IONTOPHORETIC DELIVERY OF BUPRENORPHINE

Abstract: A method of non-invasively administrating a therapeutic dose of buprenorphine to a patient is disclosed. This is accomplished by iontophoretically passing buprenorphine through a predetermined area of skin of the patient, in which the therapeutic dose of buprenorphine is capable of providing an analgesic effect to the patient for a selected period of time. An iontophoretic device for non-invasively administrating the therapeutic dose of buprenorphine to a patient is also disclosed.

Description: IONTOPHORETIC DELIVERY OF BUPRENORPHINE FIELD OF THE INVENTION The present invention relates to the iontophoretic transdermal delivery of buprenorphine. More specifically, the present invention concerns such delivery of buprenorphine at a flux sufficient to achieve a therapeutic dose, especially the therapeutic management of pain. BACKGROUND OF THE INVENTION Buprenorphine is an opioid agonist-antagonist with partial opioid agonist activity and has,until the present invention, never been administered in vivo via iontophoretic transdermal delivery. Presently, buprenoφhine is administered by injection and sublingually for the control of moderate to severe pain. It has also been used as an adjunct to anesthesia and in the treatment of opioid dependence. Buprenorphine is approximately thirty (30) times more potent than morphine. C 29 H 42 NO 4 Cl is Buprenorphine's chemical formula, its molecular weight is 468 (free base) and at pH<8 buprenorphine has a charge of +1. Buprenorphine has the following chemical structure: Following intra-muscular injection (i.m.) analgesia is apparent within thirty minutes and lasts up to six hours. A slow but prolonged response is achieved following sublingual administration. The dose by i.m. or slow intravenous injection for moderate to severe pain is 300 to 600mg of buprenorphine repeated every six to eight hours as required. Doses of 200 to 400mg are given sublingual every six to eight hours. Following intra-muscular administration, buprenorphine rapidly produces peak plasma concentrations. Absorption also takes place through buccal mucosa following sublingual administration. Buprenorphine is about 96% bound to plasma proteins. Plasma elimination half-lives have ranged from 1.2 to 7.2 hours; however, there is a lack of correlation between plasma concentrations and analgesic activity. Some is metabolism in the liver to N-dealkylbuprenorphine and conjugate metabolites, but buprenorphine is excreted predominantly unchanged in the feces; there is some evidence of enteroheptic recirculation. Metabolites are excreted in the urine, but very little unchanged drug. Buprenorphine is subject to considerable first-pass metabolism following oral administration (Martindale's - The Extra Pharmacopoeia 30th ed. The Pharmaceutical Press, pg. 1067-1069, incorporated herein by reference). Buprenoφhine is generally described as discussed above as a mixed agonist- antagonist acting mainly as a partial agonist at a receptors, with some antagonist activity at receptors. It has also been shown to bind , , and opioid binding sites and to have high affinity for the and receptor and lesser affinity for the receptor (Bovill JG. Which Potent Opioid? Important Criteria for Selection. Drugs 1987; 33:520-530, incoφorated herein by reference). Buprenoφhine like fentanyl, has high lipid solubility, but lower intrinsic activity. However, there are differences between buprenoφhine and a pure opioid agonist such as fentanyl, including relatively slow onset of action, prolonged duration of action, resistance to antagonism by naloxone, and lack of correlation between plasma concentrations and analgesic affects, have been explained by differences in the way buprenoφhine binds to opioid receptors. In a study in vitro buprenoφhine had slow rates of associated and disassociation from the opioid receptor when compared with fentanyl (Boas RA, Villiger JW. Clinical Actions of Fentanyl and Buprenoφhine: The Significance of Receptor Binding. BR. J. Anaesth. 1985; 57:192-196, incoφorated herein by reference). Buprenoφhine was delivered transdermally through cadaver skin as reported by Samir D. Roy, Eric Roos, and K. Sharma (J. Pharmaceutical Sci. vol. 83, no. 2, February 6, 1994). The authors estimated the transdermal delivery rate of buprenoφhine capable of inducing analgesia in humans from the pharmacokinetic parameters of the drug. Based on the parameters, the input or transdermal delivery rate can be estimated based on total body clearance and minimum effective concentration of buprenoφhine, a transdermal delivery rate of 1.9 to 2.7 g/cm 2 /L from a 20 cm 2 transdermal patch would provide adequate buprenoφhine blood levels for analgesia. The article concluded that the authors believed such delivery rates achievable because most of the transdermal formulations reported in the article provided skin fluxes several times tighter than the target delivery rate. However, as indicated in the examples contained herein the passive (transdermal) delivery of buprenoφhine delivered blood levels of buprenoφhine which over a twenty-four hour period failed to deliver human therapeutic dose of buprenoφhine. Iontophoresis is an