WO2000050004A2 - Surgical anesthesia delivery system - Google Patents

Abstract

A system, including composition and delivery device, for the delivery of anesthetics such as lidocaine in the course of soft tissue surgery, e.g., soft tissue ablation, dissection and debulking. The system finds particular use in the delivery of anesthetics such as lidocaine to urothelial surfaces and periurethelial tissues in the course of minimally invasive surgical prostatic procedures such as transurethral needle ablation (TUNA). A composition can be delivered in the form of a low viscosity gel or solution at ambient temperatures, and is adapted to form a highly viscous solution or gel in situ by increasing its viscosity in response to the elevated body temperatures or suitable means. Once gelled in situ, the composition can serve as a drug reservoir sufficient to hold the anesthetic in place, and optionally, can also serve as a conductive medium for iontophoretic delivery.

Description

SURGICAL ANESTHESIA DELIVERY SYSTEM

TECHNICAL FIELD The present invention relates to minimally invasive surgical procedures for treating such conditions as benign prostatic hyperplasia. In a related aspect, the invention relates to anesthetic compositions and techniques for use in the course of such procedures.

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of provisional application US Serial No. 60/121,233, filed February 23, 1999, the entire disclosure of which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION The surgical management of benign prostatic hyperplasia (BPH) has evolved significantly over the past decade. See, for instance, J.N. Jepsen, et al., Urology 1998 Apr;51(4A Suppl) -23-31 "Recent developments in the surgical management of benign prostatic hyperplasia", which describes the manner in which a variety of less invasive treatment modalities have been introduced and well-established surgical treatments are being reassessed.

The article describes the manner in which open prostatectomy may be the most efficient BPH treatment for relieving symptoms and improving urine flow, but it is also the most invasive and morbid. Transurethral resection of the prostate (TURP), in turn, has become the most common technique today for treatment of BPH, although open prostatectomy has been reported to have a lower perioperative mortality than TURP, and lower retreatment rates. The morbidity associated with TURP, such as impotence or urinary incontinence, has been reduced in recent years. New features, such as performing TURP under local anesthesia and the use of bipolar electrosurgical techniques, have been introduced as well.

Among other recent approaches, transurethral electrovaporization of the prostate (TVP) is a modification of TURP that has rapidly gained popularity. TVP greatly reduces TURP syndrome, provides good hemostasis, and may reduce catheterization and hospitalization times. Yet another approach, transurethral incision of the prostate (TUIP) is a safe and inexpensive procedure that is well- documented and comparable to TURP in long-term efficacy. Whereas the well-established surgical treatments primarily relieve obstruction by tissue ablation, some of the newer treatment modalities may ameliorate lower urinary tract symptoms (LUTS) in spite of minimal urodynamic change. Following some of the newer nonresection treatments, no significant postoperative reduction in prostate volume can be demonstrated. Laser treatments are based on a broad variety of techniques, generators, and fibers, of which many have initially demonstrated promising results. Well-known techniques include visually laser-assisted prostatectomy (VLAP) and interstitial laser coagulation (ILC). The laser techniques are generally not as effective as TURP, but are safe under local anesthesia on an outpatient basis with low complication rates. Finally, transurethral microwave thermotherapy of the prostate (TUMT) and radiofrequency transurethral needle ablation (TUNA) are minimally invasive, apparently safe new therapies. See, for instance, MC Beduschi et al., Mayo Clin Proc 1998 Jul;73(7):696-701 ("Transurethral needle ablation of the prostate: a minimally invasive treatment for symptomatic benign prostatic hyperplasia."). This article describes transurethral needle ablation of the prostate as a minimally invasive treatment modality for patients with bladder outlet obstruction attributable to an enlarged prostate gland. The results to date indicate that needle ablation is safe and effective for relieving symptoms in patients with benign prostatic hyperplasia, and the effect has been demonstrated to be durable for at least 2 years. Comparisons between transurethral needle ablation of the prostate and transurethral resection of the prostate (TURP) have revealed that the subjective and objective measures of response are comparable, although TURP has consistently displayed a slight advantage over needle ablation for most variables analyzed, except quality of life score. The advantages of needle ablation over TURP include: (1) performance in the office as an outpatient procedure, (2) reduced need for general or spinal anesthesia, (3) rapid recovery, and (4) minimal side effects. The following disadvantages, however, exist with needle ablation: (1) it may not be indicated or effective in patients with large prostate glands (75 g or more); (2) no prostate tissue is available for histologic evaluation; (3) no long-term efficacy or re-treatment rate data have been published, and (4) not all patients can tolerate the procedure without the use of conscious sedation and/or regional anesthesia. See also, MF Hoey, et al. "Transurethral Prostate Ablation Using Saline-

Liquid Electrode Introduced via Flexible Cystoscope", J. Endourol. 12(5):461468 (1998) and MF Hoey et al. "Fluoroscopic Imaging of a Liquid Electrode Created by Interstitial Electrolyte Infusion for High Power Radiofrequency Energy Application", pp. 1-4. Many, if not all, of these various procedures continue to be hampered, however, by the need for ways to effectively alleviate pain in the course of the procedure.

See, for instance, SA Kahn, et al. J Urol 1998 Nov;160(5):1695-700 ("An open study on the efficacy and safety of transurethral needle ablation of the prostate in treating symptomatic benign prostatic hyperplasia: the University of Florida experience.") This article describes a study of the safety and efficacy of transurethral needle ablation of the prostate in patients with moderate to severe symptoms of benign prostatic hyperplasia. The procedure was performed in 26 patients under local anesthesia using 20 cc 2% intraurethral lidocaine gel or supplemented with intravenous 1.25 to 5 mg midozolam. Of these patients 2 had a supplemental perineal block using a mixture of equal amounts of 15 cc 2% lidocaine without epinephrine and 0.25% bupivacaine, 10 underwent the procedure under general anesthesia, 2 had epidural and 4 had spinal anesthesia, and 3 had managed anesthesia care. Mean length of each procedure was 79 minutes (range 50 to 240).

