Device for transdermal electrotransport delivery of fentanyl and sufentanil

(19)

REPUBLIC

AUSTRIA

Patent Office (10) number: AT 409 720 B

CD h * cn o

<td> (12)</td><td></td><td></td>

<td> (21)</td><td>Application number:</td><td>A 9035/96</td>

<td></td><td></td><td>US96007380</td>

<td> (22)</td><td>Registration date:</td><td> 22.05.1996</td>

<td> (42)</td><td>Start of the patent term:</td><td> 15.03.2002</td>

<td> (45)</td><td>Issue date:</td><td> 25.10.2002</td>

PATENT FONT (30) Priority:

06/05/1995 US 460785 claimed. (56) Citations:

EP 529510A1 US4927408A US5203768A US5298017A US5314502A WO 9215365 (51) Intel⁷: A61N 1/30 (73) Patentee:

ALZA CORPORATION 94303 PALO ALTO (US).

(54) DEVICE FOR SELF-ADMINISTERING ANALGETICS (57) Device (10) for self-administration of analgesics by a pain patient by means of a device for transdermal delivery of an analgesic exclusively by electrotransport, the analgesic being in a hydrogel donor reservoir (26) of the device. To optimize the drug delivery, an electronic control circuit (19, 40) is provided, which functions as a dosage control circuit and ensures administration for at least one presettable time period of a predetermined duration, each of the time periods lasting a maximum of 20 minutes and the control circuit (19, 40) the number of Self-administrations limited to a maximum of 10 to 100 administrations in the first 24 hours of use.

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DVR 0078018

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The invention relates to a device for self-administration of analgesics by a pain patient by means of a device for transdermal delivery of an analgesic exclusively by electrotransport, the analgesic being located in a hydrogel donor reservoir of the device.

Such a device has become known from EP 529 510 A1. With this, the switching on and off of the power supply is effected by microelectronic components, switching on at any point in time and switching off after a predetermined period of time. A similar device is described in US Pat. No. 5,314,502. US Pat. No. 4,927,408 A, US Pat. No. 5,203,768 A and US Pat. No. 5,298,017 A as well as WO 92 15 365 deal with devices for transdermal drug administration by iontophoresis.

The transdermal delivery of drugs by diffusion through the epidermis offers improvements over more conventional methods such as subcutaneous injections or oral administration. Transdermal drug delivery avoids the first step hepatic effect encountered with oral delivery. Transdermal drug delivery also eliminates patient discomfort associated with subcutaneous injections. In addition, because of the extensive control of the delivery profile of certain types of transdermal delivery devices, transdermal delivery can provide more uniform concentrations of drugs in the patient's bloodstream over time. The term “transdermal” administration broadly encompasses administration through a body surface, such as the skin, mucous membrane or nails of a living being.

The skin functions as the primary barrier to transdermal penetration of materials into the body and is the body's primary resistance to transdermal delivery of a therapeutic such as a drug. Efforts today are focused on reducing physical resistance or improving permeability of the body Skin for drug delivery by passive diffusion.

Various methods of increasing the transdermal flow rate, mostly chemical flow improvers, have been tried.

Other attempts to increase transdermal drug delivery rates include the use of alternative energy sources such as electrical energy and ultrasonic energy. Electrically assisted transdermal delivery is also known as electrotransport. As used herein, "electrotransport" refers generally to the delivery of an agent (e.g. a drug) through a membrane such as the skin, mucous membranes, or nails. The administration is initiated or supported by the application of an electrical potential. For example, a beneficial therapeutic agent can be introduced through the skin into the human body's circulation by administering electrotransport. A widely used electrotransport process, electromigration (also called iontophoresis), involves the induced transport of charged ions. Another type of electrotransport, electroosmosis, involves the flow of a liquid containing the therapeutic agent to be administered under the action of an electric field. Yet another type of electrotransport process, electroporation, involves the formation of temporary pores in a biological membrane by the application of an electric field. Through the pores, a remedy can either passively (ie without electrical assistance) or actively (ie under the action of an electrical potential). However, in any given electrotransport process, more than one of these processes, including at least some “passive” diffusion, can occur simultaneously to some extent. Consequently, the term "electrotransport" as used herein is to be interpreted in the broadest sense to encompass the electrically induced or amplified transport of at least one therapeutic agent that is charged, uncharged, or a mixture thereof, regardless of the particular mechanism or mechanisms by which or to whom the remedy is actually transported.

In the case of electrotransport devices, at least two electrodes are used which are in electrical contact with an area of ​​skin, the nails, a mucous membrane or another body surface. An electrode, commonly known as a donor electrode, is the electrode from which the medicinal product is administered to the body. The other electrode, typically called the "counter" electrode, is used to complete the electrical circuit through the body. If z. B. the drug to be administered to the body is positively charged (ie, a cation), so is

AT 409 720 B the anode is the donor electrode, the cathode being the counter electrode that is used to close the circuit. When the drug is negatively charged (ie, an anion), the cathode is the donor electrode and the anode is the counter electrode. In addition, both the anode and the cathode can be viewed as donor electrodes when both anionic and cathionic drug ions are to be administered, or when uncharged dissolved drugs are to be administered.

