal drug delivery device 26 comprises a permeation enhancer reservoir 28, backing member 30, drug reservoir 32, adhesive layer 34 and strippable release liner 36.
- the rate controlling membrane has been omitted.
- device 26 is preferably heat sealed around its periphery, as indicated by line 38.
- FIGURE 3 Another embodiment of the invention is shown in FIGURE 3.
- Device 40 incorporates the drug and the permeation enhancer into a common reservoir 42 rather than in separate reservoirs.
- the device has an impermeable backing 44 and a pharmaceutically acceptable in-line contact adhesive 46 which may also contain a specified amount of drug and/or permeation enhancer as a primary dose.
- Device 40 also has a strippable release liner 48.
- Device 40 is further provided with a rate controlling membrane 50. The entire device is sealed along its periphery, as shown by line 52.
- the drug will be present in the reservoir 42 either wholly in solution or in both dissolved and undissolved form dispersed uniformly through the reservoir.
- the initial loading of drug in layer 42 will depend on its solubility in the continuous phase and the intended lifetime of system 40.
- Layer 42 may include diluents, stabilizers, vehicles, gelling agents and the like, in addition to the drug and enhancers.
- This layer may also contain one or more covehicles, such as water, to alter the solubility of the drug in said phase.
- the loading of enhancers in the reservoir will depend upon the rate at which the enhancers are administered to the skin from the system to achieve the desired degree of drug permeability enhancement over the treatment period.
- Rate controlling membrane 50 may be made of a dense or microporous polymer film that has the requisite permeability to the drug and enhancers. This membrane controls the rate at which at least one of the enhancers or the drug, is administered to the skin.
- the respective fluxes of the drug and enhancers through layer 50 will depend upon the thickness of the layer and the permeabilities of the drug and the enhancers through the layer.
- the rate controlling membrane 50 is substantially impermeable to other components of layer 42. Examples of the types of polymer films that may be used to make layer 50 are disclosed in U.S. Pat. Nos. 3, 797,494 and 4,031,894, both of which are incorporated herein by reference.
- FIGURE 4 illustrates still another embodiment of the invention, system 54, where the drug, GMO and ethanol are incorporated into a common reservoir 56.
- system 54 is comprised of an impermeable backing 58, an in-line contact adhesive 60 and a strippable release liner 62.
- System 54 is preferably heat sealed around its periphery, as illustrated by line 64. In this embodiment, the rate controlling membrane has been omitted.
- FIGURE 5 illustrates a system 66 which provides for an adhesive overlay 68 to maintain the system on the skin 70.
- Means 68 for adhering the system to the skin may be fabricated together with or separately from the remaining elements.
- the multilaminate system 66 is comprised of a GMO/ethanol gel layer 72, a rate controlling membrane 74 and a drug reservoir 76.
- an adhesive overlay is preferable to an in-line contact adhesive particularly when components of the system which may adversely affect the adhesive properties of an in-line adhesive.
- impermeable backing layer 78 is preferably sized slightly larger than the ethanol reservoir 72 to provide a peripheral area around the reservoir 72, which would be free of any material which may seep from under the base of reservoir 72 and adversely interact with the adhesive in overlay 68.
- a strippable release liner would also be provided with the system 66, to be removed prior to use.
- the GMO/ethanol permeation enhancer according to this invention produces fluxes substantially greater than obtained from the use of GMO and ethanol alone.
- a suitable formulation for the delivery of hydrocortisone would be comprised of about 42-76 wt% of GMO and about 17-38 wt% ethanol in water containing an excess of hydrocortisone dispersed therethrough.
- Such formulations are capable of providing hydrocortisone fluxes within the range of 5-33 lg/cm 2 -hr, when applied directly to the skin.
- Fig. 7 is a phase diagram of the water/GMO/ethanol system at room temperature (22#C) and 35#C on which compositions D, E, F and G have been plotted.
- compositions D,E and F all fall within the portion of the diagram in which the composition exists as single phase solution and they all produced fluxes that were higher than that obtained from composition G which exists as 2 phase composition.
- the compositions can be selected such that they fall within the portion of their phase diagram in which the compositions exist as a single phase.
- a transdermal device fabricated as shown in FIGURE 1 for the delivery of hydrocortisone would have the following composition: a MEDPAR backing layer 12; permeation enhancer reservoir 14 comprised of an ethanol gel 98 w% of 95% ethanol and 2 w% of hydroxypropylcellulose; an EVA 9% VA rate controlling membrane 16; a polymeric drug reservoir 18 comprised of 30 w% hydrocortisone, 30 w% glycerol monooleate and 40 w% EVA 40% VA; a pharmaceutically acceptable in-line contact adhesive 20 and a strippable release liner 22.
