CA2123428A1 - Drug delivery device - Google Patents
Drug delivery deviceInfo
- Publication number
- CA2123428A1 CA2123428A1 CA002123428A CA2123428A CA2123428A1 CA 2123428 A1 CA2123428 A1 CA 2123428A1 CA 002123428 A CA002123428 A CA 002123428A CA 2123428 A CA2123428 A CA 2123428A CA 2123428 A1 CA2123428 A1 CA 2123428A1
- Authority
- CA
- Canada
- Prior art keywords
- drug
- transdermal device
- electrode
- reservoir
- transdermal
- 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
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
- A61N1/303—Constructional details
Abstract
A transdermal device for the controlled administration of a drug to the skin comprises a reservoir (12) for the drug and an electric circuit which includes an electrode system (13, 14) which is operable to actively transport the drug in a controlled manner from the reservoir (12) towards the skin for transport therethrough, the skin not being part of the electric circuit, and the drug passing through an electrode (13) of said electrode system (13, 14) during the active transport to the skin. The electrode (13) is disposed between the reservoir (12) for the drug and an optional transit chamber (15). The electrode (13) can be permeable to the drug or the electrode can function as a gate, being permeable to the drug in the open condition and less permeable to the drug in the closed condition. The operation of the gate can be determined by the composition or the structure of the electrode (13). The device achieves drug delivery rates comparable to those achieved with iontophoretic devices.
Description
2 212 3 4 2 8 PCI`/IE92/00021 Description Drug deliverv device Technical Field This invention relates to a transdermal device for the 5 administration of drugs to the skin and, more particularly, to a device for the systemic delively of drugs by the transdermal route involving uptake of a given drug by the skin.
Background Art The administration of drugs percutaneously or transdennally has 10 a number of advantages and is favoured in the case where drugs are not effectively administered by the oral route but where systemic administration is required. This is especially true for drugs which are subject to a first-pass hepatic metabolism or which are susceptible to deactivation by digestive enzymes.
There are also a number of problems associated with the administration of drugs by the transdermal route, for example, a rate of upt~ke of drug which is therapeutically effective may not be achievable. The use of penetradon enhancers~ for example, dimethylsulphoxide, N,N~imethylformamide and others is employed 20 to promote uptake. However, such penetradon enhancers are not always effecdve or sufficient to achieve adequate percutaneous absorption.
Also the manufacture of stable transdelmal devices can be a problem because it may not be possible to find a carner medium which can maintain the drug in a stable condition until use and from which the 25 drug can be successfully transported to and into the skin following application of the transde~nal device at the site of administration.
For some drugs such as glyceryl trinitrate fluctuations in blood level rather than a continuous constant level is required. Thus ~ere is a 2 12~428 2 need for devices or systems capable of periodic or pulsed drug delivery.
For drugs that are not amenable to passive administration by the percutaneous route or for drugs that are effectively percutaneously S absorbed as charged molecules, iontophoretic drug delivery is gaining increasing popularity.
However, iontophoretic drug delivery also has a number of problems, not least of which is the trauma caused by burns and pain' ' which may be associated with the use of this type of delivery which 10 involves migration of drug molecules in the skin under the influence of an eleetric field. Hence conventional iontophoresis as a means of drug delivery may not achieve good patient compliance.
One solution for dealing with the problems associated with iontophoresis is the electrode deviee of U.S. Patent No. 4,722,726, one 15 of ~he stated objects of which is to provide an iontophoretic dmg delivery deviee that inhibits the eurrent earrying eapacity of ions in the calTier medium ~at eompete with the active ingredient and lead to progressive diminution of effeetive drug transfer during dle iontophoretic delivery thereof.
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U.S. Patent No. 4,731,049 discloses a eell for electrieally eontrolled transde~al drug delivery by iontophoresis. The drug is ' bound on an-ion exchange resin or medium or an immobilized ligand affinity medium loeated in die drug reservoir. Drug delivery oceurs upo~ the applieation of an electrical current of generally small proportions to the reservoir or to an adjaeent ion reservoir separated from ~e drug reservoir by a semi-permeable membrane.
It is an objeet of the present invention to provide a deviee and me~od for the deliveIy of drugs by the percutaneous route which obviates the trauma,in the form of burns and discomfort experienced by ~e patient and yet aehieves an uptake and control of drug by skin which is enhanced when compared to conventional passive delivery.
WO 93/09842 2 12 3 4 2 8 I'CI`/IE92/00021 Investigations earried out by us have shown that by using an electrie eireuit within a deviee to actively transport drug from a drug reservoir forming part of said device, but wherein the skin does not form part of the eircuitry of the device in eontradistinetion to an S iontophoretie device, one aehieves drug delivery rates greater than those aehieved with eonventional passive delivery.
Diselosure of Invention Aeeordingly, the invention provides a transdermal device for the eontrolled administration of a drug to the skin, whieh eomprises a 10 reservoir for the drug and an eleetric cireuit which includes an eleetrode system whieh is operable to aetively transport the drug in a eontrolled manner from said reservoir towards the skin for transport therethrough, the skin not being part of said eleetrie eireuit, and the drug passing through an eleetrode of said eleetrode system during said 15 aetive ~ansport to the skin.
In the present Speeifieation the terms drug and aetive ingredient are used interehangeably.
In one embodiment, the deviee ineludes an eleetrode whieh is permeable to said drug.
The eleetrode whieh is penneable to the drug to be administered can eonsist of a porous metallie material. Thus the eleetrode ean eonsist, for e~cample, of a metal gauze or mesh, of a woven metallic material or of a metal laminate. ~uitable metals inelude platinum, silver or a eoated or uneoated metal alloy. Other suitable eleetrodes inelude earbon or earbon-based eleetrodes.
The eleetrode ean also be defined by a elosed filament of metal or other eondueting material defining a ring, a square or other suitable geometrie shape.
WO 93/09842 1. PCI'/IE92/0002t .~,~"
2123~28 4 Alternatively, the electrode which is permeable to the drug being administered can consist of porous carbon sheeting or of a range of polymeric materials, including conducting polymers, with the required conductivity such as those described in the Handbook of Conducting S Polymers Vol I and II; T.A. Skotheim, publishers Marcell Dekker Inc.
(1986).
The function of said electrode is to spread an appropriate electrical potential.
In a second embodiment, the device according to the invention 10 includes an electrode which functions as a gate, being permeable to said drug in the open condition and less permeable to said drug in the closed condition. The operation of the gate can be determined by the compositi~n of the electrode or, alternatively, by the structure thereof.
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~n the case where the operation of the gate is determined by the 15 composition of the electrode, the electrode is suitably composed of a polymeric material with the requisite properties.
When the electrode according to said first or second embodiment is a polymeric material, the polymeric material is suitably one that is susceptible to ion doping or, alternatively, is a polymeric material 20 having ion exchange properties. Polymers which are susceptible to ion doping can be of the donor t~pe or the acceptor type. Following the tcrminology of serniconductor technology the polymers can be described as n-type or ~type, as appropriate. Suitable examples of polymers with ion exchange properties include both anion e~cchange 25 resins and cation exchange resins as d~e circumstances require. Suitable resins are marketed by Rohm and Haas company under the Trade Mark Amberlite. Other suitable materials include fluorinated ion exchange polymers such as that sold under ~e Trade Mark Na~lon.
The electrode hereinbefore described can span the width of the 30 reservoir, while having any geometric shape or structure herein described. With such an electrode, the surface thereof distal from the WO 93/09842 2 12 ~ 4 2 8 PCI/IE92/00021 reservoir can be placed in contact with the skin in use. With such an arrangement (hereinafter referred to as AlTangement I) the drug passes through the electrode and enters the skin having been actively transported to the skin sur~ace by the electrode system of the device S which includes the electrode hereinbefore described and a further electrode disposed elsewhere in the device, so as to complete the electric circuit.
In an altemative embodiment, the electrode is disposed between the reservoir for the drug and a transit chamber therefor (hereinafter 10 referred to as Arrangement II).
The relative sizes of the reservoir and the transit chamber will depend on the particular drug or drugs to be administered. However, in gene~al the transit chamber will be of a lesser volume than the reservoir. The reservoir and transit chamber, if present, together with lS the electrode disposed therebetween combined will normally have a thickness of less than S.0 mm, in particular, in the range 0.2-3.0 mm, more especially 1.0-3.0 mm.
Using an arrangement of a reservoir and a transit chamber as hereinbefore described, a measured quantity of drug can be actively 20 transported at selected-intervals of time, such as once-a-day, to the transit chamber from whence it enters the sWn over a given period of time.
The polarity of the electrodes is set according to the charge on the ion which is to be transported. The current density is suitably in the 25 range Q2-1.1 mA cm-2. However, much larger current densities than those employed in conventional iontophoretic devices can be used. The absolute value being dependent on ~e thickness of the transit chamber, if such is present. I~ the case of the device according to the invention it is contemplated that a current density greater than the latter range 30 could be used without causing skin trauma because the skin does not fonn part of the circuitry.
WO 93/09842 P~/IE92/00021 2123~28- 6 The device according to the invention allows the use of higher eleetrical potentials than those employed in conventional iontophoresis.
In an embodiment of the device which allows for periodic or pulsed drug delivery, the polarity of the electrodes and the magnitude S of the voltage ean be systemadeally altered.
The reservoir can be formed of a shaped mass of a material in which the drug is distributed or contained for storage.
The transit chamber can either be composed of the same material as the reservoir or of a different material.
Suitably the material of each of the reservoir and the transit ehamber is a gel.
Preferred gel materials are formed from gel forming agents selected from plant extracts, gums, s~nthetic or natural polysaccharides, polypeptides, alginates and synthetic polymers or a 15 mi~cture thereof.
Espeeially preferred gel materials are formed from the gel fonning agents agar and earrageenan.
Suitable plant extraets inelude agar, ispaghula, psyllium, eydonia and eeratonia or a mixture ~hereof.
` 20 Examples of suitable gums inelude guar gum, aeaeia gum, ghatti gum, karaya gum and tragaeanth gum or a mixture thereof.