Furthermore, electrotransport delivery devices generally require at least one reservoir or source of the beneficial agent to be administered to the body. Examples of such donor reservoirs include a pouch or cavity, a sponge or pillow, and a hydrophilic polymer or gel matrix. Such reservoirs are electrically connected to or interposed between the anode or the cathode and the body surface to provide a fixed or renewable source of one or more medicinal products or drugs. Electrotransport devices also typically have a source of electrical energy, such as one or more batteries. Typically, one pole of the energy source is electrically connected to the donor electrode at a time, while the other pole is electrically connected to the counter electrode. Since the rate of electrotransport drug delivery has been shown to be approximately proportional to the electrical current delivered by the device, many electrotransport devices typically have an electrical control unit that controls the voltage and / or current to the device. through the electrodes, whereby the rate of drug administration can be regulated. In these control circuits, various electrical components are used to control the amplitude, polarity, the course over time, the waveform, etc. of the electrical current and / or the electrical voltage of the energy source. S. z. B. U.S. Patent 5,047,007, McNichols et al.

Today commercially available electrotransport devices for transdermal drug delivery (e.g., the Phoresor sold by Lomed, Inc. of Salt Lake City, UT, the Dupel inotophoresis system sold by Empi, Inc. of St. Paul, MN, sold by Wescor, Inc. in Logan, UT, Webster Sweat Inducer Model 3600) generally used a table-top electrical power supply and a pair of electrodes for skin contact. The donor electrode contains a drug solution, while the counter electrode contains a solution of a biocompatible electrolyte salt. The power supply has electrical controls for adjusting the amount of electrical current flowing through the electrodes. The "satellite" electrodes are connected to the electrical power supply unit by (e.g. 1 to 2 m) long electrically conductive wires or cables. The wire connections can be interrupted and limit the patient's freedom of movement. Wires between the electrodes and controls can also be annoying and uncomfortable for the patient. Other examples of table-top electrical power units with "satellite" electrode units are shown in US Pat. No. 4,141,359 (Jacobson et al, see FIGS. 3 and 4), US Pat. No. 5,006,108 (LaPrade, see FIG. 9) ) and U.S. Patent 5,254,081 (Maurer et al).

Recently, small, self-contained electrotransport delivery devices have been proposed which can be worn on the skin, sometimes inconspicuously under clothing. Such small independent electrotransport delivery devices are e.g. For example, in U.S. Patent 5,224,927 (Tapper), U.S. Patent 5,224,928 (Sibalis et al), and U.S. Patent 5,246,418 (Haynes et al).

Recently there have also been proposals to use electrotransport devices with a reusable control unit, which are designed for use with drug-containing multiple units. The drug-containing units are simply disconnected from the control unit when the drug runs out, whereupon a fresh drug-containing unit is connected to the control unit. In this way, the relatively expensive hardware components of the facility (e.g. Batteries, LEDs, circuit hardware, etc.) remain in the reusable control unit and the relatively less expensive donor reservoir and counter reservoir matrices remain in the single drug-containing use / disposable unit, thereby reducing the overall cost of electrotransport delivery. Examples of electrotransport devices with a reusable control unit attached to a drug containing unit are shown in U.S. Patent 5,320,597 (Sage Jr. et al), U.S. Patent 5,358,483 (Sibalis), U.S. Patent 5,135,479 (Sibalis et al) al, Fig. 12) and in GB patent application 2,239,803 (Devane et al).

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In the advancement of electrotransport devices, hydrogels for use as medicaments and electrolyte reservoir matrices have become particularly preferred, partly because of the fact that water is the preferred liquid solvent in electrotransport applications because of its excellent biocompatibility with other liquid solvents such as alcohols and glycols. Drug delivery is. Hydrogels have a high equilibrium water content and can quickly absorb water. In addition, hydrogels tend to have good biocompatibility with the skin and mucosal membranes.

Of particular interest in transdermal administration is the administration of analgesic medicaments for the treatment of mild or severe pain. Control of the rate and duration of drug administration is particularly important when administering analgesic drugs transdermally in order to avoid the potential risk of overdosing and the discomfort of inadequate dosing.

One class of analgesics used in transdermal administration is the synthetic opiates, a group of 4-aniline-piperidines. The synthetic opiates, e.g. B. fentanyl and certain of its derivatives, such as sufentanil, are particularly suitable for transdermal administration. These synthetic opiates are characterized by the rapid onset of analgesia, high effectiveness and short action times. They are 80 or 800 times stronger than morphine. These drugs are weak bases, that is, amines, the main fraction of which is cationic in acidic media.