Other investigators have begun to look into the issue of pain management. See, for instance, M. Issa, et al., "The prostate anesthetic block for outpatient prostate surgery" Issa MM, Ritenour C, Greenberger M, Hollabaugh R Jr, Steiner M World J Urol 1998;16(6):378-83 This article describes how a simple and effective prostate anesthetic block may allow more procedures to be done in an outpatient or office setting. A perineal prostatic block was effective for pain control whether lidocaine or lidocaine/bupivacaine was used as determined by visual analog scale, linear pain scale, or global pain questionnaire. The use of intravenous (i.v.) sedation did not influence the efficacy of the prostate anesthetic block. See also, UA Fontanella, et al., Br J Urol 1997 Mar;79(3):414-20, ("Bladder and urethral anaesthesia with electromotive drug administration (EMDA): a technique for invasive endoscopic procedures."), which describes a study to assess the efficacy of the electromotive administration of lignocaine and adrenalin as local anaesthesia (EMDA/LA) for invasive lower urinary tract procedures. Electric current generators, catheters and electrodes were designed and fabricated, using defined electrochemical principles, to carry out EMDA/LA of the bladder and prostatic urethra of 91 patients who underwent 27 bladder-mapping biopsies, 62 transurethral resections (TURs) of bladder tumours, 21 transurethral incisions on the prostate or bladder neck incisions, 12 TURs of the prostate (122 operations in total) and nine miscellaneous interventions, all using rigid instruments.

In five of the 122 procedures, the pain was described as intolerable; six were recorded as painful but tolerable, and the remaining 111 procedures were recorded as having minimal to no discomfort. Side-effects were few; there was no clinical evidence of lignocaine toxicity and serial serum lignocaine levels measured in four patients were innocuous. The authors concluded that EMDA/LA provides safe, effective anaesthesia for most invasive endoscopic procedures in the lower urinary tract.

See also, MA Jewett et al., "Electromotive drug administration of lidocaine as an alternative anesthesia for transurethral surgery", J Urol 1999 Feb;161(2):482-5, which describes a multicenter study to evaluate the safety, efficacy and cost of electromotive drug administration of intravesical lidocaine to produce bladder local anesthesia as an alternative to traditional methods of spinal or general anesthesia. A total of 94 patients were enrolled in the study who had either a bladder tumor that required cold cup bladder biopsy with fulguration for possible recurrence, a bladder tumor treated with transurethral resection/fulguration, or benign prostatic hyperplasia carcinoma treated with transurethral resection. Pain scores using a Verbal Rating Scale were recorded for each individual biopsy, fulguration and resection event. Data for direct and indirect costs were collected using a standardized form for each patient to capture the details of the procedure, including times, drugs and disposables for each patient. The authors found a significant reduction in pain for patients who received electromotive intravesical lidocaine compared to no anesthesia for biopsy (p<0.03). Similarly, electromotive intravesical lidocaine for bladder biopsy and transurethral bladder tumor resection/fulguration was associated with higher patient satisfaction compared to previous treatments (p<0.00002). In contrast, electromotive intravesical lidocaine was insufficient for 3 of 6 transurethral prostatic resections. The authors concluded that electromotive intravesical lidocaine may be a safe, effective and affordable form of anesthesia for the ambulatory care of patients requiring transurethral bladder biopsy, resection or fulguration with a potential for cost savings.

Lidocaine is an injectable local anesthetic used extensively in dentistry and medicine. It is generally delivered as the hydrochloride salt, and in an aqueous medium, dissociates to produce a positively charged lidocaine molecule appropriate for iontophoresis. Iontophoresis has been used to deliver lidocaine to the tympanic membrane of the ear during surgery, and to anesthetize the skin prior to needle insertion or minor surgical procedures. Lidocaine is commonly applied to the urethra before instrumentation or catheterization. It is typically administered in a hydroxyproplymethylcellulose gel which contains 2% lidocaine hydrochloride, although lidocaine compositions of higher concentrations are available as well, e.g., the line of First Choice® Premixes available from Abbott Laboratories, which includes generic lidocaine solutions in concentrations of 2, 4 and 8 mg/ml.

It appears, therefore, that passive diffusion of lidocaine from gels, such as those currently used in urology, provides some level of pain control at the urothelium. However, traumatizing the urothelium, e.g., by the insertion of a catheter without adequate anesthesia, is thought to increase the intensity of pain from all subsequent insults during a minimally invasive surgical procedure. While it is not known whether there are pain receptors in the body of the prostate, it is apparent that if heat or extreme pressure reaches the prostatic capsule, there is likely to be a pain response.

Other references have described either the electromotive administration of drugs into diseased prostatic tissue (U.S. Patent No. 5,843,016, assigned to Physion S.r.L) and a prostatic drug delivery catheter incorporating balloons at either end (U.S. Patent No. 5,419,763, originally assigned to CorTrak Medical, Inc.). Anesthetic techniques and compositions that are more efficient than present lidocaine jellies, particularly for pre-treatment of the urethra, are clearly needed. Also needed, in order for minimally invasive surgical (e.g., prostatic) techniques to reach their full potential, are methods and compositions for use in effectively alleviating the pain that can be associated with such procedures. Preferably, such approaches will be widely applicable to most, if not all, of the various surgical approaches currently being developed or considered.

BRIEF DESCRIPTION OF THE DRAWING In the Drawing:

Figure 1, shows a TUNA catheter modified to deliver a drug composition.

Figure 2 shows the shaft segment of the catheter of Figure 1.

Figure 3 shows a cross section taken through section (3) of the shaft segment.

Figure 4 shows a cross section taken through section (4) of the drug delivery device.

Figure 5 shows an alternative cross sectional construction of the shaft segment.

Figure 6 shows an alternate embodiment of a shaft segment.

Figure 7 shows a cross section taken through section (3) in Figure 6

Figure 8 shows a cross section taken through section (4) of the drug delivery device.

Figure 9 shows an alternative embodiment in cross section.

Figure 10 shows a longitudinal sectional view through the manifold.

Figure 11 shows a device for use in infusing drug through needles. Figure 12 shows a mechanism for injecting drug into hollow electrodes.

Figure 13 shows an embodiment having a swellable, permeable membrane.

Figure 14 shows a cross section taken through section (4) of Figure 13.

Figure 15 shows a structure adapted to be inserted into the endoscope lumen.

Figure 16 shows item 48 of Figure 15 in its deployed position. Figure 17 shows a sectional view through the catheter shaft.

Figure 18 shows an alternative embodiment useful with the lumen of Figure 1.

