CA2167526A1 - Monoglyceride/lactate ester permeation enhancer - Google Patents
Monoglyceride/lactate ester permeation enhancerInfo
- Publication number
- CA2167526A1 CA2167526A1 CA002167526A CA2167526A CA2167526A1 CA 2167526 A1 CA2167526 A1 CA 2167526A1 CA 002167526 A CA002167526 A CA 002167526A CA 2167526 A CA2167526 A CA 2167526A CA 2167526 A1 CA2167526 A1 CA 2167526A1
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- Canada
- Prior art keywords
- lactate
- drug
- mixture
- permeation
- reservoir
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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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
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
Abstract
A composition of matter for application to a body surface or membrane to administer a drug by permeation through the body surface or membrane, the composition comprising, in combination, the drug to be administered, in a therapeutically effective amount; and a permeation-enhancing mixture comprising a monoglyceride or a mixture of monoglycerides, and a lactate ester or a mixture of lactate esters.
Description
WO 95/09006 PCT/US9~/11120 MONOG~YCF~IDE/I ~CTATF F~;TER PF~MEATION F~IHANCER
~FI ~TFn Appl IcATloNs ;
This is a continuation-in-part of US application Serial No. 08/129,494, filed September 29, 1993, which application is incorporated herein in its entirety by reference and benefit is claimed of its filing date.
FIFI n OF THE INVFNTION
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 5 drugs when incorporated in transdermal drug delivery systems. More particularly, but without limitation thereto, this invention relates to the transdermal delivery of drugs utilizing a permeation-enhancing mixture of a monoglyceride and a lactate ester. Still more particularly, but without limitation thereto, this invention relates to the transdermal delivery of drugs 10 utilizing a permeation-enhancing mixture of a monoglyceride and a lactate ester wherein the monoglyceride and lactate ester are present in the composition in specific weight percentages.
R~CKGROUND OF THE INVFNTION
The 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 US Patent Numbers 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894;
4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222;
4,568,343; 4,573,995; 4,588,580; 4,645,502; 4,704,282; 4,788,062;
WO 95/09006 PCT/US94/11120 ~
~ ~ ~7 ~26 2 4,816,258; 4,849,226; 4,908,027; 4,943,435; and 5,004,610. The disclosures of the above patents are incorporated herein by reference.
In many instances, drugs which would appear to be ideal candidates for transdermal delivery are found to have such low permeability through intact skin that they cannot be delivered at therapeutically effective rates from reasonably sized systems.
In an effort to increase skin permeability, it has been proposed to pretreat the skin with various chemicals or to concurrently deliver the drug in the presence of a permeation enhancer. Various materials have been 0 suggested for this purpose, as described in US Pat. Nos. 3,472,931, 3,527,864, 3,896,238, 3,903,256, 3,952,099, 4,046,886, 4,130,643, 4,130,667, 4,299,826, 4,335,115, 4,343,798, 4,379,454, 4,405,616 and 4,746,515, all of which are incorporated herein by reference; British Pat. No.
1,001,949; and Idson, Percutaneous Absorption, J. Pharm. Sci., vol. 64, No.
b6, June 1975, pp 901-924 (particularly 919-921).
To be considered useful, 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 20 reasonably sized system (preferably 5-50 cm2) 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 capable of delivering drugs without producing topical reactions, burning or tingling 2~ sensations.
W095/09006 2 ~ 6~5~6 PCT/US94111120 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.
While it is known in the art to combine permeation enhancers, see, 5 eg, European Patent Publication numbers 0295411 and 0368339, this invention utilizes a novel combination of a monoglyceride and a lactate ester.
Furlher, the invention utilizes specific weight percentages of the novel components, the monoglyceride and lactate ester, ie, 15 to 25 wt% of monoglyceride and 8 to 25 wt% of lactic acid ester. The combined effect 10 and, further, specific weight percentages, produces a significant and surprising improvement ie, more than an additive effect over use of either a monoglyceride or a lactate ester alone, as well as over the combination of monoglyceride and lactate ester in specified weight percentages.
~UMMARY OF THE INVENTION
The present invention relates to improved compositions and methods for improving the penetration of a broad category of beneficial agents that produce little or no skin irritation. The system of the invention comprises a carrier or matrix adapted to be placed in drug- and permeation-enhancing mixture-transmitting relation to the selected skin or other body site. The 20 carrier or matrix contains suffficient amounts of drug and the permeation-enhancing mixture to continuously coadminister to the site, over a predetermined delivery period, the drug, in a therapeutically effective amount, and the permeation-enhancing mixture of a monoglyceride and a lactate ester, present in specific concentrations, ie, 15 to 25 wt% of 25 monoglyceride and 8 to 25 wt% of a lactate ester, preferably 20 wt%
monoglyceride and 12 wt% lactate ester in an amount effective to enhance the permeation of the drug to the skin.
2 t ~,~5~
As used herein, the term "transdermal" deiivery or application refers to the delivery or application of agents by passage through skin, mucosa and/or other body surfaces by topical appiication or by iontophoresis.
As used herein, the term "therapeutically effective" amount or rate 5 refers to the amount or rate of drug or active agent needed to effect the desired therapeutic result.
As used herein, the term "monoglyceride" refers to glycerol monooleate, glycerol monolaurate and glycerol monolinoleate, or a mixture thereof. Monoglycerides are generally available as a mixture of 10 monoglycerides, with the mixture deriving its name from the monoglyceride present in the greatest amount. In a preferred embodiment of this invention, the permeation enhancer monoglyceride component is glycerol monolaurate.
As used herein, the term "glycerol monooleate" refers to glycerol monooleate itself or a mixture of glycerides wherein glycerol monooleate is present in the greatest amount.
As used herein, the term "glycerol monolaurate" refers to glycerol monolaurate itself or a mixture of glycerides wherein glycerol monolaurate is present in the greatest amount.
As used herein, the term "glycerol monolinoleate" refers to glycerol 20 monolinoleate itself or a mixture of glycerides wherein glycerol monolinoleate is present in the greatest amount.
As used herein, the term "lactate ester" or "lactic ester of an alcohol"
refers to ethyl lactate, lauryl lactate, myristyl lactate or cetyl lactate, or amixture thereof. Preferably, the lactate ester is lauryl lactate or ethyl lactate 25 or a mixture thereof.
~ WO 95/09006 2 1 6 7 5 2 6 PCT/US94/11120 As used herein, the term "substantial portion of the time period"
means at least about 60% of the time period, preferably at least about 90%
of the time period. Correlatively, the term "substantially constant" means a variation of less than about +20%, preferably less than about +10%, over a 5 substantial portion of the time period.
As used herein, the term "permeation enhancing mixture" refers to a mixture comprising one or more lactate esters and one or more monoglycerides. The monoglyceride or mixture, preferably, glycerol monolaurate, is present in the range of about 15 to about 25 weight percent.
10 The second component, ie, a lactic acid ester, eg, lauryl, myristyl, cetyl, ethyl, methyl or oleic acid, benzoic acid or lactic acid is present in the rangeof about 8 to about 25 weight percent. More preferably, the pell"ealion enhancer mixture by weight comprises 20% monoglyceride and 12% lactic acidl ester.
As used herein, the term "predetermined delivery period" or "extended time period" refers to the delivery of drug for a time period of from several hours to seven days or longer. Preferably, the time period is from 16 hours to 3 or 4 days.
As used herein, the term "permeation enhancing amount or rate"
20 refers to the rate or amount that provides increased permeability of the application site to the drug.
As used herein, the term "poly-N-vinyl amide" means a cross-linked poly-N-vinyl amide or combination of poly-N-vinyl amide such as poly-N-vinylmethylacetamide, poly-N-vinylethylacetamide, poly-N-vinylmethyl-25 isobutyramide, poly-N-vinyl-2-pyrrolidone, poly-N-vinylpyrrolidone, poly-N-vinyl-2-piperidone, poly-N-vinyl-caprolactam, poly-N-vinyl-5-methyl-2-pyrrolidone. poly-N-vinyl-3-methyl-2-pyrrolidone, and WO 95/09006 2 1 6 ~ 5 2 6 PCT/US94111120 ~
the like. Preferably, the poly-N-vinyl amide is poly-N-vinyl-2-pyrrolidone (more preferably Polyplasdone XL~), Polyplasdone XL-10~), GAF).
BRIFF DESCRIPTION OF THE DRAWINGS
The invention will be described in further detail with reference to the 5 accompanying drawings wherein:
FIG. 1 is a cross-sectional view of one embodiment of the transdermal drug delivery system according to this invention;
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;
FIG. 4 is a cross-sectional view of yet another embodiment of the transdermal drug delivery system of this invention;
FIG. 5 is a graph of the flux of alprazolam through human epidermis 15 at 35C, in vitro, with glycerol monolaurate and lauryl lactate.
FIG. 6 is a graph of the flux of alprazolam through human epidermis at 35C, in vitro, with glycerol monolaurate and lauryl lactate.
FIG. 7 is a graph of the flux of estradiol through human epidermis at 35C, in vitro, with glycerol monolaurate and lauryl lactate.
FIG. 8 is a graph of the flux of testosterone through human epidermis at 35C, in vitro, with glycerol monolaurate and lauryl lactate.
WO9St09006 2 ~ 5~ PCT/US94/11120 FIG. 9 is a bar graph of the cumulative flux of alprazolam through c human epidermis at 35C, in vitro, with varying weight percents of glycerol monolaurate and lauryl lactate.
FIG. 10 is a graph of the cumulative flux of testosterone through human epidermis at 35C, in vitro, with various flux enhancers.
FIG. 11 is a bar graph showing the effect of various concentrations of glycerol monolaurate and lauryl lactate on the flux of alprazolam through human epidermis at 35C, in vitro.
DESCRIPTION OF THE INVENTION
0 This invention co-delivers one or more monoglycerides and one or more lactate esters to aid in delivery of drugs across the skin. In addition, thereto this invention calls for the monoglycerides and lactate esters to be present in a specific concentrations eg, 15-25 wt% and 8-25 wt%, respectively. The combined effect and preferred concentrations according to this invention have been shown to produce dramatic, ie, more than an additive, increases in the permeation of drugs when compared to the use of either a lactate ester or a monoglyceride alone or in unspecified weight percentages. Improved enhancement of permeation according to this invention can be obtained over a relatively wide range of lactate ester/monoglyceride weight percentages given above, however, the inventors have found that 20 wt% and 12 wt% of the monoglyceride and lactate ester, respectively, provides the greatest enhancement without any negative side effect.
The present invention in one embodiment is directed to a composition of matter for application to a body surface or membrane to administer a drug WO 95/09006 2 1 6 7 5 ~ 6 8 PCTtUS94tlll20 ~
by permeation through the body surface or membrane, the composition comprising, in combination:
(a) the drug to be administered, in a therapeutically effective amount; and (b) a permeation-enhancing mixture comprising:
(i) 15 to 25 wt% of a monoglyceride or a mixture of monoglycerides, and (ii) 8 to 25 wt% of a lactate ester or a mixture of lactate esters.
0 The drug may be present in the composition in an amount ranging from 0.01 to 50% by weight. The permeation-enhancing mixture preferably contains the monoglyceride and lactate ester in 20 wt% and 12 wt%, respectively.
This invention finds particular usefulness in enhancing drug permeability across skin. It is also useful, however, in enhancing flux across mucosa. Further, this invention is useful in delivery of both systemically and topically active drugs. According to our invention, the permeation-enhancing mixture and the drug to be delivered are placed in drug- and permeation-enhancing mixture-transmitting relationship to the appropriate body surface, 20 preferably in a pharmaceutically acceptable carrier therefor, and maintained in place for the desired period of time.
The drug and the permeation-enhancing mixture 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, 25 gel, cream, suppository or sublingual or buccal tablet, for example. When used in the form of a liquid, ointment, lotion, cream or gel applied directly tothe skin, it is preferable, although not required, to occlude the site of administration. Such compositions can also contain other permeation WO 95~'~3~G i PCT/US94/11120 ~t 6~6 enhancers, stabilizers, dyes, diluents, pigments, vehicles, inert fillers, excipients, gelling agents, vasoconstrictors, and other components of topical compositions as are known to the art.
