WO1997041920A1

WO1997041920A1 - Iontophoretic delivery of a therapeutic agent to treat erectile dysfunction

Info

Publication number: WO1997041920A1
Application number: PCT/US1997/008147
Authority: WO
Inventors: Keith R. Hildebrand
Original assignee: Iotek, Inc.
Priority date: 1996-05-09
Filing date: 1997-05-09
Publication date: 1997-11-13

Abstract

An apparatus (10) and method for treating erectile dysfunction in a user having a urethra and a corpus cavernosa. A member is configured to deliver the drug into the urethra. The member has a reservoir that is loaded with a drug. The drug causes increased intracavernosal pressure. First and second electrodes (16, 22) are configured to be placed in electrical communication with a power supply. The first electrode (16) is positioned adjacent to the reservoir.

Description

IONTOPHORETIC DELIVERY OF A THERAPEUTIC AGENT TO TREAT ERECTILE DYSFUNCTION

TECHNICAL FIELD The present invention relates to an apparatus and method for treating erectile dysfunction, and more particularly, to an apparatus and method of iontophoretically delivering a drug to treat erectile dysfunction.

BACKGROUND Localized drug delivery is advantageous in the treatment of erectile dysfunction. Various types of erectile dysfunction include impotence and priapism, which is a persistent and painful erection. A dysfunction can result from either physiological or psychological factors. If a physiological problem, impotence is generally characterized by blood flow to and from the penis remaining in balance. This balance prevents the retention of a sufficient amount blood to cause rigid dilation of the corpus cavemosa and spongiosa.

Common treatments for erectile dysfunctions include injecting a drug into the corpora of the penis with a syringe or other needle-type device, surgically inserting a prosthesis or other mechanical apparatus, and delivering a drug into the urethra and waiting for drug to be absorbed. Each of these methods include unsatisfactory features such as pain or excessive delay in delivery of drug.

In another known apparatus and method for treating impotence, a dose of a drug is carried on an applicator. The applicator is inserted into the urethra and the dose is applied through transurethral administration. In yet another known apparatus and method, the inner surface of a condom is coated with drug. The user must place the condom on his penis and then wait for drug to become absorbed through his skin and cause an erection. These apparatuses and methods have several shortcomings. For instance, they rely on passive diffusion of drugs. As a result, the drug's penetration into tissue is both limited and slow. In fact, these treatments might take as long as 20 to 30 minutes before they are effective. Furthermore, an excessive amount of drug is placed on the applicator in order to get enough of the drug to the user' s corpora cavemosa and spongiosa. Thus, much of the drug is wasted or can be transferred to the partner.

One alternative drug delivery technique is to inject the drug directly into the corpora cavemosa. Direct injection can achieve quick results and minimize waste. However, injection through the skin of the penis is also painful. Repeatedly puncturing the skin can cause scaring or infection. Additionally, a fear of needles often causes a patient to decline this form of pharmacotherapy or discontinuing therapy after a short trial period. As a result, direct injection is not a practical method of delivering the drug.

Therefore, there is a need for an apparatus and method of treating impotence that is quick acting and minimizes waste. There is also a need for an apparatus and method of treating impotence that minimize discomfort for the user and does not puncture his skin.

S2W&BX.

The present invention is directed to an apparatus for delivering a drug to the urethra to treat erectile dysfunction in a patient having a urethra and a corpus cavemosa. The apparatus comprises means for delivering the drug into the urethra and means for transporting the drug from the urethra to the corpus cavemosa. An alternative embodiment of the invention comprises a member configured to deliver the drug into the urethra. The member has a reservoir that is loaded with the drug. The drug causes increased intracavemosal pressure. The invention further comprises means for transporting the drug from the urethra to the corpus cavemosa.

Another alternative embodiment of the present invention comprises a member configured to deliver the drug into the urethra. The member has a reservoir that is loaded with a drug. The drug causes increased intracavemosal pressure. First and second electrodes are configured to be placed in electrical communication with a power supply. The first electrode is positioned adjacent to the reservoir.