Figure 19 shows the embodiment of Figure 18 with the drug cage deployed. Figure 20 shows the drug cage deployed in a prostatic urethra. Figure 21 shows a cross sectional view of the deployed cage in the prostatic urethra.

Figure 22 shows an alternative embodiment of Figure 1. Figure 23 shows a cross section of Figure 22 through (4).

SUMMARY OF THE INVENTION The present invention provides a delivery composition having particular application in the delivery of drugs such as anesthetics (e.g., lidocaine) in the course of soft tissue surgery, e.g., soft tissue ablation, dissection and debulking. In a related aspect, the invention provides a delivery device adapted to deliver such a composition, preferably by minimally invasive means, as well as a system that includes both the delivery composition and delivery device. In another aspect, the invention provides a method of preparing such a system and its components, as well as a method of using the system or its components.

In a particularly preferred embodiment, a delivery composition of this invention can be used to deliver active agents, such as anesthetics, to any or all urothelial surfaces and periurethral tissues, especially in the prostatic urethra, to the bladder neck and/or to the lining of the pendulous urethra, in order to alleviate pain in the course of minimally invasive surgical prostatic procedures. In one such embodiment, the system is used in combination with a radiofrequency transurethral needle ablation (TUNA) system, in order to anesthetize the tissue site prior to radio- frequency ablative surgery. In yet another embodiment, the system incorporates various aspects of the TUNA system itself in order to provide the added benefit of iontophoretic delivery, e.g., where one or more electrodes of the TUNA device are incorporated for use in creating an electric field for the iontophoretic delivery of anesthetic. In such an embodiment, the delivery composition itself can serve as a conductive medium that can be used to iontophoretically enhance the delivery, making use, at least in part, of the available electrodes provided by the ablation device. A preferred composition of this invention is provided in the form of a hydrogel, and particularly preferred is a thermally reversible gel. The terms "thermally reversible gel" and "thermosetting gel", will be used interchangeably in connection with the present composition, to refer to a composition that can exists (and/or can be delivered) in the form of a low viscosity gel or solution at ambient temperatures (lower than body temperature), but is adapted to form a viscous solution or gel in situ by increasing its viscosity in response to the elevated body temperatures, or by other suitable means. Once gelled in situ, the composition can serve as a drug reservoir sufficient to hold the anesthetic in place, and optionally, can also serve as a conductive medium for iontophoretic delivery.

A preferred composition, for instance, comprises between about 0.5% and about 30% by weight, and more preferably between about 5 % and about 30% by weight of a gelling component (e.g., polyoxyalkylene block copolymer), and between about 2% and about 10 % drug (preferably anesthetic, and more preferably lidocaine). Such a composition can further include one or more solvents and/or co-solvents for the drug, e.g., between about 2% and about 15% propylene glycol, and between about 2% and about 20% glycerin, in order to provide a ternary solvent system for lidocaine. Optionally, the composition can be buffered (e.g., with lOOmM to about 500 mM Tris) to a pH sufficient to provide both a biocompatible pH as well as a desired combination of both charged and uncharged drug species. The composition can also contain other additives and ingredients, e.g., between about 0.1% and about 1% by weight of a cellulosic gum such as carboxymethylcellulose, in order to improve the adhesion of the gel to tissue.

Lidocaine is commonly applied to the urethra before instrumentation or catheterization. It is administered in a hydroxyproplymethylcellulose gel which contains 2% lidocaine hydrochloride, with the pH adjusted to between 6 and 7. Since biological membranes contain a high lipid content, only lipophilic molecules can cross them readily. However, since the pKa of lidocaine is 7.8, less than 15% is in the uncharged, lipophilic state. Applicants have discovered the manner in which a drug such as lidocaine can be formulated to provide an optimal combination of such properties as charged/uncharged proportions, tissue adhesion, gel formation, tissue compatibility, lubricity, and ultimately, biological effect. By adjusting the initial proportion of charged to uncharged species, those skilled in the art will be able to provide a desired combination of both passive delivery (by diffusion of uncharged species into and/or through tissue membranes) and iontophoretic delivery (using the charged species). In one aspect, the present invention provides an anesthesia system for use with transurethral surgery on the prostate. The system provides a composition and optional device for rapidly anesthetizing the urothelium before instrumentation, and then anesthetizing the prostate gland, facilitated by iontophoresis if desired. To accomplish these objectives, a thermosetting gel has been developed which, in a particularly preferred embodiment, includes about 4% lidocaine hydrochloride and has a controlled pH of between about 6.5 and about 7.5. Such a gel preferably includes a polymeric ingredient such as poloxamer 407, a block copolymer composed of polyoxyproplyene and polyoxyethylene.

While not intending to be bound by theory, it appears that lidocaine can exist and be effectively delivered in at least two forms, using a composition of this invention. In one form, the drug is uncharged, and in turn, able to readily diffuse into and through tissue membranes. In the other, charged, form, the drug is amenable to being delivered iontophoretically based on its charge. Polymer molecules such as poloxamer 407 molecules can associate in an aqueous environment to form micelles, which causes gelation at temperatures above approximately 25 °C. Uncharged lidocaine (free base) is believed to be sequestered in the micelles, providing a pool of lipophilic lidocaine which can readily penetrate the urothelium.

The lidocaine remaining in the aqueous compartment is distributed between the charged lidocaine hydrochloride and the uncharged lidocaine free base, with the relative amounts dependent (at least in part) on the pH. It is thus possible to provide adequate pools of both uncharged lidocaine, available for passive diffusion into the urothelium before instrumentation, and charged lidocaine hydrochloride for delivery via iontophoresis after insertion of an iontophoretic device. The gel has the additional advantage of being applied as a viscous liquid, and therefore achieving good surface contact with the urothelium. Also, poloxamer 407 is a nonionic surfactant and adheres to membranes. It thus remains where placed and minimizes damage to the urothelium due to friction during insertion of instruments into the urethra.

As an added feature, and in addition to the desired anesthetic effect, preferred compositions provide the further benefit of more effective lubrication for insertion of instruments. While not intending to be bound by theory, it would appear that this improved lubrication is due, in large part, to adherence of the gelled composition to the urothelium, and to the surfactant properties of poloxamer 407.

