IE900364A1 - Two-part device for the controlled delivery of an active ingredient - Google Patents

Abstract

A two-part device that is adapted to be worn by a subject for the controlled debvery of an active ingredient to the skin of the subject under the influence of an iontophoretic or electro-osmotic force, comprising: a first reusable part housing a programmable controlling member; means for selecting a given program; and a second disposable and replaceable part comprising an electrode unit containing said active ingredient and having at least one active electrode disposed in, but isolated from, a skincontacting surface defining a counter electrode and further containing an associated power source for delivery of said active ingrddient; said second part being integrally engageable with said first part in a manner so as to select a program applicable to said active ingredient and said program when activated brings about the controlled delivery of active ingredient from the electrode unit to the skin.

Description

This invention relates to a two-part device for the controlled delivery of an active ingredient to the skin under the influence of an iontophoretic or electro-osmotic force.

The technique of iontophoresis has been used on a limited 5 scale in medical therapy. Iontophoresis is the process of moving ions into surface tissues with the aid of an electrical current. The technique was discovered nearly a century ago, but it is only in recent years that much interest has been shown in it as a method of local drug administration of ions; its chief proponents 0 are to be found in the disciplines of dermatology, dentistry and otolaryngology. It is a safe, well documented method of introducing ions or polar substances into the skin by the application of a direct current between two electrodes placed on the skin of the patient. One advantage claimed for iontophoresis as a technique for drug administration is that systemic toxicity is virtually eliminated, since only a small amount of drug is delivered. (Gangarosa L.P. et al. (1978) J. Pharm. Sci., £Z, 14391443).

Iontophoretic devices are known from our sister company’s Patent Application No. 1854/86, EP-A-0 060 451, EP-A-0 058 920, GB-A-2 104 388, New Zealand Patent Specification No. 184,551 and U.S. Patent Specification Nos. 4,474,570, 4,557,723, 4,622,031 and 4,731,049. One problem encountered with many such known iontophoretic devices concerns the battery power/size ratio for batteries used to operate such devices. In order to keep such devices of reasonable dimensions for use in the administration of active ingredient to at least ambulatory subjects being treated, the battery must be relatively small. However, the power requirements of such devices when actively delivering active ingredient are such that the battery has a relatively short life span.

IE 90364 It is envisaged that many drugs will require quite different delivery programs when administered by the iontophoretic route. Thus for effective therapy some drugs will require slow continuous delivery over relatively long periods of time, for example 12 hours or more, while other drugs will require to be delivered for 20 min. every 8 hours or so or perhaps as infrequently as every 3 days. Thus calcitonin for use in the treatment of osteoporosis would suitably be administered once every three days. In order to cover all such treatment regimens, it 0 would not be practicable to leave it up to a patient or, indeed, a doctor or pharmacist to set up the device on each occasion to match the required delivery program.

It is an object of the present invention to provide a device for the controlled delivery of an active ingredient to the skin under the influence of an iontophoretic or electro-osmotic force which overcomes the aforementioned disadvantage of known iontophoretic devices.

It is a further object of the present invention to provide a device for the controlled delivery of an active ingredient to the skin under the influence of an iontophoretic or electro-osmotic force which can be programmed to deliver a multiplicity of active ingredients according to selected delivery programs.

Accordingly, the invention provides a two-part device for the controlled delivery of an active ingredient to the skin under the influence of an iontophoretic or electro-osmotic force, comprising a first part housing a programmable controlling member and an associated power source and a second part comprising an electrode containing said active ingredient, said electrode being engageable with said first part in a manner so as to select a program applicable to said active ingredient and said program when activated brings about the controlled delivery of active ingredient from the electrode to the skin.

IE 90364 Thus the first part of the two-part device according to the invention contains the microelectronics and memory necessary to perform a multiplicity of different drug delivery schedules and the second part is engageable with the first part in such a manner that it indicates to the first part what drug is contained in the second part and how it should be delivered.