In other embodiments, the drug and permeation enhancing mixture 5 would be administered from a transdermal delivery device as more fully described below. Examples of suitable transdermal delivery devices are illustrated in Figures 1, 2, 3 and 4. In the drawings, the same reference numbers are used throughout the different figures to designate the same or similar components. The figures are not drawn to scale.
In Figure 1, transdermal delivery device 10 comprises a reservoir 12 containing the drug and the permeation-enhancing mixture. Reservoir 12 is pre~erably in the form of a matrix containing the drug and permeation enhancing mixture dispersed therein. Reservoir 12 is sandwiched between a backing layer 14 and an in-line contact adhesive layer 16. The device 10 15 adheres to the surface of the skin 18 by means of the adhesive layer 16.
The adhesive layer 16 may optionally contain the permeation enhancing mixture and/or drug. A strippable release liner (not shown in Figure 1) is normally provided along the exposed surface of adhesive layer 16 and is removed prior to application of device 10 to the skin 18. Optionally, a rate-20 conltrolling membrane (not shown) may be present between the reservoir 12and the adhesive layer 16.
Alternatively, as shown in Figure 2, transdermal therapeutic device 20 may be attached to the skin or mucosa of a patient by means of an adhesive overlay 22. Device 20 is comprised of a drug- and permeation enhancing 25 mixture-containing reservoir 12 which is preferably in the form of a matrix conlaining the drug and the enhancing mixture dispersed therein. A backing layer 14 is provided adjacent one surface of reservoir 12. Adhesive overlay 22 rnaintains the device on the skin and may be fabricated together with, or WO 9~,~0900C ~ ~ 6~ ~ 6 PCT/US94/11120 provided separately from, the remaining elements of the device. With certain formulations, the adhesive overlay 22 may be preferable to the in-line contact adhesive 16 as shown in Figure 1. Backing layer 14 is preferably slightly larger than reservoir 12, and in this manner prevents the materials in 5 reservoir 12 from adversely interacting with the adhesive in overlay 22.
Optionally, a rate-controlling membrane (not shown in Figure 2) may be provided on the skin-proximal side of reservoir 12. A strippable release liner 24 is also provided with device 20 and is removed just prior to application of device 20 to the skin.
In Figure 3, transdermal delivery device 30 comprises a drug- and permeation enhancing mixture-containing reservoir ("drug reservoir") 12 substantially as described with respect to Figure 1. Permeation enhancer reservoir ("enhancer reservoir") 26 comprises the permeation enhancing mixture dispersed throughout and the drug at or below saturation when in 5 equilibrium. Enhancer reservoir 26 is preferably made from substantially the same matrix as is used to form drug reservoir 12. A rate-controlling membrane 28 for controlling the release rate of the permeation enhancer from enhancer reservoir 26 to drug reservoir 12 is placed between the two reservoirs. A rate-controlling membrane (not shown in Figure 3) for 20 controlling the release rate of the enhancer from drug reservoir 12 to the skin may also optionally be utilized and would be present between adhesive layer 16 and reservoir 12.
The rate-controlling membrane may be fabricated from permeable, semipermeable or microporous materials which are known in the art to 25 control the rate of agents into and out of delivery devices and having a permeability to the permeation enhancer lower than that of drug reservoir 12.
Suitable materials include, but are not limited to, polyethylene, polyvinyl acetate, ethylene n-butyl acetate and ethylene vinyl acetate copolymers.
WO 9~i/09006 PCT/US94/11120 2 ~ 6 ;~ 5~
Superimposed over the permeation enhancer reservoir 26 of device 30 is a backing 14. On the skin-proximal side of reservoir 12 are an adhesive layer 16 and a strippable liner 24 which would be removed prior to application of the device 30 to the skin.
In the embodiments of Figures 1, 2 and 3, the carrier or matrix material of the reservoirs has sufficient viscosity to maintain its shape without oozing or flowing. If, however, the matrix or carrier is a low-viscosity flowable material such as a liquid or a gel, the composition can be fully enclosed in a pouch or pocket, as known to the art from US Pat. No.
0 4,379,454 (noted above), for example, and as illustrated in Figure 4. Device 40 shown in Figure 4 comprises a backing member 14 which serves as a protective cover for the device, imparts structural support, and substantially keeps components in device 40 from escaping the device. Device 40 also includes reservoir 12 which contains the drug and permeation enhancing mixh~re and bears on its surface distant from backing member 14 a rate-controlling membrane 28 for controlling the release of drug and/or permeation enhancing mixture from device 40. The outer edges of backing member 14 overlay the edges of reservoir 12 and are joined along the perimeter with the outer edges of the rate-controlling membrane 28 in a fluid-tight arrangement. This sealed reservoir may be effected by pressure, fusion, adhesion, an adhesive applied to the edges, or other methods known in the art. In this manner, reservoir 12 is contained wholly between backing member 14 and rate-controlling membrane 28. On the skin-proximal side of rate-controlling membrane 28 are an adhesive layer 16 and a strippable liner 24 which would be removed prior to appiication of the device 40 to the skin.
In an alternative embodiment of device 40 of Figure 4, reservoir 12 contains the permeation enhancing mixture and the drug at or below saturation. The drug at saturation and an additional amount of permeation WO 95/09006 ~ PCT/US94/11120 enhancing mixture are present in adhesive layer 16 which acts as a separate reservoir.
The drug and the permeation enhancing mixture can be co-extensively administered to human skin or mucosa by direct application to 5 the skin or mucosa in the form of an ointment, gel, cream or lotion, for example, but are preferably administered from a skin patch or other known transdermal delivery device which contains a saturated or subsaturated formulation of the drug and the enhancer. The formulation is non-aqueous based and designed to deliver the drug and the permeation enhancing 10 mixture at the necessary fluxes. Typical non-aqueous gels are comprised of silicone fluid or mineral oil. Mineral oil-based gels also typically contain 1-2wt% of a gelling agent such as colloidal silicon dioxide. The suitability of a particular gel depends upon the compatibility of its constituents with both the drug and the permeation enhancing mixture and any other components in 15 the formulation.
The reservoir matrix should be compatible with the drug, the permeation enhancer and any carrier therefor. The term "matrix" as used herein refers to a well-mixed composite of ingredients fixed into shape.
When using a non-aqueous-based formulation, the reservoir matrix is 20 preferably composed of a hydrophobic polymer. Suitable polymeric ~dl~ices are well known in the transdermal drug delivery art, and examples are listed in the above-named patents previously incorporated herein by reference. A
typical laminated system would comprise a polymeric membrane and/or matrix such as ethylene vinyl acetate (EVA) copolymers, such as those 25 described in US Pat. No. 4,144,317, preferably having a vinyl acetate (VA) content in the range of from about 9% up to about 60% and more preferably about 9% to 40% VA. Polyisobutylene/oil polymers containing from 4-25%
high molecular weight polyisobutylene and 20-81% low molecular weight ~ WO 95/05~C~ PCT/US94111120 2 1 6752~
polyisobutylene with the balance being an oil such as mineral oil or polyisobutynes may also be used as the matrix material.
The amount of drug present in the therapeutic device and required to achieve an effective therapeutic result depends on many factors, such as the minimum necessary dosage of the drug for the particular indication being treated; the solubility and permeability of the matrix, of the adhesive layer and of the rate-controlling membrane, if present; and the period of time for which the device will be fixed to the skin. The minimum amount of drug is determined by the requirement that sufficient quantities of drug must be present in the device to maintain the desired rate of release over the given period of application. The maximum amount for safety purposes is determined by the requirement that the quantity of drug present cannot exceed a rate of release that reaches toxic levels.
The drug is normally present in the matrix or carrier at a conce"l,dlion in excess of saturation, the amount of excess being a function of the desired length of the drug delivery period of the system. The drug may, however, be present at a level below saturation without departing from this invention as long as the drug is continuously administered to the skin or mucosal site in an amount and for a period of time sufficient to provide the desired therapeutic rate.
The permeation enhancing mixture is dispersed through the matrix or carrier, preferably at a concentration sufficient to provide permeation-enhancing amounts of enhancer in the reservoir throughout the anticipated administration period. Where there is an additional, separate permeation - 25 enhancer matrix layer as well, as in Figures 3 and 4, the permeation enhancer normally is present in the separate reservoir in excess of saturation.
W095/09006 2 t ~`~526 PCT/US94/11120 ~
The unexpected effects of the specific weight percentages of the components of the permeation enhancer mixture is due, in part to the solubility of the monoglyceride in the lactic acid ester. It is known that monoglycerides by themselves are effective permeation enhancers. The 5 enhancement occurs by the solubilization of the monoglyceride in the lipid layer of the skin. The solubilization of the monoglyceride in the lipid layer increases as a function of lactic acid ester concentration. For example, the solubility of glycerol monolaurate in lauryl lactate is 350 mg/g of solution when the solution is stirred. GML is practically insoluble in, for example, an 10 EVA 40 matrix. Thus, the amount of GML dissolved, ie, free GML is dictated by and proportional to the lauryl lactate loading in the polymer.
Based on the GML solubility of 350 mglg, free GML conce"l,dlions based upon varying weight percents of lauryl lactate in EVA 40 are as follows:
15 Wt% I ~uryl Lactate Wt% GML in Solution 1 2% 4.2%
20% 7.0%
27% 9.5%
30% 1 0.5%
Thus, based upon the amount of GML in solution it would have appeared that the higher wt% of lauryl lactate would have resulted in a higher level of free GML and thus greater efficacy in increasing permeation.
However, as shown by the examples, the preferred formulations, containing 20 wt% GML and 12 wt% lauryl lactate, were equally effective in enhancing 25 drug permeability as those containing 20 wt% GML and 20 wt% lauryl lactate. While the invention is directed to a permeation enhancing mixture containing a monoglyceride or monoglyceride mixture from 15 to 25 wt% and a lactic acid ester present from 8 to 25 wt%, the 20 wt% monoglyceride and 12 wt% lactic acid ester is preferred because it is as effective as the higher 2 ~ 2~
percentage lactic acid ester compositions yet it delivers less of a lactic acid ester which is a known potential irritant.
In addition to drug and the permeation enhancing mixture, which are essential to the invention, the matrix or carrier may also contain dyes, 5 pigments, inert fillers, excipients and other conventional components of pharmaceutical products or transdermal devices known to the art.
Because of the wide variation in skin permeability from individual to individual and from site to site on the same body, it may be preferable that drug and the permeation enhancing mixture be administered from a 10 rate-controlled transdermal delivery device. Rate control can be obtained either through a rate-controlling membrane or adhesive or both as well as through the other means.
A certain amount of drug will bind reversibly to the skin, and it is accordingly preferred that the skin-contacting layer of the device include this 15 amount of the agent as a loading dose.
The surface area of the device of this invention can vary from less than 1 cm2 to greater than 200 cm2. A typical device, however, will have a surface area within the range of about 5-50 cm2.
The devices of this invention can be designed to effectiveiy deliver 20 drug for an extended time period of from several hours up to 7 days or longer. Seven days is generally the maximum time limit for application of a single device because the adverse affect of occlusion of a skin site increases with time and the normal cycle of sloughing and replacement of the skin cells occurs in about 7 days.
The method of this invention comprises:
W0 95/09006 2 T ~ ~ 5 2 ~ PCT/US94/11120 ~
(a) administering a drug, in a therapeutically effective amount, to the area of skin over the time period; and (b) coadministering the permeation-enhancing mixture according to this invention to the area of skin.
The composition delivered by the method contains a permeation enhancing mixture, ie, 15 to 25 wt% or a monoglyceride or monoglyceride mixture and 8 to 25 wt% of a lactate ester and enough drug to provide systemic administration of drug through the skin for a predetermined period of time to provide an effective therapeutic result.
It is believed that this invention has utility in connection with the delivery of drugs within the broad class normally delivered through body surfaces and membranes, including skin. As used herein, the expressions "drug" and "agent" are used interchangeably and are intended to have their broadest interpretation as to any therapeutically active substance which is 15 delivered to a living organism to produce a desired, usually beneficial, effect.