attractive dosage form for the therapeutic management of pain. Its ability to rapidly deliver drugs to the systemic circulation and to control delivery profiles is particularly well-suited to the delivery of narcotic analgesics. SUMMARY OF THE INVENTION One embodiment of the present invention provides for an iontophoretic device for the iontophoretic delivery of buprenorphine. The iontophoretic device has (a) a current distributing member; (b) an ionized substance reservoir containing an ionized or ionizable substance, in electrical communication with the current distributing member and adapted to be placed in ionic communication with the epithelial surface; and wherein said ionized or ionizable substance is buprenoφhine; (c) an electrolyte reservoir containing an electrolyte, in electrical communication with an indifferent electrode and in ionic communication with an epithelial surface; (d) an electrical power source in current delivering connection with the current distribution member and the electrolyte reservoir. This device is capable of delivering an amount of buprenoφhine to a patient over a period of time which is provides a therapeutic concentration of buprenoφhine capable of providing an analgesic effect to the patient. Another embodiment of the present invention is a method of non-invasively administrating a therapeutic concentration of buprenorphine to a patient. Buprenoφhine is iontophoretically passed through a predetermined area of skin of the patient and a therapeutic concentration of buprenoφhine, wherein such therapeutic concentration of buprenoφhine is capable of providing an analgesic effect to the patient. DETAILED DESCRIPTION OF THE FIGURES FIGURE 1 depicts Fig.lA an intra-muscular calibration curve based on which the delivered dose was determined and Fig. IB plasma profiles of intra-muscular doses of buprenoφhine in man and swine. The human data represented is from Bullingham, et al. Clin. Pharmacol. Therap. vol. 28, no. 5, P 667, 1980, incorporated herein by reference. FIGURE 2 depicts iontophoresis calibration curve formulated from the areas under the curves of intra-muscular bolus doses in swine. FIGURE 3 compares the delivery from a 24-hour constant-current episode at 1.6 niA, a 1-hour episode at 1.6 mA and passive delivery. FIGURE 4 depicts the cumulative AUCs and corresponding delivered dose of the episodes in Figure 3. FIGURE 5 depicts an embodiment of the iontophoretic device of this invention. DETAD ED DESCRD7TION OF THE INVENTION The present invention relates to a method of non-invasively administrating a therapeutic concentration of buprenoφhine to a patient. Buprenoφhine is iontophoretically passed through a predetermined area of skin of the patient and a therapeutic concentration of buprenoφhine, wherein such therapeutic concentration of buprenoφhine is capable of providing an analgesic effect to the patient. Another embodiment of the present invention relates to an iontophoretic device for non-invasively administrating a therapeutic concentration of buprenoφhine to a patient, such therapeutic concentration of buprenoφhine being capable of providing an analgesic effect to the patient. (a) a current distributing member; (b) an ionized substance reservoir containing an ionized or ionizable substance, in electrical communication with the current distributing member and adapted to be placed in ionic communication with the epithelial surface; wherein said ionized or ionizable substance is a buprenoφhine. This device is capable of delivering an amount of buprenorphine effective for providing an analgesic effect in the patient to whom its delivered for a selected period of time; and (c) an electrolyte reservoir containing an electrolyte, in electrical communication with an indifferent electrode and in ionic communication with the epithelial surface; (d) an electrical power source in current delivering connection with the current distribution member and the electrolyte reservoir. The iontophoretic device of the present invention may by way of example and not limitation include the following component and materials. A. The Current Distributing Member (active electrode) The iontophoretic electrode of the invention includes a current distributing member which conveys electrical current into the iontophoretic reservoirs for the delivery of an ionized substance. The current distributing member is constructed of any of a large variety of electrically conductive materials, including both inert and sacrificial materials. Inert conductive materials are those electrically conductive materials which, when employed in the iontophoretic devices of the invention, do not themselves undergo or participate in electrochemical reactions. Thus, an inert material distributes without being eroded or depleted due to the distribution of current, and conducts current through the generating ions by either reduction or oxidation of water. Inert conductive materials typically include, for example, stainless steel, platinum, gold, and carbon or graphite. Alternatively, the current distributing member may be constructed from a sacrificial conductive material. A material may be considered sacrificial if, when employed as an electrode in an