Suitable synthetie and natural polysaecharides include aLtcyleelluloses, hydroxyalkyleelluloses, eellulose ethers, eellulose esters, nitroeelluloses, dextrin, agar, eaIrageenan, peetin, furcellaran and stareh or stareh derivatives and mixtures thereof. An example of a preferred stareh derivative is sodium stareh glycolate. Especially WO 93/09842 2 ~ 2 ~ ~ 2 8 PCl /IE92/00021 preferred polysaccharides include agar and carrageenan as hereinbefore indicated.
Suitable polypeptides include zein, gelatin, colhgen and polygeline or a mixture thereof.
Suitable alginates inelude alginic acid, propylene glycol alginate and sodium alginate or a mixture thereof.
An especially preferred synthetic polymer is a carboxyvinyl polymer sold under the Trade Mark Carbomer.
As used herein the term "agar" is synonymous with "agar-agar".
Other semi-solid ,ype bases inelude, in particular, media whieh fonn liquid erystalline phases sueh as distilled monoglyeerides sold under the Trade Mark MYVEROL.
However, the reservoir andlor the transit ehamber, if present, ean equally be formed as a shaped mass of any suitable solid or semi-solid medium fonned with the aid of a solidifying agent. As used herein, the t~rm solidifying agent embraees hardening, setting, suspending, thiekening and lîke agents.
In the ease of the reservoir, the drug or drugs will be uniformly distributed in the solid, semî-solid or liquid medium~
The surfaee area of the reservoir and the transit ehamber, when present, is preferably in the range 1-10 em2, more espeeially 2-7 em The reservoir will suitably eontain the drug in an amount of 5-100 mg.
The reservoir ean inelude one or more auxiliary agents seleeted from an antimierobial agent or a preserving agent, an antioxidant, a pH
WO 93/09842 PCI'/IE92/00021 , . .
2123~28 8 controlling agent, a plasticizer, a surfactant, a penetration enhancer, a humectant, a local anaesthetic or a rubefacient.
Preferred antimicrobiaVpreserving agents include benzalkonium chloride, cetrimide (cetyltrimethylammonium bromide), benzoic acid, S benzyl alcohol, Parabens (Trade Mark for the methyl-, ethyl-, propyl-and butyl-esters of para-hydroxybenzoic acid) chlorhexidine, chlorobutanol, phenylmercuric acetate, borate and nitrate, potassium sorbate, sodium benzoate, sorbic acid and thiomersal (mercurithiosalicylate) or a mixture thereof.
Preferred antioxidants include sodium metabisulphite, butylated hydroxyanisole and butylated hydroxytoluene or a mixture thereof.
Preferred pH controlling agents include citric acid and sodium citrate.
Preferred plasticizers include diethylphthalate, dibutylphthalate 15 and tributylcitrate or a mixture thereo - Preferred surfactants include sodium lauryl sulphate, diethylene glycol monostearate, propylene glycol monostearate, polyethylene -glycols as sold under ~e Trade Mark Macrogol, polysorbates and polyvinyl alcohol or a mixture thereof.
~0 Prcferred penetration~enhancers include dimethylsulphoxide, N,N- dime~ylacetamide, N,N-dimethylformamide, 2~-pyrrolidone, N-methyl-2-pyrrolidone, 1-dodecylazacyclo-heptan-2-one, fatty acids such as oleic acid and salts thereof and terpenes or a mixture thereof.
A preferred humectant is glycerol.
Preferred local anaesthetics include lidocaine, benzocaine, lignocaine, methocaine, butylaminobenzoate and procaine or a mixture ~creof. The device would include a local anaesthetic mainly to suppress irritation at the site of application thereof.
WO 93/09842 PCI`/IE92/00021 9- .
In order to form the reservoir and/or the transit charnber, the respeetive elements are formed separately by adding the gelling agent or the solidifying agent, as appropriate, to a solvent in an amount ~at will result in a suitably semi-solid or solid mass. The mixture thereby S obtained is mixed and optionally heated depending on the agent used so as to produee a uniform medium.
The solvent used is preferably water. However, the solvent used may also suitably be an aleohol sueh as ethanol or stearyl alcohol, glycerol, propylene glycol, polyethylene glycol or a silicone or a 10 mixture thereof, including a mixture with water.
In the case of the reservoir, the drug and any auxiliary agents as hereinbefore deseribed are then added and the resulting mixture mixed to uniformity. The shaped mass which forms the reservoir/transit ehamber, as appropriate, is formed by moulding, cutting, punehing or l$ slieing the solid or semi-solid mixture so as to form dises or layers of ~e mi~ture as required in a manner known per se.
The drug reservoir for use in the device aeeording to the invention ean also be a liquid eontained in a ehamber, said ehamber having a drug pe~neable membrane assoeiated therewith for transport 20 of the drug to the slcin in use, optionally through a transit ehamber, if present.
With ~e deviee aeeording to the invention it is possible to administer a d~ug whieh is not normally eapable of being administered in effeetive amounts passively by ~e transdermal route and to eontrol, 25 in the sense of inereasing or deereasing, the delivery of drugs ~at do penetrate the slun passively.
Examples of drugs whieh ean be administered using the transdennal device aeeording to the invention include nicotine, salbutamol and physostigmine and salts thereof.
WO 93/09842 PCl`/lE92/00021 2123q28 10 Preferred drugs for use in the device according to the invention are basic compounds and basic salts and zwitterionic compounds, including peptides.
When the device according to the invention includes a transit S chamber, said transit chamber can include a different drug to that contained in the reservoir.
According to a further embodiment of the invention, a number of electrodes can be disposed in said reservoir.
The transdermal device according to the invention can includé
10 controlling means operable by a user to selectively transport a drug within and from said reservoir. Furthermore, the transdermal device according to the invention can be programmable.
The device according to the invention can include means for achieving a periodic or pulæd delivery of drug.
The electric circuit will include a power source which will suitabiy comprise conventional miniature or "light-weight" batteries.
For example, conventional sheet batteries and microbatteries may be used.
The transdermal device according to the invention will comprise 20 a housing for the various elements thereof.
, Preferably, the reservoir, transit chamber, if present, and at least one ekctrode define a unit which is detachably mounted in the housing.
When the transdermal device according to the invention is programmable, a programmable controlling member will be located in 25 the housing together with the counter electrode, the power source and other components of the electric circuit. The programmable controlling member will comprise the microelectronics and memory necessary to WO 93/09842 2 1 2 3 ~ 2 8 PCME92/00021 - , 11 achieve a predetennined mode and timing of drug transport within the device.
The unit may be engageable with the housing in such a manner so as to select a programme applicable to the alctive ingredient in the S reservoir such that the programme, when activated, brings about controlled transport of active ingredient in said reservoir at selected intervals of time.
The unit can be replaceable as required, such as every day or `
once-a-week or even twice-daily. For example, in order to achieve the 10 correct diurnal variation required for certain drugs it may be necessary to replace the device twice-daily.
The unit can be adapted to engage with and affix to the housing in any suitable m~er, such as by clipping, snap-fit screwing, wedgîng, bayonetjoint or otherwise securing the respective parts 15 together.
The unit can also be provîded with mechanical or electrical contact n~ans ~adapted to select a programme applicable to the active ingredient contained in th~ e reservoir, which the prog=able allurolling member identifios as contai:ning the or each active ~0 ing~dient and wliich said~coi~i~member thus recognises should - - bc tlansported according to a prescnbed regimen~
Thus the housing and unit can have one or more co-operating electncal contact(s) which on engagement of the respective parts select a given programme.
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Preferably, the housing includes means for indicating that the active ingredient is being actively transported and thus delivered at any given time.
The device may also include means for indicating that the power source has failed or weakened.
WO 93/09842 PCI'/IE92/00021 2123~28 12 The electrical circuit can include alarm means to alert a patient when it is time for the active ingredient to be delivered, in particular, in circumstances where the device is not worn continuously.
Such alarm means can comprise a timing circuit which will give S a signal such as a bleep which will prompt the user to apply the device to his body.
The housing or the unit preferably includes means for activating the programme when the respective parts are in the engaged positiori.
The means for activating the programme can be an ON/OFP switch.
10 Such a switch can be of the type which is activated to the ON position only when the device is in situ on the body of a patient to be treated.
The ON/OFP switch may be activated to the ON position by pressure exerted by an attachment means when affixed to the body of a patient.
The electric circuit suitably includes means for monitoring and 15 indicating the content of the active ingredient in the reservoir. The inclusion of such means would alert a subject undergoing a treatment regimen using the device if the content of active ingredient is not present in an amount effective for a given treatment.
The electric circuit preferably includes overriding means 20 whereby a subject can activate the device to transport and deliver active ing~edient at other-than a pre-set time up-to a predetennined maximum number of such activations.
Preferably, the housing and the unit, when in the engaged position, form a single unit, the exterior surface of which, in use, 25 simulates the face of a time piece and the single unit is attached to or molmted in a strap or bracelet for application of the de~ice to a limb of a body.
More generally, the device according to the invention can be secured to the body in conventional manner such as by adhesive means, 30 including bioadhesive means, straps, bracelets, and like securing means.
WO 93/09842 2 12 3 4 2 8 PCI`/IE92/00021 The housing suitably includes a liquid crystal display (LCD). The LCD may disphy culTent, voltage, timing and other readings as hereinbefore indicated. The unit may include an ammeter and also a voltage adjuster under the control of a control circuit. The latter circuit S may also include a galvanostat which keeps the current constant despite varying resistance of the skin.
The device according to the invention is preferably applied to the flexor surface of the forearm, including the wrist, and also the ankle.
1~ general, such sites show the greatest consistency from individual to 10 individual in te~ms of drug absorption relative to other sites for drug administration because of the amount of tissue at such sites. Blood vessels are found close to the surface of the skin at such sites which facilitates the up-take of drugs into the systemic circulation.
The reservoir and/or the transit chamber, if present, can be 15 housed in a receptacle which is drug impermeable, ~ereby, ensuring a unidirectional transport of drug towards to the skin.
The invention will be fur~er illustrated by the following description of an embodiment thereof given by way of example only with reference to the accompanying Drawings.