In an in v / Vo study to determine the plasma concentration, Thysman and Preat (Anesth. Analg. 77 (1993), p. 61-66) compared a simple fentanyl and sufentanil diffusion for electrotransport administration in a citrate buffer at pH 5. The simple diffusion did not produce any appreciable plasma concentration. The plasma levels achievable were dependent on the maximum flux of drug that could cross the skin and on the pharmacinetic properties of the drug, such as clarity and volume distribution. Electrotransport delivery had a remarkably reduced lag time (ie, the time to reach peak plasma levels) of 1.5 hours versus 14 hours compared to passive transdermal pillows. The conclusions of the researchers were that the electrotransport of these analgesic drugs can effect a more rapid control of pain than classic pillows and that the pulsed delivery of drugs (by controlled electric current) was comparable to the constant administration of classic pillows. S. also z. B. Thysman et al, Int. J. Pharma, 101: 105-113 (1994), V. Preat et al, Int. J. Pharma, 96 (1993), pp 189-196 (sufentanil), Gourlav et al, Pain, 37 (1989), pp 193-202 (fentanyl), Sebel et al, Eur. J. Clin. Pharmacol, 32: 529-531 (1987) (fentanyl and sufentanil). The passive, ie by means of diffusion, and the electrically assisted transdermal administration of analgesic narcotics, such as fentanyl, to induce analgesia have both been described in the patent literature. S. z. B. U.S. Patent 4,588,580 (Gale et al) and U.S. Patent 5,232,438 (Theeuwes et al).

In recent years, attention in the management of post-operative pain has been turned to the development of other than electrotransport delivery. Particular attention has been paid to devices and systems which, within predetermined limits, enable the patient to control the amount of analgesic that the patient receives. The general experience with these types of devices has been that control of the administration of an analgesic by the patient has resulted in the administration of smaller amounts of analgesic than would have been the case when the dosage was prescribed by a physicist. Self-administration or patient-controlled self-administration has come to be known (and hereinafter referred to as patient-controlled analgesia, PCA).

Known PCA devices are typically electromechanical pumps which require large capacity electrical power sources, e.g. B. AC or large capacity multiple batteries that are bulky. Because of their bulkiness and complexity, commercially available PCA devices generally require that the patient be confined to a bed or other substantially fixed location. Known PCA devices deliver a drug to the patient by means of an intravenous line or a catheter which must be introduced into the intended vein, artery or other organ by a qualified medical-technical person. This process requires that the skin barrier must be broken in order to

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To administer analgesic (see U.S. Patent 5,232,448, Zdeb). Thus, when using commercially available PCA devices, the PCA requires the presence of highly specialized medical-technical personnel to initiate and monitor the PCA operation, which means that there is a risk of infection for the carer. Furthermore, the commercially available PCA devices are somewhat painful to use even because of the percutaneous (ie intravenous or subcutaneous) intervention.

There has been little in the art in the field of transdermal electrotransport devices that can compete with conventional PCAs in terms of the amount of drug administered to achieve adequate analgesia and in a patient-controlled manner. Furthermore, there would be little progress in creating a hydrogel tuning for analgesic electrotransport, especially for transdermal electrotransport administration of fentanyl, which has long-lasting stability and application properties that are comparable to patient-controlled electromechanical pumps for e.g. intravenous administration of an analgesic. Thus, there is a need to provide an analgesic vote in an appropriate facility to take advantage of the convenience of electrotransport delivery in a small, self-contained patient-controlled facility.

The present invention provides a device for improved transdermal electrotransport delivery of fentanyl and its analogs, particularly sufentanil. The device of the present invention creates a greater degree of efficacy in electrotransport delivery of analgesic fentanyl or sufentanil at the same time as it creates a greater degree of patient safety and comfort in pain management. The above and other advantages of the present invention are achieved according to the invention with a device of the type mentioned at the outset in that an electronic control circuit (19, 40) is provided which functions as a dosing control circuit and ensures administration for at least one presettable time period of a predetermined duration, wherein each of the time periods lasts a maximum of 20 minutes and the control circuit limits the number of self-administrations to a maximum of 10 to 100 administrations in the first 24 hours of use.

The present invention relates to a device for administering fentanyl or sufentanil by means of transdermal electrotransport for the treatment of mild to severe pain after major surgical interventions. A transdermal electrotransport dose of about 20 pg to about 60 pg of fentanyl administered over an administration period of up to about 20 minutes is therapeutically effective for treating mild to severe postoperative pain in human patients weighing more than about 35 kg. Preferably, the amount of fentanyl administered is between about 35 µg and 45 µg over an administration period of about 5 to 15 minutes, and most preferably about 40 µg over 10 minutes. Because fentanyl has a relatively short distribution half-life once administered to the human body (ie, about 3 hours), the means for inducing analgesia preferably includes means for maintaining the analgesia so induced. Thus, the device for transdermal delivery of fentanyl by electrotransport preferably has means for delivering at least one additive, more preferably from about 10 to 100 additives, and most preferably from about 20 to 80 additives, such as equal doses of fentanyl over subsequent equal administration times during a 24-month period Hour period. The ability to deliver multiple identical doses from a fentanyl electrotransport transdermal delivery device also creates the ability to treat larger numbers of patients where different patients require different amounts of fentanyl to control their pain. By creating the possibility of administering multiple small transdermal doses of fentanyl by means of electrotransport, the patients can organize themselves to administer only that amount of fentanyl that is necessary to bear their pain and no more.

Further advantages and a full understanding of the specific adaptations, variations of the connections and physical properties of the present invention can be obtained from a review of the following drawings, detailed description, example and the appended claims.