In general, this includes therapeutic agents in all of the major therapeutic areas, including, but not limited to, ACE inhibitors, adenohypophyseal hormones, adrenergic neuron blocking agents, adrenocortical steroids, inhibitors of the biosynthesis of adrenocortical steroids, alpha-adrenergic 20 agonists, alpha-adrenergic antagonists, selective alpha-two-adrenergic agonists, analgesics, antipyretics and anti-inflammatory agents, androgens, local anesthetics, general anesthetics, antiaddictive agents, antiandrogens, antiarrhythmic agents, a"lia~li"l~alic agents, anticholinergic agents, anticholinesterase agents, anticoagulants, antidiabetic agents, antidiarrheal 25 agents, antidiuretic, antiemetic and prokinetic agents, antiepileptic agents,antiestrogens, antifungal agents, antihypertensive agents, antimicrobial agents, anli~ raine agents, antimuscarinic agents, antineoplastic agents, antiparasitic agents, antiparkinson's agents, antiplatelet agents, antiprogestins, antithyroid agents, antitussives, antiviral agents, atypical ~ WO 95/09006 PCT/US94/11120 antidepressants, azaspirodecanediones, barbiturates, benzodiazepines, benzothiadiazides, beta-adrenergic agonists, beta-adrenergic antagonists, selective beta-one-adrenergic antagonists, selective beta-two-adrenergic agonists, bile salts, agents affecting volume and composition of body fluids, 5 butyrophenones, agents affecting calcification, calcium channel blockers, cardiovascular drugs, catecholamines and sympathor~ elic drugs, cholinergic agonists, cholinesterase reactivators, dermatological agents, diphenylbutylpiperidines, diuretics, ergot alkaloids, estrogens, ganglionic blocking agents, ganglionic stimulating agents, hydantoins, agents for control 10 of gastric acidity and treatment of peptic ulcers, hematopoietic agents, hista",i"es, hislar"ille antagonists, 5-hydroxytry,.tdl"i"e antagonists, drugs for the treatment of hyperlipoproteinemia, hypnotics and sedatives, immunosuppressive agents, laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular blocking agents, organic nitrates, opioid analgesics 15 and antagonists, pancreatic enzymes, phenothiazines, progestins, prostaglandins, agents for the treatment of psychiatric disorders, retinoids, - sodium channel blockers, agents for spasticity and acute muscle spasms, succinimides, thioxanthenes, thrombolytic agents, thyroid agents, tricyclic antidepressants, inhibitors of tubular transport of organic compounds, drugs 20 affecting uterine motility, vasodilators, vilamills and the like.
Representative drugs include, by way of example and not for purposes of limitation, bepridil, dillia em, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nitredipine, verapamil, dobutamine, isoproterenol, carteolol, labetalol, levobunolol, nadolol, penbutolol, pindolol, propranolol, 25 sotalol, timolol, acebutolol, atenolol, betaxolol, esmolol, metoprolol, albuterol, bitolterol, isoetharine, metaproterenol, pirbuterol, ritodrine, terbutaline, alclometasone, aldosterone, amcinonide, beclomethasone dipropionate, betamethasone, clobetasol, clocortolone, cortisol, cortisone, corticosterone, desonide, desoximetasone, 11-desoxycorticosterone, 11-desoxycortisol, 30 dexamethasone, diflorasone, fludrocortisone, flunisolide, fluocinolone, WO9S/09006 2 t ~526 PCT/US94/11120 ~
fluocinonide, fluorometholone, flurandrenolide, halcinonide, hydrocortisone, medrysone, 6a-methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tetrahydrocortisol, triamcinolone, benoxinate, benzocaine, bupivacaine, chloroprocaine, cocaine, dibucaine, dyclonine, 5 etidocaine, lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, tetracaine, alfentanil, chloroform, clonidine, cyclopropane, desflurane, diethyl ether, droperidol, enflurane, etomida~e, fentanyl, halothane, isoflurane, ketamine hydrochloride, meperidine, methohexital, methoxyflurane, morphine, propofol, sevoflurane, sufentanil, thiamylal, 10 thiopental, aceLall,i,lophen, allopurinol, apazone, aspirin, auranofin, aurothioglucose, colchicine, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, gold sodium thiomalate, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefenamic acid, mesalamine, methyl salicylate, nabumetone, naproxen, oxyphenbutazone, phenacetin, phenylbutazone, 15 piroxicam, salicylamide, salicylate, salicylic acid, s~ls~l~te, sulf~s~l~7ine, sulindac, tolmetin, acetophenazine, chlorpro",a~i,le, fluphenazine, mesoridazine, perphenazine, thioridazine, trifluoperazine, triflupromazine, disopyramide, encainide, flecainide, indecainide, mexiletine, moricizine, phenytoin, procainamide, propafenone, quinidine, tocainide, cisapride, 20 domperidone, dronabinol, haloperidol, metoclopramide, nabilone, prochlorperazine, promethazine, thiethylperazine, trimethobenzamide, buprenorphine, butorphanol, codeine, dezocine, diphenoxylate, drocode, hydrocodone, hydromorphone, levallorphan, levorphanol, loperamide, meptazinol, methadone, nalbuphine, nalmefene, nalorphine, naloxone, 25 naltrexone, oxycodone, oxymorphone, pentazocine, propoxyphene, isosorbide dinitrate, nitroglycerin, theophylline, phenylephrine, ephedrine, pilocarpine, furosemide, tetracycline, chlorpheniramine, ketorolac, bromocriptine, guanabenz, prazosin, doxazosin, and flufenamic acid.
Preferably, the drug is a benzodiazepine, such as alprazolam, 30 brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, W095/09006 ~ 1 67526 PCT/US94/11120 demoxepam, di~er~m, flullla~ellil, flurazepam, h~l~7ep~m, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, tema7er~ triazolam, and the like; an antimuscarinic agents, such as anisotropine, atropine, clidinium, cyclopentolate, dicyclomine, flavoxate, 5 glycopyrrolate, hexocyclium, hol,,dl,u~ine, ipratropium, isopropamide, mepenzolate, methantheline, oxyphencyclimine, pirenzepine, propantheline, scopolamine, telenzepine, tridihexethyl, tropicamide, and the like; an estrogen such as chlorotrianisene, diethylstilbestrol, estradiol, estradiol cypionate, estradiol valerate, estrone, estrone sodium sulfate, estropipate, 10 ethinyl estradiol, mestranol, quinestrol, sodium equilin sulfate and the like; an androgen, such as danazol, fluoxymesterone, methandrostenolone, methylte~losteroile, nandrolone decanoate, nandrolone phenpropionate, oxandrolone, oxymetholone, stanozolol, testolactone, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, and 15 the like; or a progestin such as ethynodiol diacetate, gestodene, hydroxyprogesterone caproate, levonorgestrel, medroxyprogesterone acetate, meyesLIol acetate, norethindrone, norethindrone acetate, norethynodrel, norgestrel, progesterone, and the like.
Preferably, a device for the transdermal administration of a drug, at a 20 therapeutically effective rate, comprises:
(a) a reservoir comprising:
(i) a therapeutically effective amount of a drug or active agent, (ii) 15 to 25% by weight monoglyceride or mixture of monoglycerides, (iii) 8 to 25% by weight lactic acid ester, and (iv) the remainder ethylene vinyl acetate copolymer;
(b) a backing on the skin-distal suRace of the reservoir; and (c) means for maintaining the reservoir in drug- and permeation enhancing mixture-transmitting relation with the skin.
W095/09006 2 t ~ PCT/US94/11120 Preferably, the monoglyceride is glycerol monolaurate and the lactic acid ester is lauryl lactate.
More preferably, a device for the transdermal administration of the drug, at a therapeutically effective rate, comprises:
(a) a reservoir comprising:
(i) 5 to 40% by weight drug, (ii) 20% by weight glycerol monolaurate, (iii) 12% by weight lauryl lactate, and (iv) 28 to 63% by weight ethylene vinyl acetate copolymer;
(b) a backing on the skin-distal sur~ace of the reservoir; and (c) means for maintaining the reservoir in drug- and permeation enhancing mixture-l,d"sn,illi"g relation with the skin.
In one embodiment, the reservoir further comprises 5-25% by weight cross-linked poly-N-vinyl-2-pyrrolidone, eg, N-vinyl-2-pyrrolidone XL-10, 15 G&F). Preferably, the backing is a breathable backing, such as NRU-100-C(~) (Flexcon, Spencer, MA). If an occluded backing is used, preferably it is Medpar~) (3M, St. Paul, MN). Preferably, the means for maintaining the reservoir in drug and permeation enhancing mixture transn,iLLi~19 relation with the skin is an acrylic contact adhesive, such as MSP041991P, 3M.
20 Preferably, the ethylene vinyl acetate copolymer has a acetate content of 33% or 40%.
The aforementioned patents describe a wide variety of materials which can be used for fabricating the various layers or components of the transdermal drug delivery devices according to this invention. This invention 25 therefore col,le,nplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions. The following -WO 9Si~ S PCT/US94/11120 exampies are offered to illustrate the practice of the present invention and are not intended to limit the invention in any manner.
The drug/permeation enhancer reservoir was prepared by mixing 5 ethylene vinyl acetate copolymer having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam (GYMA Labs of America, Garden Cit,v, NJ), glycerol monolaurate (Grindsted ML 90, Grindsted Products A/S, Brabrand, Denmark) and lauryl lactate (Van 10 Dyk, Inc., Belleview, NJ) were then added. The mixture was blended for approxilllaLely 20 minutes at 54-56C and 30 rpm. After blending, the mixture was quickly cooled to 4045C, and calendered to a 13 mil thick film. The film was then laminated to an acrylic contact adhesive (MSPO419910, 3M) on one side and a Medpar~ backing (3M, St. Paul, 15 Minn.) or NRU-100-C~) backing (Flexcon, Spencer, MA) on the opposite side. The laminate was then cut into circles using a stainless steel punch.
The composition of the drug reservoirs is shown in Table 1.
WO 9J~ t 6 ~ 5 ~ 6 PCTrUS94/11120 ~
Drug/Permeation Enhancer Reservoir Col"posilion (weight per.,er,l) Figure 5 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 (15/20/20/45) al,~,ra,olal"/glycerol monolaurate/lauryl lactate/EVA 40 (15/10/30/45) dl,~,rd,olam/lauryl lactate/EVA 40 0 (15/30/55) Figure 6 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 (15/20/20/45) alpra,old,n/glycerol monolaurate/EVA 40 (15/20/65) Circular pieces of human-epidermis were mounted on horizontal permeation cells with the stratum corneum facing the donor compartment of the cell. The release liner of the system was then removed and the system was centered over the stratum corneum side of the epidermis. A known 20 volume of the receptor solution (0.01 M potassium phosphate at pH 6 containing 2% isopropanol) that had been equilibrated at 35C was placed in the receptor compartment. Air bubbles were removed from the receptor compartment; the cell was capped and placed in a water bath-shaker at 35C.
A given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35C. The receptor solutions were stored in capped vials at 4C until assayed for alprazolam content by HPLC. From the drug concentration and the volume of the receptor solutions, the area of ~ W0951~05 2 ~ 6 7 5 26 PCT~S94/11120 permeation and the time interval, the flux of the drug through the epidermis was c~lcul~ted as follows: (drug concentration x volume of receptor)/(area x time) = flux (,ug/cm2 hr). The fluxes achieved for the dirrerlj"t systems are shown in Figures 5 and 6. As can be seen in Figures 5 and 6, the fluxes 5 obtained from the systems containing glycerol monolaurate and lauryl lactate were significantly higher than the fluxes obtained from the systems containing either glycerol monolaurate or lauryl lactate.
The drug/permeation enhancer reservoir was prepared by mixing 10 ethylene vinyl acetate copolymer having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam, glycerol monolaurate and lauryl lactate were then added. The mixture was blended for approximately 20 minutes at 54-56C and 30 rpm. After blending, the mixture was quickly cooled to 40-45C, and calendered to a 5 mil thick film.