Preferably, the second part has an associated power source which supplies the power to deliver the active ingredient through the skin from the electrode. The power source will suitably comprise conventional miniature or light-weight batteries. For example, conventional sheet batteries and microbatteries may be used. Suitable batteries are alkaline batteries and lithium batteries of the type used in hearing aids and watches.

For pharmaceutical stability and other reasons, the electrode can be replaceable as required such as every day or every week.

The second part may comprise a plurality of spaced-apart and isolated electrodes arranged on a first surface adapted for contact with the skin. The plurality of electrodes may be concentrically arranged and spaced-apart by means of an insulating material.

Recent studies indicate that such an arrangement of a plurality of electrodes facilitates delivery of active ingredient by minimizing current requirements for such delivery as well as minimizing any skin irritation associated with the use of the device.

The second part of the device is adapted to engage with and affix to the first part in any suitable manner such as by clipping, screwing or otherwise securing the respective parts together, such that the first surface of the second part is adjacent to and IE 90364 contactable with the skin when the device is attached to a limb or elsewhere on the body of a subject to be treated in use.

On a second surface of the second part remote from said first surface, the second part is provided with mechanical or electrical contact means adapted to select a program applicable to the active ingredient contained in the or each electrode and which the programmable controlling member identifies as containing the or each active ingredient and which said controlling member thus recognises should be administered 0 according to a prescribed regimen.

According to one embodiment of the invention said second part has a plurality of electrical contacts arranged on a second surface remote from said first surface and which on engagement of the respective first and second parts selects a given program.

The second part may select a given program by means of a bar code readable by said first part. Preferably, once said second part engages said first part it is moved relative thereto enabling said bar code to be scanned by a light source in said first part.

According to a second embodiment of the invention said second part has one or more projection(s) engageable with one or more cooperating aperture(s) in said first part, the or each aperture housing a microswitch which is activated on engagement of the parts to select a given program.

Preferably, the first part includes an electrical circuit with means for indicating an active ingredient is being actively delivered. This feature is desirable for example to reassure the subject being treated that he or she is receiving the prescribed active ingredient.

IE 90364 The electrical circuit may also include means for indicating that a power source has failed or weakened.

Preferably in circumstances where the device is not worn continuously, the electrical circuit includes alarm means to alert a subject when it is time for the active ingredient to be delivered. Such alarm means will suitably comprise a timing circuit which will give a bleep which will prompt the user to apply the device to the body.

The first or second part preferably includes means for 1 0 activating the program when said first and second parts are in the engaged position. The means for activating the program may be an ON/OFF switch. In a preferred embodiment the ON/OFF switch is activated to the ON position only when the device is in situ on the body of a subject to be treated. The ON/OFF switch may be activated to the ON position by pressure exerted by an attachment means when affixed to the body of said subject.

The electrical circuit suitably includes means for monitoring and indicating the content of the active ingredient in the device. The inclusion of such means would alert a subject undergoing a treatment regimen using the device if the content of active ingredient was not present in an amount effective for a given treatment. For example, the presence of such means would indicate evaporation of an active ingredient from the device if such had occurred.

The electrical circuit preferably includes overriding means whereby a subject can activate the device to deliver active ingredient at other than a pre-set time up to a predetermined maximum number of such activations. For example, in patient controlled analgesia, the patient might be permitted to give himself one or two extra shots of analgesic, for example morphine, over a predetermined period of time, but any further IE 90364 activation of the device would be impossible until a further predetermined time period had elapsed.

The current used can be in the region of 0.01-10 mA per cm2. For example, the device most usually will operate at 0.1 to 0.7 mA, preferably around 0.5 mA. The current may be constant, variable or pulsed according to a given program of active ingredient delivery.

As indicated above, the second part may be designed so as to be thrown away after a predetermined time in a continuing treatment regimen.

When the second part of the device has a plurality of electrodes, the individual electrodes can contain two or more different active ingredients. In such an embodiment the electrical circuit optionally includes means for activating the electrodes containing the different active ingredients independently of each other so that they are delivered to the skin at different times.