iontophoretic device of the invention, the material is eroded or depleted due to its oxidation or reduction. Such erosion or depletion occurs when the materials and formulations used in the iontophoresis device enable a specific electrochemical reaction, such as when a silver electrode is used with a formulation containing chloride ions. In this situation, the current distributing member would not cause electrolysis of water, but would itself be oxidized or reduced. Typically, for anodes, a sacrificial material would include an oxidizable metal such as silver, zinc, copper, etc. In contrast to the hydroxyl and hydronium ions electrochemically generated via an inert material, the ions electrochemically generated via a sacrificial material would include metal cations resulting from oxidation of the metal. Metal/metal salt anodes may also be employed. In such cases, the metal would oxidize to metal ions, which would then be precipitated as an insoluble salt. For cathodes, the current distributing member may be constructed from any electrically conductive material provided an appropriate electrolyte formulation is provided. For example, the cathodic current distributing member may be constructed from a metal/metal salt material. A preferred cathodic material is a silver/silver halide material. In such embodiments, a metal halide salt is preferably employed as the electrolyte. In this case, the device would electrochemically generate halide ions from the electrode as the metal is reduced. Also, accompanying silver ions in a formulation would be reduced to silver metal and would deposit (plate) onto the electrode. In other embodiments, the cathode material may be an intercalation material, an amalgam, or other material which can take electrolyte cations such as sodium out of solution, below the reduction potential of water. In addition, other materials may be used which permit the plating out of a metal from the appropriate electrolyte solution. Thus, metals such as silver, copper, zinc, and nickel, and other materials, such as carbon, may be employed when an appropriate metal salt such as silver nitrate or zinc sulfate is in solution in the electrolyte reservoir. While such materials may develop increased resistivity as a metal plates out during use, they are not eroded or depleted during use as cathodic current distributing members. They are therefore not strictly "sacrificial" in this context. Additional types of materials useful as current distributing members according to the invention are disclosed in detail in a co-pending application entitled Low-Cost Electrodes for an Iontophoretic Device , by N. Reddy et al., Serial No. 08 / 536, 029, filed on September 29, 1995 (Attorney Docket P-3066), the disclosure of which is incorporated by reference herein. The current distributing member may take any form known in the art, such as the form of a plate, foil layer, screen, wire, or dispersion of conductive particles embedded in a conductive matrix. B. The Electrolyte Reservoir 1. Electrolytes In the iontophoretic devices of the invention, an electrolyte reservoir is arranged in electrical communication with a current distributing member. Typically, electrical communication requires that electrons from the current distributing member are exchanged with ions in the electrolyte reservoir upon the application of electrical current. Such electrical communication is preferably not impeded to any excessive degree by any intervening material(s) used in the construction of the iontophoretic device. In other words, the resistivity of the interface is preferably low. The electrolyte reservoir comprises at least one electrolyte, i.e., an ionic or ionizable component which can act to conduct current toward or away from the current distributing member. Typically, the electrolyte comprises one or more mobile ions, the selection of which is dependent upon the desired application. Examples of suitable electrolytes include aqueous solutions of salts. A preferred electrolyte is an aqueous solution of NaCl, having a concentration of less than 1 mole/liter (< 1 M), more preferably at about physiological concentration. Other electrolytes include salts of physiological ions including, but not limited to, potassium, (K + ), chloride (Cl " ), and phosphate (PO 4 " ). The salt and its concentration may be selected as desired for particular applications. Other species may be selected by the skilled artisan for inclusion in the electrolyte reservoir. Such other reservoir species include, without limitation, chelation agents (e.g., citrate ions, EDTA) surfactants (e.g., non-ionic, cationic, or anionic), buffers, ionic excipients, osmolarity adjusters (e.g., polyethylene glycols, sugars), ionic antibiotics, penetration enhancers (e.g., alkanols), stabilizers, enzyme inhibitors, preservatives, thickening agents (e.g., acrylic acids, cellulosic resins, clays, polyoxyethylenes), and the like. Alternatively, the electrolyte may comprise a material which is itself relatively immobile in the absence of an electric field, but which acts to deliver mobile ions in the presence of an electric field. In the latter case, the electrolyte may more properly be termed an "ion source." Examples of