- permeation enhancer reservoir 14 comprised of an ethanol gel 98 w% of 95% ethanol and 2 w% of hydroxypropylcellulose
- an EVA 9% VA rate controlling membrane 16
- a polymeric drug reservoir 18 comprised of 30 w% hydrocortisone, 30 w% glycerol monooleate and 40 w% EVA 40% VA
- EXAMPLE III Various ethanol/glycerol monooleate donor compositions were tested with hydrocortisone to measure their effect upon the drug flux across human epidermis at 35#C into an aqueous sink. Test data were obtained using a 2.2 cm 2 horizontal flux cell with 2.5 ml donor solutions and 21 ml receptor solutions. Solution Composition (wt%) Average Drug Flux Ethanol GMO lq/cm 2 -hr
- the flux was also measured with 20/80, 40/60 and 60/40 ethanol/GMO ratios. It was found that the hydrocortisone flux from the ethanol/GMO compositions increased as the amount of ethanol increased. Additionally, the effect of the inclusion of water in the donor composition was also studied. Lower hydrocortisone fluxes were observed when the donor compositions had separated into two phases. On the other hand, water content did not significantly affect the drug flux from single phase donor compositions.
- EXAMPLE IV Various ethanol/glycerol monooleate donor compositions were tested with tetracaine to measure their effect upon the drug flux across human epidermis at 35#C. Test data were obtained using a 1.13 cm 2 wet-wet horizontal flux cell with 2.5 ml donor solution and 10 ml receptor solutions (pH 4.5 acetate buffer, 0.05 M).
- ethanol/GMO permeation enhancer compositions of this invention provides for the rapid onset of therapeutic effect. This is very beneficial when an anesthetic is being transder ally administered prior to a painful procedure such as injection, venipuncture, or minor surgery.
- a topical anesthetic which can be used for such purpose is tetracaine, the topical application of which has been found to require at least one hour to achieve adequate anesthesia.
- Incorporation of the GMO/ethanol enhancer of our invention into a tetracaine gel however dramatically reduces the time of onset of anesthesia to about 30 minutes after placement on the skin.
- Double blind testing was done on 10 subjects.
- An active gel formulation was placed on each subject's right antecubital fossa and a placebo was simultaneously positioned on the left.
- the gels (0.6 gm) were placed in 5 cm 2 PVC cups covered with two polyester cloth discs and had the following composition (wt%):
- Phenethyl Alcohol 7 % 7 % The gels were left in place for 30 minutes. Anesthesia was evaluated by standard venipuncture technique using a 22 gauge needle without drawing blood at each site, within 5 minutes after removal of the formulations. The subjects were then asked whether they felt no pain, slight/mild pain (like a pinprick) or moderate pain (like venipuncture). At the active sites, five subjects reported no pain, three reported slight/mild pain and the remaining two reported moderate pain. At the placebo sites, two subjects reported no pain, three reported slight/mild pain and the remaining five reported moderate pain. Six hours after removal, eight subjects continued to feel anesthesia at the active sites, and all subjects felt no anesthesia at the placebo sites.
- a transdermal device fabricated as shown in FIG. 2 for the delivery of tetracaine comprises a MEDPAR backing layer 30; permeation enhancer reservoir 28 comprised mainly of an ethanol gel 98 w% of 95% ethanol and 2 w% of hydroxypropylcellulose; a polymeric drug reservoir 32 comprised of 30 w% tetracaine 30 w% GMO and 40 w% EVA 40; a pharmaceutically acceptable in-line contact adhesive 34 and a strippable release liner 36.
- permeation enhancer reservoir 28 comprised mainly of an ethanol gel 98 w% of 95% ethanol and 2 w% of hydroxypropylcellulose
- a polymeric drug reservoir 32 comprised of 30 w% tetracaine 30 w% GMO and 40 w% EVA 40
- a pharmaceutically acceptable in-line contact adhesive 34 and a strippable release liner 36.
- Lidocaine is a topical anesthetic .which can be used in conjunction with minor surgical procedures.
- EMLA topical ointment containing lidocaine
- a vehicle composition according to this invention comprising 41.6 wt% ethanol, 30 wt% GMO (Myverol brand available from Eastman Kodak) and 28.4 wt% water was prepared, to which was added 34 wt% lidocaine base.