The present invention will be described below in conjunction with the accompanying drawings

AT 409 720 B described; 1 shows an exploded diagrammatic view of an electrotransport drug administration device according to the invention, FIG. 2 shows a diagram to show the quality of analgesia in patients treated with transdermal electrotransport fentanyl as a function of time, and FIG. 3 shows a diagram to show the intensity of pain with transdermal electrotransport fentanyl treated patients as a feature currently.

The present invention provides an electrotransport delivery device for a fentanyl or sufentanil salt and a method of using the same to achieve an analgesic effect on the body system comparable to the effect of known IV treated patient controlled analgesic pumps. The invention provides an electrotransport delivery device for delivering fentanyl or sufentanil through a body surface, e.g. B. the skin, to achieve the analgesic effect. The fentanyl or sufentanil salt is kept ready in a donor reservoir of the electrotransport delivery device, preferably as an aqueous salt solution.

The dose of the fentanyl delivered by transdermal electrotransport for human patients with a body weight of 35 kg and more is about 20 pg to about 60 pg over an administration period of up to 20 minutes.A dosage of about 35 pg to about 45 pg and am is preferred Most preferred is a dosage of about 40 pg for the duration of administration. The device according to the invention further preferably has means for administering about 10 to 100 and more preferably about 20 to 80 additives such as doses over a period of 24 hours in order to achieve and maintain the analgesic effect.

The dose of sufentanil administered by transdermal electrotransport is about 2.3 pg to about 7.0 pg over an administration time of up to about 20 minutes for human patients with a body weight of 35 kg and more. A dosage of about 4 pg to about 5.5 pg is preferred and a dosage of about 4.7 pg is most preferred for the duration of administration. The device according to the invention also preferably has means for administering about 10 to 100, more preferably about 20 to 80, additives of the same doses over a period of 24 hours in order to achieve and maintain the analgesic effect.

The anodic reservoir configuration containing fentanyl / sufentanil salt for transdermal administration of the above-mentioned fentanyl / sufentanil doses by means of electrotransport preferably consists of an aqueous solution of a water-soluble fentanyl / sufentanil salt, such as HCl or citrate salts. Most preferably the aqueous solution is contained in a hydrophilic polymer matrix, such as a hydrogel matrix. The fentanyl / sufentanil salt is present in an amount sufficient to deliver the above-mentioned doses transdermally by electrotransport over a period of up to 20 minutes per administration to produce an analgesic effect on the body system. The fentanyl / sufentanil salt typically comprises from about 1 to 10% by weight of the donor reservoir composition (including the weight of the polymer matrix) on a fully hydrated basis, and more preferably from about 1 to 5% by weight of the donor reservoir composition on a fully hydrated basis. Although not critical to this aspect of the invention, the preferred electrotransport current density is typically in the range of about 50 to 150 pA / cm² and the electrotransport current applied is typically in the range of about 150 to 240 pA.

The fentanyl / sufentanil salt-containing anodic hydrogel may suitably be made from several materials, but is preferably made from a hydrophilic polymer material, preferably one that is polar in nature so that it enhances drug stability. Suitable polar polymers for the hydrogel matrix consist of various synthetic and naturally occurring polymer materials. A preferred hydrogel formulation contains a suitable hydrophilic polymer, a buffer, a humectant, a thickener, water, and a water-soluble fentanyl or sufentanil salt (e.g., an HCl salt). A preferred hydrophilic polymer matrix is ​​polyvinyl alcohol, such as a washed and fully hydrolyzed polyvinyl alcohol (PVOH), e.g. B. Mowiol 66-100 available from Hoechst Aktiengesellschaft. A suitable buffer is an ion exchange resin which is a copolymer of methacrylic acid and divinylbenzene in both acidic and salt forms. An example of such a buffer is a mixture of polacrilin (the copolymer of methacrylic acid and divinylbenzene from Rohm &amp; Haas, Philadelphia, PA) and its potassium salt. A mixture of the acidic and potassium salt forms of polacrilin functions as a polymeric buffer to adjust the pH of the hydrogel to around pH 6. The use of the humectant in the hydrogel setting promotes the avoidance of dampness6

AT 409 720 B keitsverlusten the hydrogel. An example of a suitable humectant is guar gum. Thickeners are also helpful in hydrogel tuning. For example, a polyvinyl alcohol thickener such as hydroxypropylmethyl cellulose (e.g., Methocel K100MP, available from Dow Chemical, Midland, MI) helps modify the rheology of a hot polymer solution as it is dispensed into a mold or cavity.

The hydroxypropyl methycellulose increases viscosity when cooled and remarkably reduces the tendency of a cooled polymer solution to overfill the mold or cavity.

In a preferred embodiment, the fentanyl / sufentanil salt containing anodic hydrogel formulation contains about 10 to 15% by weight polyvinyl alcohol, 0.1 to 0.4% by weight resin buffer and about 1 to 2% by weight fentanyl or sufentanil salt, preferably the hydrochloride salt . The rest are water and ingredients such as humectants, thickeners, etc. The polyvinyl alcohol (PVOH) based hydrogel formulation is prepared by mixing all of the materials, including the fentanyl or sufentanil salt, in a single vessel at elevated temperatures of about 90 ° C to 95 ° C for at least about 0.5 hour. The hot mixture is poured into a foam mold and stored at a freezing temperature of about -35 ° C overnight to polymerize the PVOH. After warming up to room temperature, a resilient elastomeric gel is obtained, which is suitable for the electrotransport of fentanyl.