ion sources according to the invention include polyelectrolytes, ion exchange membranes and resins, non-ionic buffers which become ionic upon pH change, and other known ion sources. Alternatively, the electrolyte reservoir may contain counterions that form a soluble salt with an electrochemically generated ion. For example, in an apparatus employing a silver anodal current distributing member, a suitable counterion might be acetate or nitrate. Such counterions are useful when other means are provided for sequestering electrochemically generated ions. Thus, the electrolyte reservoir can provide at least one ion of the same charge as the electrochemically generated ion, to permit current to be conducted, and at least one oppositely charged ion. C. The Ionized Substance (Drug) Reservoir The reservoir structure of the iontophoretic apparatus of the invention further includes an ionized substance reservoir. The ionized substance reservoir must be in ionic communication with an epithelial surface. The construction of the ionized substance reservoir must be consistent with the requirements for ionic communication with the epithelial surface and electrical communication with the current distribution member. Accordingly, the structure of the ionized substance reservoir would vary, depending upon the desired application. The ionized substance reservoir may include a liquid, semi-liquid, semi-solid, or solid material. With a flowable material, the ionized substance reservoir preferably further comprises means for at least substantially inhibiting the flow of the contents out of the reservoir. In such situations, the flow of the contents is desirably minimized when the device is in storage. For example, a membrane may be deployed to surround the contents of the ionized substance reservoir. In certain situations the flow of the contents of the reservoir may be minimized while in storage, but increased in use. For example, a surrounding membrane may increase in porosity, permeability, or conductivity upon the application of an electric field across the membrane. Examples of such membranes are disclosed in U.S. Patent Nos. 5,080,546; 5,169,382; and 5,232,438, the disclosures of which are incoφorated by reference herein. In preferred embodiments, the ionized substance reservoir is constructed to retain its physical integrity and to inherently resist migration and loss of the ionized substance. Such embodiments include those in which the ionized substance reservoir includes a solid or semi-solid material such as a gel or other polymeric material. In an especially preferred embodiment, the ionized substance reservoir includes a polymeric film in which the substance to be iontophoretically delivered is dispersed. The mobility of the substance to be delivered is substantially increased by the application of the electric field, permitting effective delivery across the target epithelial surface. Such a film need not contain any significant amount of hydrating material. In preferred embodiments, a cross-linked hydrogel in the electrolyte reservoir, because it inherently contains significant amounts of water, can serve as a water reservoir during iontophoresis. It may be desirable to provide the solution of active ingredient with a buffer. The ion of the buffer of like charge to the drug ion should have low ionic mobility. The limiting ionic mobility of this ion is preferably no greater that 1 x 10 " cm 2 /volt-sec. D. The Ionizable Substance (Drug) for Iontophoretic Delivery An ionic drug can be delivered from either the anode, the cathode, or both simultaneously. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode or anode will be the active electrode and the negative electrode or cathode will serve to complete the electrochemical circuit. Alternatively, if the ionic substance to be delivered is negatively charged, then the negative electrode will be the active electrode and the positive electrode will be the indifferent electrode. However, it is to be understood that an anodic configuration may be used to drive positively charged chemical modifications of the buprenoφhine without departing from the spirit of the invention. It is believed that this invention has utility in connection with the delivery of active ingredients within the broad class of buprenorphine as well as chemical modifications of buprenoφhine. E. Protective Backing The iontophoretic apparatus of the invention may also include a suitable backing film positioned on top of the electrolyte reservoir. The backing film provides protection against contamination and damage to the current distributing member, if present, and the electrolyte reservoir of the apparatus. F. Release Liner The iontophoretic apparatus of the invention optionally includes a release liner which may fixed to the underside of the ionized substance reservoir by an adhesive. The release liner protects the surface of the ionized substance reservoir which contact the epithelial surface from contamination and damage when the device is not in use. When the device is ready for use, the release liner may be peeled off to expose the epithelial contacting surface of the ionized substance reservoir for application of the device to a