The compositions of reservoirs are shown in Table 2.
-Plasma Levels of Alprazolam (ng/mL) Composition of Reservoir 24 hrs 48 hrs alprazolam/glycerol monolaurate/
EVA 40 (15%/20%/65%) 0.2 0.2 alprazolam/glycerol monolaurate/lauryl Iactate/EVA 40 (15%/20%/20%/45%) 0.7 1.2 WO 95/09006 2 1 6 7 ~ 2 ~ PCTIUS94111120 ~
This film was then laminated to an acrylic contact adhesive (MSP041991P, 3M) on one side and Medpart~) backing (3M) on the opposite side. The laminate was then cut into 5 cm2 square. As can be seen in Table 3, the plasma levels for the combination of glycerol monolaurate and lauryl lactate was significantly higher than the plasma level for glycerol monolaurate alone.
The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate copolymer having a vinyl acetate content of 28 percent ("EVA 28", U.S.I. Chemicals, Illinois) and cross-linked poly-N-vinyl-2-pyrrolidone (Polyplasdone XL-10~), GAF) in an internal mixer (Bra Bender type mixer) until the EVA 28 pellets fused. Estradiol, glycerol monolaurate and lauryl lactate were then added. The mixture was blended, and calendered to a 4.0 mil thick film. The compositions of the reservoir is given in Table 3.
Drug/Permeation Enhancer Reservoir Composition (weight percent) Estradiol/glycerol monolaurate/lauryl lactate/EVA 28/N-vinyl-2-pyrrolidone (2.5120120152.515) This film was then laminated to an acrylic contact adhesive (147-123-4, Adhesive Research Co.) on one side and dermaFlex NRU-100-C~) -backing (Flexcon Co.) on the opposite side. The film was then cut into circles and taped to prevent edge release.
WO 9S~5J^6 2 t 6 7 ~ 2 6 PCT/US94/11120 For each device tested, the adhesive was placed against the stratum corneum side of a disc of human epidermis that had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device 5 covered with epidermis was attached to the flat side of the Teflon holder of arelease rod using nylon netting and nickel wire. The rods were reciprocated in a fixed volume of receptor solution (distilled water). The entire receptor solution was changed at each sampling time. The temperature of the receptor solution in the water bath was maintained at 35C.
The receptor solutions were stored in capped vials at 4C until assayed for estradiol content by HPLC. The fluxes achieved for the different systems are shown in Figure 7.
The drug/permeation enhancer reservoir was prepared by mixing 15 ethylene vinyl acetate copolymer having a vinyl acetate content of 28 percent ("EVA 28", U.S.I. Chemicals, Illinois) and cross-linked poly N-vinyl-2-pyrrolidone (Polyplasdone XL~g), GAF) in an internal mixer (Bra Bender type mixer) until the EVA 28 pellets fused. Testosterone, glycerol monolaurate and lauryl lactate were then added. The mixture was blended, 20 and calendered to a 4.0 mil thick film. The compositions of the reservoir is given in Table 4.
WO 95~'~9~ ^6 PCT/US94/11120 2 ~ ~5~ --Drug/Permeation Enhancer Reservoir Composition (weight percent) testosterone/glycerol monolaurate/lauryl lactate/EVA 28/N-vinyl-2-pyrrolidone (512012015015) This film was then laminated to an acrylic contact adhesive (147-123-4, Adhesive Research Co.) on one side and dermaFlex NRU-100-C~) backing (Flexcon Co.) on the opposite side. The film was then cut into 10 circles and taped to prevent edge release.
For each device tested, the adhesive was placed against the stratum corneum side of a disc of human epidermis that had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device 15 covered with epidermis was attached to the flat side of the Teflon holder of a release rod using nylon netting and nickel wire. The rods were reciprocated in a fixed volume of receptor solution (distilled water). The entire receptor solution was changed at each sampling time. The temperature of the receptor solution in the water bath was maintained at 35C.
20The receptor solutions were stored in capped vials at 4C until assayed for testoslerone content by HPLC. The fluxes achieved for the different systems are shown in Figure 8.
The drug/permeation enhancer reservoir was prepared by mixing 25ethylene vinyl acetate copolymer having a vinyl acetate content of 40 ~ wo 9~,0s~^~ 2 1 6 7 5 2 6 PCT~S94/11120 percent ("EVA 40", U.S.I. Chemicals, Illinois) in an internai mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam, glycerol monolaurate and lauryl lactate were then added. The mixture was blended for approximately 20 minutes at 54-56C and 30 rpm. After blending, the mixture was quickly cooled to 4045C, and calendared to a 5 mil thick film.
The composition of the drug reservoirs is shown in Table 5.
Drug/Permeation Enhancer Reservoir Composition (weight percent) ~o Figure 9 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 This film was then laminated to an acrylic contact adhesive (MSP041991P,3M) on one side and Medpa~ or NRU-100-C~ backing (Flexcon, Spencer, MA) on the opposite side. The laminate was then cut into circles using a stainless steel punch.
WO 95/09006 PCT/US9~/11120 _ Circular pieces of human-epidermis were mounted on horizontai permeation cells with the stratum corneum facing the donor compartment of the cell. The release liner of the system was then removed and the system was centered over the stratum corneum side of the epidermis. A known 5 volume of the receptor solution (0.01 M potassium phosphate at pH 6 containing 2% isopropanol) that had been equilibrated at 35C was placed in the receptor compartment. Air bubbles were removed; the cell was capped and placed in a water bath-shaker at 35C.
At given time intervals, the entire receptor solution was removed from 10 the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35C. The receptor solutions were stored in capped vials at 4C until assayed for alprd~old", content by HPLC. The fluxes achieved for the different systems are shown in Figure 9. As is demonstrated by Figure 9, a system containing 20% GML and 12% LL
15 provided a superior cumulative flux of alprazolam.
The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate copolymer having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) and optionally cross-linked poly 20 N-vinyl- 2-pyrrolidone (Polyplasdone XL~, GAF) in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Testosterone, glycerol monolaurate and lauryl lactate were then added. The mixture was blended, and calendered to a 4.0 mil thick film. The compositions of the reservoir is given in Table 6.
WO 95,'~ ^6 PCT/US94/11120 ;
Drug/Permeation Enhancer Reservoir Composition (weight percent) testosterone/glycerol monolaurate/lauryl lactate/EVA 40 (512012015015) testosterone/glycerol monolaurate/myristyl lactate/myristyl alcohol/EVA 40 (20/20/12/48) testosterone/glycerol monolaurate/lauric acid/EVA 40 (20/20/12/48) testosterone/glycerol monolaurate/Tween 20/EVA 40 (20/20/10/50) testosterone/glycerol monolaurate/lauryl lactate/EVA 40 (20/20/12/48) tesloslerone/glycerol monolaurate/lauryl lactate/N-vinyl-2-pyrrolidone/EVA 40 (20/20/12/16/32) This film was then laminated to an acrylic contact adhesive (MSP041991P, 3M) on one side and Medpart~) or NRU-100-C~) backing on 20 the opposite side. The laminate was then cut into circles and taped to prevent edge release.
For each device tested, the adhesive was placed against the stratum corneum side of a disc of human epidermis that had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that 25 none of the device edge was exposed to the receptor solution. The device covered with epidermis was attached to the flat side of the Teflon holder of a release rod using nylon netting and nickel wire. The rods were reciprocated in a fixed volume of receptor solution (0.1% Benzoic acid). The entire WO 9 ,/O~OOG PCT/US94/11120 2~67526 receptor solution was changed at each sampling time. The temperature of the receptor solution in the water bath was maintained at 35C.
The receptor solutions were stored in capped vials at 4C until assayed for testosterone content by HPLC. The fluxes achieved for the 5 different systems are shown in Figure 10.
The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate copolymer having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, lllinois) in an internal mixer (Bra 10 Bender type mixer) until the EVA 40 pellets fused. Alprazolam, glycerol monolaurate and lauryl lactate were then added. The mixture was blended, and calendered to a 5.0 mil thick film. The composition of the reservoirs are given in Table 7.
Drug/Permeation Enhancer Reservoir Composition (weight percent) Alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 Alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 Alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 Alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 Alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 ~ W095/09006 2 1 6 7~ 26 PCT/US94/11120 The film was then laminated to an acrylic contact adhesive (MSPO41991P, 3M) on one side and Medpar~) or NRU-100-C~ backing (Flexcon Co.) on the opposite side. The film was then cut into circles and taped to prevent drug release from the edges.
For each device tested, the adhesive was placed against the stratum corneum side of a disc of human epidermis that had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device covered with epidermis was attached to the flat side of the Teflon holder of a release rod using nylon netting and nickel wire. The rods were reciprocated in a fixed volume of receptor solution (0.01M potassium phosphate at pH 6 containing 2% isopropanol). The entire receptor solution was changed at each sampling time. The temperature of the receptor solution in the water bath was maintained at 35C.
The receptor solutions were stored in capped vials at 4C until assayed for alprazolam content by HPLC. The fluxes achieved for the different systems are shown in Figure 11.
This invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.
~FI ~TFn Appl IcATloNs ;
This is a continuation-in-part of US application Serial No. 08/129,494, filed September 29, 1993, which application is incorporated herein in its entirety by reference and benefit is claimed of its filing date.
FIFI n OF THE INVFNTION
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 5 drugs when incorporated in transdermal drug delivery systems. More particularly, but without limitation thereto, this invention relates to the transdermal delivery of drugs utilizing a permeation-enhancing mixture of a monoglyceride and a lactate ester. Still more particularly, but without limitation thereto, this invention relates to the transdermal delivery of drugs 10 utilizing a permeation-enhancing mixture of a monoglyceride and a lactate ester wherein the monoglyceride and lactate ester are present in the composition in specific weight percentages.
R~CKGROUND OF THE INVFNTION
The 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 US Patent Numbers 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894;
4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222;
4,568,343; 4,573,995; 4,588,580; 4,645,502; 4,704,282; 4,788,062;
WO 95/09006 PCT/US94/11120 ~
~ ~ ~7 ~26 2 4,816,258; 4,849,226; 4,908,027; 4,943,435; and 5,004,610. The disclosures of the above patents are incorporated herein by reference.
In many instances, drugs which would appear to be ideal candidates for transdermal delivery are found to have such low permeability through intact skin that they cannot be delivered at therapeutically effective rates from reasonably sized systems.
In an effort to increase skin permeability, it has been proposed to pretreat the skin with various chemicals or to concurrently deliver the drug in the presence of a permeation enhancer. Various materials have been 0 suggested for this purpose, as described in US Pat. Nos. 3,472,931, 3,527,864, 3,896,238, 3,903,256, 3,952,099, 4,046,886, 4,130,643, 4,130,667, 4,299,826, 4,335,115, 4,343,798, 4,379,454, 4,405,616 and 4,746,515, all of which are incorporated herein by reference; British Pat. No.
1,001,949; and Idson, Percutaneous Absorption, J. Pharm. Sci., vol. 64, No.
b6, June 1975, pp 901-924 (particularly 919-921).
To be considered useful, 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 20 reasonably sized system (preferably 5-50 cm2) 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 capable of delivering drugs without producing topical reactions, burning or tingling 2~ sensations.
W095/09006 2 ~ 6~5~6 PCT/US94111120 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.
While it is known in the art to combine permeation enhancers, see, 5 eg, European Patent Publication numbers 0295411 and 0368339, this invention utilizes a novel combination of a monoglyceride and a lactate ester.
Furlher, the invention utilizes specific weight percentages of the novel components, the monoglyceride and lactate ester, ie, 15 to 25 wt% of monoglyceride and 8 to 25 wt% of lactic acid ester. The combined effect 10 and, further, specific weight percentages, produces a significant and surprising improvement ie, more than an additive effect over use of either a monoglyceride or a lactate ester alone, as well as over the combination of monoglyceride and lactate ester in specified weight percentages.