The hydrogel adjustments are used in an electrotransport device as explained below. A suitable electrotransport device has an anodic donor electrode, preferably made of silver, and a cathodic counter-electrode, preferably made of silver chloride. The donor electrode is in electrical contact with the donor reservoir, which contains the aqueous solution of a fentanyl / sufentanil salt. As discussed above, the donor reservoir is preferably a hydrogel formulation. The counter-reservoir also preferably has a hydrogel formulation that contains a (e.g., aqueous) solution of a biocompatible electrolyte, such as a citrate-buffered saline solution. The anodic and cathodic hydrogel reservoirs preferably each have a skin contact area of ​​about 1 to 5 cm² and more preferably about 2 to 3 cm². The anodic and cathodic hydrogel reservoirs preferably have a thickness of about 0.05 to 0.25 cm, and more preferably about 0.15 cm. The electrotransport current applied is about 150 μΑ to about 240 μΑ, depending on the desired analgesic effect. A substantially constant direct current is most preferred as the electrotransport current during the metering time.

Reference is now made to Figure 1 which shows one embodiment of an electrotransport device that can be used in accordance with the invention. 1 shows an exploded perspective view of an electrotransport device with an activation switch in the form of a push-button switch 12 and a display in the form of a light-emitting diode (LED) 14. The device 10 consists of an upper housing 16, a circuit board unit 18, a lower housing 20, an anode 22, a cathode 24, an anode reservoir 26, a cathode reservoir 28 and a skin-friendly adhesive film 30. The upper housing 16 has lateral wings 15 which assist in holding the device 10 'against the skin of a patient. The upper housing 16 is preferably made from an injection moldable elastomer (e.g., ethylene vinyl acetate). The circuit board unit 18 has an integrated circuit 19 which is connected to discrete components 40 and a battery 32. The circuit board 18 is attached to the housing 16 with feet (not shown in FIG. 1) which protrude through openings 13a and 13b and the ends of which are heated or melted in order to hold the circuit board 18 on the housing 16 at a distance. The lower housing 20 is fastened to the upper housing 16 by means of the adhesive film 30, the top side 34 of which is glued to both the lower housing 20 and the upper housing 16 including the underside of the blades 15.

A button battery 32, preferably a lithium cell, is arranged on the underside of the circuit board 18 (only partially shown). Other battery types can also be provided for supplying the device 10.

The outputs of the circuit board 18 (not shown in FIG. 1) are in contact with the electrodes 22, 24 through openings 23, 23 'in recesses 25, 25' formed in the lower housing 20 by means of electrically conductive adhesive strips 42, 42 '. The electrodes 22, 24, on the other hand, are in direct mechanical and electrical contact with the upper sides 44, 44 'of the medicament reservoirs

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26, 28. The undersides 46, 46 'of the drug reservoirs 26, 28 contact the patient's skin through openings 29, 29' in the adhesive film 30. After pressing the push-button switch 12, the electronic circuit on the circuit board 18 sends a predetermined direct current to the electrodes / Reservoirs 22, 26 and 24, 28 for a dispensing interval of a predetermined length, for example about 10 minutes. Preferably, the device transmits to the user a visible and / or audible confirmation of the activation of the drug delivery or bolus by means of the LED 14, which lights up, and / or an audible tone signal, e.g. B. a "beeper". An analgesic drug, e.g. B. fentanyl, through the patient's skin, e.g. B. on the arm, administered for the predetermined administration period (z. B. 10 minutes). In practice, the user receives feedback on the start of the duration of drug administration (LED 14 is switched on) and / or audible signals (a “beep” from the “beeper”).

The anode 22 is preferably made of silver and the cathode 24 is preferably made of silver chloride. Both reservoirs 26 and 28 are preferably made of a polymeric hydrogel. The electrodes 22, 24 and the reservoirs 26, 28 are held in the lower housing 20. For the fentanyl and sufentanil salts, the anodic reservoir 26 is the “donor” reservoir, which contains the drug, whereas the cathodic reservoir 28 contains a biocompatible electrolyte.

The push button switch 12, the electronic circuitry on the board unit 18 and the battery 32 are glued between the upper housing 16 and the lower housing 20. The upper housing 16 is preferably made of rubber or some other elastomeric material. The lower housing 20 is preferably made of a plastic or elastomeric flat material (e.g. Polyethylene), which can be simply poured to form the depressions 25, 25 'and easily cut to form the openings 23, 23'. The assembled device 10 is preferably water-resistant (ie, splash-proof) and most preferably water-tight. The system has a low profile that adapts easily to the body and thus allows freedom of movement at and around the carrying point. The anodic drug reservoir 26 and the cathodic salt reservoir 28 are disposed on the skin contact side of the device 10 with sufficient spacing to prevent accidental electrical shorting during normal handling and use.