In another aspect, the invention provides a delivery device for use in delivering the composition to a site within the body, e.g., through the urethra and to the prostate. In one embodiment, the delivery conduit is provided in the form of a dedicated, stand-alone device (e.g., syringe, cannula, etc.) that can be inserted and used to deliver the composition. In another embodiment the delivery conduit is provided in the form of a conduit (e.g., lumen) associated with a surgical device such as a TUNA ablation device, and more preferably with a conduit that exists in the instrument itself, and that is used, or can be adapted for use in the delivery and/or recovery of fluids. In a related embodiment, the present invention provides an ablation device comprising a delivery conduit, the conduit either serving an inherent role in the device itself, or the device being retrofitted with such a conduit in order to accommodate the delivery of a composition of this invention, or to accommodate the delivery of a conventional liquid formulation or a combination of liquid and gel formulations. Examples of suitable devices that are particularly amenable for use with the composition and method of this invention, include those described in US Patent Nos. 5,469,524; 5,754,717; and 5,802,229, the disclosures of each of which are incorporated herein by reference. Surgical procedures frequently require tissue incision, dissection, ablation or debulking. This can be accomplished by using surgical devices that deliver radio frequency, microwave, or laser energy, cause thermal energy changes (heating or cooling), or deliver cytotoxic agents to the site being treated. Representative devices are described in US Patent Nos. 5,431,649, 5,725,524, 5,807,395, 5,421,819, 5,531676, 5,536,240, 5,464,437, 5,413,588, 5,643,335, 5,509,929, 5,649,973, 5,469,524, 5,802,229. Examples of tissues requiring such treatment include debulking of the prostate in the treatment of benign prostatic hypertrophy, debulking of soft tissue tumors, formation of ablation lines on the heart to treat atrial fibrillation. Any of these procedures may be facilitated or rendered more efficacious by delivery of a drug at the treatment site simultaneous with the surgical treatment. In the present invention, drug delivery may be by topical application and passive absorption, direct injection, or optionally, by active iontophoretic delivery.

The composition, method, and system of this invention provide an optimal combination of performance characteristics desired for a pain control device or technology for providing anesthesia adequate to permit the use of minimally invasive instruments in physician offices or day surgical center environments, e.g., to treat the prostate. In particular, the preferred system provides a number of attributes, including:

• the ability to provide and maintain a reservoir of drug at the targeted tissue site, for a period of time sufficiently long to allow passive diffusion of drug into tissue, thereby causing a local anesthetic effect, and • the ability to simultaneously and/or sequentially use the reservoir for iontophoretic drug delivery (iontophoresis), thereby accelerating the onset of anesthetic effect and,

• the ability to lubricate tissue and protect it from trauma and abrasion caused by instrument placement, manipulation and removal As described herein, the present invention provides a system that includes both a composition and a delivery device that can be used, for instance, to provide anesthesia in the course of BPH surgery.

The drug (e.g., anesthetic) is optionally iontophoretically delivered, preferably using the electrodes of the radiofrequency (RF) ablation instrument. Applicants have discovered the manner in which existing RF devices can be retrofitted and/or designed in a manner that permits them to deliver an efficacious amount of anesthetic.

The present invention further provides an RF ablation electrode, and/or a controller modified to provide direct current.

DETAILED DESCRIPTION

An anesthetic of the present invention is provided in the form of a composition containing a thermal reversible gel (e.g., a drug composition whose viscosity increases to approximately 100,000 cps at body temperature, creating a stable drug depot). Such a composition can be delivered once or repeatedly and from either a dedicated device or from the distal portion of a catheter or other instrument. Given the present description, those skilled in the art will be able to identify and/or prepare thermosetting gels suitable for use in this invention. Examples of thermosetting gels that can be used to prepare a composition are described, for instance, in US Patent Nos. 5,298,260; 5,300,295; 5,306,501; 5,587,175; and 5,593,683, the disclosures of each of which are incorporated herein by reference.

A thermosetting gel of this invention is provided in the form of a pharmaceutical composition containing one or more pharmacologically active medicaments (preferably anesthetics), useful in providing treatment to a localized site (e.g., body cavity) of a mammalian body. The composition provides a physiologically acceptable medium having a controlled (e.g., buffered) pH. In certain preferred embodiments, the composition provides an osmotically balanced vehicle so as to provide an isotonic mixture which can be adjusted to be iso-, hyper-, or hypo-osmotic with respect to body fluids.

Suitable classes of active agents (e.g., drugs) which can be delivered by the drug delivery system of the present invention include antibacterial substances such as B-lactam and aminoglycoside antibiotics, tetracyclines; anti-inflammatories such as cortisone, hydrocortisone, dexamethasone, etc.; analgesics, anesthetics, such as lidocaine, procaine, xylocaine, and the like, antineoplastics such as adriamycin, flurouracil, methotrexate, asparaginase and the like; antifungals and antiprotozoals. Any of these compounds may be delivered in pharmacologically effective amounts alone or in combinations. In a preferred embodiment the composition comprises: a) an amount of a polyoxyalkylene block copolymer (e.g., a poloxamer) sufficient to cause the composition to increase in viscosity in situ and in response to body temperature, and b) a pharmacologically effective amount of a drug selected from the group consisting of anesthetics (e.g., lidocaine). Optionally, and preferably the composition further includes solvents or cosolvents for use in maintaining the drug in solution, and the components of a buffer system sufficient to provide a desired pH, and in turn, a desired ratio of charged to uncharged drugs such as lidocaine.

In a preferred embodiment, where the composition is to be used in the course of RF ablative surgery of the prostate, the anesthetic comprises lidocaine, and more preferably in a final concentration of between about 1% and about 10%, more preferably between about 2% and about 5%, and even more preferably between about 3% and about 8%, and most preferably between about 3% and about 5% by weight of the composition.