20 Blief Description of the Drawings Fig. 1 is a schematic representation of a transdermal device according to the invention (Arrangement II);
Fig. 2 is a circuit diagram of the circuit employed in the device depicted in Fig. l;
Pig. 3 is a graphic representation of nicotine release profile (mg) versus time (h.) for a device according to the invention relative to controls as hereinafter described;
WO 93/09842 PCI`/IE92/0002t 2123~28 ~
Fig. 4 is a graphic representation of the effect of the current density through a device according to the invention on the quantity of nicotine released (mg) as a function of time (h) as hereinafter described;
S Fig. 5 is a graphic representation of the quantity of drug released (mg) versus time (h.) for 20 mg nicotine-containing discs across human stratum corneum in a device according to the invention reladve to a control;
Fig. 6 is a graphic representation of the delivery of physostigmine hemisulphate (mg) across Sha-Sh~ mouse skin in an Arrangement I-type device according to the invention using different currents versus time (h) relative to passive delivery;
Fig. 7 is a graphic representation of the delivery of physostigmine salicylate (mg) across Sha-Sha mouse skin in an Arrangement I-type device according to the invention using different currents versus dme (h) relative to passive deliveIy;
i Fig. 8 is~a graphic repreæntation of the delivery ofphyso~bgmine salicylate (mg) across Sha-Sha mouse skin in an Anangement l-type device according to the invention using differem cunQ~ versus time (h) relative to passive delivery, using a different drug loading and surface area relative to that used in reladon to Fig. 7; and ` Fig. 9 is a graphic representation of the delivery of physostigmine salicylate (mg) across whole thickness human ~daver skin in an Arraligement I-type device according to the invendon using different currents versus time ~(h) rélative to passive deli~very.
~ .
, 2i2`~4`~
WO 93/Og842 PCI`/IE92/00021 Best Mode for carrving out the ~vention Refer,ring to Fig. 1 there is illustrated a transdermal device indieated generally at 10 eomprising a housing 11 for a reservoir 12 for a drug uniformly distributed in agar gel and an electric eireuit S whieh ineludes an electrode 13 of platinum mesh gauze (Johnson Matthey 52 mesh Lot No. 625590) which is permeable to said drug and a further electrode 14, the eleetrode 13 separating the reservoir 12 from a transit ehamber 15 also eomposed of agar gel. The deviee 10 depieted in Fig. 1 is a deviee of the type herein referred to as an i"
10 Arrangement II.
The housing 11 also includes a programmable controlling unit 16 with appropriate eircuitry and a power supply 17.
The electrode 13 is eonneeted by a lead 18 through a touch -button 19 to the eireuitry in the housing 11. The eleetrode 14 eonsists 15 of a foil of platinum whieh is eonneeted to the eireuitry in the housing 11 by a lead 20 having an assoeiated toueh button 21 and whieh when the deviee is aetivated to transport drug within the reservoir 12 allows the eir,euit to be eompleted.
The reservoir 12, the eleetrode 13 and the transit ehamber 15 20 define a unit whieh is releaseably attaehable to the housing 11 by means of a eor~eetor 22 disposed on a surfaee 23 of an insuJating material sueh as a suitable phsties material. The eonneetor 22 is engageable in a reeognition position 24 in the housing 11. The eonnector 22 on engagernent of the aforementioned unit with the housing 11 seleets a 25 given programme applieable to the drug eontained in the reservoir 12 and said programme when aetivated brings about the desired transport of the drug to the transit ehamber 15 and hence by passive diffusion thereafter to the skin.
The programrnable eontrolling unit 16 includes an ammeter 25, a 30 galvanostat 26 and an LCD 27 with appropriate switehing arrangements whieh ean display current, voltage and time and a time keeping WO 93/09842 PCI`/ID2/00021 ~r~
212~28 16 component with provision for an audible alarm which alerts a subject when it is time for the drug to be delivered, if the device is not worn continuously. The unit 16 also includes an ON/OFF button 28 for activating the program when the unit comprising the reservoir 12, and 5 the housing 11 are in the engaged position and an override button 29 whereby a patient can activate the device to transport the drug at other than a pre-set time up to a predetermined maximum number of such activations as hereinbefore described.
An LED (light emitting diode) 30 is also provided in the unit 16 10 to indicate satisfactory operation of the device, for example so as to indicate that the drug is being actively transported. The LED 30 also indicates if the power supply 17 has faihd or weakened and will give an indication of the content of the drug in the assembled device.
The device 10 is attached to the site of application by means of a 15 strap 31 having at the free ends thereof the cooperating elements of a conventional clasp 32.
The main components of the circuit employed in the device 10 are depicted in the circuit diagram corresponding to Pig. 2. Said components are as follows:
.
PC - a programmable controlling circuit, including an audible alann means;
PS - a power supply;
A - an ammeter, G - a galvanostat;
SS - a selector switch;
O - an override switch;
WO 93/Og842 212 3 4 2 8 PCME92/1~0021 LCD - a liquid crystal display for current, voltage, time, etc. as selected; and LED - a visible signal of delivery of drug, failur~ or weakening of power supply, or content of drug in the device 10.
S RP - a recognitionposition.
Most of the foregoing features can be incolporated into an appropriate microchip.
ln V~ Studies - Arrangement II.
A series of in vitro experiments were carried OUt to assess the transdermal device according to the invention of the type herein referred to as an Arrangement II. ln these experiments an artificial membrane of Visking (Visking is a Trade Mark) and human stratum eorneum were used as the barriers to diffusion into glass, custom built di~usion eells based on a commercially available Franz eell (Franz, TJ., (1975); J. Invest. Dermatol. 64, 190). An assembly eonsisting of a reservoir, transit chamber, eleetrodes, ga~vanostat and ammeter of the t~pe used in the transde1mal device depicted in Fig. 1 and a voltmeter was plaeed on top of the eell and secured in place by means of a Teflon (Tefion is a Trade Mark) holder.
For the experiments with Visking the solution used in the receptor compartment of the eell was distilled water, whereas for the expeliments using human stratum corneum a phosphate buffer at pH
7.4 was used in the reeeptor compartment. The phosphate buffer solution of pH 7.4 used in the latter experiments was prepared using disodium bydrogen orihophosphate (BDH) 14.7g/1 and sodium dihydrogen phosphate (Riedel-deHaen) 2.66g~ in distilled water. The re~eptor solution was stirred throughout the experiment by a star-headed magnet to provide control of the cell hydrodynamics.
WO 93/09842 PCI`/IE92/00021 2123~28 1~
The cell was immersed in a water bath, the temperature of which was kept constant at 37C to mimic body temperature. Samples of receptor solution were withdrawn through the side arm or sample port of the cell at regular intervals during the course of the experiments and 5 replaced by fresh receptor soludon in conventional manner.
The Visking membrane was prepared from 4 cm length sections of Visking tubing 18/32 which were boiled in distilled water before use to free the membrane of any impurities.
Human stratum comeum membrane was prepared in accordance 10 with the method of Kligman, A.M. and Christophers, E. ((1963) Archives Dermatology 88, 702-705). The stratum corneum and the epidennis were separated from the other skin layers from a section of full thickness abdominal skin and the excess subcutaneous fat removed.
The remainder of the tissue was imme~sed in distilled water at 60C
15 for 2 min. The usual trypsinisation step to remove the epidermis was omitted. This was considered to be unnecessary as it is known that the stratum corneum is the rate limiting banier to diffusion of drugs dlrough the skin. ~e stratum corneum was then stretched onto a wire mesh delmal side down and dried overnight in a desiccator at 25%
20 relative humidity. When dry, it was sealed in a plastics sachet and stored in a fridge until needed.
Preparation of Discs.
Discs of gel No. (1) (Oxoid Ltd. Lot No. 238 14790) were prepared by adding 4% of the solid to distilled water (2~nl) and the 25 resultant mixture was heated slowly. When hot, the viscous solution was poured into a standard size petri dish and allowed to set. Circular discs 1.84 cm. in diameter were cut out and used as the transit chamber in the assembly. A range of discs ranging in thickness from 0.10-0.45cm were studied.
The drug loaded discs to serve as the reservoir in the assemUy were also made of No. (1) gel in which the drug was dissolved.The WO 93/09842 PCl`/IE92/00021 2123~28 drug loaded discs were prepared in the same manner as for the discs to serve as the transit ehamber with the addition of the requisite amount of drug prior to the heating step. The drugs used in the evaluation of the deviee were nieotine (vaeuum distilled, The Nieobrand Company, S Coleraine, County Derry, Northern Ireland.) and salbutamol sulphate B.P.. Cireular dises, with a eross-seetional area of 2.67 em2 and a volume of 1.81 em3 were eut as required. For both salbutamol and nieotine the drug dissolved in water with a little stirring.
Analytical Methods Salbutamol was detected in the samples withdrawn from the diffusion eell by high performanee liquid chromatography (HPLC).
HPLC samples were injected onto a ~ Bondapak Clg Radical-Pak (Bondapak and Radical-Pak are Trade Marks) reversed eolumn using a Waters 712 WISP (WISP is a Trade Mark) auto-injeetor. The method of deteetion employed was UV speetroseopy using a Waters model 455-LCUV speetrophotometer. The mobile phase consisted of acetonitrile (Lab Sean) (92:8) eontaining 12g~1 NaH2po4. The flow rate was set at ~nl/m~. The detection wavelength was set at 276nm. The injection volume of the sample under analysis was 20111. An external standard method was used by means of a Waters 740 Data Module integrator to caleulate ~e eoneentration of salbutamol. Using this method a sha~p peak was observed at a retention time of 6 min. The system was - prog~mmed to recalibrate the standard after every S samples in order to optimise the aeeuraey of the analysis.
Detelmination of nieotine was achieved by W spectroscoW
using a PYE Unieam SP8200 UV/VIS Spectrophotometer with ~e det~ction wavelength set at 260 nm.
Control assemblies eomprised: a) an assembly eonsisting of a reservoir (single gel system); b) an assembly consisting of a reservoir superimposed on a transit chamber (double gel system); and c) an WO 93/09842 PCI'/IE92J00021 assembly as for b) but with a platinum mesh disposed between the reservoir and the transit chamber.
Permeation Studies Across Membranes.
Release of both salbutamol and nicotine from control b) showed S a release profile characteristic of a passive system. The lag-time for the delivery through control b) was greater than the value obtained from control a), indicating retarded transport when a transit chamber is present.