The device 10 adheres to the body surface (e.g. the skin) of the patient with the aid of the adhesive film 30, which has an upper side 34 and a body contact side 36. The side 36 has adhesive properties which ensure that the device 10 remains in place during the normal activities of the user on the body and still permits tolerable removal after the predetermined period of wear (e.g. 24 hours). The top 34 adheres to the lower housing 20 and holds the electrodes and medicament reservoirs within the housing recesses 25, 25 ′ and the lower housing 20 to the upper housing 16.

The push button switch 12 is located on top of the device 10 and is easy to operate through clothing. To activate the device for dispensing the drug, the push-button switch 12 is preferably activated within a short period of time, e.g. B. three seconds, pressed twice, whereby the likelihood of inadvertent activation of the device 10 is minimized.

Upon actuation of the switch, an audible alarm signal indicates the start of drug administration, with the circuit delivering a predetermined level of direct current to the electrodes / reservoirs for a predetermined administration time (e.g., 10 minutes). The LED 14 remains switched on during the entire duration of the administration and thus indicates that the device 10 is in the active administration state. The battery preferably has sufficient capacity to continuously power the device 10 at the predetermined DC level for the entire period of wear (e.g. 24 hours).

Preferably, the concentration of the fentanyl or sufentanil in the solution in the donor reservoir is maintained at or above the level at which the transdermal electrotransport of the fentanyl / sufentanil flow is independent of the drug concentration in the donor reservoir during the electrotransport administration period. The transdermal electrotransport fentanyl flux begins to depend on the concentration of the fentanyl salt in the aqueous solution when the fentanyl salt concentration falls below about 11 to 16 mM. The 11 to 16 millimolar concentration (mM) is calculated based only on the volume of liquid solution used8

AT 409 720 B, which is used in the donor reservoir, but not the total volume of the reservoir. In other words, the 11 to 16 mM concentration does not include the volume of the reservoir represented by the reservoir matrix (e.g., hydrogel or other matrix) material. Furthermore, the 11 to 16 mM concentration is based on the number of moles of the fentanyl salt, not the equivalent number of moles of the free fentanyl base contained in the donor reservoir solution. For fentanyl HCl, the 11 to 16 mM concentration is approximately 4 to 6 mg / ml equivalent. Other fentanyl salts (e.g. Fentanyl citrate) have slightly different concentration ranges on a weight basis based on the difference in molecular weight of the counterion of the particular fentanyl salt in question. When the fentanyl salt concentration falls below about 11 to 16 mM, the transdermal electrotransport fentanyl flux begins to decrease markedly, even if the applied electrotransport current remains constant. To ensure a predictable fentanyl flow at a particular level of electrotransport current, the fentanyl concentration in the solution contained in the donor reservoir is therefore preferably kept above 11 mM and more preferably above 16 mM. Except for fentanyl, water-soluble salts of sufentanil also have a minimal solution concentration in the water, below which the transdermal electrotransport flow becomes dependent on the concentration of the sufentanil salt in the solution. The minimum concentration is about 1.7 mM for sufentanil, which is equivalent to about 1 mg / ml for sufentanil citrate.

Since fentanyl and sufentanil are both bases, the salts of fentanyl and sufentanil are typically acidic additive salts, e.g. B. citrate salts, hydrochloride salts, etc. The acidic additive salts of fentanyl typically have a water solubility of about 25 to 30 mg / ml. The additive acid salts of sufentanil typically have a water solubility of about 45 to 50 mg / ml. If these salts are in solution (e.g. aqueous solution), then the salts dissolve and form protonated fentanyl or sufentan anions and counterions (e.g. citrate or chloride) anions. As such, the fentanyl / sufentan anilations are delivered from the anodic electrode of an electrotransport delivery device. For transdermal electrotransport delivery, silver anodic electrodes have been suggested as a way to maintain pH stability in the anodic reservoir. S. z. B. U.S. Patent 5,135,477 (Untereker at al) and U.S. Patent 4,752,285 (Petelenz et al). These patents also address the inadequacies of using anodic silver electrodes in an electrotransport delivery device, namely that the introduction of a current through the silver anode causes the silver to oxidize (Ag -&gt; Ag⁺ + e '), thereby forming silver cations that compete with the cationic drug for electrotransport delivery to the skin. Silver ion migration into the skin leads to a temporary epidermal discoloration (TED) of the skin. In accordance with the teachings of these patents, the cationic fentanyl and sufentanil are preferably used as halogen salts (e.g. Hydrochloride salt) so that the electrochemically generated silver ions react with the drug counterions (i.e. halogen ions) to produce a substantially insoluble silver halide (Ag⁺ + X '- ► AgX). In addition to these patents, WO 95/27 530 (Phipps et al) teaches the use of supplementary sources of chloride ions in the form of high molecular weight chloride resins in the donor reservoir of a transdermal electrotransport delivery device. These resins are highly effective in providing sufficient chlorides to prevent silver ion migration and associated skin discoloration when fentanyl or sufentanil is transdermally administered by electrotransport using a silver anodic electrode.