Poloxamers useful in this invention have the general formula HO(C H₄O)_a(C H₆O)_b(C H O)_cH, where a and c are approximately equal, and b is at least 15. See, for instance, L. Reeve, in Handbook of Biodegradable Polymers, A.J. Domb, ed., Harwood Academic Publishers, the disclosure of which is incorporated herein by reference. A particularly preferred poloxamer is commercially available and known as poloxamer 407, having the formula (C₂H₄O)₉₈(C H₆O)₆₇(C₂H₄O) H. A device for use in delivering a composition of this invention can take any suitable form, including as a stand alone, dedicated device, or in the form of a surgical instrument modified to deliver such a composition, or as a surgical instrument that already provides the features (e.g., delivery conduit) suitable for delivering the composition. Dedicated devices can include, for instance, syringes and cystoscopes that are, or can be adapted to deliver such a composition to the desired site. More preferably, and particularly with regard to the delivery of anesthetics in the course of ablative prostate surgery, the composition is delivered in a manner that makes the most advantage of whatever surgical instruments are to be positioned at the target site. Ablative devices particularly useful in connection with the present invention include those using radio-frequency to destroy tissue. See, for instance, US Patent Nos. 5,370,675, 5,421,819, 5,531,676, and 5,536,240 (each assigned to Vidamed, Inc.) and US Patent Nos. 5,725,524, and 5,807,395 (each assigned to Medtronic, Inc.), the disclosures of each of which are incorporated herein by reference. Applicants have discovered that each of these and other devices can be used, or adapted for use, in accomplishing both passive and iontophoretic delivery of a composition as described herein. Such devices, if need be, can be modified by including a lumen or catheter to deliver the composition, as well as one or more electrodes and a source of direct current. Structural modifications to the device itself can include the use of such features as porous balloons, expanding mesh sheaths, sealing balloons, and permeable membranes, e.g., in conjunction with a delivery catheter, which can be used alone or in suitable combination to contain a drug reservoir comprising the composition (e.g., in the form of a high viscosity gel, a hydrogel, or other absorbent polymer adapted to expand upon hydration).

The electrode can be formed of conductive materials such as silver, stainless steel, or carbon, and can be located on the device or catheter itself, to optimize drug distribution to the urethra and prostate. The current source is adapted to deliver direct current of constant, regulated amperage in order to optimize the iontophoretic distribution of drug into the urethra and prostate. The composition and method of this invention can be adapted and used with other devices as well, including those that rely on microwave energy, laser energy, or thermal energy changes (heating and/or cooling), in order to destroy soft tissue such as prostatic tissue. Representative devices of these types are described, for instance, in US. Patent Nos. 5,649,973; 6,620,480; 5,509,929; and 5,464,437.

Such devices can be modified in any suitable manner, e.g., to include an additional conduit or lumen for the delivery of the composition, or to use one or more existing conduits or lumen. The devices can also be modified to perform the additional function of iontophoresis, e.g., by removing barriers that would otherwise be insulating or by including materials that would serve as an electrode. The present invention provides for the optional delivery of drug (e.g., lidocaine) in a variety of modes, including passive and/or iontophoretic delivery. For instance, using a gel depot, as described herein, iontophoretic delivery can be accomplished by the use of an intrinsic electrode within the prostatic urethra. A thermosetting gel, containing the drug of interest, can be delivered at the distal portion of the catheter, being injected at the proximal end via a suitable port. The port is continuous with a lumen that extends between the external sheath or surface and the internal surface of an existing endoscopic lumen. This lumen, in turn, has exit ports at multiple locations at the distal (operating) tip of the catheter; such ports could cover the distal 3-6 cm of the catheter. Optionally, the distal tip containing the ports can be coated with a conductive material that can serve as an iontophoretic electrode. The surface of the catheter below the tip to the proximal end is insulated. This surface electrode is connected to a conductor such as a wire that is embedded in the wall of the catheter and exits the catheter at a suitable electrical connector, which can be attached via a wire to a regulated DC power source. A drug depot is created by injecting a suitable amount of drug containing gel (described above) at the injection port. The gel will exit the catheter at all ports and create a depot of drug around the circumference of the distal tip of the catheter, preferentially in the prostatic urethra. Such depot can be used for passive delivery of drug. In addition, iontophoresis of drug from this depot can be effected by applying either a constant or intermittent DC current from a regulated power source (located in the RF generator portion of the device) to the surface electrode. An iontophoretic circuit is created by positioning a standard return electrode on the surface of a patient's body at a suitable position such as the hip or abdomen.

Iontophoresis is a means of conveying ions or charged molecules through a biological membrane using direct electrical current. See, for instance, S. Singh, et al., Medicinal Research Reviews, 13(5):569-521 (1993), J. Singh, et al., Drug Design and Delivery 4:1-12 (1989), C. Costello et al., Phys. Ther. 75(6):554-563 (1995), A. Ernst, et al., Am. J. Emerg. Med. 13(l):17-20 (1995), and S. Greenbaum, et al., J. Dermatol. Surg. Oncol. 20:579-583 (1994), the disclosures of each of which are incorporated herein by reference.