The extent to which the transit chamber acts by retarding the 10 delivery of drug can be explained in terms of gel thickness in that chamber. Decreasing the thickness of the gel results in an increased rate of drug penetration through the Visking membrane. Thus, reducing the thickness of the transit chamber enhances the initial rate of drug transport.
- 15 As might be expected greater quantities of drug were released from gels that contained higher initial concentrations. Increasing the concentration of drug in the reservoir was also seen to reduce the lag-time.
Incorporation of the platinum gauze (control c)) between the two ~0 gels cons~ ng the double gel system introduces a new barrier to drug diffusion. Tbe degree to which the platinum acted as a barrier to drug diffusion depended on the pore size of the mesh itself. The greater the void surface area on the gauze the faster the rate of drug penetration.
lntroduction of a silver gauze barrier between the two gels also served 25 as a barrier to drug permeation and ~since the degree of void area for drug penetration was less than that in the platinum gauze membrane, the rate of drug release was hindered to a greater extent.
WO 93/09842 2 12 3 4 2 8 PCI`/IE92/00021 Device According to the Invention.
Application of a potential difference across the reservoir between the gauze and the electrode applied to the side fur~est away fron~ the membrane barrier results in an increase in the rate of penetration of 5 drug through the double gel system. The ensuing electric current results in the movement of charged ions in the drug loaded gel. The basis for this electrolytic movement is provided by Faraday's laws of electrolysis. In the device according to the invention the drug ions are carried through the reservoir from the solid platinum electrode to the 10 platinum gauæ electrode. This results in a build up of drug concentration at the interface between the gels. However, due to the porous nature of the gauze membrane, ions gathering at the surface of the electrode may pGrmeate into the second gel (transit chamber) which is initially unloaded, resulting in enhanced movement of drug through 15 the gauze barrier and into the unloaded gel. This provides a means whereby the concentration of drug in the unloaded gel can be controlled and maintained. The actual diffusion of the drug across the Vislcing barrier is controlled and depends on the concentration that has been built up in the originally unloaded gel in the transit chamber.
The overall rate of delivery (Rtotal) of drug from the assembly can be described by the combination of electrically assisted (ReleC) and passive transport (Rp) as Rtot~ = Rp + Relec .
It should be emphasised heK that the transport through the membIane in ~e next phase of delivery talces place by diffusion and is not assisted by cunent as in the case of conventional iontophoretic systems where the membrane (i.e. skin) fo~ns part of the electric circuit.
By comparison with both control b) and control c), the enhancement in drug penetration is clearly evident. Release rates for ~e three systems are shown to be of the order, platinum barrier system < double gel system c device according to the invention as shown in - 21239~28 22 Fig. 3 which is a comparison of release profiles in the receptor compartment of the diffusion cell obtained from control b) (_), control c) (~) and the device according to the invention (_) using a current of 0.5 mA.
S The effect of applying a range of currents 0.5-3.0 mA to the device according to the invention, is shown in Fig. 4. As the current is increased the rate of drug transport into the receptor compartment of the diffusion cell also increases and as is the case for single gel iontophoretic systems the release profiles tend to become linear with time. In Fig. 4, curve ~ represents 0.5 mA, curve + represents 1.0 mA, curve _ represents 2.0 mA and curve ~ represents 3.0 mA.
Permeadon Studies Across Excised Human Stratum Corneum.
.
Preliminary investigations across excised human stratum comeum have illustrated similar trends in drug penetration from the dcvice according to the invention to those observed using Visking ie., ~he same order of drug permeation is observed for each of the three double gel systems namely controls b) and c) and the device according to the invention. The degree of permeability using a 20 mg nicotine patch (11.04 mg/ml), unloaded gel thickness of 2.2mrn for the double gel system, gives quitc a~slow release of nicotine (Fig. 5). Application of an elcctrical potcntial rcsulting in a current of 0.5 mA flowing ~hrough the rescrvoir gives an approximate 2 fold enhancement in drug palctration. In Fig. 5, curve ~ represents control b) and curve _ represents the device according to the~ invention. The effect of passing greater culTents through the drug loaded gels needs to be investigated as studies to date have been confined to the use of a 0.5 mA current.
~Vitro Studies - Arran~ement 1.
A further series of in vitro experiments were carried out using as biological membranes Sha-Sha mouse skin and whole thickness human skin in conjunction with a device according to the invention without a transit chamber and herein referred to as Arrangement I.
WO 93/09842 212 3 4 2 8 PCI`/IE92/00021 The condidons were generally as set out for the in vitro studies carried out on Arrangement II, except as hereinafter described. Thus, in these experiments a carbon-based porous electrode (3M Company) was used.
The dNg employed was physosdgmine either as the hemisulphate or S salicyhte.
Experiment a).
Drug: physosdgmine hemisulphate.
Drug loading: 15.3mg (=7.84mg/ml).
Vehicle: 4% agar/water.
Surface area: 2.37 cm2.
Receptor solution: isotonic phosphate buffer, pH 7.4.
Membrane: Sha-Shamouseskin.
The results are depicted in Fig. 6.
In Fig. 6 curve E~ represents conventional passive delivery 15 (QOOmA) while the remaining curves represent delivery from I. Curve represents a current of O.5mA, curve -rcpresents a current of l.OmA and O represents a current of 2.0mA. A
greater ~ban tenfold Ihanan~ in transport is evident with A~gement I.
Experiment b).
Drug: physostigmine salicylate.
Drug loading: l9.5mg (=lOmg/ml).
Vehicle: 4% agar/water.
Surface area: 2.37 cm2.
Receptor solution: isotonic phosphate buffer, pH 7.4.
Membrane: Sha-Shamouseskin.
The results are depicted in Fig. 7.
WO 93/09842 PCI`/IE92/00021 2123~28 In Fig. 7 curve 13 represents conventional passive delivery (O.OOmA) while the remaining curves represent delivery from Arrangement I. Curve represents a current of 0.5mA, curve -represents a current of l.OmA and O represents a current of 2.0mA. It S will be observed from Pig. 7 that an even greater enhancement in transport is evident when the salt form of the drug is changed to the salicylate.
Experiment c).
Drug: physostigmine salicylate.
Drug loading: 30mg (=lOmg/ml).
Vehicle: 4% agar/water.
Surface area: 7.00 cm2.
Receptor solution: isotonic phosphate buffer, pH 7.4.
Membrane: Sha-Shamouseskin.
The results are depicted in Fig. 8.
In Fig. 8 curve El represents a current of 1.475mA, curve represents a culTent of 2.950mA and represents a current of 4.525mA. A fur~er relative enhancement in transport is evident under ~he conditions used in Experiment c) relative to Experiment b).
Experiment d).
Drug: physostigmine salicylate.
Drug loading: 19.5mg (=lOmg/ml).
Vehicle: 4% agar/water.
Surface area: 2.37 cm2.
Receptor solution: isotonic phosphate buffer, pH 7.4.
Membrane: Whole thickness human cadaver skin.
The results are depicted in Fig. 9.
WO 93/09842 PCI`/IE92/00021 ` 2123428 Fig. 9 shows enhanced delivery of physostigmine from Arrangement I when compared with conventional passive transport (curve ~ (O.OOmA)). In Fig. 9 curve represents a current of O.5mA, curve represents a current of l.OmA and O represents a current of 5 2.0mA.
The experiment shows that Arrangement I was also effective when dle Sha-Sha mouse skin was replaced by whole thickness human skin.
This invention is not limited to the embodiments described above 10 which may be modified and/or varied without departing from the scope of ~e invention.
' '` " '1` ~ r
Background Art The administration of drugs percutaneously or transdennally has 10 a number of advantages and is favoured in the case where drugs are not effectively administered by the oral route but where systemic administration is required. This is especially true for drugs which are subject to a first-pass hepatic metabolism or which are susceptible to deactivation by digestive enzymes.
There are also a number of problems associated with the administration of drugs by the transdermal route, for example, a rate of upt~ke of drug which is therapeutically effective may not be achievable. The use of penetradon enhancers~ for example, dimethylsulphoxide, N,N~imethylformamide and others is employed 20 to promote uptake. However, such penetradon enhancers are not always effecdve or sufficient to achieve adequate percutaneous absorption.
Also the manufacture of stable transdelmal devices can be a problem because it may not be possible to find a carner medium which can maintain the drug in a stable condition until use and from which the 25 drug can be successfully transported to and into the skin following application of the transde~nal device at the site of administration.
For some drugs such as glyceryl trinitrate fluctuations in blood level rather than a continuous constant level is required. Thus ~ere is a 2 12~428 2 need for devices or systems capable of periodic or pulsed drug delivery.
For drugs that are not amenable to passive administration by the percutaneous route or for drugs that are effectively percutaneously S absorbed as charged molecules, iontophoretic drug delivery is gaining increasing popularity.
However, iontophoretic drug delivery also has a number of problems, not least of which is the trauma caused by burns and pain' ' which may be associated with the use of this type of delivery which 10 involves migration of drug molecules in the skin under the influence of an eleetric field. Hence conventional iontophoresis as a means of drug delivery may not achieve good patient compliance.
One solution for dealing with the problems associated with iontophoresis is the electrode deviee of U.S. Patent No. 4,722,726, one 15 of ~he stated objects of which is to provide an iontophoretic dmg delivery deviee that inhibits the eurrent earrying eapacity of ions in the calTier medium ~at eompete with the active ingredient and lead to progressive diminution of effeetive drug transfer during dle iontophoretic delivery thereof.
.
U.S. Patent No. 4,731,049 discloses a eell for electrieally eontrolled transde~al drug delivery by iontophoresis. The drug is ' bound on an-ion exchange resin or medium or an immobilized ligand affinity medium loeated in die drug reservoir. Drug delivery oceurs upo~ the applieation of an electrical current of generally small proportions to the reservoir or to an adjaeent ion reservoir separated from ~e drug reservoir by a semi-permeable membrane.
It is an objeet of the present invention to provide a deviee and me~od for the deliveIy of drugs by the percutaneous route which obviates the trauma,in the form of burns and discomfort experienced by ~e patient and yet aehieves an uptake and control of drug by skin which is enhanced when compared to conventional passive delivery.
