Device for iontophoretic administration of drugs

Details Device for iontophoretic administration of drugs Device for iontophoretic administration of drugs

2000-09-25

2002-08-27

Wayner, William (Department: 3763)

Surgery

Means for introducing or removing material from body for...

Infrared, visible light, ultraviolet, x-ray or electrical...

C604S294000, C604S501000

Reexamination Certificate

active

06442423

ABSTRACT:

FIELD OF THE INVENTION
The present invention concerns a device for iontophoretic administration of drugs and more particularly to administration of drugs to the eye.
BACKGROUND OF THE INVENTION
The introduction of various drugs to the cornea of the eye, for example, administration of antibiotics for the treatment of microbial keratitus, is a complicated procedure. Presently, the routine treatment of microbial keratitus (MK) includes topical administration of highly concentrated antibiotics every 30 to 60 minutes day and night for several days. It should be noted that the bioavailability of a drug when administered in eye drops is very low (less than 1% of the administered dose) due to continuous rinsing of the drug by the tears.
An alternative method of administration of drugs is, by subconjunctival injections of antibiotics several times a day into the eye. The injections require a physician, are very painful and may cause severe complications such as perforation of the globe and scarring of the conjunctiva. Systematic administration of antibiotics is not effective in a vascular cornea.
Thus, there has been a constant search for development of alternative delivery techniques for overcoming the existing problems of administration of drugs to the eye. Some encouraging studies indicate efficacy of use of contact lenses soaked with highly concentrated antibiotics. However, these lenses may not be tolerable by patients with MK who commonly have inflamed and swollen conjunctiva and eye lids. There also have been some trials with liposomes incorporated with medicaments and use of laser, but these trials did not gain significant clinical acceptance.
Iontophoreesis (INT) is a noninvasive method which allows penetration of high concentrations of ionized molecules, such as drugs, into the tissue with the help of an electric current. In the past this method was utilized for anesthesia, for myringectomy, for diagnostic sweat testing in patients with cystic fibrosis and for administration of vidarabine in cases of herpes simplex. The drugs administered were steroids, antibiotics, peptides and analgesics. In ophthalmology, iontophoresis had been experimentally used in several animal studies to evaluate its efficacy in concentrating the drugs into the cornea or the eye. Barza
(1)
showed that transscleral INT using solutions may induce bactericidal concentrations of gentamicin (for several hours) in the vitreous of the monkey eye. Furthermore, repeated Electro Retino Graphia (ERG) tests did not show damage to the retina. Similar studies in the rabbit eyes presented high concentrations of gentamicin, cefazoline and ticarcillin in the vitreous
(2)
. Iontophoresis was also efficient for treatment of microbial endophthalmitis in the rabbit eye. It has been reported
(3)
that INT of tobramycin was more effective than topical administration of tobramycin for experimentally induced keratitus in the rabbit eye. INT of gentamicin via the cornea in aphakic rabbit eye revealed high levels of gentamicin in the vitreous. Finally, INT increased the penetration of ketaconazole (an antifungal drug) into the animals' anterior chamber
(4)
.
The major limitations of INT in all prior art reports and trials were in the use of drug solutions which required complicated design of instruments needed in order to keep the fluid drug solution in contact with the desired tissue during the process of the iontophoresis. Handling of fluids to ensure their contact with a desired tissue is tricky, since the fluids leak, and form bubbles that reduce the efficacy of ionthophoretic process.
Another approach to iontophoretic administration of drugs to the eye was described by Grossman, who reported that marked concentrations of gentamicin can be transferred into the rabbit comes by INT when the drug gentamicin was incorporated in soft agar gel (instead of in a liquid solution)
(5,6)
. However, the use of agar has major limitations as follows: agar is a biologic material, so that each batch preparation of the agar results in slightly different products causing problems in the reproducibility of the drug administration; the shelf life of agar is very limited, it has to be kept in a refrigerated and moist environment rendering it impractical for prolonged storage; agar is fragile and requires expertise to be placed directly in contact with the ocular surface without breaking; and finally some of the agar material will always stay on the ocular surface, causing irritation, eye redness and inflammation.
It would have been highly desirable to provide a device for iontophoretic administration of drugs to the eye which would be easy to operate, safe and would minimize damage to the eye.
SUMMARY OF THE INVENTION
The present invention concerns a device for iontophoretic administration of charged drugs to the eye comprising:
an applicator formed with a receiving portion adapted for holding a replaceable hydrogel carrier loaded with said drug and allowing contact of the carrier with a surface of the eye;
an electric current generating element, for generating currents not higher than about 1000 &mgr;Amp, being electrically coupled to the said receiving portion such that the current once generated passes through the hydrogel carrier in a direction essentially normal to said surface;
a timing element for activating the electrical current generating element for pre-set periods of time not exceeding 120 seconds; and
a switch for activating said timing device.
The device of the present invention is suitable for safe administration of iontophoretic drugs into the eye which do not exceed pre-set periods, and do not exceed maximum level of electric current. The device of the invention enables safe reproducible and repeated administration of drugs to the eye.
The term “charged drugs” refers to drugs which may be a priori charged, to the drugs which become charged in a solution with which the hydrogel carrier is loaded, as well as to drugs which are initially not charged, but become charged in the presence of an electrical current.
Examples of commonly used charged drugs include antibiotics such as: gentamicin, tobramycin, vancomycin; antifungal drugs including: miconazole, ketoconazole; anti-inflammatory agents such as: ibuprofen and its derivatives; timolol; steroids; anti glaucoma agents such as: pilocarpine; anticancer agents such as mitomicin C, methotrexate and 5-FU which are delivered to treat cancer of the eye or cornea; local anesthetics which are delivered to the eye and to the conjuctiva to anesthetize the eye before a treatment or reduce pain, such as lidocaine, bupivacaine and benoxinate.
The term “eye” refers to the external regions of the eyes and includes the cornea, conjuctiva, sclera, eye lids and lid margins.
The device comprises an applicator having a receiving portion which can hold a replaceable hydrogel carrier, that is loaded with the drug. The applicator is in the form which allows contact of the carrier and the surface of the eye. The applicator may be held by a specific external fixing device, for example, during an operation to ensure its position, but preferably, for ease of operation it should be hand held. The applicator may form a separate component of the device of the invention, or alternatively, the whole device of the invention may be in the form of a single instrument wherein the applicator is an integral part thereof.
The applicator has a receiving portion, for example in the form of an indention, or in the shape of a half-circle ring for holding a replaceable hydrogel carrier which is loaded with the drug. Preferably the indention is conical or cylindrical to accommodate a hydrogel carrier having a corresponding shape. Typically, the applicator or the whole device (when applicator is integral with the device) is in the shape of an elongated rod where the receiving portion is at the end of the rod.
The device includes an electrical current generating element which can be battery operated or connected to an external AC power source, for the generation of currents which are not higher than about 1000 &mgr;Amp.

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