The invention is further illustrated by the following examples, which are illustrative but do not limit the scope of the invention.

EXAMPLE 1

The following studies were conducted to determine the transdermal electrotransport dosage level required to achieve acceptable levels of analgesia in human patients suffering from mild to severe postoperative pain. The study was conducted in 132 postoperative male and female patients who were expected to experience mild to severe pain after surgery, including orthopedic (shoulder, knee, long bones) and abdominal (urological, gynecological) operations. the

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Patients wore one of two different electrotransport fentanyl HCl delivery devices on the upper arm for 24 hours after surgery. Both devices gave an electrotransport current for an administration time of 10 minutes after activating the push button switch on the device. The first device was worn by 79 of the 132 patients and delivered an electrotransport current of 150 μM, with which a mean fentanyl dose of 25 μg was administered during the 10-minute administration period. The second device was worn by 53 of the 132 patients and delivered an electrotransport current of 240 μM, with which a mean fentanyl dose of 40 pg was administered during the 10-minute administration period.

In both facilities, patients could self-administer up to 6 doses every hour. The patients with the first facility (i.e. 25 μg dose) could apply a maximum of 144 doses. Patients with the second facility (ie 40 μg dose) were allowed to use up to a maximum of 80 doses.

Both devices were two-part systems that included a reusable control unit and a single disposable unit containing a drug. Each drug unit contained an anodic donor gel containing fentanyl HCl and a cathodic counter gel containing a saline solution. All gels had skin contact areas of 2 cm² and a thickness of 0.16 cm. The weight of the donor gels was approximately 350 mg. The anodic donor gels in the 25 μg dose and 40 μg dose systems were of the same size and composition; only the level of the emitted electrotransport current was different. The cathodic counter-electrodes each had a gel based on PVOH which contained a citrate-buffered saline solution. A cathodic silver chloride electrode was laminated to one surface of the counter gel. The anodic 25 pg and 40 pg dose gels had the following composition:

<td>material</td><td>Weight</td>

<td>water</td><td> 73,2</td>

<td>PVOH</td><td> 10,0</td>

<td>Fentanyl HCl</td><td> 1,4</td>

<td>Polacrilin</td><td> 0,3</td>

<td>Polacrilin Potassium</td><td> 0,1</td>

<td>Glycerin</td><td> 5,0</td>

<td>Cholestyramine resin</td><td> 10,0</td>

All patients were given intravenous fentanyl up to an acceptable level of analgesia immediately after surgery in a recovery room. Within 3 hours of surgery, when the patients had reached normal hospital discharge standards and were able to operate the electrotransport delivery device they carried, the patients were taken to a caregiver where they transdermally the fentanyl themselves Were able to administer electrotransport to treat their pain, in which case Since electrotransport fentanyl administration was inadequate to control pain, patients were given supplemental fentanyl intravenously to achieve the desired analgesia.

In the 25 pg dose group, 38 of the 79 patients (i.e. 48%) did not need any supplementary IV fentanyl after leaving the recovery room. In the 40 μg dose group, 47 of the 53 patients (i.e. 89%) did not need any supplementary IV fentanyl after leaving the recovery room. Based on these percentages, it was determined that the 25 µg dose treatment was sufficient to control the pain associated with these types of surgery in approximately half of the patients. The 40 pg dose treatment was sufficient to control the pain associated with these types of surgery in approximately 90% of the patients tested. Since the 25 μg dose treatment was analgesically effective in about half of the patients, treatments with lower doses of about 20 to 30 μg and preferably about 20 to 25 μρ fentanyl over the same dosage times (ie up to 20 minutes) is also effective and is not subject to inadvertent overdose in the control of lighter acute pain such as hernia surgery, kidney stones, arthritis complaints, laparoscopy and other circumstances where less pain than major surgery occurs

AT 409 720 B occur. The correspondingly lower dosage for sufentanil is about 2.3 pg to about 3.5 pg and preferably about 2.3 pg to 2.9 pg over the same metering times (ie up to 20 minutes).

Pain intensity was estimated initially immediately prior to activation of the first desired dose and then again after 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 hours after the first activation of the devices. Patients were asked to estimate pain intensity by marking a 10 cm strip on a scale from 1 to 100, with 1 for no pain and 100 for most severe pain. The quality of the analgesia was rated excellent, good, satisfactory, or unsatisfactory according to the same schedule as that for the pain intensity measurement by ranking.

The quality of analgesia and pain intensity data for the 53 patients using the 40 pg dose electrotransport device are shown in Figures 2 and 3, respectively.

The skin areas under the anodic and cathodic gel were examined after 1, 6 and 24 hours after the devices had been removed and examined for local effects (e.g. irritation). The effect data are shown in Table 1.