Yet another alternative embodiment of the present invention is directed to a method of treating erectile dysfunction in a user. The user has a penis, a urethra, and corpora cavemosa. The urethra defines a lumen and has a urothelium lining. The method comprises the steps of: delivering a drug into the lumen, and phoretically transporting drug from the lumen to the penile tissue, the drug causing increased intracavemosal pressure.

DESCRIPTION OF THE DRAWINGS

Figure 1 is a cross-sectional view of a probe designed for treating erectile dysfunction. Figure 2 is a perspective view of the probe shown in Figure 1.

Figure 3 is a cross-sectional view of an alternative embodiment of the probe shown in Figure 1. Figure 4 is a perspective view of the probe shown in Figure 1.

Figure 5 is an alternative embodiment of the probe shown in Figure 1.

DETAILED DESCRIPTION A preferred embodiment as well as several alternative embodiments of the invention will be described in detail with reference to the drawings, wherein like reference numerals represent like parts and assemblies throughout the several views. Reference to these embodiments does not limit the scope of the invention, which is limited only by the scope of the claims. In general terms, the present invention is directed to an apparatus and method for the treatment of erectile dysfunction. The invention is directed to a treatment tool that contains a drug. The treatment tool is in the form of a probe or catheter. The probe contains a reservoir that contains a drug and is configured to be inserted into the user's urethra. The drug can be prostaglandin E₁ (PGEj_) , phentolamine, prazosin, 3-morpholinosydnonamine, papaverine, vasoactive intestinal peptide, sodium nitroprusside, or combinations thereof. The reservoir can be a chamber or a material that can be impregnated with or otherwise contain drug.

When the probe is inserted into the user's urethra, the drug can be phoretically transported from the probe to the user's penile tissue. The drug causes vasodilation, which increases intracavemosal pressure and induces an erection. The drug can be combined with other drugs such as other vasoactive drugs and penetration enhancers. Figure 1 shows an embodiment of the present invention that relates to a device, generally shown as 10, for the treatment of male erectile dysfunction. The device 10 is generally a catheter or probe 11 having a distal portion 12 and a proximal portion 13. The distal portion 12 has tip 15, and the proximal portion 13 has an opposite tip 17. In a preferred embodiment, the length of the probe 11 is between 1 cm and 4 cm. The most preferred length is between 2 cm and 3 cm. However, one skilled in the art will realize that the preferred length can vary depending on the length of the urethra 14.

An electrode 16 is operably connected to the probe 11 and covers most of the probe's surface. Alternatively, the probe 11 could be coated with an electrically conductive material. The probe 11 should be made from an electrically insulated material. The electrode 16 or metallic coating is preferably made from platinum, silver, silver/silver-chloride (Ag/AgCl) , carbon fiber, stainless steel, or gold. A lead 18 is operably connected to the electrode 16, passes through the probe 11, and is then connected to a control box 20. The control box 20 contains a power supply and electronics (not shown) for generating waveforms, i.e., a signal generator. Such electronics are well known in the art.

In an alternative embodiment, the probe 11 is formed from an electrically conductive material thereby eliminating the need for a separate electrode 16 or metallic coating. In this alternative embodiment, the lead 18 will pass an electric current directly to the probe.

A patch-type electrode 22 for placement on the skin of the user is also attached to the control box 20 via lead 26. The patch-type electrode can be placed on the skin of the penis 24. The patch-type electrode 22 can be either reusable or disposable. However, a reusable electrode is preferred. The power supply and/or electronics for generating waveforms may be attached to the back of the patch-type electrode 22 to form a single unit. The power supply and electronics are preferably miniaturized and light weight if they are combined into a single unit with the patch-type electrode 22. One skilled in the art will realize that a circumferential penile band (not shown) is an alternative to the patch-type electrode 22. A sheath 28 covers the probe 11 and the entire electrode 16. The sheath 28 can be made from any material that can be impregnated with, or otherwise contain, and release drug. The material can be configured to naturally release drug or to release drug only if subjected to some type of active delivery mechanism such as iontophoresis or phonophoresis. Examples of suitable materials include a polymer matrix such as a hydrogel, a foam such as an open-cell foam or a hydrophilic foam, and any other suitable material that can contain and release the agent.