The power source of the first part may be a power source of the type defined for the separate power source associated with the second part, when such an additional power source is used or a power source as hereinafter defined.

Preferably the first and second parts, when in the engaged position, form a single unit, the exterior surface of which, in use, simulates the face of a time piece and said unit is mounted in a strap or bracelet for attachment to a limb of a body. The unit will suitably include a liquid crystal display (LCD). The LCD may display current, 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 control circuit may also include a galvanostat which regulates the current constant despite varying resistance of the skin.

IE 90364 In a preferred embodiment the exterior surface of the unit will resemble a wrist watch and the power source of the first part will be a long-term battery of the type which lasts for three or more years. Therefore a person undergoing a course of treatment with a device according to the invention would only have to purchase the first part of the device once for a long term course of therapy.

The or each active ingredient can be in liquid form contained in a reservoir defining part of the or each electrode, 0 said reservoir having an active ingredient permeable membrane forming at least part of said first surface of said second part of the device. Such constructions of electrode are known.

Alternatively, the active ingredient may be dispersed in a matrix of a solid, semi-solid or mucilaginous material and having an active ingredient permeable membrane associated therewith forming at least part of said first surface of said second part of the device. The matrix material is suitably a hydrogel, polyurethane, silicone or other material known in the art for holding a drug in a stable condition prior to release to the skin.

Suitable materials for forming a matrix for use in an electrode for the device according to the invention include, for example, plant extracts, vegetable oils, gums, synthetic or natural polysaccharides, polypeptides, alginates, hydrocarbons, synthetic polymers, minerals and silicon compounds and mixtures thereof. Such materials are solidifying or gel-forming agents which upon mixing and/or heating with the active ingredient and optionally one or more auxiliary material(s) in a solvent or mixture of solvents form a matrix with the active ingredient and auxiliary material(s), if present, dispersed therethrough.

The term solidifying agent as used herein also embraces thickening, hardening, setting, suspending or like agents.

IE 90364 Suitable plant extracts include agar, ispaghula, psyllium, cydonia and ceratonia or a mixture thereof. The term agar is synonymous with agar-agar.

A suitable vegetable oil is hydrogenated castor oil.

Examples of suitable gums include guar gum, acacia gum, ghatti gum, karaya gum and tragacanth gum or a mixture thereof.

Suitable synthetic and natural polysaccharides include alkylcelluloses, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, nitro celluloses, dextrin, agar, carrageenan, 0 pectin, furcellaran and starch or starch derivatives and mixtures thereof. An example of a preferred starch derivative is sodium starch glycolate. Especially preferred polysaccharides include agar and carrageenan.

Suitable polypeptides include zein, gelatin, collagen and polygeline or a mixture thereof.

Suitable alginates include alginic acid, propylene glycol alginate and sodium alginate or a mixture thereof.

Preferred hydrocarbons include soft paraffin and hard paraffin, especially white petrolatum.

Especially preferred synthetic polyers are a carboxyvinyl polymer sold under the Trade Mark CARBOMER or a polyurethane. The polyurethanes are preferably those of the polyether type which are available commercially from The Dow Chemical Company under the Trade Name Pellethane.

Suitable minerals include bentonite, hectorite, aluminium magnesium silicate and magnesium silicate or a mixture thereof.

IE 90364 Suitable compounds based on silicon include colloidal silicon dioxide, silicones, polysiloxanes and silica gels or a mixture thereof.

In the case of a hydrogel the solvent used is preferably 5 water. The solvent used may also suitably be an alcohol such as ethanol or stearyl alcohol, glycerol, propylene glycol, polyethylene glycol or silicone or a mixture thereof, including a mixture of water.

Suitable auxiliary materials may include one or more of the following: an antimicrobial agent, preservative, antioxidant, pHcontrolling agent, plasticizer, surfactant, penetration enhancer, humectant, local anaesthetic, or rubefacient.