- 0.5 g of the mixture so formed was absorbed into a 0.75 in. diameter foam pads, applied to facial cheek skin on human volunteers and maintained in place by means of 1.625 in. diameter adhesive overlay for 15 minutes and 30 minutes.
- the sites were checked for pain by needle penetration. No pain was detected on some of the punctures and pain was observed at a penetration of 2 mm, primarily at the periphery of the site. No difference between the quality of anesthesia at 15 and 30 minutes was observed.
- EXAMPLE VIII The lidocaine fluxes from various ethanol/GMO compositions according to this invention through cadaver skin into an aqueous sink at 35#C were compared to the flux obtained from other vehicles and the results are shown in Figs. 8 and 9.
- the compositions identified as A, B, C and D had the following formulations to which were added sufficient lidocaine to maintain the samples saturated with lidocaine throughout the experiment: A. 40 wt% sucrose monococoate (SMC) in ethanol/water B. 60 wt% ethanol, 40 wt% GMO
- a therapeutic agent would comprise: a MEDPAR backing layer 44; an enhancer/drug reservoir 42 which would be comprised mainly of single phase solution of 95% ethanol and GMO having an excess of the drug to be delivered dispersed therethrough; an EVA 9 rate controlling membrane 50; a pharmaceutically acceptable in-line contact adhesive 46; and a strippable release line 48.
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Abstract
Description
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO90900552A NO900552L (en) | 1988-06-09 | 1990-02-06 | MEDIUM TO INCREASE PERMEABILITY THROUGH THE SKIN. |
DK033590A DK33590A (en) | 1988-06-09 | 1990-02-08 | PERMEATIVE AGENTS INCLUDING ETHANOL AND GLYCEROL MONOOLEATE |
FI900636A FI900636A0 (en) | 1988-06-09 | 1990-02-08 | PERMEATION SEEKANDE AEMNE INNEFATTANDE ETANOL OCH GLYCERINMONOE. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US20480888A | 1988-06-09 | 1988-06-09 | |
US204,808 | 1988-06-09 |
Publications (1)
Publication Number | Publication Date |
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WO1989011872A1 true WO1989011872A1 (en) | 1989-12-14 |
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ID=22759518
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1989/002506 WO1989011872A1 (en) | 1988-06-09 | 1989-06-08 | Permeation enhancer comprising ethanol and glycerol monooleate |
Country Status (7)
Country | Link |
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EP (1) | EP0378644A1 (en) |
JP (1) | JPH03501386A (en) |
AU (1) | AU611307B2 (en) |
DK (1) | DK33590A (en) |
FI (1) | FI900636A0 (en) |
PT (1) | PT90784A (en) |
WO (1) | WO1989011872A1 (en) |
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EP0488137A2 (en) * | 1990-11-30 | 1992-06-03 | Nitto Denko Corporation | Preparation for transdermal drug administration |
WO1998016212A1 (en) * | 1996-10-14 | 1998-04-23 | Kowa Company, Ltd. | Local anesthetic for external use |
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US9271830B2 (en) | 2002-12-05 | 2016-03-01 | Abbott Medical Optics Inc. | Accommodating intraocular lens and method of manufacture thereof |
US9504560B2 (en) | 2002-01-14 | 2016-11-29 | Abbott Medical Optics Inc. | Accommodating intraocular lens with outer support structure |
US9603703B2 (en) | 2009-08-03 | 2017-03-28 | Abbott Medical Optics Inc. | Intraocular lens and methods for providing accommodative vision |
US9814570B2 (en) | 1999-04-30 | 2017-11-14 | Abbott Medical Optics Inc. | Ophthalmic lens combinations |
US9968441B2 (en) | 2008-03-28 | 2018-05-15 | Johnson & Johnson Surgical Vision, Inc. | Intraocular lens having a haptic that includes a cap |
CN108883078A (en) * | 2016-03-24 | 2018-11-23 | 株式会社梅德瑞科思 | With the patch for preventing misuse characteristic |
US11707354B2 (en) | 2017-09-11 | 2023-07-25 | Amo Groningen B.V. | Methods and apparatuses to increase intraocular lenses positional stability |