A hydrogel is lubricous and will aid the insertion and removal of the probe 11 into and out of the urethra 14. The sheath 28 might also include a porous inner membrane that can provide additional structure to support the hydrogel. Polymer matrices are discussed in United States Patent Application Serial No. 08/291,394, filed on August 16, 1994 and entitled Polymer Matrix Drug Delivery Apparatus and Method, the disclosure of which is incorporated by reference. The entire probe 11 and sheath combination can be detachable from the lead 18 and disposable after use. In this embodiment, the lead 18 can be attached to the probe with a male/female connector (not shown) . However, other types of connectors can be used. If the sheath 28 is permanently mounted on the probe 11, the entire probe/sheath combination is disposable and should be discarded after each use. Alternatively, the sheath 28 can be removable. In this embodiment, the sheath 28 is disposable and the probe 11 is reusable. In either embodiment, the outer diameter of the sheath 28 is preferably between 2 mm and 3 mm when placed on the probe 11.

Sheath 28 contains a drug or therapeutic agent that can increase intracavemosal pressure when administered via the urethra. Such drugs include prostaglandin E₂ (PGE_X) , phentolamine, prazosin, 3- morpholinosydnonamine (SIN-1) , papaverine, vasoactive intestinal peptide, sodium nitroprusside, or combinations thereof. Each drug can be combined with other drugs that are effective for treating erectile dysfunction and/or with an adjuvant. Examples of combinations of drugs include phentolamine with one of papaverine, vasoactive intestinal peptide, SIN-1, or sodium nitroprusside.

The molecular formula for SIN-1 is C₆H₁₀N₄O₂.HCI, which also can be represented as:

A preferred VIP has amino acid sequence His- Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys- Gin-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-lie-Leu-Asn-NH₂ The structural formula for PGE-_L is represented as :

OH

The structural formula for phentolamine is represented as :

The structural formula for prazosin is represented as:

The structural formula for papaverine is represented as:

The adjuvant can be a penetration enhancer, which promotes rapid delivery of drug across the urothelium and into the penile tissue. Examples of penetration enhancers include, but are not limited to: dodecyl 2- (N.N. -dimethylamino)propionate; 1,8-CN;

1- [2- (decylthio)ethyl] azacyclopentan-2-one; l-dodecylazacycloheptan-2-one; oleic acid; dimethylsulfoxide; 1-menthol; protamine sulfate and

1-lauryl-2-pyrrolidone.

Removable sheaths or probe/sheath combinations that already contain the proper dose of drug might be sold at pharmacies. Alternatively, the user might soak the sheath 28 in a solution that contains the prescribed drug. The sheath 28 will then absorb drug. The sheath

28 is then ready to use.

Alternative embodiments might include structures that will help control the flow of drug from the sheath 28 and into the tissue. For example, the sheath 28 might contain nonporous end caps, which are discussed above. Additionally, only a portion of the sheath's 28 circumference might be electrically conductive. This configuration will help control the flow of drug from the sheath 28 toward the corpora cavemosa 32. The drug could then only escape through the electrically conductive portion of the sheath 28.

The probe 11 could include either a macroporous balloon or a microporous balloon as an alternative to the removable sheath. In this type of embodiment, the balloon preferably has pores over only a portion of its circumference. This configuration of pores will help control the flow of drug toward the corpora cavemosa. Microporous and macroporous balloons were discussed in United States Patent 5,286,254, the disclosure of which is hereby incorporated by reference.