The current is applied between two electrodes, an anode and a cathode. One electrode is placed at the site where the charged drug is to cross the membrane, the other is placed on the skin at a distant site. To deliver a positively charged drug, the anode is placed at the site of delivery and the drug is driven across the membrane toward the cathode. A negatively charged drug is driven across the membrane by the cathode toward the anode. Compared to diffusion, iontophoresis generally increases the rate of drug penetration across a biological membrane. Although iontophoresis can be used to achieve constant plasma levels of a drug, it is frequently used to provide site-specific therapeutic levels of a drug while the systemic concentration remains low. It is thus possible to minimize the risk of toxicity. As described with reference to the figures, a TUNA catheter can be modified to include one or more inflatable balloons located at the distal tip and proximal to the surface electrode of the catheter. These balloons can be expanded to create a liquid tight chamber in the prostatic urethra via a lumen or lumens connecting the balloons to a valved port where air or liquid can be injected to inflate the balloons. In use, the catheter is inserted into the prostatic urethra, the balloons are inflated, and drug can be injected to create a fluid drug reservoir. In this embodiment, the surface electrode consists of a set of conductors that are located in grooves on the surface of the catheter to prevent contact of the conductors with the urothelium. Such grooves can be circumferential or parallel to the axis of the catheter and can be made of a variety of materials including silver and carbon, either of which can be applied to the surface via a variety of manufacturing methods such as lithography. While passive delivery of drug can be effected by this device, iontophoretic delivery will often be a preferred embodiment. Iontophoretic delivery of drug can also be accomplished via injection into tissue, such as prostate tissue. As described herein, the RF needles used in the TUNA device (or other minimally invasive surgical devices with an operating or endoscopic lumen) can be made hollow and can be used to inject a solution of drug into the prostatic tissue. The needles are connected to a port in the proximal portion of the catheter (the operator's end) into which a suitable drug can be injected. Both needles can serve as electrodes to deliver either continuous or pulsed DC current from a source in the RF generator; a circuit is completed by use of a return electrode located on the skin of the patient at a suitable location on the body such as the hip or abdomen. Internal migration of drug can be influenced both by the position of the TUNA needles within the prostate and the amount and duration of current applied. Passive and iontophoretic delivery of drug, such as lidocaine, can also be accomplished using an intrinsic reservoir. In this embodiment, the distal portion (of suitable length) of the catheter contains an intrinsic reservoir or depot of drug that can be applied to an appropriate segment or segments of the urethra. This reservoir is achieved by packaging a suitable polymer, for example sodium acrylate, on the reservoir surface of the distal tip. The polymer used must absorb liquid quickly and expand upon hydration. This process will provide a stable depot of drug solution and will, by expansion, intimately contact the urethral tissue. To prevent sloughing of the polymer, it is coated with a permeable membrane of suitable material. The polymer reservoir is loaded with drug solution by injection of drug from a valved port on the proximal end of the catheter. This port is connected by a lumen running in the wall of the catheter to the area of the reservoir. Fluid exits the lumen at multiple ports located beneath the reservoir. To provide a smooth surface, the external diameter of the catheter is reduced in the area beneath the reservoir so that the diameter of the reservoir portion of the catheter in the unhydrated state is identical to the external diameter of the catheter. Beneath the reservoir, the surface of the catheter contains an electrically conductive material which is connected through the body of the catheter via a suitable conductor such as a wire to a DC source in the RF generator. The DC source can supply either pulsed or continuous current to the conductor beneath the reservoir, to effect iontophoresis. The circuit is completed with a return electrode as described herein. A drug delivery catheter can also be used in conjunction with the TUNA device. In such an embodiment a catheter can be inserted in the endoscope lumen of the TUNA device. This catheter contains a central lumen used to deliver drug solution or gel which is injected from the proximal (operator) end. The gel or solution is delivered at the distal end, where such delivery surface is of a length appropriate to the application. The catheter diameter narrows at this distal end and terminates in a tip which can be inflated through a parallel lumen. The narrow portion of the distal tip is coated with a conductor that is connected via a wire embedded in the wall of the catheter to a proximal connector that allows application of a pulsed or constant DC current. Solutions or gels, as above, can be injected from the proximal end of the catheter and will emerge from ports in the narrow part of the distal segment of the catheter. If the tip balloon is inflated, a seal at the bladder end of the urethra will be effected; the body of the TUNA catheter will provide a seal at its tip, which is located near the external sphincter. Passive delivery can occur from the depot or solution deposited in the urethra; iontophoresis can be used if an external electrode is provided to close the DC circuit.

In these embodiments it will generally be preferable to have the external surface (and any other surface in direct contact with the body) fabricated with an electrically non-conductive material, e.g., in the form of a coating or sheath. This will prevent the iontophoretic electrical current from being diverted from the target and inadvertently energizing the proximal (operator end) of the device. An alternative embodiment of this invention is the use of a hydratable polymeric reservoir located over the conductor on the narrow distal segment of the drug catheter. This reservoir can be hydrated via the drug lumen and either passive or active delivery can be effected. Both of these embodiments can be utilized though any cystoscope with an operating lumen, particularly those utilized by other ablative catheters for treatment of BPH. An expanding porous mesh with nonporous ends on the surface of a TUNA device permits the use of a drug solution or gel. The surface beneath the mesh is coated with conductor as above; solution or gel exits through multiple ports in catheter body under the mesh structure. In an alternative embodiment, a porous balloon filled with a viscous gel, in combination with iontophoresis, can be used as well.

The present invention will be further described with reference to the Drawing, wherein Figure 1, illustrates a generically modified TUNA catheter comprised of a shaft (1) featuring an electrically non-conductive surface (3), and electrically conductive surface (4), a non-conductive distal tip segment (5) from which RF electrodes (6 and 7) and non-conductive sheaths surrounding them (8 and 9), and a manifold (2) containing fluid port (10 ) in communication with lumen (11) and drug port (12) in communication with conductive surface (4), electrical connectors (13 and 14) in communication with RF electrodes (6 and 7), electrical connector (15) in connection with iontophoretic delivery electrode (4), an endoscopic receptacle (16) and a set of positioning levers (17) and (18 ) for the extension and retraction of the RF electrodes (6 and 7) and insulators (8 and 9) respectively.

Figure 2 illustrates the shaft (1) segment of one such catheter embodiment. Such a shaft being 12 - 18 French (4-6 mm diameter) where the nonconductive segment (3) is comprised of shaft material (19) which is a multilumen polymeric material which is rigid or semirigid, yet a thermal insulating plastic.

Cross section Figure 3, through section (3) of shaft (1) shows a central lumen (20) for the insertion of optical endoscope and fluids from port (10), two lumens (21) containing insulators (8 and 9) and electrodes (6 and 7), one lumen (22) containing iontophoretic conductor (23), and lumen (24) for transport of drug from port (12) to electrode (25).

Cross section Figure 4, through section (4) illustrates one embodiment of the drug delivery device, comprising RF electrode conductors and insulators (21) bridging shaft (3) with tip (5), inner tubular structure (26) featuring endoscope lumen (20) and iontophoretic conductor (23), drug reservoir (27) in communication with drug lumen (24), and electrode (25) featuring a plurality of holes (28) for the egress of drug solution or gel into the prostatic urethra to contact the urethral surface, and electrical connection (29) between conductor (23) and electrode (25).

Alternatively, cross section Figure 5 illustrates a construction in which the electrode (25) is applied to the inner tubing (26) and where the surface (4) is non- conductive but retains the plurality of holes (28) for the egress of drug solution or gel into the prostatic urethra to contact the urethral surface. Figure 6 illustrates an alternate embodiment of the shaft (1) segment. In this concept, the electrode segment (4) is axiaily retained between two elastic balloon structures one of which (30) is inflated near the bladder neck, and another of which (31) is inflated in the urethra distal to the prostate. These structures serve to isolate the prostatic urethra from the bladder and distal urethra for site specific drug delivery. Cross section Figure 7, through section (3) of shaft (1) [as in figure 3] shows a central lumen (20) for the insertion of optical endoscope and fluids from port (10), two lumens (21) containing insulators (8 and 9) and electrodes (6 and 7), one lumen (22) containing iontophoretic conductor (23), and lumen (24) for transport of drug from port (12) to electrode (25). In addition, two lumens are represented: (32) feeds fluid or air from a new manifold port (34) to balloon (30) and lumen (not shown, but location identified at 33) feeds fluid or air from a new manifold port (35) to balloon (31).