WO 93/09842 2 12 3 4 2 8 I'CI`/IE92/00021 Investigations earried out by us have shown that by using an electrie eireuit within a deviee to actively transport drug from a drug reservoir forming part of said device, but wherein the skin does not form part of the eircuitry of the device in eontradistinetion to an S iontophoretie device, one aehieves drug delivery rates greater than those aehieved with eonventional passive delivery.
Diselosure of Invention Aeeordingly, the invention provides a transdermal device for the eontrolled administration of a drug to the skin, whieh eomprises a 10 reservoir for the drug and an eleetric cireuit which includes an eleetrode system whieh is operable to aetively transport the drug in a eontrolled manner from said reservoir towards the skin for transport therethrough, the skin not being part of said eleetrie eireuit, and the drug passing through an eleetrode of said eleetrode system during said 15 aetive ~ansport to the skin.
In the present Speeifieation the terms drug and aetive ingredient are used interehangeably.
In one embodiment, the deviee ineludes an eleetrode whieh is permeable to said drug.
The eleetrode whieh is penneable to the drug to be administered can eonsist of a porous metallie material. Thus the eleetrode ean eonsist, for e~cample, of a metal gauze or mesh, of a woven metallic material or of a metal laminate. ~uitable metals inelude platinum, silver or a eoated or uneoated metal alloy. Other suitable eleetrodes inelude earbon or earbon-based eleetrodes.
The eleetrode ean also be defined by a elosed filament of metal or other eondueting material defining a ring, a square or other suitable geometrie shape.
WO 93/09842 1. PCI'/IE92/0002t .~,~"
2123~28 4 Alternatively, the electrode which is permeable to the drug being administered can consist of porous carbon sheeting or of a range of polymeric materials, including conducting polymers, with the required conductivity such as those described in the Handbook of Conducting S Polymers Vol I and II; T.A. Skotheim, publishers Marcell Dekker Inc.
(1986).
The function of said electrode is to spread an appropriate electrical potential.
In a second embodiment, the device according to the invention 10 includes an electrode which functions as a gate, being permeable to said drug in the open condition and less permeable to said drug in the closed condition. The operation of the gate can be determined by the compositi~n of the electrode or, alternatively, by the structure thereof.
.
~n the case where the operation of the gate is determined by the 15 composition of the electrode, the electrode is suitably composed of a polymeric material with the requisite properties.
When the electrode according to said first or second embodiment is a polymeric material, the polymeric material is suitably one that is susceptible to ion doping or, alternatively, is a polymeric material 20 having ion exchange properties. Polymers which are susceptible to ion doping can be of the donor t~pe or the acceptor type. Following the tcrminology of serniconductor technology the polymers can be described as n-type or ~type, as appropriate. Suitable examples of polymers with ion exchange properties include both anion e~cchange 25 resins and cation exchange resins as d~e circumstances require. Suitable resins are marketed by Rohm and Haas company under the Trade Mark Amberlite. Other suitable materials include fluorinated ion exchange polymers such as that sold under ~e Trade Mark Na~lon.
The electrode hereinbefore described can span the width of the 30 reservoir, while having any geometric shape or structure herein described. With such an electrode, the surface thereof distal from the WO 93/09842 2 12 ~ 4 2 8 PCI/IE92/00021 reservoir can be placed in contact with the skin in use. With such an arrangement (hereinafter referred to as AlTangement I) the drug passes through the electrode and enters the skin having been actively transported to the skin sur~ace by the electrode system of the device S which includes the electrode hereinbefore described and a further electrode disposed elsewhere in the device, so as to complete the electric circuit.
In an altemative embodiment, the electrode is disposed between the reservoir for the drug and a transit chamber therefor (hereinafter 10 referred to as Arrangement II).
The relative sizes of the reservoir and the transit chamber will depend on the particular drug or drugs to be administered. However, in gene~al the transit chamber will be of a lesser volume than the reservoir. The reservoir and transit chamber, if present, together with lS the electrode disposed therebetween combined will normally have a thickness of less than S.0 mm, in particular, in the range 0.2-3.0 mm, more especially 1.0-3.0 mm.
Using an arrangement of a reservoir and a transit chamber as hereinbefore described, a measured quantity of drug can be actively 20 transported at selected-intervals of time, such as once-a-day, to the transit chamber from whence it enters the sWn over a given period of time.
The polarity of the electrodes is set according to the charge on the ion which is to be transported. The current density is suitably in the 25 range Q2-1.1 mA cm-2. However, much larger current densities than those employed in conventional iontophoretic devices can be used. The absolute value being dependent on ~e thickness of the transit chamber, if such is present. I~ the case of the device according to the invention it is contemplated that a current density greater than the latter range 30 could be used without causing skin trauma because the skin does not fonn part of the circuitry.
WO 93/09842 P~/IE92/00021 2123~28- 6 The device according to the invention allows the use of higher eleetrical potentials than those employed in conventional iontophoresis.
In an embodiment of the device which allows for periodic or pulsed drug delivery, the polarity of the electrodes and the magnitude S of the voltage ean be systemadeally altered.
The reservoir can be formed of a shaped mass of a material in which the drug is distributed or contained for storage.
The transit chamber can either be composed of the same material as the reservoir or of a different material.
Suitably the material of each of the reservoir and the transit ehamber is a gel.
Preferred gel materials are formed from gel forming agents selected from plant extracts, gums, s~nthetic or natural polysaccharides, polypeptides, alginates and synthetic polymers or a 15 mi~cture thereof.
Espeeially preferred gel materials are formed from the gel fonning agents agar and earrageenan.
Suitable plant extraets inelude agar, ispaghula, psyllium, eydonia and eeratonia or a mixture ~hereof.
` 20 Examples of suitable gums inelude guar gum, aeaeia gum, ghatti gum, karaya gum and tragaeanth gum or a mixture thereof.
Suitable synthetie and natural polysaecharides include aLtcyleelluloses, hydroxyalkyleelluloses, eellulose ethers, eellulose esters, nitroeelluloses, dextrin, agar, eaIrageenan, peetin, furcellaran and stareh or stareh derivatives and mixtures thereof. An example of a preferred stareh derivative is sodium stareh glycolate. Especially WO 93/09842 2 ~ 2 ~ ~ 2 8 PCl /IE92/00021 preferred polysaccharides include agar and carrageenan as hereinbefore indicated.
Suitable polypeptides include zein, gelatin, colhgen and polygeline or a mixture thereof.
Suitable alginates inelude alginic acid, propylene glycol alginate and sodium alginate or a mixture thereof.
An especially preferred synthetic polymer is a carboxyvinyl polymer sold under the Trade Mark Carbomer.
As used herein the term "agar" is synonymous with "agar-agar".
Other semi-solid ,ype bases inelude, in particular, media whieh fonn liquid erystalline phases sueh as distilled monoglyeerides sold under the Trade Mark MYVEROL.
However, the reservoir andlor the transit ehamber, if present, ean equally be formed as a shaped mass of any suitable solid or semi-solid medium fonned with the aid of a solidifying agent. As used herein, the t~rm solidifying agent embraees hardening, setting, suspending, thiekening and lîke agents.
In the ease of the reservoir, the drug or drugs will be uniformly distributed in the solid, semî-solid or liquid medium~
The surfaee area of the reservoir and the transit ehamber, when present, is preferably in the range 1-10 em2, more espeeially 2-7 em The reservoir will suitably eontain the drug in an amount of 5-100 mg.
The reservoir ean inelude one or more auxiliary agents seleeted from an antimierobial agent or a preserving agent, an antioxidant, a pH
WO 93/09842 PCI'/IE92/00021 , . .
2123~28 8 controlling agent, a plasticizer, a surfactant, a penetration enhancer, a humectant, a local anaesthetic or a rubefacient.
Preferred antimicrobiaVpreserving agents include benzalkonium chloride, cetrimide (cetyltrimethylammonium bromide), benzoic acid, S benzyl alcohol, Parabens (Trade Mark for the methyl-, ethyl-, propyl-and butyl-esters of para-hydroxybenzoic acid) chlorhexidine, chlorobutanol, phenylmercuric acetate, borate and nitrate, potassium sorbate, sodium benzoate, sorbic acid and thiomersal (mercurithiosalicylate) or a mixture thereof.
Preferred antioxidants include sodium metabisulphite, butylated hydroxyanisole and butylated hydroxytoluene or a mixture thereof.
Preferred pH controlling agents include citric acid and sodium citrate.
Preferred plasticizers include diethylphthalate, dibutylphthalate 15 and tributylcitrate or a mixture thereo - Preferred surfactants include sodium lauryl sulphate, diethylene glycol monostearate, propylene glycol monostearate, polyethylene -glycols as sold under ~e Trade Mark Macrogol, polysorbates and polyvinyl alcohol or a mixture thereof.
~0 Prcferred penetration~enhancers include dimethylsulphoxide, N,N- dime~ylacetamide, N,N-dimethylformamide, 2~-pyrrolidone, N-methyl-2-pyrrolidone, 1-dodecylazacyclo-heptan-2-one, fatty acids such as oleic acid and salts thereof and terpenes or a mixture thereof.
A preferred humectant is glycerol.
Preferred local anaesthetics include lidocaine, benzocaine, lignocaine, methocaine, butylaminobenzoate and procaine or a mixture ~creof. The device would include a local anaesthetic mainly to suppress irritation at the site of application thereof.
WO 93/09842 PCI`/IE92/00021 9- .
In order to form the reservoir and/or the transit charnber, the respeetive elements are formed separately by adding the gelling agent or the solidifying agent, as appropriate, to a solvent in an amount ~at will result in a suitably semi-solid or solid mass. The mixture thereby S obtained is mixed and optionally heated depending on the agent used so as to produee a uniform medium.
The solvent used is preferably water. However, the solvent used may also suitably be an aleohol sueh as ethanol or stearyl alcohol, glycerol, propylene glycol, polyethylene glycol or a silicone or a 10 mixture thereof, including a mixture with water.
In the case of the reservoir, the drug and any auxiliary agents as hereinbefore deseribed are then added and the resulting mixture mixed to uniformity. The shaped mass which forms the reservoir/transit ehamber, as appropriate, is formed by moulding, cutting, punehing or l$ slieing the solid or semi-solid mixture so as to form dises or layers of ~e mi~ture as required in a manner known per se.