A wide range of active ingredients may be administered by means of the device according to the invention. Preferably, the active ingredient is a drug which is not normally free to pass through the skin without the assistance of an electrical current. However, even drugs which have a reasonable ability to pass through the skin without the assistance of an electrical current may benefit from being administered by means of a device in accordance with the invention, since administration by this route eliminates many of the problems associated with gastrointestinal and rectal absorption.

Suitable drugs which can be administered by means of the device in accordance with the invention include, for example, analgesics, antiasthmatic agents, antirheumatic agents, agents active on the central nervous system, peptides and hormones. Especially suitable active ingredients include fentanyl, hydromorphone, methadone, morphine, orcipreniline, salbutamol, sodium chromoglycate, diclofenac, indomethacin, piroxicam, clonidine, fluphenazine, nicotine, calcitonin, desmopressin, erythropoeitin, GH, insulin, LHRH, PTH or vasopressin or a IE 90364 pharmaceutically acceptable salt or ester thereof or a mixture thereof.

The invention also provides a method of delivering an active ingredient by the iontophoretic route, which comprises applying to a subject to whom it is desired to administer said active ingredient a device as hereinbefore described.

The device according to the invention overcomes the need for the patient or the doctor to have any involvement with the device per se. This is important since it is unlikely the device or 0 method in accordance with the invention would be clearly understood by either the patient or the doctor. Accordingly, the doctor would be advised that drug X had been proven to be effective when administered for example daily on the basis of a 20 min. passage of current every 8 hours and that the electrode could supply seven days of treatment. For this purpose the doctor would then merely prescribe a single device and for example three months supply of electrodes for replacement on a weekly basis. The patient would then wear the device suitably like a watch so that the fact that the patient is taking medication would not be noticeable to third parties. The patient's involvement would be restricted to replacing the electrode each week and thereafter would have no further involvement in his medication. Neither the pharmacist nor the doctor would need to do any programming to the device, since this would be done in the factory and done in such a way that the device is programmed to accept all of the electrodes that would be likely to be used in conjunction therewith. The type of program which could be accommodated in the device in accordance with the invention is essentially unlimited. Accordingly, such devices could be reprogrammed as desired to include new programs for new treatment regimens as and when they arise.

IE 90364 The invention will be further illustrated by the following description of embodiments thereof with reference to the accompanying drawings in which: Fig. 1 is a schematic representation of a two-part device 5 for the controlled delivery of an active ingredient according to the invention; Fig. 2 is a plan view of the second part of the device shown in Fig. 1; Fig. 3 is a section on the line Ill-Ill in Fig. 2; 0 Fig. 4 is a schematic representation of an alternative construction for use as the second part of the device shown in Fig. 1; and Fig. 5 is a circuit diagram of the circuit employed in the device according to Fig. 1.

Referring to Fig. 1 of the drawings, there is indicated generally at 10 a two-part device for the controlled delivery of an active ingredient to the skin under the influence of an iontophoretic force. The device 10 comprises a first part 11 housing a programmable controlling unit 12 with appropriate circuitry and an associated power supply 13, and a second part 14 having a plurality of spaced-apart electrodes 15 arranged on a first surface 16 (Figs. 2 and 3) adapted for contact with the skin in use. Each electrode 15 contains an active ingredient 17 uniformly dispersed in agar gel 18. Each electrode is in the form of a well 19 with the base 20 thereof being defined by a layer of an electrically conducting material 21 which is connected to the circuitry in the first part 11 of the device 10 by a lead 22 having an associated touch button 23. 90364 The second part 14 is releasably attachable to said first part 11 by means of a connector 24 disposed on a second surface 25 of said second part 14 remote from said first surface 16. The second surface 25 is composed of an insulating material such as a suitable plastics material. The connector 24 is engageable in a recognition position 26 on the first part 11 of the device 10. The connector 24 on engagement of the first and second parts, selects a given program applicable to said active ingredient 17 and said program when activated brings about the controlled delivery of active ingredient 17 from each said electrode to the skin. Each of the wells 19 has a wall 27 of an insulating material which electrically isolates said wells 19 from the first surface 16 of the second part 14 of the device. The first surface 16 is composed of an electrically conducting material such as aluminium, platinum, silver or tin and defines a counter electrode 28 connected by a lead 29 through a touch button 30 to the circuitry in the first part 11 of the device and which electrode 28, in use, allows the circuit to be completed when the device 10 is applied to the skin and is activated to deliver the active ingredient.