Cross section Figure 8, through section (4) illustrates one embodiment of the drug delivery device, comprising RF electrode conductors and insulators housings (21) bridging shaft (3) with tip (5), inner tubular structure (26) featuring endoscope lumen (20) and iontophoretic conductor (23), drug reservoir (27) in communication with drug lumen (24), and recessed electrode (36), and a non-conductive perforated surface (37) featuring a plurality of holes (28) for the egress of drug solution or gel, and electrical connection (29) between conductor (23) and recessed electrode (25).

Alternative embodiment; cross section Figure 9, through section (4) illustrates a network of recessed conductive electrode (38) with ports (28) and conductors arranged around the central endoscopic lumen (20).

Figure 10, is a longitudinal sectional view through the manifold (2) illustrating the two luer ports (34 and 35) which receive gas or fluid transmitted through lumen (33 and 32) to balloons (31) and (30) respectively. Alternatively, the two balloons could be filled from the same common lumen rather than two separate lumens. Figure 11, illustrates a design concept by which drug can be infused through needles (38 and 39). Further, the needles could be contained within insulated sheaths (8) and (9) as in Figure 1. After infusing tissue with drug from the hollow needles, the two needle electrodes can be used to deliver constant RF current to ablate the tissue. Figure 12, illustrates a mechanism within (2) by which drug can be injected into the hollow electrodes (38) and/or (39) from luer fitting (40) and/or (41) through flexible polymeric tubing (42) (43). The positioning levers (17) and (18 ) for the extension and retraction of the RF / iontophoresis electrodes slides forward and backward and the electrical conductor (44) attached to hollow electrodes (38 and 39) can slide with the mechanism and is terminated in a connector which attaches to either the RF generator or Iontophoresis constant current generator or a device which delivers both RF and Iontophoretic constant current.

Figure 13 represents an embodiment in which the drug hydrates a partially hydrated polymeric hydrogel (28A), thus swelling and providing a conductive path to the urothelium. The shaft has a nonconductive segment (3) and a distal tip (5) as in previous figures 1, 2, 6, and 11. Also illustrated is a drug delivery segment (4) comprised of a reservoir (27) around a polymeric tube containing lumen (20) for endoscope insertion, and cannula housing RF electrodes (6 and 7) and sheaths (8 and 9). Figure 14 is a cross sectional view through the reservoir/electrode segment (4) of figure 13. Endoscope lumen (20) of tubular structure (26) is surrounded by reservoir (27) within a perforated tubular conductor (25) featuring a plurality of holes (28) which communicate with a partially hydrated polymeric hydrogel (28A) covered by a permeable membrane (47) which has shape (45) and swells to shape (46) when hydrated. The swelling permeable membrane extends beyond the catheter surface to create intimate contact with surrounding urothelium. Figure 15 illustrates a structure which in its 2 mm diameter size can be inserted into the endoscope lumen of figure 1 (and its embodiments) or in its 6 mm diameter size can be a stand-alone instrument for the delivery of drugs. In either case the structure (48), an inflatable torus balloon, can be extended from the catheter shaft

(49) surrounding it by pushing inner shaft (53) distally. With the soft polymer tip extended (as shown in Figure 16) the space between the shaft (49) and tip (48) becomes the reservoir for containing the drug. The drug is injected into luer fitting

(50) through torus lumen (51) into the created reservoir (52). The balloon is inflated Figure 16, (48) and thus anchored at the bladder neck by applying either air or fluid pressure from another luer fitting connected to and communicating with lumen (54). Constant current can be applied through connector (15) to conductor (23) to conductive surface (electrode) (25) for iontophoretic drug delivery. Figure 17 is a sectional view through the catheter shaft.

Figure 18 illustrates another device for delivering drug from a catheter extended from the endoscope lumen (20) of Figure 1, or a stand-alone device. In the first embodiment the catheter diameter is < 2 mm, and in the latter > 6 mm. Figure 18 shows the device with drug cage retracted against the catheter shaft.

Figure 19, shows the catheter with the drug cage deployed. Deployment is achieved by axiaily compressing the braided structure (56) with sleeve (56A). This compression shortens the cage length while enlarging its diameter. The end segments of the drug cage (59) are non-porous and hence contain the fluid injected into the cage when in contact with urothelium tissue.

Figure 20 shows the drug cage deployed in a prostatic urethra and Figure 21 shows a cross sectional view of the deployed cage in the prostatic urethra.

Figure 22 illustrates an embodiment of Figure 1, where a porous balloon (57) surrounds drug reservoir (27). In this device the drug is delivered to the reservoir (27) through a lumen from a luer fitting, as in previous embodiments. Figure 23, is a cross section of Figure 22 taken through (4). The endoscope lumen (20) within the tubular member (26) joins segments (3) and (5). Drug in the reservoir is pressurized and exits through a plurality of ports (28) in the conductive surface (25) thus distending a porous balloon (57) to a new distended shape (58) which creates intimate contact with the drug, the balloon, and the surrounding urothelium as the drug exits the pores of the balloon. Needle shafts (21) connect the shaft (3) with the tip (5) to extend RF electrodes (6 and 7) and sheaths (8 and 9). Conductor (23) connects the conductive surface (25) with the electrical connector (15) and hence the constant current iontophoretic generator. Figure 23, is a cross section of figure 22 through (4).