patient. G. Indifferent Electrode Iontophoretic devices require at least two electrodes to provide a potential to drive drug ions into the skin of a patient. Both electrodes are disposed to be in intimate electrical contact with the skin thereby completing the electrochemical circuit formed by the anode pad and cathode pad of the iontophoretic device. The electrode pads may be further defined as an active electrode from which an ionic drug is delivered into the body. An indifferent or ground electrode serves to complete the electrochemical circuit. Various types of electrodes may be employed such as is described in United States application entitled Low-Cost Electrodes for an Iontophoretic Device , by Reddy et al., Serial No. 08/ 536, 029 filed September 29, 1995. As depicted in Figure 5 an embodiment of the iontophoretic device of this invention 50 is configured as follows: an anode patch 10, having an anode electrode compartment 11 in ionic communication with a skin contacting compartment 13. The skin contacting compartment 13 and the anode electrode compartment 11 maybe separated by a compartment separation means (membrane) 17. The anode electrode compartment 11 also contains an anode 14 and an electrolyte (anolyte) 15. The skin contacting compartment is attached to the patient's skin 36. A cathode patch 20, having a cathode electrode compartment 21 in ionic communication with a skin contacting compartment 23. The skin contacting compartment 23 and the cathode electrode compartment 21 maybe separated by a compartment separation means (membrane) 27. The cathode electrode compartment 21 also contains an cathode 24 and an electrolyte (catholyte) 25. The skin contacting compartment is attached to the patient's skin 36. The results of the following experiments demonstrate successful delivery of buprenoφhine with iontophoresis which suggests that iontophoresis is an appropriate means of administering highly lipophilic agents. This is an unexpected result. In the past, the criteria for deliverability with iontophoresis included physiochemical characteristics at physiological conditions (pH 7-8) such as : high hydrophilicity , high aqueous solubility, and non-neutral charge. Hydrophilicity is measures by the relative distribution of the compound in non-aqueous and aqueous phases (typically oil and water). Distribution coefficients less than 1 indicate that the molecule prefers an aqueous environment. Likewise, high distribution coefficients (D o/w > 1) indicate lipophilic tendencies. Because iontophoresis is believed to occur along hydrophilic pathways in the skin, low distribution coefficients are often desirable; hence, high aqueous solubility is preferred. Finally, a non-neutral net charge allows the molecule to be directly influenced and transported by the electrical field (or current). However, the physiochemical properties of buprenoφhine do not match the typically 'preferred' characteristics iontophoreable compounds; yet, we were able, as the following examples show to demonstrate high levels of delivery with rapid onset of peak plasma levels in swine. Furthermore, the iontophoretic plasma levels were several fold higher than passive delivery of buprenoφhine (even with an ethanol- enhanced formulation in the passive device). The results of the following examples suggest that the criteria for appropriates candidates for iontophoresis can be expanded to include highly-lipophilic agents. Perhaps the new physiochemical characteristics can be described as follows at physiological pH: distribution: D 0/w < 50 (perhaps higher) aqueous solubility: S > 0.01 mg/ml charge: non-neutral While the present invention has been described in connection with iontophoresis, it should be appreciated that it may be used in connection with other principles of active introduction, i.e., motive forces. Accordingly, the invention is understood to be operative in connection with electrophoresis, which includes the movement of particles in an electric field toward one or the other electric pole (anode or cathode), and electroosmosis, which includes the transport of uncharged compounds due to the bulk migration of water induced by an electric field. Also it should be appreciated that the patient or subject may include humans as well as animals. EXAMPLES Iontophoretic and passive transdermal delivery studies were carried out on weanling Yorkshire swine (20-30 kg). Plasma levels of drug were measured using a commercially available radioimmunoassay (DPC, Inc.). A four-parameter logistic calibration model was used to calibrate experimental samples and assay sensitivity (minimum detectable concentration) was typically below 40 pg/ml in plasma. Buprenorphine HC1 was loaded into the anode compartment of an iontophoretic patch, and iontophoresis was carried out on swine as listed below. Plasma samples were drawn periodically and analyzed for Buprenoφhine. The delivered dose was determined in reference to the intra-muscular calibration curve in Figure 1. Operating conditions for the experiments were as follows: Anode: 10 mg/ml Buprenoφhine HC1 (pH4 citrate buffer) Cathode: 100 mM sodium chloride/ Ag, AgCl cathode Current: 1.2-4.8 mA Area: 6-8 cm 2 Duration: 1-24 hours (as