The programmable controlling unit 12 includes an ammeter 31, a galvanostat 32, an LCD 33 with appropriate switching arrangements which can display current, voltage and time and an audible alarm which alerts a subject when it is time for the active ingredient to be delivered, if the device is not worn continuously. The unit 12 also includes an ON/OFF button 34 for activating the program when the first and second parts are in the engaged position and an override button 35 whereby a subject can activate the device to deliver active ingredient at other than a pre-set time up to a predetermined maximum number of such activations as hereinbefore described.

An LED (light emitting diode) 36 is also provided in the unit 12 to indicate satisfactory operation of the device, for example IE 90364 so as to indicate that an active ingredient is being actively delivered. The LED also indicates if the power supply 13 has failed or weakened and will give an indication of the content of the active ingredient in the assembled device.

The device 10 is attached to the site of application by means of a strap 37 having at the free ends thereof the cooperating elements of a conventional clasp 38.

An alternative embodiment of a second part 14' for the device 10 is depicted in Fig. 4. The second part 14' has a plurality of electrodes 15’ concentrically arranged on a first surface 16' adapted for contact with the skin in use. The electrodes 15' are spaced apart from concentrically arranged rings of a metallic conducting material defining a plurality of counter electrodes 28', the latter being spaced apart from immediately adjacent electrodes 15' by a series of concentrically arranged rings of insulating material 39. In other respects, the second part 14' of the device depicted in Fig. 4 resembles the second part 14 of the device depicted in Figs. 1-3.

The main components of the circuit employed in the device are depicted in the circuit diagram corresponding to Fig. 5.

Said components are as follows: PC - a programmable controlling circuit, including an audible alarm means; PS - a power supply; A - an ammeter; G - a galvanostat; SS - a selective switch; . ; r' IE 90364 O - an override switch LCD - a liquid crystal display for current, voltage, time, etc. as selected; and LED - a visible signal of delivery of active ingredient, failure of weakening of power supply, or content of active ingredient in the device 10.

Most of the foregoing features can be incorporated into an appropriate microchip.

It will be appreciated that the second part 14/14' of the 10 device 10 may have a separate power source associated therewith as hereinbefore described for supplying the power necessary to deliver the active ingredient to the skin in use. When the device 10 contains two power supplies, i.e. one associated with each of the first and second parts, such power sources will be arranged in parallel.

This invention is not limited to the embodiments described above which may be modified and/or varied without departing from the scope of the invention.

Claims (25)

1. A two-part device for the controlled delivery of an active ingredient to the skin under the influence of an iontophoretic or electro-osmotic force, comprising a first part housing a 5 programmable controlling member and an associated power source and a second part comprising an electrode containing said active ingredient, said electrode being engageable with said first part in a manner so as to select a program applicable to said active ingredient and said program when activated brings about 1 0 the controlled delivery of active ingredient from the electrode to the skin.

2. A device according to Claim 1, wherein the second part has an associated power source.

3. A device according to Claim 1 or 2, wherein the second part 1 5 comprises a plurality of spaced-apart and isolated electrodes arranged on a first surface adapted for contact with the skin.

4. A device according to Claim 3, wherein said electrodes are concentrically arranged and spaced-apart by means of an insulating material. 20 5. A device according to any preceding claim when dependent on Claim 3, wherein said second part has a plurality of electrical contacts arranged on a second surface remote from said first surface and which on engagement of the respective first and second parts selects a given program. 25 6. A device according to any one of Claims 1-4, wherein the second part selects a given program by means of a bar code readable by said first part. IE 90364 ._. 17 7. A device according to Claim 6, wherein once said second part engages said first part it is moved relative thereto enabling said bar code to be scanned by a light source in said first part. 8. A device according to any one of Claims 1-4, wherein said

5. Second part has one or more projection(s) engageable with one or more cooperating aperture(s) in said first part, the or each aperture housing a microswitch which is activated on engagement of the parts to select a given program.