By way of example, a lidocaine hydrochloride (4%) gel is prepared having the following ingredients:

Ingredient Amount (w/w%^)

Deionized water 57.5

Poloxamer 407 16.0

Propylene glycol 12.0 Glycerin 10.0

Lidocaine HCl 4.0

Carboxymethylcellulose 0.5

Total 100.0

The lidocaine gel can be applied to the urethra using the following protocol. Approximately 30 minutes before the procedure, draw up 10 ml of 4% lidocaine HCl formulation (chilled to approximately 10°C), into a 10 ml syringe using a sterile 18G needle. Store in refrigerator until used. When the patient is prepared for application of the gel, remove the gel-filled syringe from the refrigerator and attach a sterile 16 French catheter. Instill 1-2 cc's into the meatus to a depth of about 2 cm; be sure that the opening of the meatus is well coated. Wait 10 to 15 seconds. Express another 1-2 cc aliquot into the urethra and gently insert the catheter further. Continue until it reaches the external sphincter. Express another 1-2 cc aliquot, and gently insert the catheter through the sphincter. Continue as above until the catheter reaches the bladder neck. Slowly withdraw the catheter, expressing the remainder of the gel into the urethra as the catheter is withdrawn. Use the entire 10 ml volume.

Numerous characteristics and advantages of the invention have been set forth in the foregoing description. It will be understood, however, that this disclosure is, in many respects, only illustrative. Changes may be made in details, particularly in matters of shape, size, arrangement of parts without exceeding the scope of the invention.

Table 1

Table 2

Claims

CLAIMS What is claimed is:

1. A composition for the delivery of one or more active agents to a tissue site, comprising a composition adapted to be delivered to the tissue site in the course of a minimally invasive surgical procedure selected from the group consisting of tissue incision, dissection, ablation and debulking performed using a surgical device that delivers radio frequency, microwave, or laser energy, or causes thermal energy changes at the site being treated, the composition having a biocompatible pH and comprising a thermosetting gel component and a pharmacologically effective amount of an active agent.

2. A composition according to claim 1 wherein the tissues comprise urothelial and/or periurethral tissues, and the active agent comprises a drug for alleviating pain.

3. A composition according to claim 2 wherein the composition provides a pH of between about 6.5 and about 7.5 and comprises (by weight, based on the weight of the delivered composition): a) between about 0.5% and about 30% by weight of a thermosetting gel component, and b) between about 1% and about 10% of an active agent in the form of an anesthetic.

4. A composition according to claim 3 wherein the composition is provided in sterile form, and wherein: a) the thermosetting gel component comprises an amount of a polyoxyalkylene block copolymer sufficient to cause the composition to increase in viscosity in situ and in response to body temperature, and b) the active agent comprises lidocaine at a concentration of between about 3% and 8% by weight.

5. A composition according to claim 1 further comprising one or more solvents and/or co-solvents adapted to provide a ternary solvent system for the active agent, in order to provide a desired combination of both uncharged species of the active agent, for diffusion into and/or through tissue membranes, and charged species, for iontophoretic delivery.

6. A composition according to claim 5 wherein the solvents and/or co- solvents comprise between about 2% and about 15% propylene glycol, and between about 2% and about 20% glycerin, based on the weight of the delivered composition.

7. A composition according to claim 1 further comprising one or more additives adapted to improve the adhesion of the composition to tissue, the additive(s) comprising a cellulosic gum present at a concentration (by weight, based on the weight of the delivered composition) of between about 0.1% and about 1 %.

8. A composition according to claim 1 wherein the composition, once gelled in situ, is adapted to serve as a reservoir sufficient to hold the active agent in place, and to also serve as a conductive medium for iontophoretic delivery of the active agent.

9. A composition according to claim 2 wherein the urothelial and/or periurethial tissues are selected from the prostatic urethra, the bladder neck, and the lining of the pendulous urethra.

10. A composition according to claim 2 wherein the composition is an aqueous system provided in sterile form, provides a pH of between about 6.5 and about 7.5 and comprises (by weight, based on the weight of the delivered composition): a) between about 5 % and about 30% by weight of a thermosetting gel component in the form of a polyoxyalkylene block copolymer, b) between about 1% and about 10% of an active agent comprising lidocaine HCl, c) between about 2% and about 15% propylene glycol, d) between about 2% and about 20% glycerin, and d) between about 0.1% and about 1 % carboxymethylcellulose, wherein the composition, once gelled in situ, is adapted to serve as a reservoir sufficient to hold the active agent in place, and to also serve as a conductive medium for iontophoretic delivery of the active agent, and the urothelial and/or periurethial tissues are selected from the prostatic urethra, the bladder neck, and the lining of the pendulous urethra.

11. A delivery device adapted to deliver a composition according to claim 1 to a tissue site within the body, the device selected from the group consisting of: a) a delivery conduit provided in the form of a dedicated, stand-alone device adapted to be inserted into the body and used to deliver the composition to the tissue site, and b) a surgical ablation system adapted to provide a delivery conduit for use in delivering the composition to the tissue site in the course of incision, dissection, ablation or debulking surgery.

12. A delivery device according to claim 11, wherein the device is adapted to deliver the composition by minimally invasive means.

13. A delivery device according to claim 12 wherein the device is a dedicated device selected from the group consisting of porous balloons, expanding mesh sheaths, sealing balloons and permeable membranes.

14. A delivery device according to claim 12 wherein the device comprises a catheter associated with a surgical ablation system.

15. A delivery device according to claim 14 wherein the system comprises a radiofrequency transurethral needle ablation system.

16. A delivery device according to claim 15 wherein the ablation system comprises an electrode and/or a controller modified to provide direct current.

17. A system comprising a composition according to claim 1 and a delivery device according to claim 11.

18. A method of delivering one or more active agents to a tissue site, the method comprising the step of providing a composition according to claim 1, and delivering the composition to the tissue site in the course of a minimally invasive surgical procedure selected from the group consisting of tissue incision, dissection, ablation and debulking performed using a surgical device that delivers radio frequency, microwave, or laser energy, or causes thermal energy changes at the site being treated.

19. A method of delivering an active agent to urothelial and/or periurethral tissues, in order to alleviate pain in the course of minimally invasive surgical prostatic procedures, the method comprising the steps of: a) providing a composition according to claim 1, b) providing a delivery device according to claim 11 , and c) employing the delivery device to deliver the composition to the tissue site.

20. A method according to claim 19 wherein the delivery device is provided as a component of a radiofrequency transurethral needle ablation system, which comprises an electrode and/or a controller modified to provide direct current, and the method comprises the step of employing one or more electrodes of the ablation system to provide an electric field for the iontophoretic delivery of the active agent from the composition.

21. A radio-frequency ablation device comprising an electrode and/or a controller modified to provide direct current.