US11903939B2 (en) | 2016-03-24 | 2024-02-20 | Medrx Co., Ltd. | Patch preparations with accidental use prevention features |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE8804214L (en) * | 1988-11-22 | 1990-05-23 | Jean Cassuto | ANTI-INFLAMMATORY AND ANTI-INFECTIVE MEDICINE |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US4335115A (en) * | 1976-11-01 | 1982-06-15 | The Procter & Gamble Company | Anti-acne composition |
EP0267617A1 (en) * | 1986-11-14 | 1988-05-18 | Theratech, Inc. | Penetration enhancement with binary system of cell envelope disordering compounds and lower alcohols |
US4764379A (en) * | 1987-08-24 | 1988-08-16 | Alza Corporation | Transdermal drug delivery device with dual permeation enhancers |
-
1989
- 1989-06-08 JP JP50691689A patent/JPH03501386A/en active Pending
- 1989-06-08 PT PT9078489A patent/PT90784A/en not_active Application Discontinuation
- 1989-06-08 AU AU37716/89A patent/AU611307B2/en not_active Ceased
- 1989-06-08 WO PCT/US1989/002506 patent/WO1989011872A1/en not_active Application Discontinuation
- 1989-06-08 EP EP19890907548 patent/EP0378644A1/en not_active Ceased
-
1990
- 1990-02-08 FI FI900636A patent/FI900636A0/en not_active Application Discontinuation
- 1990-02-08 DK DK033590A patent/DK33590A/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4335115A (en) * | 1976-11-01 | 1982-06-15 | The Procter & Gamble Company | Anti-acne composition |
EP0267617A1 (en) * | 1986-11-14 | 1988-05-18 | Theratech, Inc. | Penetration enhancement with binary system of cell envelope disordering compounds and lower alcohols |
US4764379A (en) * | 1987-08-24 | 1988-08-16 | Alza Corporation | Transdermal drug delivery device with dual permeation enhancers |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0488137A2 (en) * | 1990-11-30 | 1992-06-03 | Nitto Denko Corporation | Preparation for transdermal drug administration |
EP0488137A3 (en) * | 1990-11-30 | 1993-02-03 | Nitto Denko Corporation | Preparation for transdermal drug administration |
US5368860A (en) * | 1990-11-30 | 1994-11-29 | Nitto Denko Corporation | Preparation for transdermal drug administration |
WO1998016212A1 (en) * | 1996-10-14 | 1998-04-23 | Kowa Company, Ltd. | Local anesthetic for external use |
AU731946B2 (en) * | 1996-10-14 | 2001-04-05 | Kowa Company, Ltd. | Local anesthetic for external use |
US9814570B2 (en) | 1999-04-30 | 2017-11-14 | Abbott Medical Optics Inc. | Ophthalmic lens combinations |
US9504560B2 (en) | 2002-01-14 | 2016-11-29 | Abbott Medical Optics Inc. | Accommodating intraocular lens with outer support structure |
US9271830B2 (en) | 2002-12-05 | 2016-03-01 | Abbott Medical Optics Inc. | Accommodating intraocular lens and method of manufacture thereof |
US10206773B2 (en) | 2002-12-05 | 2019-02-19 | Johnson & Johnson Surgical Vision, Inc. | Accommodating intraocular lens and method of manufacture thereof |
US9039760B2 (en) | 2006-12-29 | 2015-05-26 | Abbott Medical Optics Inc. | Pre-stressed haptic for accommodating intraocular lens |
US9968441B2 (en) | 2008-03-28 | 2018-05-15 | Johnson & Johnson Surgical Vision, Inc. | Intraocular lens having a haptic that includes a cap |
US9011532B2 (en) | 2009-06-26 | 2015-04-21 | Abbott Medical Optics Inc. | Accommodating intraocular lenses |
US10052194B2 (en) | 2009-06-26 | 2018-08-21 | Johnson & Johnson Surgical Vision, Inc. | Accommodating intraocular lenses |
US9603703B2 (en) | 2009-08-03 | 2017-03-28 | Abbott Medical Optics Inc. | Intraocular lens and methods for providing accommodative vision |
CN108883078A (en) * | 2016-03-24 | 2018-11-23 | 株式会社梅德瑞科思 | With the patch for preventing misuse characteristic |
US11903939B2 (en) | 2016-03-24 | 2024-02-20 | Medrx Co., Ltd. | Patch preparations with accidental use prevention features |
US11707354B2 (en) | 2017-09-11 | 2023-07-25 | Amo Groningen B.V. | Methods and apparatuses to increase intraocular lenses positional stability |
Also Published As
Publication number | Publication date |
---|---|
AU611307B2 (en) | 1991-06-06 |
EP0378644A1 (en) | 1990-07-25 |
PT90784A (en) | 1989-12-29 |
DK33590D0 (en) | 1990-02-08 |
FI900636A0 (en) | 1990-02-08 |
JPH03501386A (en) | 1991-03-28 |
DK33590A (en) | 1990-02-08 |
AU3771689A (en) | 1990-01-05 |
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