6. 9. A device according to any preceding claim, wherein the first 1 0 part includes an electrical circuit with means for indicating an active ingredient is being actively delivered.

7. 10. A device according to Claim 9, wherein the electrical circuit includes means for indicating that a power source has failed or weakened. 15

8. 11. A device according to Claim 9 or 10, wherein the electrical circuit includes alarm means, where the device is not worn continuously, to alert a subject when it is time for the active ingredient to be delivered.

9. 12. A device according to any one of Claims 9-11, wherein the 20 electrical circuit includes means for monitoring and indicating the content of the active ingredient in the device.

10. 13. A device according to any preceding claim, wherein the electrical circuit includes overriding means whereby a subject can activate the device to deliver active ingredient at other than 25 a pre-set time up to a predetermined maximum number of such activations. IE 90364

11. 14. A device according to any preceding claim, wherein the second part is adapted to be replaced after a predetermined time in a continuing treatment regimen.

12. 15. A device according to any preceding claim when dependent on 5 Claim 3 or 4, wherein the individual electrodes contain two or more different active ingredients.

13. 16. A device according to Claim 15, wherein the electrical circuit optionally includes means for activating the electrodes containing the different active ingredients independently of each 1 0 other so that they are delivered to the skin at different times.

14. 17. A device according to any preceding claim, wherein the first and second parts, when in the engaged position, form a single unit, the exterior surface of which, in use, simulates the face of a time piece and said unit being mounted in a strap or bracelet for 1 5 attachment to a limb of a body.

15. 18. A device according to any preceding claim, wherein the active ingredient is in liquid form contained in a reservoir defining part of the or each electrode, said reservoir having an active ingredient permeable membrane forming at least part of said 20 first surface of said second part of the device.

16. 19. A device according to any one of Claims 1-17, wherein the active ingredient is dispersed in a matrix of a solid, semi-solid or mucilaginous material and having an active ingredient permeable membrane associated therewith forming at least part 25 of said first surface of said second part of the device.

17. 20. A device according to Claim 19, wherein the matrix material is a hydrogel, polyurethane or silicone material. 90364

18. 21. A device according to any preceding claim, wherein the first or second part includes means for activating the program when said first and second parts are in the engaged position.

19. 22. A device according to Claim 18, wherein the means for 5 activating the program is an ON/OFF switch.

20. 23. A device according to Claim 22, wherein the ON/OFF switch is activated to the ON position only when the device is in situ on the body of a subject to be treated.

21. 24. A device according to Claim 23, wherein the ON/OFF switch 10 is activated to the ON position by pressure exerted by an attachment means when affixed to the body of said subject.

22. 25. A device according to any preceding claim, wherein the active ingredient is selected from an analgesic, an antiasthmatic agent, an antirheumatic agent, an agent active on the central nervous 1 5 system, a peptide or a hormone.

23. 26. A device according to Claim 25, wherein the active ingredient is selected from fentanyl, hydromorphone, methadone, morphine, orcipreniline, salbutamol, sodium chromoglycate, diclofenac, indomethacin, piroxicam, clonidine, fluphenazine, nicotine, 20 calcitonin, desmopressin, erythropoeitin, GH, insulin, LHRH, PTH or vasopressin or a pharmaceutically acceptable salt or ester thereof.

24. 27. A device according to Claim 1, substantially as hereinbefore described with particular reference to and as illustrated in the 25 accompanying drawings.

25. 28. A method of delivering an active ingredient by the iontophoretic route, which comprises applying to a subject to IE 90364 whom it is desired to administer said active ingredient a device according to any one of Claims 1-27.