noted) Passive patch: 25 mg/ml BupHCl (citrate buffer/50% ethanol) An iontophoresis calibration curve was formed from the areas under the curves of intra-muscular bolus doses in swine (Figure 2). This allowed estimation of intramuscular-equivalent dose delivered in the iontophoresis experiments. The calibrated dose range is 4-25 g/kg: therefore, the delivered dose can be estimated only within the corresponding AUC range of 3-10 nghr/ml. The therapeutic dose range is defined by the typical single and daily doses in humans; that is, 300-1000 g Buprenoφhine in 75 kg or 3-13 g/kg. This region is indicated by a shaded area. The effect of applied current on iontophoretic delivery of buprenoφhine in the same animal is illustrated in Figure 2. Three levels of current (6cm 2 active area) were applied in six hour episodes to the same animal. Plasma levels of buprenoφhine increased with increasing currents. At the end of the episode, plasma concentrations decreased rapidly in the first two hours, followed by a slow decrease for the remainder of the period. The delivered dose (inset) achieves or exceeds therapeutic targets of 3- 10 g/kg. Plasma levels of buprenoφhine are sustained at near-constant levels by applying current continuously over long periods. Figure 3 compares the delivery from a 24-hour constant-current episode at 1.6 mA, a 1-hour episode at 1.6 mA, and passive delivery. The 24-hour iontophoresis system achieves peak levels by the first sample while the passive system shows an extended lag period. The cumulative AUCs and corresponding delivered dose of the episodes in Figure 3 are shown in Figure 4. Clearly, in comparison to passive delivery, iontophoresis achieves therapeutic levels rapidly and sustains them for long periods. Furthermore, short episodes of iontophoresis are capable of achieving therapeutic levels quickly and in a sustained fashion. Since iontophoresis is generally believed to occur along hydrophilic pathways, lipophilic agents such as buprenoφhine represent a significant challenge to iontophoretic delivery. At physiological conditions, buprenoφhine is a monovalent cation below pH 8, and its low aqueous solubility (<0.1 mg/ml) and high liphophilicty (D 0/w > 50) suggest that its charge is at least partially shielded form the electrical field. Despite these 'unpreferred' characteristics, delivery is consistent with therapeutic doses in man, and peak plasma levels of drug are achieved rapidly. The successful delivery buprenorphine with iontophoresis might be attributed, in part, to its initial acidic formulation and the acid environment of the outer layers of skin. At low pH, buprenoφhine is reasonable soluble (>10 mg/ml), with relatively low liphophilicity (D o/w <5). During iontophoresis, buprenoφhine migrates from the patch into the so-called "acid mantle" of the skin which maintains a pH range of 4.5-6.5. Deeper into the (>100 m) physiological conditions of pH 7.4 are encountered, and the drug becomes more lipophilic. Clearance from these neutral-pH, lipophilic regions might account for the extended release profiles observed after short episodes of iontophoresis. In summary, iontophoresis is capable of delivery buprenorphine at levels consistent with prescribed daily doses in man. In comparison to passive delivery, iontophoresis achieves peak blood levels rapidly, and the total delivered dose can be controlled by adjusting the applied current. Short episodes of iontophoresis are also effective in delivering therapeutic quantities of buprenorphine. The demonstrated control of delivery and the rapid onset of blood levels make iontophoresis attractive delivery technique for therapeutic pain-management.

Claims: WHAT IS CLAIMED IS 1. A method of non-invasively administrating a therapeutic dose of buprenoφhine to a patient comprising the step of iontophoretically passing the buprenoφhine through a predetermined area of skin of the patient wherein such therapeutic dose of buprenoφhine is capable of providing an analgesic effect to the patient for a selected period of time. 2. An iontophoretic device for non-invasively administrating a therapeutic dose of buprenorphine to a patient, such therapeutic dose of buprenorphine being capable of providing an analgesic effect to the patient comprising: (a) a current distributing member; (b) an ionized substance reservoir containing an ionized or ionizable substance, in electrical communication with current distributing member and adapted to be placed in ionic communication with an epithelial surface, wherein said ionized or ionizable substance is buprenoφhine; and (c) an electrolyte reservoir containing an electrolyte, in electrical communication in different electrode and in ionic communication with an epithelial surface wherein said device is capable of delivering an amount of buprenoφhine effective capable of providing an analgesic effect to the patient for a selected period of time; (d) an electrical power source in current delivering connection with the current distribution member and the electrolyte reservoir.

Inventors: DENUZZIO JOHN D, DENUZZIO, JOHN, D.
Applicants: BECTON DICKINSON CO, BECTON DICKINSON AND COMPANY
Application year: 1997
Main classification: A61N1
IPC codes: A61N1