~UMMARY OF THE INVENTION
The present invention relates to improved compositions and methods for improving the penetration of a broad category of beneficial agents that produce little or no skin irritation. The system of the invention comprises a carrier or matrix adapted to be placed in drug- and permeation-enhancing mixture-transmitting relation to the selected skin or other body site. The 20 carrier or matrix contains suffficient amounts of drug and the permeation-enhancing mixture to continuously coadminister to the site, over a predetermined delivery period, the drug, in a therapeutically effective amount, and the permeation-enhancing mixture of a monoglyceride and a lactate ester, present in specific concentrations, ie, 15 to 25 wt% of 25 monoglyceride and 8 to 25 wt% of a lactate ester, preferably 20 wt%
monoglyceride and 12 wt% lactate ester in an amount effective to enhance the permeation of the drug to the skin.
2 t ~,~5~
As used herein, the term "transdermal" deiivery or application refers to the delivery or application of agents by passage through skin, mucosa and/or other body surfaces by topical appiication or by iontophoresis.
As used herein, the term "therapeutically effective" amount or rate 5 refers to the amount or rate of drug or active agent needed to effect the desired therapeutic result.
As used herein, the term "monoglyceride" refers to glycerol monooleate, glycerol monolaurate and glycerol monolinoleate, or a mixture thereof. Monoglycerides are generally available as a mixture of 10 monoglycerides, with the mixture deriving its name from the monoglyceride present in the greatest amount. In a preferred embodiment of this invention, the permeation enhancer monoglyceride component is glycerol monolaurate.
As used herein, the term "glycerol monooleate" refers to glycerol monooleate itself or a mixture of glycerides wherein glycerol monooleate is present in the greatest amount.
As used herein, the term "glycerol monolaurate" refers to glycerol monolaurate itself or a mixture of glycerides wherein glycerol monolaurate is present in the greatest amount.
As used herein, the term "glycerol monolinoleate" refers to glycerol 20 monolinoleate itself or a mixture of glycerides wherein glycerol monolinoleate is present in the greatest amount.
As used herein, the term "lactate ester" or "lactic ester of an alcohol"
refers to ethyl lactate, lauryl lactate, myristyl lactate or cetyl lactate, or amixture thereof. Preferably, the lactate ester is lauryl lactate or ethyl lactate 25 or a mixture thereof.
~ WO 95/09006 2 1 6 7 5 2 6 PCT/US94/11120 As used herein, the term "substantial portion of the time period"
means at least about 60% of the time period, preferably at least about 90%
of the time period. Correlatively, the term "substantially constant" means a variation of less than about +20%, preferably less than about +10%, over a 5 substantial portion of the time period.
As used herein, the term "permeation enhancing mixture" refers to a mixture comprising one or more lactate esters and one or more monoglycerides. The monoglyceride or mixture, preferably, glycerol monolaurate, is present in the range of about 15 to about 25 weight percent.
10 The second component, ie, a lactic acid ester, eg, lauryl, myristyl, cetyl, ethyl, methyl or oleic acid, benzoic acid or lactic acid is present in the rangeof about 8 to about 25 weight percent. More preferably, the pell"ealion enhancer mixture by weight comprises 20% monoglyceride and 12% lactic acidl ester.
As used herein, the term "predetermined delivery period" or "extended time period" refers to the delivery of drug for a time period of from several hours to seven days or longer. Preferably, the time period is from 16 hours to 3 or 4 days.
As used herein, the term "permeation enhancing amount or rate"
20 refers to the rate or amount that provides increased permeability of the application site to the drug.
As used herein, the term "poly-N-vinyl amide" means a cross-linked poly-N-vinyl amide or combination of poly-N-vinyl amide such as poly-N-vinylmethylacetamide, poly-N-vinylethylacetamide, poly-N-vinylmethyl-25 isobutyramide, poly-N-vinyl-2-pyrrolidone, poly-N-vinylpyrrolidone, poly-N-vinyl-2-piperidone, poly-N-vinyl-caprolactam, poly-N-vinyl-5-methyl-2-pyrrolidone. poly-N-vinyl-3-methyl-2-pyrrolidone, and WO 95/09006 2 1 6 ~ 5 2 6 PCT/US94111120 ~
the like. Preferably, the poly-N-vinyl amide is poly-N-vinyl-2-pyrrolidone (more preferably Polyplasdone XL~), Polyplasdone XL-10~), GAF).
BRIFF DESCRIPTION OF THE DRAWINGS
The invention will be described in further detail with reference to the 5 accompanying drawings wherein:
FIG. 1 is a cross-sectional view of one embodiment of the transdermal drug delivery system according to this invention;
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;
FIG. 4 is a cross-sectional view of yet another embodiment of the transdermal drug delivery system of this invention;
FIG. 5 is a graph of the flux of alprazolam through human epidermis 15 at 35C, in vitro, with glycerol monolaurate and lauryl lactate.
FIG. 6 is a graph of the flux of alprazolam through human epidermis at 35C, in vitro, with glycerol monolaurate and lauryl lactate.
FIG. 7 is a graph of the flux of estradiol through human epidermis at 35C, in vitro, with glycerol monolaurate and lauryl lactate.
FIG. 8 is a graph of the flux of testosterone through human epidermis at 35C, in vitro, with glycerol monolaurate and lauryl lactate.
WO9St09006 2 ~ 5~ PCT/US94/11120 FIG. 9 is a bar graph of the cumulative flux of alprazolam through c human epidermis at 35C, in vitro, with varying weight percents of glycerol monolaurate and lauryl lactate.
FIG. 10 is a graph of the cumulative flux of testosterone through human epidermis at 35C, in vitro, with various flux enhancers.
FIG. 11 is a bar graph showing the effect of various concentrations of glycerol monolaurate and lauryl lactate on the flux of alprazolam through human epidermis at 35C, in vitro.
DESCRIPTION OF THE INVENTION
0 This invention co-delivers one or more monoglycerides and one or more lactate esters to aid in delivery of drugs across the skin. In addition, thereto this invention calls for the monoglycerides and lactate esters to be present in a specific concentrations eg, 15-25 wt% and 8-25 wt%, respectively. The combined effect and preferred concentrations according to this invention have been shown to produce dramatic, ie, more than an additive, increases in the permeation of drugs when compared to the use of either a lactate ester or a monoglyceride alone or in unspecified weight percentages. Improved enhancement of permeation according to this invention can be obtained over a relatively wide range of lactate ester/monoglyceride weight percentages given above, however, the inventors have found that 20 wt% and 12 wt% of the monoglyceride and lactate ester, respectively, provides the greatest enhancement without any negative side effect.
The present invention in one embodiment is directed to a composition of matter for application to a body surface or membrane to administer a drug WO 95/09006 2 1 6 7 5 ~ 6 8 PCTtUS94tlll20 ~
by permeation through the body surface or membrane, the composition comprising, in combination:
(a) the drug to be administered, in a therapeutically effective amount; and (b) a permeation-enhancing mixture comprising:
(i) 15 to 25 wt% of a monoglyceride or a mixture of monoglycerides, and (ii) 8 to 25 wt% of a lactate ester or a mixture of lactate esters.
0 The drug may be present in the composition in an amount ranging from 0.01 to 50% by weight. The permeation-enhancing mixture preferably contains the monoglyceride and lactate ester in 20 wt% and 12 wt%, respectively.
This invention finds particular usefulness in enhancing drug permeability across skin. It is also useful, however, in enhancing flux across mucosa. Further, this invention is useful in delivery of both systemically and topically active drugs. According to our invention, the permeation-enhancing mixture and the drug to be delivered are placed in drug- and permeation-enhancing mixture-transmitting relationship to the appropriate body surface, 20 preferably in a pharmaceutically acceptable carrier therefor, and maintained in place for the desired period of time.
The drug and the permeation-enhancing mixture 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, 25 gel, cream, suppository or sublingual or buccal tablet, for example. When used in the form of a liquid, ointment, lotion, cream or gel applied directly tothe skin, it is preferable, although not required, to occlude the site of administration. Such compositions can also contain other permeation WO 95~'~3~G i PCT/US94/11120 ~t 6~6 enhancers, stabilizers, dyes, diluents, pigments, vehicles, inert fillers, excipients, gelling agents, vasoconstrictors, and other components of topical compositions as are known to the art.
In other embodiments, the drug and permeation enhancing mixture 5 would be administered from a transdermal delivery device as more fully described below. Examples of suitable transdermal delivery devices are illustrated in Figures 1, 2, 3 and 4. In the drawings, the same reference numbers are used throughout the different figures to designate the same or similar components. The figures are not drawn to scale.
In Figure 1, transdermal delivery device 10 comprises a reservoir 12 containing the drug and the permeation-enhancing mixture. Reservoir 12 is pre~erably in the form of a matrix containing the drug and permeation enhancing mixture dispersed therein. Reservoir 12 is sandwiched between a backing layer 14 and an in-line contact adhesive layer 16. The device 10 15 adheres to the surface of the skin 18 by means of the adhesive layer 16.
The adhesive layer 16 may optionally contain the permeation enhancing mixture and/or drug. A strippable release liner (not shown in Figure 1) is normally provided along the exposed surface of adhesive layer 16 and is removed prior to application of device 10 to the skin 18. Optionally, a rate-20 conltrolling membrane (not shown) may be present between the reservoir 12and the adhesive layer 16.
Alternatively, as shown in Figure 2, transdermal therapeutic device 20 may be attached to the skin or mucosa of a patient by means of an adhesive overlay 22. Device 20 is comprised of a drug- and permeation enhancing 25 mixture-containing reservoir 12 which is preferably in the form of a matrix conlaining the drug and the enhancing mixture dispersed therein. A backing layer 14 is provided adjacent one surface of reservoir 12. Adhesive overlay 22 rnaintains the device on the skin and may be fabricated together with, or WO 9~,~0900C ~ ~ 6~ ~ 6 PCT/US94/11120 provided separately from, the remaining elements of the device. With certain formulations, the adhesive overlay 22 may be preferable to the in-line contact adhesive 16 as shown in Figure 1. Backing layer 14 is preferably slightly larger than reservoir 12, and in this manner prevents the materials in 5 reservoir 12 from adversely interacting with the adhesive in overlay 22.
Optionally, a rate-controlling membrane (not shown in Figure 2) may be provided on the skin-proximal side of reservoir 12. A strippable release liner 24 is also provided with device 20 and is removed just prior to application of device 20 to the skin.
In Figure 3, transdermal delivery device 30 comprises a drug- and permeation enhancing mixture-containing reservoir ("drug reservoir") 12 substantially as described with respect to Figure 1. Permeation enhancer reservoir ("enhancer reservoir") 26 comprises the permeation enhancing mixture dispersed throughout and the drug at or below saturation when in 5 equilibrium. Enhancer reservoir 26 is preferably made from substantially the same matrix as is used to form drug reservoir 12. A rate-controlling membrane 28 for controlling the release rate of the permeation enhancer from enhancer reservoir 26 to drug reservoir 12 is placed between the two reservoirs. A rate-controlling membrane (not shown in Figure 3) for 20 controlling the release rate of the enhancer from drug reservoir 12 to the skin may also optionally be utilized and would be present between adhesive layer 16 and reservoir 12.
The rate-controlling membrane may be fabricated from permeable, semipermeable or microporous materials which are known in the art to 25 control the rate of agents into and out of delivery devices and having a permeability to the permeation enhancer lower than that of drug reservoir 12.
Suitable materials include, but are not limited to, polyethylene, polyvinyl acetate, ethylene n-butyl acetate and ethylene vinyl acetate copolymers.
WO 9~i/09006 PCT/US94/11120 2 ~ 6 ;~ 5~
Superimposed over the permeation enhancer reservoir 26 of device 30 is a backing 14. On the skin-proximal side of reservoir 12 are an adhesive layer 16 and a strippable liner 24 which would be removed prior to application of the device 30 to the skin.
In the embodiments of Figures 1, 2 and 3, the carrier or matrix material of the reservoirs has sufficient viscosity to maintain its shape without oozing or flowing. If, however, the matrix or carrier is a low-viscosity flowable material such as a liquid or a gel, the composition can be fully enclosed in a pouch or pocket, as known to the art from US Pat. No.