The drug reservoir for use in the device aeeording to the invention ean also be a liquid eontained in a ehamber, said ehamber having a drug pe~neable membrane assoeiated therewith for transport 20 of the drug to the slcin in use, optionally through a transit ehamber, if present.
With ~e deviee aeeording to the invention it is possible to administer a d~ug whieh is not normally eapable of being administered in effeetive amounts passively by ~e transdermal route and to eontrol, 25 in the sense of inereasing or deereasing, the delivery of drugs ~at do penetrate the slun passively.
Examples of drugs whieh ean be administered using the transdennal device aeeording to the invention include nicotine, salbutamol and physostigmine and salts thereof.
WO 93/09842 PCl`/lE92/00021 2123q28 10 Preferred drugs for use in the device according to the invention are basic compounds and basic salts and zwitterionic compounds, including peptides.
When the device according to the invention includes a transit S chamber, said transit chamber can include a different drug to that contained in the reservoir.
According to a further embodiment of the invention, a number of electrodes can be disposed in said reservoir.
The transdermal device according to the invention can includé
10 controlling means operable by a user to selectively transport a drug within and from said reservoir. Furthermore, the transdermal device according to the invention can be programmable.
The device according to the invention can include means for achieving a periodic or pulæd delivery of drug.
The electric circuit will include a power source which will suitabiy comprise conventional miniature or "light-weight" batteries.
For example, conventional sheet batteries and microbatteries may be used.
The transdermal device according to the invention will comprise 20 a housing for the various elements thereof.
, Preferably, the reservoir, transit chamber, if present, and at least one ekctrode define a unit which is detachably mounted in the housing.
When the transdermal device according to the invention is programmable, a programmable controlling member will be located in 25 the housing together with the counter electrode, the power source and other components of the electric circuit. The programmable controlling member will comprise the microelectronics and memory necessary to WO 93/09842 2 1 2 3 ~ 2 8 PCME92/00021 - , 11 achieve a predetennined mode and timing of drug transport within the device.
The unit may be engageable with the housing in such a manner so as to select a programme applicable to the alctive ingredient in the S reservoir such that the programme, when activated, brings about controlled transport of active ingredient in said reservoir at selected intervals of time.
The unit can be replaceable as required, such as every day or `
once-a-week or even twice-daily. For example, in order to achieve the 10 correct diurnal variation required for certain drugs it may be necessary to replace the device twice-daily.
The unit can be adapted to engage with and affix to the housing in any suitable m~er, such as by clipping, snap-fit screwing, wedgîng, bayonetjoint or otherwise securing the respective parts 15 together.
The unit can also be provîded with mechanical or electrical contact n~ans ~adapted to select a programme applicable to the active ingredient contained in th~ e reservoir, which the prog=able allurolling member identifios as contai:ning the or each active ~0 ing~dient and wliich said~coi~i~member thus recognises should - - bc tlansported according to a prescnbed regimen~
Thus the housing and unit can have one or more co-operating electncal contact(s) which on engagement of the respective parts select a given programme.
.
Preferably, the housing includes means for indicating that the active ingredient is being actively transported and thus delivered at any given time.
The device may also include means for indicating that the power source has failed or weakened.
WO 93/09842 PCI'/IE92/00021 2123~28 12 The electrical circuit can include alarm means to alert a patient when it is time for the active ingredient to be delivered, in particular, in circumstances where the device is not worn continuously.
Such alarm means can comprise a timing circuit which will give S a signal such as a bleep which will prompt the user to apply the device to his body.
The housing or the unit preferably includes means for activating the programme when the respective parts are in the engaged positiori.
The means for activating the programme can be an ON/OFP switch.
10 Such a switch can be of the type which is activated to the ON position only when the device is in situ on the body of a patient to be treated.
The ON/OFP switch may be activated to the ON position by pressure exerted by an attachment means when affixed to the body of a patient.
The electric circuit suitably includes means for monitoring and 15 indicating the content of the active ingredient in the reservoir. The inclusion of such means would alert a subject undergoing a treatment regimen using the device if the content of active ingredient is not present in an amount effective for a given treatment.
The electric circuit preferably includes overriding means 20 whereby a subject can activate the device to transport and deliver active ing~edient at other-than a pre-set time up-to a predetennined maximum number of such activations.
Preferably, the housing and the unit, when in the engaged position, form a single unit, the exterior surface of which, in use, 25 simulates the face of a time piece and the single unit is attached to or molmted in a strap or bracelet for application of the de~ice to a limb of a body.
More generally, the device according to the invention can be secured to the body in conventional manner such as by adhesive means, 30 including bioadhesive means, straps, bracelets, and like securing means.
WO 93/09842 2 12 3 4 2 8 PCI`/IE92/00021 The housing suitably includes a liquid crystal display (LCD). The LCD may disphy culTent, voltage, timing and other readings as hereinbefore indicated. The unit may include an ammeter and also a voltage adjuster under the control of a control circuit. The latter circuit S may also include a galvanostat which keeps the current constant despite varying resistance of the skin.
The device according to the invention is preferably applied to the flexor surface of the forearm, including the wrist, and also the ankle.
1~ general, such sites show the greatest consistency from individual to 10 individual in te~ms of drug absorption relative to other sites for drug administration because of the amount of tissue at such sites. Blood vessels are found close to the surface of the skin at such sites which facilitates the up-take of drugs into the systemic circulation.
The reservoir and/or the transit chamber, if present, can be 15 housed in a receptacle which is drug impermeable, ~ereby, ensuring a unidirectional transport of drug towards to the skin.
The invention will be fur~er illustrated by the following description of an embodiment thereof given by way of example only with reference to the accompanying Drawings.
20 Blief Description of the Drawings Fig. 1 is a schematic representation of a transdermal device according to the invention (Arrangement II);
Fig. 2 is a circuit diagram of the circuit employed in the device depicted in Fig. l;
Pig. 3 is a graphic representation of nicotine release profile (mg) versus time (h.) for a device according to the invention relative to controls as hereinafter described;
WO 93/09842 PCI`/IE92/0002t 2123~28 ~
Fig. 4 is a graphic representation of the effect of the current density through a device according to the invention on the quantity of nicotine released (mg) as a function of time (h) as hereinafter described;
S Fig. 5 is a graphic representation of the quantity of drug released (mg) versus time (h.) for 20 mg nicotine-containing discs across human stratum corneum in a device according to the invention reladve to a control;
Fig. 6 is a graphic representation of the delivery of physostigmine hemisulphate (mg) across Sha-Sh~ mouse skin in an Arrangement I-type device according to the invention using different currents versus time (h) relative to passive delivery;
Fig. 7 is a graphic representation of the delivery of physostigmine salicylate (mg) across Sha-Sha mouse skin in an Arrangement I-type device according to the invention using different currents versus dme (h) relative to passive deliveIy;
i Fig. 8 is~a graphic repreæntation of the delivery ofphyso~bgmine salicylate (mg) across Sha-Sha mouse skin in an Anangement l-type device according to the invention using differem cunQ~ versus time (h) relative to passive delivery, using a different drug loading and surface area relative to that used in reladon to Fig. 7; and ` Fig. 9 is a graphic representation of the delivery of physostigmine salicylate (mg) across whole thickness human ~daver skin in an Arraligement I-type device according to the invendon using different currents versus time ~(h) rélative to passive deli~very.
~ .
, 2i2`~4`~
WO 93/Og842 PCI`/IE92/00021 Best Mode for carrving out the ~vention Refer,ring to Fig. 1 there is illustrated a transdermal device indieated generally at 10 eomprising a housing 11 for a reservoir 12 for a drug uniformly distributed in agar gel and an electric eireuit S whieh ineludes an electrode 13 of platinum mesh gauze (Johnson Matthey 52 mesh Lot No. 625590) which is permeable to said drug and a further electrode 14, the eleetrode 13 separating the reservoir 12 from a transit ehamber 15 also eomposed of agar gel. The deviee 10 depieted in Fig. 1 is a deviee of the type herein referred to as an i"
10 Arrangement II.
The housing 11 also includes a programmable controlling unit 16 with appropriate eircuitry and a power supply 17.
The electrode 13 is eonneeted by a lead 18 through a touch -button 19 to the eireuitry in the housing 11. The eleetrode 14 eonsists 15 of a foil of platinum whieh is eonneeted to the eireuitry in the housing 11 by a lead 20 having an assoeiated toueh button 21 and whieh when the deviee is aetivated to transport drug within the reservoir 12 allows the eir,euit to be eompleted.
The reservoir 12, the eleetrode 13 and the transit ehamber 15 20 define a unit whieh is releaseably attaehable to the housing 11 by means of a eor~eetor 22 disposed on a surfaee 23 of an insuJating material sueh as a suitable phsties material. The eonneetor 22 is engageable in a reeognition position 24 in the housing 11. The eonnector 22 on engagernent of the aforementioned unit with the housing 11 seleets a 25 given programme applieable to the drug eontained in the reservoir 12 and said programme when aetivated brings about the desired transport of the drug to the transit ehamber 15 and hence by passive diffusion thereafter to the skin.
The programrnable eontrolling unit 16 includes an ammeter 25, a 30 galvanostat 26 and an LCD 27 with appropriate switehing arrangements whieh ean display current, voltage and time and a time keeping WO 93/09842 PCI`/ID2/00021 ~r~
212~28 16 component with provision for an audible alarm which alerts a subject when it is time for the drug to be delivered, if the device is not worn continuously. The unit 16 also includes an ON/OFF button 28 for activating the program when the unit comprising the reservoir 12, and 5 the housing 11 are in the engaged position and an override button 29 whereby a patient can activate the device to transport the drug at other than a pre-set time up to a predetermined maximum number of such activations as hereinbefore described.
An LED (light emitting diode) 30 is also provided in the unit 16 10 to indicate satisfactory operation of the device, for example so as to indicate that the drug is being actively transported. The LED 30 also indicates if the power supply 17 has faihd or weakened and will give an indication of the content of the drug in the assembled device.
The device 10 is attached to the site of application by means of a 15 strap 31 having at the free ends thereof the cooperating elements of a conventional clasp 32.