As shown in Figure 2, an alternative embodiment might include a stop leg 34 that is substantially perpendicular to and operably connected to the proximal end of the probe 11. The stop leg 34 prevents the probe 11 from being inserted too far into the urethra 30. Stop leg 34 is located at a distance from the tip 15 that allows an appropriate length of the catheter 11 to be inserted into the urethra. As discussed above, the stop leg is most preferably between 1 cm and 4 cm from the tip 15, and most preferably between 2 cm and 3 cm from the tip 15. However, one skilled in the art will realize that the distance can vary according to the length of the urethra. Additionally, enough of the probe is between the stop leg 34 and the opposite tip 17 of the probe so that a user can grip the probe 11 in order to insert it and remove it from the urethra. The probe can also include a finger grip 35 positioned between the stop leg 34 and the opposite tip 17, which aids insertion and removal of the probe .

One skilled in the art will understand that there are other embodiments that can prevent the probe from being inserted too far. For example, the diameter of the proximal end of the probe might widen to a larger diameter than the distal end. Alternatively, the proximal end might contain a lip or a disk (not shown) that circumscribes the perimeter of the probe 11.

Figure 3 shows another alternative embodiment. This embodiment includes a bi-polar electrode configuration that includes a first electrode 38, which is connected to a first lead 40 that extends through a probe 42 to the control box 20. The probe also includes a second electrode 44 and a third electrode 46 that are on oppositely disposed ends of the first electrode 38. The second electrode 44 and the third electrode 46 are both connected to a second lead 48, which in turn is connected to the control box 20. During drug delivery, the first electrode 38 has an opposite polarity from the second and third electrodes 44 and 46. One skilled in the art will realize that there are other electrode configurations. Figure 5 illustrates another alternative embodiment of the probe. In this embodiment, the probe 52 has a cavity 54, an electrode 55, a lead 57, a stop leg 59, and a finger grip 61. Small apertures 56 pass from the cavity 54 to the surface of the probe 52. The sheath 28 has an inside surface 58 that covers the apertures 56 in the surface of the probe 52. The probe 52 also has a larger hole 60 that passes from the cavity 54 to the surface of the probe 52. A septum 62 seals the larger hole 58. In order to load the sheath 28 with a drug, the drug is injected through the septum 62 with a syringe. The drug will then pass into the cavity 54, through the small apertures 56, and into the sheath 28.

Use of the erectile dysfunction probe is shown in Figures 1 and 4. More specifically, the catheter is inserted 3 cm to 4 cm into the urethra 14. If only a portion of the removable sheath 28 is electrically conductive, then that portion should be facing toward the top of the penis 24 so that drug has a direct path to the corpora cavemosa 32. The patch-type electrode 22 is then placed on the top of the penis 24 so that it is directly over the probe 11. Alternatively, the patch 22 could be placed on the abdomen or thigh. If a bi- polar design is used (Figure 3) , the application of the patch-type electrode 22 is not necessary.

After the probe 11 and patch-type electrode 22 are in place, the control box 20 is activated so that an electric current will flow between the electrodes 16 and 22 and through the corpora cavemosa 32. The electric current will transport drug from the removable sheath 28, through the tissue of the penis 24, and into the corpora cavemosa 32. The control box 20 is activated for only about 1 to 5 minutes to deliver a therapeutic dose of drug. After the treatment is complete, the probe 11 and the patch-type electrode 22 should be removed.

The electrical current is preferably between 0.1 mA and 20 mA and can have either direct current or a waveform with a frequency preferably between 0 and 500 KHz. Additionally, the iontophoretic current can be gradually increased to the level recommended for delivery, which will minimize any physical discomfort of the user. The preferred duty cycle of a waveform is between 20% and 100%. A variety of waveforms can be used with the present invention including square waves and sawtooth waves . Waveforms are discussed in more detail in United States Patent Application Serial No. 08/110,109, filed August 20, 1993 and entitled SYNCHRONOUS IONTOPHORESIS DRUG DELIVERY, the issue fee for which was paid on November 21, 1995 and the disclosure of which is hereby incorporated be reference. When the probe 11 is inserted into the urethra 30, the removable sheath 28 should be in intimate contact with the urethral mucosa 50. In order to ensure contact, an alternative embodiment might include expansion means such as an inflatable balloon, an expandable basket, or a slidable electrode. These expansion means are describe in more detail in United States Application Serial No. 08/291,394, filed on August 16, 1994 and entitled Polymer Matrix Drug Delivery Apparatus and Method, the disclosure of which is was incorporated by reference above.