0 4,379,454 (noted above), for example, and as illustrated in Figure 4. Device 40 shown in Figure 4 comprises a backing member 14 which serves as a protective cover for the device, imparts structural support, and substantially keeps components in device 40 from escaping the device. Device 40 also includes reservoir 12 which contains the drug and permeation enhancing mixh~re and bears on its surface distant from backing member 14 a rate-controlling membrane 28 for controlling the release of drug and/or permeation enhancing mixture from device 40. The outer edges of backing member 14 overlay the edges of reservoir 12 and are joined along the perimeter with the outer edges of the rate-controlling membrane 28 in a fluid-tight arrangement. This sealed reservoir may be effected by pressure, fusion, adhesion, an adhesive applied to the edges, or other methods known in the art. In this manner, reservoir 12 is contained wholly between backing member 14 and rate-controlling membrane 28. On the skin-proximal side of rate-controlling membrane 28 are an adhesive layer 16 and a strippable liner 24 which would be removed prior to appiication of the device 40 to the skin.
In an alternative embodiment of device 40 of Figure 4, reservoir 12 contains the permeation enhancing mixture and the drug at or below saturation. The drug at saturation and an additional amount of permeation WO 95/09006 ~ PCT/US94/11120 enhancing mixture are present in adhesive layer 16 which acts as a separate reservoir.
The drug and the permeation enhancing mixture can be co-extensively administered to human skin or mucosa by direct application to 5 the skin or mucosa in the form of an ointment, gel, cream or lotion, for example, but are preferably administered from a skin patch or other known transdermal delivery device which contains a saturated or subsaturated formulation of the drug and the enhancer. The formulation is non-aqueous based and designed to deliver the drug and the permeation enhancing 10 mixture at the necessary fluxes. Typical non-aqueous gels are comprised of silicone fluid or mineral oil. Mineral oil-based gels also typically contain 1-2wt% of a gelling agent such as colloidal silicon dioxide. The suitability of a particular gel depends upon the compatibility of its constituents with both the drug and the permeation enhancing mixture and any other components in 15 the formulation.
The reservoir matrix should be compatible with the drug, the permeation enhancer and any carrier therefor. The term "matrix" as used herein refers to a well-mixed composite of ingredients fixed into shape.
When using a non-aqueous-based formulation, the reservoir matrix is 20 preferably composed of a hydrophobic polymer. Suitable polymeric ~dl~ices are well known in the transdermal drug delivery art, and examples are listed in the above-named patents previously incorporated herein by reference. A
typical laminated system would comprise a polymeric membrane and/or matrix such as ethylene vinyl acetate (EVA) copolymers, such as those 25 described in US Pat. No. 4,144,317, preferably having a vinyl acetate (VA) content in the range of from about 9% up to about 60% and more preferably about 9% to 40% VA. Polyisobutylene/oil polymers containing from 4-25%
high molecular weight polyisobutylene and 20-81% low molecular weight ~ WO 95/05~C~ PCT/US94111120 2 1 6752~
polyisobutylene with the balance being an oil such as mineral oil or polyisobutynes may also be used as the matrix material.
The amount of drug present in the therapeutic device and required to achieve an effective therapeutic result depends on many factors, such as the minimum necessary dosage of the drug for the particular indication being treated; the solubility and permeability of the matrix, of the adhesive layer and of the rate-controlling membrane, if present; and the period of time for which the device will be fixed to the skin. The minimum amount of drug is determined by the requirement that sufficient quantities of drug must be present in the device to maintain the desired rate of release over the given period of application. The maximum amount for safety purposes is determined by the requirement that the quantity of drug present cannot exceed a rate of release that reaches toxic levels.
The drug is normally present in the matrix or carrier at a conce"l,dlion in excess of saturation, the amount of excess being a function of the desired length of the drug delivery period of the system. The drug may, however, be present at a level below saturation without departing from this invention as long as the drug is continuously administered to the skin or mucosal site in an amount and for a period of time sufficient to provide the desired therapeutic rate.
The permeation enhancing mixture is dispersed through the matrix or carrier, preferably at a concentration sufficient to provide permeation-enhancing amounts of enhancer in the reservoir throughout the anticipated administration period. Where there is an additional, separate permeation - 25 enhancer matrix layer as well, as in Figures 3 and 4, the permeation enhancer normally is present in the separate reservoir in excess of saturation.
W095/09006 2 t ~`~526 PCT/US94/11120 ~
The unexpected effects of the specific weight percentages of the components of the permeation enhancer mixture is due, in part to the solubility of the monoglyceride in the lactic acid ester. It is known that monoglycerides by themselves are effective permeation enhancers. The 5 enhancement occurs by the solubilization of the monoglyceride in the lipid layer of the skin. The solubilization of the monoglyceride in the lipid layer increases as a function of lactic acid ester concentration. For example, the solubility of glycerol monolaurate in lauryl lactate is 350 mg/g of solution when the solution is stirred. GML is practically insoluble in, for example, an 10 EVA 40 matrix. Thus, the amount of GML dissolved, ie, free GML is dictated by and proportional to the lauryl lactate loading in the polymer.
Based on the GML solubility of 350 mglg, free GML conce"l,dlions based upon varying weight percents of lauryl lactate in EVA 40 are as follows:
15 Wt% I ~uryl Lactate Wt% GML in Solution 1 2% 4.2%
20% 7.0%
27% 9.5%
30% 1 0.5%
Thus, based upon the amount of GML in solution it would have appeared that the higher wt% of lauryl lactate would have resulted in a higher level of free GML and thus greater efficacy in increasing permeation.
However, as shown by the examples, the preferred formulations, containing 20 wt% GML and 12 wt% lauryl lactate, were equally effective in enhancing 25 drug permeability as those containing 20 wt% GML and 20 wt% lauryl lactate. While the invention is directed to a permeation enhancing mixture containing a monoglyceride or monoglyceride mixture from 15 to 25 wt% and a lactic acid ester present from 8 to 25 wt%, the 20 wt% monoglyceride and 12 wt% lactic acid ester is preferred because it is as effective as the higher 2 ~ 2~
percentage lactic acid ester compositions yet it delivers less of a lactic acid ester which is a known potential irritant.
In addition to drug and the permeation enhancing mixture, which are essential to the invention, the matrix or carrier may also contain dyes, 5 pigments, inert fillers, excipients and other conventional components of pharmaceutical products or transdermal devices known to the art.
Because of the wide variation in skin permeability from individual to individual and from site to site on the same body, it may be preferable that drug and the permeation enhancing mixture be administered from a 10 rate-controlled transdermal delivery device. Rate control can be obtained either through a rate-controlling membrane or adhesive or both as well as through the other means.
A certain amount of drug will bind reversibly to the skin, and it is accordingly preferred that the skin-contacting layer of the device include this 15 amount of the agent as a loading dose.
The surface area of the device of this invention can vary from less than 1 cm2 to greater than 200 cm2. A typical device, however, will have a surface area within the range of about 5-50 cm2.
The devices of this invention can be designed to effectiveiy deliver 20 drug for an extended time period of from several hours up to 7 days or longer. Seven days is generally the maximum time limit for application of a single device because the adverse affect of occlusion of a skin site increases with time and the normal cycle of sloughing and replacement of the skin cells occurs in about 7 days.
The method of this invention comprises:
W0 95/09006 2 T ~ ~ 5 2 ~ PCT/US94/11120 ~
(a) administering a drug, in a therapeutically effective amount, to the area of skin over the time period; and (b) coadministering the permeation-enhancing mixture according to this invention to the area of skin.
The composition delivered by the method contains a permeation enhancing mixture, ie, 15 to 25 wt% or a monoglyceride or monoglyceride mixture and 8 to 25 wt% of a lactate ester and enough drug to provide systemic administration of drug through the skin for a predetermined period of time to provide an effective therapeutic result.
It is believed that this invention has utility in connection with the delivery of drugs within the broad class normally delivered through body surfaces and membranes, including skin. As used herein, the expressions "drug" and "agent" are used interchangeably and are intended to have their broadest interpretation as to any therapeutically active substance which is 15 delivered to a living organism to produce a desired, usually beneficial, effect.
In general, this includes therapeutic agents in all of the major therapeutic areas, including, but not limited to, ACE inhibitors, adenohypophyseal hormones, adrenergic neuron blocking agents, adrenocortical steroids, inhibitors of the biosynthesis of adrenocortical steroids, alpha-adrenergic 20 agonists, alpha-adrenergic antagonists, selective alpha-two-adrenergic agonists, analgesics, antipyretics and anti-inflammatory agents, androgens, local anesthetics, general anesthetics, antiaddictive agents, antiandrogens, antiarrhythmic agents, a"lia~li"l~alic agents, anticholinergic agents, anticholinesterase agents, anticoagulants, antidiabetic agents, antidiarrheal 25 agents, antidiuretic, antiemetic and prokinetic agents, antiepileptic agents,antiestrogens, antifungal agents, antihypertensive agents, antimicrobial agents, anli~ raine agents, antimuscarinic agents, antineoplastic agents, antiparasitic agents, antiparkinson's agents, antiplatelet agents, antiprogestins, antithyroid agents, antitussives, antiviral agents, atypical ~ WO 95/09006 PCT/US94/11120 antidepressants, azaspirodecanediones, barbiturates, benzodiazepines, benzothiadiazides, beta-adrenergic agonists, beta-adrenergic antagonists, selective beta-one-adrenergic antagonists, selective beta-two-adrenergic agonists, bile salts, agents affecting volume and composition of body fluids, 5 butyrophenones, agents affecting calcification, calcium channel blockers, cardiovascular drugs, catecholamines and sympathor~ elic drugs, cholinergic agonists, cholinesterase reactivators, dermatological agents, diphenylbutylpiperidines, diuretics, ergot alkaloids, estrogens, ganglionic blocking agents, ganglionic stimulating agents, hydantoins, agents for control 10 of gastric acidity and treatment of peptic ulcers, hematopoietic agents, hista",i"es, hislar"ille antagonists, 5-hydroxytry,.tdl"i"e antagonists, drugs for the treatment of hyperlipoproteinemia, hypnotics and sedatives, immunosuppressive agents, laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular blocking agents, organic nitrates, opioid analgesics 15 and antagonists, pancreatic enzymes, phenothiazines, progestins, prostaglandins, agents for the treatment of psychiatric disorders, retinoids, - sodium channel blockers, agents for spasticity and acute muscle spasms, succinimides, thioxanthenes, thrombolytic agents, thyroid agents, tricyclic antidepressants, inhibitors of tubular transport of organic compounds, drugs 20 affecting uterine motility, vasodilators, vilamills and the like.
Representative drugs include, by way of example and not for purposes of limitation, bepridil, dillia em, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nitredipine, verapamil, dobutamine, isoproterenol, carteolol, labetalol, levobunolol, nadolol, penbutolol, pindolol, propranolol, 25 sotalol, timolol, acebutolol, atenolol, betaxolol, esmolol, metoprolol, albuterol, bitolterol, isoetharine, metaproterenol, pirbuterol, ritodrine, terbutaline, alclometasone, aldosterone, amcinonide, beclomethasone dipropionate, betamethasone, clobetasol, clocortolone, cortisol, cortisone, corticosterone, desonide, desoximetasone, 11-desoxycorticosterone, 11-desoxycortisol, 30 dexamethasone, diflorasone, fludrocortisone, flunisolide, fluocinolone, WO9S/09006 2 t ~526 PCT/US94/11120 ~
fluocinonide, fluorometholone, flurandrenolide, halcinonide, hydrocortisone, medrysone, 6a-methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tetrahydrocortisol, triamcinolone, benoxinate, benzocaine, bupivacaine, chloroprocaine, cocaine, dibucaine, dyclonine, 5 etidocaine, lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, tetracaine, alfentanil, chloroform, clonidine, cyclopropane, desflurane, diethyl ether, droperidol, enflurane, etomida~e, fentanyl, halothane, isoflurane, ketamine hydrochloride, meperidine, methohexital, methoxyflurane, morphine, propofol, sevoflurane, sufentanil, thiamylal, 10 thiopental, aceLall,i,lophen, allopurinol, apazone, aspirin, auranofin, aurothioglucose, colchicine, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, gold sodium thiomalate, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefenamic acid, mesalamine, methyl salicylate, nabumetone, naproxen, oxyphenbutazone, phenacetin, phenylbutazone, 15 piroxicam, salicylamide, salicylate, salicylic acid, s~ls~l~te, sulf~s~l~7ine, sulindac, tolmetin, acetophenazine, chlorpro",a~i,le, fluphenazine, mesoridazine, perphenazine, thioridazine, trifluoperazine, triflupromazine, disopyramide, encainide, flecainide, indecainide, mexiletine, moricizine, phenytoin, procainamide, propafenone, quinidine, tocainide, cisapride, 20 domperidone, dronabinol, haloperidol, metoclopramide, nabilone, prochlorperazine, promethazine, thiethylperazine, trimethobenzamide, buprenorphine, butorphanol, codeine, dezocine, diphenoxylate, drocode, hydrocodone, hydromorphone, levallorphan, levorphanol, loperamide, meptazinol, methadone, nalbuphine, nalmefene, nalorphine, naloxone, 25 naltrexone, oxycodone, oxymorphone, pentazocine, propoxyphene, isosorbide dinitrate, nitroglycerin, theophylline, phenylephrine, ephedrine, pilocarpine, furosemide, tetracycline, chlorpheniramine, ketorolac, bromocriptine, guanabenz, prazosin, doxazosin, and flufenamic acid.