TABLE 1

<td>hours</td><td>ETS</td><td>brand</td><td>edema</td><td>Redness</td><td>extent</td><td>itch</td><td>Papules</td><td>Pustules</td>

<td>after</td><td>Skin-</td><td></td><td> (%)</td><td> (%)</td><td>d. Redness</td><td> (%)</td><td> (%)</td><td> (%)</td>

<td>acceptance</td><td>area</td><td></td><td></td><td></td><td> (%)</td><td></td><td></td><td></td>

<td> 1</td><td>anode</td><td> 0</td><td> 74</td><td> 15</td><td> 19</td><td> 91</td><td> 92</td><td> 100</td>

<td></td><td></td><td> 1</td><td> 8</td><td> 49</td><td> 32</td><td> 6</td><td> 6</td><td> 0</td>

<td></td><td></td><td> 2</td><td> 19</td><td> 36</td><td> 49</td><td> 4</td><td> 2</td><td> 0</td>

<td></td><td>cathode</td><td> 0</td><td> 92</td><td> 72</td><td> 74</td><td> 94</td><td> 94</td><td> 100</td>

<td></td><td></td><td> 1</td><td> 6</td><td> 19</td><td> 13</td><td> 4</td><td> 6</td><td> 0</td>

<td></td><td></td><td> 2</td><td> 2</td><td> 9</td><td> 13</td><td> 2</td><td> 0</td><td> 0</td>

<td> 6</td><td>anode</td><td> 0</td><td> 74</td><td> 15</td><td> 17</td><td> 89</td><td> 92</td><td> 100</td>

<td></td><td></td><td> 1</td><td> 11</td><td> 43</td><td> 34</td><td> 8</td><td> 8</td><td> 0</td>

<td></td><td></td><td> 2</td><td> 15</td><td> 40</td><td> 49</td><td> 4</td><td> 0</td><td> 0</td>

<td></td><td></td><td> 3</td><td> 0</td><td> 2</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td></td><td>cathode</td><td> 0</td><td> 92</td><td> 68</td><td> 68</td><td> 91</td><td> 91</td><td> 100</td>

<td></td><td></td><td> 1</td><td> 4</td><td> 19</td><td> 13</td><td> 9</td><td> 6</td><td> 0</td>

<td></td><td></td><td> 2</td><td> 4</td><td> 9</td><td> 19</td><td> 0</td><td> 4</td><td> 0</td>

<td></td><td></td><td> 3</td><td> 0</td><td> 4</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td> 24</td><td>anode</td><td> 0</td><td> 83</td><td> 34</td><td> 36</td><td> 91</td><td> 96</td><td> 98</td>

<td></td><td></td><td> 1</td><td> 9</td><td> 40</td><td> 38</td><td> 8</td><td> 4</td><td> 2</td>

<td></td><td></td><td> 2</td><td> 8</td><td> 26</td><td> 36</td><td> 2</td><td> 0</td><td> 0</td>

<td></td><td></td><td> 3</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td></td><td>cathode</td><td> 0</td><td> 91</td><td> 70</td><td> 70</td><td> 91</td><td> 89</td><td> 98</td>

<td></td><td></td><td> 1</td><td> 6</td><td> 19</td><td> 15</td><td> 8</td><td> 8</td><td> 0</td>

<td></td><td></td><td> 2</td><td> 4</td><td> 8</td><td> 15</td><td> 2</td><td> 4</td><td> 2</td>

<td></td><td></td><td> 3</td><td> 0</td><td> 4</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td>Redness:</td><td></td><td></td><td></td><td></td><td>Itch:</td><td></td><td></td><td></td>

<td>0 = none</td><td></td><td></td><td></td><td></td><td>0 = none</td><td></td><td></td><td></td>

<td colspan="3">1 = hardly noticeable redness</td><td></td><td></td><td>1 = weak</td><td></td><td></td><td></td>

<td colspan="2">2 = noticeable redness</td><td></td><td></td><td></td><td>2 = medium</td><td></td><td></td><td></td>

<td colspan="2">3 = deep redness</td><td></td><td></td><td></td><td>3 = strong</td><td></td><td></td><td></td>

Edema, papules, pustules Extent of redness:

AT 409 720 B = none = &lt;50% of the skin area =&gt; 50% of the skin area

EXAMPLE 2

Two anodic donor reservoirs containing fentanyl hydrochloride were prepared with PVOH-based gels having the following compositions:

Donor gel formulations:

<td>material</td><td>Wt%</td><td>Weight⁰/</td>

<td>distilled water</td><td> 86,3</td><td> 85,3</td>

<td>washed PVOH</td><td> 12,0</td><td> 12,0</td>

<td>Fentanyl HCl</td><td> 1,7</td><td> 1,7</td>

<td>Hydroxymethyl cellulose</td><td></td><td> 1,0</td>

Both formulations were mixed with water and PVOH at a temperature between 92 ° C. and 98 ° C., and then fentanyl hydrochloride was added and then mixed further. The liquid gel was then pumped into molds with cup-shaped cavities. The molds were placed in a -35 ° C freezer overnight to crosslink the PVOH. The gels can be used as anodic donor reservoirs suitable for electrotransport fentanyl delivery for patient analgesia.

In summary, the invention provides a device for improving the transdermal electrotransport of water-soluble salts of fentanyl and sufentanil. The electrotransport device preferably has a silver anodic donor electrode and a hydrogel-based donor reservoir. The electrotransport device is preferably a device controlled by the patient. The hydrogel formulation contains a concentration of drug sufficient to provide an acceptable level of analgesia.