EXAMPLES

Example 1 Animal Model Demonstrating Effectiveness of

Iontophoretically Transporting Drugs to Penile Tissue

This example demonstrates a method for evaluating the clinical effectiveness of iontophoretically transporting drugs to penile tissue. This example does not limit the scope of the invention which is limited only by the scope of the claims.

A quantity of dogs sufficient to yield at least two dogs per group are divided into groups for control administration of saline and administration of each test drug. The drug is administered using an intraurethral delivery device, as described above. For example, the delivery device can include a probe covered with an open cell foam sheath formed from polyurethane. The sheath is loaded with a drug solution at the desired concentration, for example, about 1 mg/ml to about 50 mg/ml .

The drug is iontophoretically transported to the penile tissue of the dogs receiving the test compound for the desired time, for example, about 5 minutes to about 30 minutes. The iontophoretic current is typically about 1 mA to about 10 mA. Intracavemosal pressure and hemodynamic parameters are monitored, typically continuously, for the desired period of time, for example, about one hour. Treatment is typically repeated twice weekly over a period of weeks, such as four weeks. Upon completion of the treatment regiment, necropsy is performed. An effective drug results in a suitable peak rise in intracavemosal pressure.

Example 2 Iontophoretically Transporting SIN-1 To Penile Tissue

This example demonstrates the clinical effectiveness of iontophoretically transporting SIN-1 to penile tissue. This example does not limit the scope of the invention, which is limited only by the scope of the claims.

Six mongrel canines were divided into three groups, each having two dogs. The weight of the dogs ranged from about 60 lbs. to about 80 lbs. A first group was administered SIN-1, a second group was administered prostaglandin E_x, and a third group was administered normal saline as a control. Administration was effected using an intraurethral delivery device that included a probe covered with an open-cell foam sheath formed from polyurethane. The sheath was loaded with a drug solution having a concentration of SIN-1 of 20 mg/ml .

The drug was iontophoretically transported to the penile tissue of one dog in each group for 15 minutes and to the penile tissue of the other dog in each group for 30 minutes. The iontophoretic current was 5 mA. Intracavemosal pressure and hemodynamic parameters were continuously recorded for a total of one hour. Treatment session occurred twice weekly for a total of four weeks, after which a necropsy was performed.

The average peak rise in intracavemosal pressure for dogs receiving SIN-1 was 54.17 cm H₂0 and 69.47 cm H₂0 given an iontophoretic delivery of 15 minutes and 30 minutes, respectively. During the treatment session, the average systolic blood pressure decreased 13.42 mmHG and 23.54 mmHG given an iontophoretic delivery of 15 minutes and 30 minutes, respectively. The average heart rate decreased by 23 bpm and increased by 47 bpm given an iontophoretic delivery of 15 minutes and 30 minutes, respectively. The results for SIN-1 are summarized in Tables 1 and 2

Results for SIN- ^■]. (15' delivery)

Intracavemosal

Time Pressure (cm H-,0)

0 14.83

15 25.33

30 48.00

45 69.00

60 63.50

1ΔBLE. 2.

Results for SIN-1 no' Deliverv)

Intracavemosal lime Pressure (cm U_ZΩL

0 23.86

15 43.43

30 78.14 45 87.71

60 93.33

Little or no change was seen in the intracavemosal pressure, systemic blood pressure, or heart rate of the control dogs receiving normal saline. During the necropsy, microscopic evaluation of the penis revealed a normal, intact urothelium with minimal chronic inflammatory changes. There was no coagulation necrosis or fibrosis. Although the description of the preferred embodiments and methods have been quite specific, it is contemplated that various modifications could be made without deviating from the spirit of the present invention. Accordingly, the scope of the present invention is only limited by the appended claims, not the above description of the preferred embodiments and methods.