Preferably, the drug is a benzodiazepine, such as alprazolam, 30 brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, W095/09006 ~ 1 67526 PCT/US94/11120 demoxepam, di~er~m, flullla~ellil, flurazepam, h~l~7ep~m, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, tema7er~ triazolam, and the like; an antimuscarinic agents, such as anisotropine, atropine, clidinium, cyclopentolate, dicyclomine, flavoxate, 5 glycopyrrolate, hexocyclium, hol,,dl,u~ine, ipratropium, isopropamide, mepenzolate, methantheline, oxyphencyclimine, pirenzepine, propantheline, scopolamine, telenzepine, tridihexethyl, tropicamide, and the like; an estrogen such as chlorotrianisene, diethylstilbestrol, estradiol, estradiol cypionate, estradiol valerate, estrone, estrone sodium sulfate, estropipate, 10 ethinyl estradiol, mestranol, quinestrol, sodium equilin sulfate and the like; an androgen, such as danazol, fluoxymesterone, methandrostenolone, methylte~losteroile, nandrolone decanoate, nandrolone phenpropionate, oxandrolone, oxymetholone, stanozolol, testolactone, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, and 15 the like; or a progestin such as ethynodiol diacetate, gestodene, hydroxyprogesterone caproate, levonorgestrel, medroxyprogesterone acetate, meyesLIol acetate, norethindrone, norethindrone acetate, norethynodrel, norgestrel, progesterone, and the like.
Preferably, a device for the transdermal administration of a drug, at a 20 therapeutically effective rate, comprises:
(a) a reservoir comprising:
(i) a therapeutically effective amount of a drug or active agent, (ii) 15 to 25% by weight monoglyceride or mixture of monoglycerides, (iii) 8 to 25% by weight lactic acid ester, and (iv) the remainder ethylene vinyl acetate copolymer;
(b) a backing on the skin-distal suRace of the reservoir; and (c) means for maintaining the reservoir in drug- and permeation enhancing mixture-transmitting relation with the skin.
W095/09006 2 t ~ PCT/US94/11120 Preferably, the monoglyceride is glycerol monolaurate and the lactic acid ester is lauryl lactate.
More preferably, a device for the transdermal administration of the drug, at a therapeutically effective rate, comprises:
(a) a reservoir comprising:
(i) 5 to 40% by weight drug, (ii) 20% by weight glycerol monolaurate, (iii) 12% by weight lauryl lactate, and (iv) 28 to 63% by weight ethylene vinyl acetate copolymer;
(b) a backing on the skin-distal sur~ace of the reservoir; and (c) means for maintaining the reservoir in drug- and permeation enhancing mixture-l,d"sn,illi"g relation with the skin.
In one embodiment, the reservoir further comprises 5-25% by weight cross-linked poly-N-vinyl-2-pyrrolidone, eg, N-vinyl-2-pyrrolidone XL-10, 15 G&F). Preferably, the backing is a breathable backing, such as NRU-100-C(~) (Flexcon, Spencer, MA). If an occluded backing is used, preferably it is Medpar~) (3M, St. Paul, MN). Preferably, the means for maintaining the reservoir in drug and permeation enhancing mixture transn,iLLi~19 relation with the skin is an acrylic contact adhesive, such as MSP041991P, 3M.
20 Preferably, the ethylene vinyl acetate copolymer has a acetate content of 33% or 40%.
The aforementioned patents describe a wide variety of materials which can be used for fabricating the various layers or components of the transdermal drug delivery devices according to this invention. This invention 25 therefore col,le,nplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions. The following -WO 9Si~ S PCT/US94/11120 exampies are offered to illustrate the practice of the present invention and are not intended to limit the invention in any manner.
The drug/permeation enhancer reservoir was prepared by mixing 5 ethylene vinyl acetate copolymer having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam (GYMA Labs of America, Garden Cit,v, NJ), glycerol monolaurate (Grindsted ML 90, Grindsted Products A/S, Brabrand, Denmark) and lauryl lactate (Van 10 Dyk, Inc., Belleview, NJ) were then added. The mixture was blended for approxilllaLely 20 minutes at 54-56C and 30 rpm. After blending, the mixture was quickly cooled to 4045C, and calendered to a 13 mil thick film. The film was then laminated to an acrylic contact adhesive (MSPO419910, 3M) on one side and a Medpar~ backing (3M, St. Paul, 15 Minn.) or NRU-100-C~) backing (Flexcon, Spencer, MA) on the opposite side. The laminate was then cut into circles using a stainless steel punch.
The composition of the drug reservoirs is shown in Table 1.
WO 9J~ t 6 ~ 5 ~ 6 PCTrUS94/11120 ~
Drug/Permeation Enhancer Reservoir Col"posilion (weight per.,er,l) Figure 5 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 (15/20/20/45) al,~,ra,olal"/glycerol monolaurate/lauryl lactate/EVA 40 (15/10/30/45) dl,~,rd,olam/lauryl lactate/EVA 40 0 (15/30/55) Figure 6 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 (15/20/20/45) alpra,old,n/glycerol monolaurate/EVA 40 (15/20/65) Circular pieces of human-epidermis were mounted on horizontal permeation cells with the stratum corneum facing the donor compartment of the cell. The release liner of the system was then removed and the system was centered over the stratum corneum side of the epidermis. A known 20 volume of the receptor solution (0.01 M potassium phosphate at pH 6 containing 2% isopropanol) that had been equilibrated at 35C was placed in the receptor compartment. Air bubbles were removed from the receptor compartment; the cell was capped and placed in a water bath-shaker at 35C.
A given time intervals, the entire receptor solution was removed from the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35C. The receptor solutions were stored in capped vials at 4C until assayed for alprazolam content by HPLC. From the drug concentration and the volume of the receptor solutions, the area of ~ W0951~05 2 ~ 6 7 5 26 PCT~S94/11120 permeation and the time interval, the flux of the drug through the epidermis was c~lcul~ted as follows: (drug concentration x volume of receptor)/(area x time) = flux (,ug/cm2 hr). The fluxes achieved for the dirrerlj"t systems are shown in Figures 5 and 6. As can be seen in Figures 5 and 6, the fluxes 5 obtained from the systems containing glycerol monolaurate and lauryl lactate were significantly higher than the fluxes obtained from the systems containing either glycerol monolaurate or lauryl lactate.
The drug/permeation enhancer reservoir was prepared by mixing 10 ethylene vinyl acetate copolymer having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam, glycerol monolaurate and lauryl lactate were then added. The mixture was blended for approximately 20 minutes at 54-56C and 30 rpm. After blending, the mixture was quickly cooled to 40-45C, and calendered to a 5 mil thick film.
The compositions of reservoirs are shown in Table 2.
-Plasma Levels of Alprazolam (ng/mL) Composition of Reservoir 24 hrs 48 hrs alprazolam/glycerol monolaurate/
EVA 40 (15%/20%/65%) 0.2 0.2 alprazolam/glycerol monolaurate/lauryl Iactate/EVA 40 (15%/20%/20%/45%) 0.7 1.2 WO 95/09006 2 1 6 7 ~ 2 ~ PCTIUS94111120 ~
This film was then laminated to an acrylic contact adhesive (MSP041991P, 3M) on one side and Medpart~) backing (3M) on the opposite side. The laminate was then cut into 5 cm2 square. As can be seen in Table 3, the plasma levels for the combination of glycerol monolaurate and lauryl lactate was significantly higher than the plasma level for glycerol monolaurate alone.
The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate copolymer having a vinyl acetate content of 28 percent ("EVA 28", U.S.I. Chemicals, Illinois) and cross-linked poly-N-vinyl-2-pyrrolidone (Polyplasdone XL-10~), GAF) in an internal mixer (Bra Bender type mixer) until the EVA 28 pellets fused. Estradiol, glycerol monolaurate and lauryl lactate were then added. The mixture was blended, and calendered to a 4.0 mil thick film. The compositions of the reservoir is given in Table 3.
Drug/Permeation Enhancer Reservoir Composition (weight percent) Estradiol/glycerol monolaurate/lauryl lactate/EVA 28/N-vinyl-2-pyrrolidone (2.5120120152.515) This film was then laminated to an acrylic contact adhesive (147-123-4, Adhesive Research Co.) on one side and dermaFlex NRU-100-C~) -backing (Flexcon Co.) on the opposite side. The film was then cut into circles and taped to prevent edge release.
WO 9S~5J^6 2 t 6 7 ~ 2 6 PCT/US94/11120 For each device tested, the adhesive was placed against the stratum corneum side of a disc of human epidermis that had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device 5 covered with epidermis was attached to the flat side of the Teflon holder of arelease rod using nylon netting and nickel wire. The rods were reciprocated in a fixed volume of receptor solution (distilled water). The entire receptor solution was changed at each sampling time. The temperature of the receptor solution in the water bath was maintained at 35C.
The receptor solutions were stored in capped vials at 4C until assayed for estradiol content by HPLC. The fluxes achieved for the different systems are shown in Figure 7.
The drug/permeation enhancer reservoir was prepared by mixing 15 ethylene vinyl acetate copolymer having a vinyl acetate content of 28 percent ("EVA 28", U.S.I. Chemicals, Illinois) and cross-linked poly N-vinyl-2-pyrrolidone (Polyplasdone XL~g), GAF) in an internal mixer (Bra Bender type mixer) until the EVA 28 pellets fused. Testosterone, glycerol monolaurate and lauryl lactate were then added. The mixture was blended, 20 and calendered to a 4.0 mil thick film. The compositions of the reservoir is given in Table 4.
WO 95~'~9~ ^6 PCT/US94/11120 2 ~ ~5~ --Drug/Permeation Enhancer Reservoir Composition (weight percent) testosterone/glycerol monolaurate/lauryl lactate/EVA 28/N-vinyl-2-pyrrolidone (512012015015) This film was then laminated to an acrylic contact adhesive (147-123-4, Adhesive Research Co.) on one side and dermaFlex NRU-100-C~) backing (Flexcon Co.) on the opposite side. The film was then cut into 10 circles and taped to prevent edge release.
For each device tested, the adhesive was placed against the stratum corneum side of a disc of human epidermis that had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device 15 covered with epidermis was attached to the flat side of the Teflon holder of a release rod using nylon netting and nickel wire. The rods were reciprocated in a fixed volume of receptor solution (distilled water). The entire receptor solution was changed at each sampling time. The temperature of the receptor solution in the water bath was maintained at 35C.
20The receptor solutions were stored in capped vials at 4C until assayed for testoslerone content by HPLC. The fluxes achieved for the different systems are shown in Figure 8.