The main components of the circuit employed in the device 10 are depicted in the circuit diagram corresponding to Pig. 2. Said components are as follows:
.
PC - a programmable controlling circuit, including an audible alann means;
PS - a power supply;
A - an ammeter, G - a galvanostat;
SS - a selector switch;
O - an override switch;
WO 93/Og842 212 3 4 2 8 PCME92/1~0021 LCD - a liquid crystal display for current, voltage, time, etc. as selected; and LED - a visible signal of delivery of drug, failur~ or weakening of power supply, or content of drug in the device 10.
S RP - a recognitionposition.
Most of the foregoing features can be incolporated into an appropriate microchip.
ln V~ Studies - Arrangement II.
A series of in vitro experiments were carried OUt to assess the transdermal device according to the invention of the type herein referred to as an Arrangement II. ln these experiments an artificial membrane of Visking (Visking is a Trade Mark) and human stratum eorneum were used as the barriers to diffusion into glass, custom built di~usion eells based on a commercially available Franz eell (Franz, TJ., (1975); J. Invest. Dermatol. 64, 190). An assembly eonsisting of a reservoir, transit chamber, eleetrodes, ga~vanostat and ammeter of the t~pe used in the transde1mal device depicted in Fig. 1 and a voltmeter was plaeed on top of the eell and secured in place by means of a Teflon (Tefion is a Trade Mark) holder.
For the experiments with Visking the solution used in the receptor compartment of the eell was distilled water, whereas for the expeliments using human stratum corneum a phosphate buffer at pH
7.4 was used in the reeeptor compartment. The phosphate buffer solution of pH 7.4 used in the latter experiments was prepared using disodium bydrogen orihophosphate (BDH) 14.7g/1 and sodium dihydrogen phosphate (Riedel-deHaen) 2.66g~ in distilled water. The re~eptor solution was stirred throughout the experiment by a star-headed magnet to provide control of the cell hydrodynamics.
WO 93/09842 PCI`/IE92/00021 2123~28 1~
The cell was immersed in a water bath, the temperature of which was kept constant at 37C to mimic body temperature. Samples of receptor solution were withdrawn through the side arm or sample port of the cell at regular intervals during the course of the experiments and 5 replaced by fresh receptor soludon in conventional manner.
The Visking membrane was prepared from 4 cm length sections of Visking tubing 18/32 which were boiled in distilled water before use to free the membrane of any impurities.
Human stratum comeum membrane was prepared in accordance 10 with the method of Kligman, A.M. and Christophers, E. ((1963) Archives Dermatology 88, 702-705). The stratum corneum and the epidennis were separated from the other skin layers from a section of full thickness abdominal skin and the excess subcutaneous fat removed.
The remainder of the tissue was imme~sed in distilled water at 60C
15 for 2 min. The usual trypsinisation step to remove the epidermis was omitted. This was considered to be unnecessary as it is known that the stratum corneum is the rate limiting banier to diffusion of drugs dlrough the skin. ~e stratum corneum was then stretched onto a wire mesh delmal side down and dried overnight in a desiccator at 25%
20 relative humidity. When dry, it was sealed in a plastics sachet and stored in a fridge until needed.
Preparation of Discs.
Discs of gel No. (1) (Oxoid Ltd. Lot No. 238 14790) were prepared by adding 4% of the solid to distilled water (2~nl) and the 25 resultant mixture was heated slowly. When hot, the viscous solution was poured into a standard size petri dish and allowed to set. Circular discs 1.84 cm. in diameter were cut out and used as the transit chamber in the assembly. A range of discs ranging in thickness from 0.10-0.45cm were studied.
The drug loaded discs to serve as the reservoir in the assemUy were also made of No. (1) gel in which the drug was dissolved.The WO 93/09842 PCl`/IE92/00021 2123~28 drug loaded discs were prepared in the same manner as for the discs to serve as the transit ehamber with the addition of the requisite amount of drug prior to the heating step. The drugs used in the evaluation of the deviee were nieotine (vaeuum distilled, The Nieobrand Company, S Coleraine, County Derry, Northern Ireland.) and salbutamol sulphate B.P.. Cireular dises, with a eross-seetional area of 2.67 em2 and a volume of 1.81 em3 were eut as required. For both salbutamol and nieotine the drug dissolved in water with a little stirring.
Analytical Methods Salbutamol was detected in the samples withdrawn from the diffusion eell by high performanee liquid chromatography (HPLC).
HPLC samples were injected onto a ~ Bondapak Clg Radical-Pak (Bondapak and Radical-Pak are Trade Marks) reversed eolumn using a Waters 712 WISP (WISP is a Trade Mark) auto-injeetor. The method of deteetion employed was UV speetroseopy using a Waters model 455-LCUV speetrophotometer. The mobile phase consisted of acetonitrile (Lab Sean) (92:8) eontaining 12g~1 NaH2po4. The flow rate was set at ~nl/m~. The detection wavelength was set at 276nm. The injection volume of the sample under analysis was 20111. An external standard method was used by means of a Waters 740 Data Module integrator to caleulate ~e eoneentration of salbutamol. Using this method a sha~p peak was observed at a retention time of 6 min. The system was - prog~mmed to recalibrate the standard after every S samples in order to optimise the aeeuraey of the analysis.
Detelmination of nieotine was achieved by W spectroscoW
using a PYE Unieam SP8200 UV/VIS Spectrophotometer with ~e det~ction wavelength set at 260 nm.
Control assemblies eomprised: a) an assembly eonsisting of a reservoir (single gel system); b) an assembly consisting of a reservoir superimposed on a transit chamber (double gel system); and c) an WO 93/09842 PCI'/IE92J00021 assembly as for b) but with a platinum mesh disposed between the reservoir and the transit chamber.
Permeation Studies Across Membranes.
Release of both salbutamol and nicotine from control b) showed S a release profile characteristic of a passive system. The lag-time for the delivery through control b) was greater than the value obtained from control a), indicating retarded transport when a transit chamber is present.
The extent to which the transit chamber acts by retarding the 10 delivery of drug can be explained in terms of gel thickness in that chamber. Decreasing the thickness of the gel results in an increased rate of drug penetration through the Visking membrane. Thus, reducing the thickness of the transit chamber enhances the initial rate of drug transport.
- 15 As might be expected greater quantities of drug were released from gels that contained higher initial concentrations. Increasing the concentration of drug in the reservoir was also seen to reduce the lag-time.
Incorporation of the platinum gauze (control c)) between the two ~0 gels cons~ ng the double gel system introduces a new barrier to drug diffusion. Tbe degree to which the platinum acted as a barrier to drug diffusion depended on the pore size of the mesh itself. The greater the void surface area on the gauze the faster the rate of drug penetration.
lntroduction of a silver gauze barrier between the two gels also served 25 as a barrier to drug permeation and ~since the degree of void area for drug penetration was less than that in the platinum gauze membrane, the rate of drug release was hindered to a greater extent.
WO 93/09842 2 12 3 4 2 8 PCI`/IE92/00021 Device According to the Invention.
Application of a potential difference across the reservoir between the gauze and the electrode applied to the side fur~est away fron~ the membrane barrier results in an increase in the rate of penetration of 5 drug through the double gel system. The ensuing electric current results in the movement of charged ions in the drug loaded gel. The basis for this electrolytic movement is provided by Faraday's laws of electrolysis. In the device according to the invention the drug ions are carried through the reservoir from the solid platinum electrode to the 10 platinum gauæ electrode. This results in a build up of drug concentration at the interface between the gels. However, due to the porous nature of the gauze membrane, ions gathering at the surface of the electrode may pGrmeate into the second gel (transit chamber) which is initially unloaded, resulting in enhanced movement of drug through 15 the gauze barrier and into the unloaded gel. This provides a means whereby the concentration of drug in the unloaded gel can be controlled and maintained. The actual diffusion of the drug across the Vislcing barrier is controlled and depends on the concentration that has been built up in the originally unloaded gel in the transit chamber.
The overall rate of delivery (Rtotal) of drug from the assembly can be described by the combination of electrically assisted (ReleC) and passive transport (Rp) as Rtot~ = Rp + Relec .
It should be emphasised heK that the transport through the membIane in ~e next phase of delivery talces place by diffusion and is not assisted by cunent as in the case of conventional iontophoretic systems where the membrane (i.e. skin) fo~ns part of the electric circuit.
By comparison with both control b) and control c), the enhancement in drug penetration is clearly evident. Release rates for ~e three systems are shown to be of the order, platinum barrier system < double gel system c device according to the invention as shown in - 21239~28 22 Fig. 3 which is a comparison of release profiles in the receptor compartment of the diffusion cell obtained from control b) (_), control c) (~) and the device according to the invention (_) using a current of 0.5 mA.
S The effect of applying a range of currents 0.5-3.0 mA to the device according to the invention, is shown in Fig. 4. As the current is increased the rate of drug transport into the receptor compartment of the diffusion cell also increases and as is the case for single gel iontophoretic systems the release profiles tend to become linear with time. In Fig. 4, curve ~ represents 0.5 mA, curve + represents 1.0 mA, curve _ represents 2.0 mA and curve ~ represents 3.0 mA.
Permeadon Studies Across Excised Human Stratum Corneum.
.
Preliminary investigations across excised human stratum comeum have illustrated similar trends in drug penetration from the dcvice according to the invention to those observed using Visking ie., ~he same order of drug permeation is observed for each of the three double gel systems namely controls b) and c) and the device according to the invention. The degree of permeability using a 20 mg nicotine patch (11.04 mg/ml), unloaded gel thickness of 2.2mrn for the double gel system, gives quitc a~slow release of nicotine (Fig. 5). Application of an elcctrical potcntial rcsulting in a current of 0.5 mA flowing ~hrough the rescrvoir gives an approximate 2 fold enhancement in drug palctration. In Fig. 5, curve ~ represents control b) and curve _ represents the device according to the~ invention. The effect of passing greater culTents through the drug loaded gels needs to be investigated as studies to date have been confined to the use of a 0.5 mA current.
~Vitro Studies - Arran~ement 1.
A further series of in vitro experiments were carried out using as biological membranes Sha-Sha mouse skin and whole thickness human skin in conjunction with a device according to the invention without a transit chamber and herein referred to as Arrangement I.