Claims

THE CLAIMED INVENTION IS:

1. An apparatus for delivering a drug to the urethra to treat erectile dysfunction in a patient having a urethra and a corpus cavemosa, the apparatus comprising: means for delivering the drug into the urethra; and means for transporting the drug from the urethra to the corpus cavemosa.

2. An apparatus for delivering a drug to the urethra to treat erectile dysfunction in a patient having a urethra and a corpus cavemosa, the apparatus comprising: a member configured to deliver the drug into the urethra, the member having a reservoir, the reservoir being loaded with the drug, the drug causing increased intracavemosal pressure; and means for transporting the drug from the urethra to the corpus cavemosa.

3. An apparatus for delivering a drug to the urethra to treat erectile dysfunction in a patient having a urethra and a corpus cavemosa, the apparatus comprising: a member configured to deliver the drug into the urethra, the member having a reservoir, the reservoir being loaded with a drug, the drug causing increased intracavemosal pressure; and first and second electrodes configured to be placed in electrical communication with a power supply; the first electrode being positioned adjacent to the reservoir.

4. A method of treating erectile dysfunction in a user, the user having a penis, a urethra, and a corpus cavemosa, the urethra defining a lumen and having a urothelium lining, the method comprising the steps of: delivering a drug into the lumen; and phoretically transporting the drug from the lumen to the penile tissue, the drug causing increased intracavemosal pressure.

5. The method of claim 4, wherein the drug is prostaglandin E_x (PGEx) , phentolamine, prazosin, 3- morpholinosydnonamine, papaverine, vasoactive intestinal peptide, sodium nitroprusside, or combinations thereof.

6. The method of claim 4 comprising the additional steps of: delivering a second drug into the lumen; and phoretically transporting the second drug to the penile tissue.

7. The method of claim 6, wherein the second drug is prostaglandin E_x (PGE-_L) , phentolamine, prazosin, 3- morpholinosydnonamine, papaverine, vasoactive intestinal peptide, sodium nitroprusside, or combinations thereof.

8. The method of claim 6 wherein the steps of phoretically transporting the drug and phoretically transporting the second drug are performed simultaneously.

9. The method of claim 6 wherein the step of delivering a second agent into the lumen includes the step of delivering an adjuvant into the lumen.

10. The method of claim 9 wherein the step of delivering an adjuvant into the lumen includes the step of delivering a penetration enhancer into the lumen.

11. The method of claim 6 wherein the step of delivering a second agent into the lumen includes the step of delivering a second vasoactive drug into the lumen.

12. The method of claim 11 wherein the step of delivering a second vasoactive drug into the lumen includes the step of delivering a second vasoactive drug selected from the group consisting essentially of : phentolamine, prostaglandin E₁₍ prazosin, vasoactive intestinal peptide, and papaverine.

13. The method of claim 4 wherein the step of phoretically transporting the drug from the lumen to the penile tissue, includes the step of iontophoretically transporting the drug from the lumen to the penile tissue .

14. A method of treating erectile dysfunction in a user having a penis and a urethra, the method comprising the steps of : providing a treatment tool having first and second electrodes and an insert end sized to be removably inserted into the male urethra, the insert end containing a drug; inserting the insert end into the urethra and placing the first and second electrodes into electrical communication with the penis; and conducting an electrical current between the first and second electrodes thereby transporting the drug to the penile tissue.

15. The method of claim 14, wherein the drug is prostaglandin E_x (PGE_X) , phentolamine, prazosin, 3- morpholinosydnonamine, papaverine, vasoactive intestinal peptide, sodium nitroprusside, or combinations thereof.