The drug/permeation enhancer reservoir was prepared by mixing 25ethylene vinyl acetate copolymer having a vinyl acetate content of 40 ~ wo 9~,0s~^~ 2 1 6 7 5 2 6 PCT~S94/11120 percent ("EVA 40", U.S.I. Chemicals, Illinois) in an internai mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Alprazolam, glycerol monolaurate and lauryl lactate were then added. The mixture was blended for approximately 20 minutes at 54-56C and 30 rpm. After blending, the mixture was quickly cooled to 4045C, and calendared to a 5 mil thick film.
The composition of the drug reservoirs is shown in Table 5.
Drug/Permeation Enhancer Reservoir Composition (weight percent) ~o Figure 9 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 This film was then laminated to an acrylic contact adhesive (MSP041991P,3M) on one side and Medpa~ or NRU-100-C~ backing (Flexcon, Spencer, MA) on the opposite side. The laminate was then cut into circles using a stainless steel punch.
WO 95/09006 PCT/US9~/11120 _ Circular pieces of human-epidermis were mounted on horizontai permeation cells with the stratum corneum facing the donor compartment of the cell. The release liner of the system was then removed and the system was centered over the stratum corneum side of the epidermis. A known 5 volume of the receptor solution (0.01 M potassium phosphate at pH 6 containing 2% isopropanol) that had been equilibrated at 35C was placed in the receptor compartment. Air bubbles were removed; the cell was capped and placed in a water bath-shaker at 35C.
At given time intervals, the entire receptor solution was removed from 10 the cells and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35C. The receptor solutions were stored in capped vials at 4C until assayed for alprd~old", content by HPLC. The fluxes achieved for the different systems are shown in Figure 9. As is demonstrated by Figure 9, a system containing 20% GML and 12% LL
15 provided a superior cumulative flux of alprazolam.
The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate copolymer having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, Illinois) and optionally cross-linked poly 20 N-vinyl- 2-pyrrolidone (Polyplasdone XL~, GAF) in an internal mixer (Bra Bender type mixer) until the EVA 40 pellets fused. Testosterone, glycerol monolaurate and lauryl lactate were then added. The mixture was blended, and calendered to a 4.0 mil thick film. The compositions of the reservoir is given in Table 6.
WO 95,'~ ^6 PCT/US94/11120 ;
Drug/Permeation Enhancer Reservoir Composition (weight percent) testosterone/glycerol monolaurate/lauryl lactate/EVA 40 (512012015015) testosterone/glycerol monolaurate/myristyl lactate/myristyl alcohol/EVA 40 (20/20/12/48) testosterone/glycerol monolaurate/lauric acid/EVA 40 (20/20/12/48) testosterone/glycerol monolaurate/Tween 20/EVA 40 (20/20/10/50) testosterone/glycerol monolaurate/lauryl lactate/EVA 40 (20/20/12/48) tesloslerone/glycerol monolaurate/lauryl lactate/N-vinyl-2-pyrrolidone/EVA 40 (20/20/12/16/32) This film was then laminated to an acrylic contact adhesive (MSP041991P, 3M) on one side and Medpart~) or NRU-100-C~) backing on 20 the opposite side. The laminate was then cut into circles and taped to prevent edge release.
For each device tested, the adhesive was placed against the stratum corneum side of a disc of human epidermis that had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that 25 none of the device edge was exposed to the receptor solution. The device covered with epidermis was attached to the flat side of the Teflon holder of a release rod using nylon netting and nickel wire. The rods were reciprocated in a fixed volume of receptor solution (0.1% Benzoic acid). The entire WO 9 ,/O~OOG PCT/US94/11120 2~67526 receptor solution was changed at each sampling time. The temperature of the receptor solution in the water bath was maintained at 35C.
The receptor solutions were stored in capped vials at 4C until assayed for testosterone content by HPLC. The fluxes achieved for the 5 different systems are shown in Figure 10.
The drug/permeation enhancer reservoir was prepared by mixing ethylene vinyl acetate copolymer having a vinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals, lllinois) in an internal mixer (Bra 10 Bender type mixer) until the EVA 40 pellets fused. Alprazolam, glycerol monolaurate and lauryl lactate were then added. The mixture was blended, and calendered to a 5.0 mil thick film. The composition of the reservoirs are given in Table 7.
Drug/Permeation Enhancer Reservoir Composition (weight percent) Alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 Alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 Alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 Alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 Alprazolam/glycerol monolaurate/lauryl lactate/EVA 40 ~ W095/09006 2 1 6 7~ 26 PCT/US94/11120 The film was then laminated to an acrylic contact adhesive (MSPO41991P, 3M) on one side and Medpar~) or NRU-100-C~ backing (Flexcon Co.) on the opposite side. The film was then cut into circles and taped to prevent drug release from the edges.
For each device tested, the adhesive was placed against the stratum corneum side of a disc of human epidermis that had been blotted dry just prior to use. The excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution. The device covered with epidermis was attached to the flat side of the Teflon holder of a release rod using nylon netting and nickel wire. The rods were reciprocated in a fixed volume of receptor solution (0.01M potassium phosphate at pH 6 containing 2% isopropanol). The entire receptor solution was changed at each sampling time. The temperature of the receptor solution in the water bath was maintained at 35C.
The receptor solutions were stored in capped vials at 4C until assayed for alprazolam content by HPLC. The fluxes achieved for the different systems are shown in Figure 11.
This invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.
Claims (15)
1. A composition of matter for application to a body surface or membrane to administer a drug by permeation through the body surface or membrane, the composition comprising, in combination:
(a) the drug to be administered, in a therapeutically effective amount; and (b) a permeation-enhancing mixture comprising:
(i) 15 to 25% by weight of a monoglyceride or a mixture of monoglycerides, and (ii) 8 to 25% by weight of a lactate ester or a mixture of lactate esters.
(a) the drug to be administered, in a therapeutically effective amount; and (b) a permeation-enhancing mixture comprising:
(i) 15 to 25% by weight of a monoglyceride or a mixture of monoglycerides, and (ii) 8 to 25% by weight of a lactate ester or a mixture of lactate esters.
2. A composition according to claim 1 wherein the monoglyceride or mixture of monoglycerides comprises 20% by weight of the composition and the lactate ester or mixture of lactate esters comprises 12% by weight of the composition.
3. A composition according to claim 1 wherein the lactate ester is selected from the group consisting of lauryl lactate, ethyl lactate, myristyl lactate, or cetyl lactate.
4. A composition according to claim 1 wherein the mixture of lactate esters is ethyl lactate and lauryl lactate.
5. A composition according to claim 3 or 4 wherein the monoglyceride is glycerol monolaurate.
6. A composition according to claim 5 wherein the glycerol monolaurate comprises 20% by weight of the composition and the lactate ester comprises 12% by weight of the composition.
7. A device for the transdermal administration, at a therapeutically effective rate, of a drug, which device comprises:
(a) a drug reservoir comprising a therapeutically effective amount of a drug and a skin permeation-enhancing amount of a permeation mixture comprising:
(i) 15 to 25% by weight of a monoglyceride or a mixture of monoglycerides, and (ii) 8 to 25% by weight of a lactate ester or a mixture of lactate esters;
(b) a backing on the skin-distal surface of the reservoir; and (c) means for maintaining the reservoir in drug- and permeation enhancing mixture-transmitting relation with the skin.
(a) a drug reservoir comprising a therapeutically effective amount of a drug and a skin permeation-enhancing amount of a permeation mixture comprising:
(i) 15 to 25% by weight of a monoglyceride or a mixture of monoglycerides, and (ii) 8 to 25% by weight of a lactate ester or a mixture of lactate esters;
(b) a backing on the skin-distal surface of the reservoir; and (c) means for maintaining the reservoir in drug- and permeation enhancing mixture-transmitting relation with the skin.
8. A device according to claim 7 further comprising: a second reservoir between the backing and the drug reservoir, the second reservoir comprising an excess of the permeation enhancing mixture and drug at or below saturation; and a rate-controlling membrane between the drug reservoir and the second reservoir.
9. A device according to claim 7 or 8 wherein the monoglyceride is glycerol monolaurate.
10. A device according to claim 7 or 8 wherein the lactate ester is selected from the group consisting of lauryl lactate, ethyl lactate, cetyl lactate, myristyl lactate.
11. A device according to claim 7 or 8 wherein the mixture of lactate esters is ethyl and lauryl lactate.
12. A device according to claim 7 or 8 wherein the monoglyceride is glycerol monolaurate and the lactate ester is ethyl lactate or lauryl lactate or a mixture thereof.
13. A device according to claim 10 or 11 wherein the monoglyceride is glycerol monolaurate.
14. A device according to claim 13 wherein the glycerol monolaurate and lactate esters comprise 20 wt % and 12 wt % of the drug containing reservoir, respectively.
15. A method for the transdermal administration of a drug, which method comprises:
(a) administering the drug at a therapeutically effective rate to an area of skin; and (b) simultaneously administering a permeation enhancing mixture comprising:
(i) 15 to 25% by weight based on the drug and permeation enhancer mixture of a monoglyceride or a mixture of monoglycerides, and (ii) 8 to 25% by weight based on the drug and permeation enhancer mixture at a lactate ester or a mixture of lactate esters;
to the area of skin at a rate which is sufficient to substantially increase the permeability of the area to the drug.
(a) administering the drug at a therapeutically effective rate to an area of skin; and (b) simultaneously administering a permeation enhancing mixture comprising:
(i) 15 to 25% by weight based on the drug and permeation enhancer mixture of a monoglyceride or a mixture of monoglycerides, and (ii) 8 to 25% by weight based on the drug and permeation enhancer mixture at a lactate ester or a mixture of lactate esters;
to the area of skin at a rate which is sufficient to substantially increase the permeability of the area to the drug.
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US12949493A | 1993-09-29 | 1993-09-29 | |
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CA002165802A Abandoned CA2165802A1 (en) | 1993-09-29 | 1994-09-29 | Monoglyceride/lactate ester permeation enhancer for oxybutynin |
CA002167526A Abandoned CA2167526A1 (en) | 1993-09-29 | 1994-09-29 | Monoglyceride/lactate ester permeation enhancer |
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CA002165802A Abandoned CA2165802A1 (en) | 1993-09-29 | 1994-09-29 | Monoglyceride/lactate ester permeation enhancer for oxybutynin |
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EP (2) | EP0721348B1 (en) |
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- 1994-09-29 JP JP51048695A patent/JP3792252B2/en not_active Expired - Fee Related
- 1994-09-29 NZ NZ275615A patent/NZ275615A/en unknown
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- 1994-09-29 EP EP94929976A patent/EP0721348B1/en not_active Expired - Lifetime
- 1994-09-29 NZ NZ274711A patent/NZ274711A/en unknown
- 1994-09-29 AT AT94929976T patent/ATE183926T1/en not_active IP Right Cessation
- 1994-09-29 EP EP94930573A patent/EP0721349A1/en not_active Ceased
- 1994-09-29 WO PCT/US1994/011226 patent/WO1995009007A1/en not_active Application Discontinuation
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- 1994-09-29 JP JP51047695A patent/JP3688293B2/en not_active Expired - Fee Related
- 1994-09-29 US US08/617,763 patent/US5747065A/en not_active Expired - Lifetime
- 1994-09-29 WO PCT/US1994/011120 patent/WO1995009006A1/en active IP Right Grant
- 1994-09-29 AU AU79647/94A patent/AU679794B2/en not_active Ceased
- 1994-09-29 US US08/637,678 patent/US5750137A/en not_active Expired - Lifetime
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NZ275615A (en) | 1996-11-26 |
EP0721348A1 (en) | 1996-07-17 |
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JP3688293B2 (en) | 2005-08-24 |
AU7924994A (en) | 1995-04-18 |
KR960704578A (en) | 1996-10-09 |
US5686097A (en) | 1997-11-11 |
AU679793B2 (en) | 1997-07-10 |
WO1995009007A1 (en) | 1995-04-06 |
WO1995009006A1 (en) | 1995-04-06 |
US5747065A (en) | 1998-05-05 |
DE69420419T2 (en) | 1999-12-23 |
AU679794B2 (en) | 1997-07-10 |
JP3792252B2 (en) | 2006-07-05 |
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