WO 93/09842 212 3 4 2 8 PCI`/IE92/00021 The condidons were generally as set out for the in vitro studies carried out on Arrangement II, except as hereinafter described. Thus, in these experiments a carbon-based porous electrode (3M Company) was used.
The dNg employed was physosdgmine either as the hemisulphate or S salicyhte.
Experiment a).
Drug: physosdgmine hemisulphate.
Drug loading: 15.3mg (=7.84mg/ml).
Vehicle: 4% agar/water.
Surface area: 2.37 cm2.
Receptor solution: isotonic phosphate buffer, pH 7.4.
Membrane: Sha-Shamouseskin.
The results are depicted in Fig. 6.
In Fig. 6 curve E~ represents conventional passive delivery 15 (QOOmA) while the remaining curves represent delivery from I. Curve represents a current of O.5mA, curve -rcpresents a current of l.OmA and O represents a current of 2.0mA. A
greater ~ban tenfold Ihanan~ in transport is evident with A~gement I.
Experiment b).
Drug: physostigmine salicylate.
Drug loading: l9.5mg (=lOmg/ml).
Vehicle: 4% agar/water.
Surface area: 2.37 cm2.
Receptor solution: isotonic phosphate buffer, pH 7.4.
Membrane: Sha-Shamouseskin.
The results are depicted in Fig. 7.
WO 93/09842 PCI`/IE92/00021 2123~28 In Fig. 7 curve 13 represents conventional passive delivery (O.OOmA) while the remaining curves represent delivery from Arrangement I. Curve represents a current of 0.5mA, curve -represents a current of l.OmA and O represents a current of 2.0mA. It S will be observed from Pig. 7 that an even greater enhancement in transport is evident when the salt form of the drug is changed to the salicylate.
Experiment c).
Drug: physostigmine salicylate.
Drug loading: 30mg (=lOmg/ml).
Vehicle: 4% agar/water.
Surface area: 7.00 cm2.
Receptor solution: isotonic phosphate buffer, pH 7.4.
Membrane: Sha-Shamouseskin.
The results are depicted in Fig. 8.
In Fig. 8 curve El represents a current of 1.475mA, curve represents a culTent of 2.950mA and represents a current of 4.525mA. A fur~er relative enhancement in transport is evident under ~he conditions used in Experiment c) relative to Experiment b).
Experiment d).
Drug: physostigmine salicylate.
Drug loading: 19.5mg (=lOmg/ml).
Vehicle: 4% agar/water.
Surface area: 2.37 cm2.
Receptor solution: isotonic phosphate buffer, pH 7.4.
Membrane: Whole thickness human cadaver skin.
The results are depicted in Fig. 9.
WO 93/09842 PCI`/IE92/00021 ` 2123428 Fig. 9 shows enhanced delivery of physostigmine from Arrangement I when compared with conventional passive transport (curve ~ (O.OOmA)). In Fig. 9 curve represents a current of O.5mA, curve represents a current of l.OmA and O represents a current of 5 2.0mA.
The experiment shows that Arrangement I was also effective when dle Sha-Sha mouse skin was replaced by whole thickness human skin.
This invention is not limited to the embodiments described above 10 which may be modified and/or varied without departing from the scope of ~e invention.
' '` " '1` ~ r
Claims (31)
1. A transdermal device (10) for the controlled administration of a drug to the skin, which comprises a reservoir (12) for the drug and an electric circuit comprising an electrode system of at least two electrodes (13,14) which is operable to actively transport the drug in a controlled manner within the device (10), the drug passing through an electrode (13) of said electrode system (13,14), characterised in that the electrodes (13,14) are disposed internally of the device (10) such that the skin does not form part of the electric circuit and in that the drug is actively transported from the reservoir (12) in the direction of the skin for transport therethrough, by energising the electrodes (13,14).
2. A transdermal device (10) according to Claim 1, wherein the device includes an electrode (13) which is permeable to said drug.
3. A transdermal device (10) according to Claim 1 or 2, wherein the electrode (13) consists of a porous metallic material.
4. A transdermal device (10) according to Claim 3, wherein the electrode (13) consists of a metal gauze.
5. A transdermal device (10) according to Claim 3, wherein the electrode (13) consists of a woven metallic material.
6 . A transdermal device (10) according to Claim 3, wherein the electrode (13) consists of a metal laminate.
7. A transdermal device (10) according to any one of Claims 3-6, wherein the metal is selected from platinum, silver or a coated or uncoated metal alloy.
8. A transdermal device (10) according to Claim 2, wherein the electrode (13) consists of carbon sheeting.
9. A transdermal device (10) according to Claim 1, wherein the device includes an electrode (13) which functions as a gate, being permeable to said drug in the open condition and less permeable to said drug in the closed condition.
10. A transdermal device (10) according to Claim 9, wherein the operation of the gate is determined by the composition of the electrode (13).
11. A transdermal device (10) according to Claim 9, wherein the operation of the gate is determined by the structure of the electrode (13).
12. A transdermal device (10) according to any one of Claims 1, 2, 9 or 10, wherein the device includes an electrode (13) which consists of a polymeric material.
13. A transdermal device (10) according to Claim 12, wherein the polymeric material is susceptible to ion doping.
14. A transdermal device (10) according to Claim 12, wherein the polymeric material has ion exchange properties.
15. A transdermal device (10) according to any one of Claims 2-14, wherein the electrode (13) spans the width of said reservoir (12).
16. A transdermal device (10) according to Claim 15, wherein the surface of the electrode (13) distal from said reservoir (12) is placed in contact with the skin in use.
17. A transdermal device (10) according to any one of Claims 2-15, wherein the electrode (13) is disposed between said reservoir (12) for the drug and a transit chamber (15) therefor.
18. A transdermal device (10) according to Claim 17, wherein the reservoir (12) is formed of a shape mass of a material in which the drug is distributed for storage.
19. A transdermal device (10) according to Claim 18, when dependent on Claim 17, wherein the transit chamber (15) is composed of the same material as the reservoir (12).
20. A transdermal device (10) according to Claim 18, when dependent on Claim 17, wherein the transit chamber (15) is composed of a material which is different to that comprising said reservoir (12).
21. A transdermal device (10) according to any one of Claims 18-20, wherein the material of each of the reservoir (12) and the transit chamber (15) is a gel.
22. A transdermal device (10) according to Claim 21, wherein the gel material is formed from a gel forming agent selected from plant extracts, gums, synthetic or natural polysaccharides, polypeptides, aliginates and synthetic polymers or a mixture thereof.
23. A transdermal device (10) according to Claim 22, wherein the gel forming agent is agar or carrageenan.
24. A transdermal device (10) according to any preceding claim, wherein the drug is one which is not normally capable of being administered passively by the transdermal route.
25. A transdermal device (10) according to any preceding claim, wherein the drug is salbutamol.
26. A transdermal device (10) according to any one of Claims 1-23, wherein the drug is nicotine.
27. A transdermal device (10) according to any preceding claim, when dependent on Claim 17, wherein the transit chamber (15) includes a different drug to that contained in the reservoir (12).
28. A transdermal device (10) according to any one of Claims 2-14 and 17-27, wherein a number of said electrodes (13, 14) are disposed in said reservoir (12).
29. A transdermal device (10) according to any preceding claim, wherein the device includes controlling means (16) operable by a user to selectively transport a drug within and from said reservoir (12).
30. A transdermal device (10) according to any preceding claim, which is programmable.
31. A transdermal device (10) according to any preceding claim, which includes means (16) for achieving a periodic or pulsed delivery of drug.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE394191 | 1991-11-13 | ||
| IE3941/91 | 1991-11-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2123428A1 true CA2123428A1 (en) | 1993-05-27 |
Family
ID=11039234
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002123428A Abandoned CA2123428A1 (en) | 1991-11-13 | 1992-11-10 | Drug delivery device |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5533995A (en) |
| EP (1) | EP0612258B1 (en) |
| JP (1) | JP3456994B2 (en) |
| AT (1) | ATE155045T1 (en) |
| AU (1) | AU664214B2 (en) |
| CA (1) | CA2123428A1 (en) |
| DE (1) | DE69220808T2 (en) |
| IL (1) | IL103711A (en) |
| NZ (1) | NZ245091A (en) |
| WO (1) | WO1993009842A1 (en) |
| ZA (1) | ZA928689B (en) |
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-
1992
- 1992-11-10 WO PCT/IE1992/000021 patent/WO1993009842A1/en active Search and Examination
- 1992-11-10 AT AT92923044T patent/ATE155045T1/en not_active IP Right Cessation
- 1992-11-10 EP EP92923044A patent/EP0612258B1/en not_active Expired - Lifetime
- 1992-11-10 DE DE69220808T patent/DE69220808T2/en not_active Expired - Lifetime
- 1992-11-10 US US08/244,094 patent/US5533995A/en not_active Expired - Lifetime
- 1992-11-10 JP JP50912893A patent/JP3456994B2/en not_active Expired - Fee Related
- 1992-11-10 CA CA002123428A patent/CA2123428A1/en not_active Abandoned
- 1992-11-10 AU AU29099/92A patent/AU664214B2/en not_active Ceased
- 1992-11-11 IL IL10371192A patent/IL103711A/en not_active IP Right Cessation
- 1992-11-11 ZA ZA928689A patent/ZA928689B/en unknown
- 1992-11-11 NZ NZ245091A patent/NZ245091A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL103711A (en) | 1997-02-18 |
| AU664214B2 (en) | 1995-11-09 |
| JP3456994B2 (en) | 2003-10-14 |
| NZ245091A (en) | 1994-03-25 |
| ATE155045T1 (en) | 1997-07-15 |
| EP0612258B1 (en) | 1997-07-09 |
| WO1993009842A1 (en) | 1993-05-27 |
| DE69220808D1 (en) | 1997-08-14 |
| AU2909992A (en) | 1993-06-15 |
| EP0612258A1 (en) | 1994-08-31 |
| IL103711A0 (en) | 1993-04-04 |
| JPH07500991A (en) | 1995-02-02 |
| DE69220808T2 (en) | 1998-01-02 |
| ZA928689B (en) | 1993-05-10 |
| US5533995A (en) | 1996-07-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |