A method of intracorporeal iontophoretic treatment of an internal hollow body organ containing a physiological ion-rich fluid environment by delivery to said hollow body organ of drug ions by means of an iontophoretic device inserted into said hollow body organ and comprising an active electrode which has the same polarity as the drug ions to be delivered. The method comprises direct measurement of the pH of said physiological fluid environment, whereby indirectly measuring its ionic composition and selecting accordingly the material of said active electrode so that it either can interact with ions contained in said physiological environment or allow the interaction of said environmental ions with water hydrolysis products so as to reduce the ionic species competitive with said drug ions during the iontophoretic process.

BACKGROUND OF THE INVENTION 
This invention relates to a method of intracorporeal iontophoretic 
treatment of body cavities or hollow organs. While in the following 
disclosure specific reference will be made to a preferred embodiment of 
the invention relating to the treatment of the bladder or prostatic 
urethra, it is to be understood that the invention is not limited to such 
treatments but equally applies to the treatment of other body organs 
meeting the conditions set forth hereinbelow, such as for example vagina. 
Iontophoresis is most frequently defined as "the introduction, by means of 
an electric current, of ions of soluble salts into the tissues of the body 
for therapeutic purposes" (Dorland's Illustrated Medical Dictionary). The 
technique of iontophoresis has been in clinical use for more than a 
century and a great number of drugs have been administered by this method. 
Some, but by no means all, of the drugs include salts of penicillin, 
gentamycin, salicylates, fluoride, dexamethasone, hydrocortisone 
lidocaine, cocaine, morphine and doxorubicin. 
By far the most common target site for iontophoretic treatments has been 
the skin, but the literature also reports a substantial number of 
treatments directed into the ears, the eyes, the tissues lining the mouth 
and the teeth. Reports of iontophoretic treatments within bodily cavities, 
other than the mouth, are very sparse. 
In 1983 Davis et al obtained a U.S. Pat. No. 4,411,648, for the purpose of 
iontophoresing heavy metal ions, such as copper and silver, into the 
bladder cavity in order to prevent infection. Davis et al described the 
insertion of both the anode and the cathode into the bladder cavity in 
order to sterilize volumes of urine within the bladder cavity by means of 
heavy metal ions derived from the electrode materials themselves. 
In chapter 97 of "FOLIA VETENNAVIA" 31, 1 (1987) there is described the 
treatment of colo-rectal cancers by iontophoresis of the drug, 
5-fluorouracil, into the tumor sites using a double balloon catheter. More 
recently two German patent applications filed in the name of Thiel et al 
(DE 3809814 and DE 3844518), described iontophoretic delivery of Proflavin 
and various cogeners into the bladder wall for treatment of bladder 
cancers. The intravesical volume of drug used was large (200 ml), the 
currents used were very large (50 m A) and, except for an insulated 
urethral section and tip, the active electrode within the bladder was an 
unshielded conductive rod. Although various adjuvants were added to 
enhance the permeability of the bladder wall, no attempts were made to 
increase the electrochemical efficiency of drug delivery. 
In spite of its inherent attractions iontophoresis has never attained 
widespread use in therapy probably because of some fundamental 
electrochemical problems which may be summarized here below. 
Theoretically, the quantity (m) of drug (D) delivered by iontophoresis is 
proportional to the applied current (I) and its time of application: 
EQU m D.apprxeq.I.t. 
Yet it has been shown unequivocally that, with iontophoretic administration 
of many drugs, the rate of drug delivery progressively diminishes with 
time. The main reason for this deterioration in performance of the 
iontophoretic system is associated with the transfer of electrical charge 
at the electrode (solid) - drug solution interface. For current to flow, 
electrical charge (electrons) must be transferred across this region. The 
electrons are derived either from dissolution of the electrode material 
and/or hydrolysis of water, at the anodic surface. For example: 
EQU Ag.fwdarw.Ag.sup.+ +e.sup.- 
EQU 2H.sub.2 O.fwdarw.4H.sup.+ +4e.sup.- +O.sub.2 .uparw. 
In either case, electrons are provided and unwanted competitive ions 
(Ag.sup.+, H.sup.+) are generated. 
At the cathode, electrons travel from the electrode into the drug solution, 
either as negatively charged ions or are again involved in the hydrolysis 
of water: 
EQU Ag/AgCl+e.sup.- --.fwdarw.Cl.sup.- 
EQU 2H.sub.2 O+2e.sup.- --.fwdarw.H.sub.2 .uparw.+2OH.sup.- 
In order to overcome the disadvantages, and in particular the reduced 
efficiency of iontophoretic processes due to the accumulation in the 
iontophoretic environment of the competitive ions originated by the 
electrodes or by the hydrolysis of water, it has been proposed (e.g. in 
U.S. Pat. Nos. 4,570,637 and 4,747,819) to coordinate the selection of the 
electrode material and that of the drug counterion so as to provide during 
the electrochemical process, ionic species interacting the one with the 
other so as to minimize or reduce the amount of water hydrolisis products 
in the iontophoretic process. 
None of the prior art references however recognized or dealt with the 
problems arising in intracorporeal iontophoresis of body cavities where an 
ion-rich physiological fluid environment exists, and none of them taught 
how to overcome such problems. 
SUMMARY OF THE INVENTION 
A main object of the present invention is that of providing a method of 
intracorporeal iontophoretic treatment of hollow body organs containing an 
ion-rich physiological environment, which has an improved coulombic 
efficiency. 
Another object of the invention is that of providing an intracorporeal 
iontophoretic process which requires reduced amounts or concentrations of 
drug and/or shorter treatment durations than required in the prior art 
processes. 
These and other objects which will appear more clearly from the following 
disclosure, are achieved by a method of intracorporeal iontophoretic 
treatment of an internal hollow body organ, containing a physiological 
ion-rich fluid environment, by delivery to said hollow body organ of drug 
ions by means of an iontophoretic device insertable in said hollow body 
organ and comprising an active electrode which has the same polarity as 
the drug ions to be delivered and is connected to an external electrical 
circuit which is also connected to a counterelectrode, wherein said method 
comprises checking the ionic composition of said physiological fluid 
environment by measuring its pH, selecting accordingly said active 
electrode from materials allowing ionic species which accumulate in said 
physiological environment during the iontophoretic process and which are 
competitive therefore with the drug ions to be diminished by reaction of 
said competitive ionic species either with the active electrode or with 
water hydrolysis products, and performing the iontophoretic treatment 
whereby diminishing said competitive ionic species. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The present invention is based on the finding that iontophoretic delivery 
of drugs into an internal body cavity suffers a loss of efficiency because 
of the electrolyte-rich environment existing therein, which interferes 
with the desired iontophoretic process. 
For instance, effective iontophoretic drug delivery into the bladder wall 
is always limited by the time of application while effective delivery into 
the prostatic urethra is potentially limited by time of application, 
because of continuous, inevitable influx of electrolyte-rich urine into 
the bladder, and the potential for some of this urine to enter the 
prostatic urethra during iontophoretic treatments. 
Immobilization, or scavenging of at least some of the urinary electrolytes 
(ions), allows prolongation of effective iontophoretic treatments and 
increased efficiency of iontophoretic treatments. This desirable result 
can be achieved by selecting anodal or cathodal materials depending on 
various incoming urinary electrolytes or by deliberately manipulating 
certain urinary electrolytes and then selecting an electrode material that 
will best immobilize these electrolytes by a specific electro-chemical 
reaction. 
On the average, urinary volume excreted over 24 hours is about 1500 ml, 
approximately 1 ml/minute. Urine is usually slightly acid (Ph 5.0-6.5 
units), and contains numerous metabolic waste products and also various 
ionized salts. The total concentration of solutes in urine usually exceeds 
that in plasma three to five fold. 
A list of pertinent urinary ions excreted over 24 hours in this "average" 
situation is defined in Table 1. 
TABLE 1 
______________________________________ 
URINARY ELECTROLYTES (mEq/24 h.) at pH &lt; 6.5 UNITS 
POSITIVE NEGATIVE 
______________________________________ 
Na.sup.+ 200 Cl.sup.- 200 
K.sup.+ 60 *HPO.sub.4.sup.2- + H.sub.2 PO.sub.4.sup.- 
40 
*NH.sup.+.sub.4 
40 SO.sub.4.sup.2- 
45 
Ca.sup.2+ 12 "Acid" salts 40 
Mg.sup.2+ 10 HCO.sub.3.sup.- + H.sub.2 CO.sub.3 
1-3 
______________________________________ 
*Highly variable 
However, there are numerous situations when pH values of urine fall to 
4.1-5.0 units (excess H ingestion or production within the body) or rise 
to 7-8 units (excess alkali ingestion). At times these are caused by 
illness, frequently they are brought about by some dietary quirk or by a 
deliberate dietary manipulation. For example, a dilute alkaline urine is 
of benefit to an individual with a propensity to form uric acid "stones" 
(gout). In this particular situation, certain urinary ionic contents, 
especially bicarbonate, chloride and HPO.sub.4.sup.2- /H.sub.2 
PO.sub.4.sup.-, differ markedly from levels of the same ions in urine of 
pH range of 5.0 to 6.5, as shown in Table 2. 
TABLE 2 
______________________________________ 
URINARY ELECTROLYTES (m Eq/24 h.) at pH &gt; 7.0 unit 
POSITIVE NEGATIVE 
______________________________________ 
Na.sup.+ 200 Cl.sup.- 20-30 
K.sup.+ 40 HPO.sub.4.sup.2- + H.sub.2 PO.sub.4.sup.- 
30-35 
NH.sub.4.sup.+ 
&lt;10 SO.sub.4.sup.2- 
45 
Ca.sup.2+ 10 "Acid" salts 40 
Mg.sup.2+ 8 HCO.sub.3.sup.- 
150-200 
______________________________________ 
Thus, as has been shown above, the pH of urine can range from about 4.1 to 
about 8.2. Usually the pH variations are determined by reactions of 
buffering hydrogen ions (H.sup.+) produced by metabolic processes. The 
three major reactions for buffering hydrogen ions are the 
bicarbonate/carbonic acid, ammonia/ammonium and hydrogen 
phosphate/dihydrogen phosphate reactions according to the following 
mechanisms: 
______________________________________ 
HCO.sub.3.sup.- + H.sup.+ .fwdarw. H.sub.2 CO.sub.3 .fwdarw. CO.sub.2 + 
H.sub.2 O pKa = 6.1 
NH.sub.3 + H.sup.+ .fwdarw. NH.sub.4.sup.+ 
pKa = 9.5 
HPO.sub.4.sup.2- + H.sup.+ .fwdarw. H.sub.2 PO.sub.4.sup.- 
pKa = 6.8 
______________________________________ 
While the first of the above buffering reactions implies pKa values far 
outside the physiological pH (about 7.4) of tissues and its only value 
resides in the body's ability to enzymatically and rapidly convert 
carbonic acid to CO.sub.2, and while the second reaction of above is slow 
in changing the acid-base balance, the third buffering system is the more 
versatile in that it has a useful pKa value, it takes place quickly so 
resulting in rapid modifications of the acid-base balance within the body 
and has the capacity of immobilizing large quantities of H.sup.+, such as 
at least 100 mM H.sup.+ daily. Therefore the method of the present 
invention takes advantage of this body buffer system. 
The method of this invention is carried out by means of any iontophoretic 
device suitable for intracorporeal applications. Illustratively such a 
device comprises a tubular catheter provided for insertion in a hollow 
body organ, for example bladder, prostatic urethra or vagina, which 
contains in its internal tubular cavity an active electrode. The internal 
cavity of the catheter is a conduit for a solution of a drug in the form 
of a salt, acid or "alkali", and the catheter is provided on its tubular 
walls with apertures or holes for the transfer of drug solution to the 
hollow body organ to be treated. 
The polarity of the active electrode used within the catheter depends on 
the polarity of the drug ion to be delivered. If the drug is in a cationic 
form, then the active electrode is a positively charged anode, while in 
the case of a drug in an anionic form the active electrode is a negatively 
charged cathode. In both cases the active electrode is connected to a 
generator of current and there is a counterelectrode which closes the 
electrical circuit and is arranged externally to the body. 
According to the present inventive method, the choice of the active 
electrode material is determined by the ionic content or composition of 
the physiological fluid environment existing in the body organ to be 
treated. Such ionic content either can be incidental or spontaneous, or it 
can be a content intentionally adjusted to a desired range. In either 
case, according to the present invention, the ionic composition of the 
physiological fluid environment is assessed through measurement of pH 
values. 
For example, with specific reference to urine environment encountered for 
example in the bladder or prostatic urethra, Tables 1 and 2 reported 
herein above show that an acid urine having a pH equal or lower than 6.5 
has a high content of chloride ions, while an alkaline urine has a much 
lesser content of Cl.sup.-. Thus it has been found that the simple 
measurement of urinary pH gives a reasonable estimate of the types and 
amounts of electrolytes in the urine. For instance two examples of 
analysis of urinary electrolytes are reported herein below showing the 
reliability of the relationship taught in the present inventive method 
between pH and the nature and content of such electrolytes. 
______________________________________ 
Urine pH = 5.8 units 
Cl.sup.- .about. 200 m Eq/24 h .about. 0.14 mEq/min 
HCO.sub.3.sup.- and H.sub.2 CO.sub.3 .about. 2 mEq/24 h 
HPO.sub.4.sup.2- /H.sub.2 PO.sub.4.sup.- .about. 1/10 
Urine pH = 7.4 units 
Cl.sup.- .about. 30 mEq/24 h .about. 0.02 mEq/min. 
HCO.sub.3.sup.- .about. 170 mEq/24 h .about. 0.12 mEq/min. 
HPO.sub.4.sup.2- /H.sub.2 PO.sub.4.sup.- .about. 6/1 
______________________________________ 
It has been found convenient according to the method of this invention to 
select the material of the active positive electrode based on the anionic 
composition of urine which can be estimated from the pH measurement. The 
material selected is such that it either reacts directly with urine anions 
or promotes or allows a reaction of such anions with the water hydrolysis 
ions, so as to achieve an overall reduction of the ionic species 
accumulating in the iontophoretic environment and competing with the drug 
ions in the iontophoretic process. 
In particular, when the drug to be delivered is in cationic form whereby 
the active electrode of choice is an anode, the following situations may 
arise. 
(a) The pH of urine is measured as &lt;6.5 units. This pH can be incidental 
pH, in which case the lower acid values may be due to dietary habits, 
certain systemic illnesses or to some specific treatment of certain 
urinary tract infections. Alternatively, this pH values may have been 
induced deliberately by a preliminary diet, for the purpose of the 
iontophoretic treatment. 
In this situation the anodic material chosen will be a metal giving 
precipitates by reaction with chloride anions, e.g. silver or copper. The 
reactions taking place will be: 
EQU Ag--.fwdarw.Ag.sup.+ ;Ag.sup.+ +Cl.sup.- --.fwdarw.AgCl (insoluble) 
EQU Cu--.fwdarw.Cu.sup.+ ;Cu.sup.+ +Cl.sup.- --.fwdarw.CuCl (insoluble) 
(b) The incidental or intentionally adjusted pH of urine is measured as 
&gt;7.0. This pH range indicates diminishing quantities of chloride ion 
(replaced by increasing quantities of bicarbonate ion) and a predominance 
of hydrogen phosphate ion over dihydrogen phosphate ion. In this case the 
anode will be selected from substantially inert conductive materials. 
With the inert electrode there is hydrolysis of water: 
EQU 2H.sub.2 O--.fwdarw.4H.sup.+ +O.sub.2 +4e.sup.- 
then urinary HPO.sub.4.sup.2- reacts with hydronium ions: 
EQU HPO.sub.4.sup.2- +H.sup.+ --.fwdarw.H.sub.2 PO.sub.4.sup.- 
Thus, H.sup.+ generated by electrolysis of water is scavenged by 
HPO.sub.4.sup.2- in urine whereby HPO.sub.4.sup.2- loses charge thus 
reducing competitive inhibition by urinary ions. 
The inert anodes can be selected from carbon, gold, platinum, stainless 
steel, chromium, nickel-chromium alloys, etc. 
c) The measured pH, as an incidental value or as an intentionally adjusted 
one, is in the range of from 6.5 to 7.0. In this case there still exists 
an abundant supply of chloride ions in the urine while the 
HPO.sub.4.sup.2- /H.sub.2 PO.sub.4.sup.- ratio varies from 1/2 at pH 6.5 
to 1.7/1 at pH 7.0. 
Therefore both chloride reactive and inert electrodes can be used, as 
specified above under points a) and b), respectively, and such electrodes 
will behave according to the respective reaction mechanisms set forth 
above to diminish either the chloride ion content or the hydronium ion 
content and the charge on hydrogen phosphate ion. 
When the drug used in the treatment is in anionic form and the active 
electrode of choice is accordingly a cathode, the options for selecting 
the cathodic material are more limited. In fact except for few cathodic 
materials, such as a Ag/AgCl cathode which delivers Cl.sup.- ions, most of 
the conductive materials used as cathodes cause hydrolysis of water with 
production of hydroxyl (OH.sup.-) ions. According to the principles of the 
present invention, the useful reaction of hydroxyls with urine ions are 
those with the dihydrogen phosphate anions and with organic acids present 
in urine according to the following mechanisms: 
EQU 2H.sub.2 O+2e.sup.- --.fwdarw.2OH.sup.- +H.sub.2 (gas) 
EQU H.sub.2 PO.sub.4.sup.- +OH.sup.- --.fwdarw.H.sub.2 O+HPO.sub.4.sup.2- 
EQU H.Org.Ac.+OH.sup.- --.fwdarw.H.sub.2 O+Org.Ac..sup.- 
While these reactions, unlike those taking place at the anode, do not 
diminish the total charge of the urinary competitive ions, they achieve a 
neutralization of the hydroxyl ions, which are much more mobile than the 
relatively bulky drug anions, whereby achieving an overall reduction of 
unwanted ionic species highly competitive with drug ions for the 
electrical current. 
Since an acid pH of urine shifts the equilibrium of the hydrogen 
phosphate/dihydrogen phosphate system towards the dihydrogen phosphate 
thus favouring the above reactions, it is preferred for the purposes of 
carrying out the method of this invention, to have, when using as active 
electrode a cathode, an acid urine. 
Therefore, if necessary, about 12-24 hours prior to the inventive 
iontophoretic treatment, the urine pH is brought by a diet, to an acid 
value, say to a pH of 4.8 to 5.5. Then the cathode material can be 
selected from any known conductive material behaving as inert cathode, 
such as gold, carbon, platinum, chromium, nickel-chromium, stainless 
steel, copper, etc. 
By applying the method according to this invention advantages are achieved 
over prior art iontophoretic methods, especially in terms of reduction of 
current intensity and/or duration of treatment, thus resulting in a much 
more effective iontophoretic drug delivery process. In particular, 
vis-a-vis current intensities of 50 mA and treatment durations of 30' 
shown in the prior art references, the method of the present invention 
will achieve a delivery of approximately equal amounts of drugs with 
currents of 15 to 30 mA for durations of 20 minutes. 
Even more importantly, this reduction in the intensity of the electrical 
current reduces the damage to tissues caused if there is inadvertent 
direct contact between the active electrodes and the tissues, e.g. the 
bladder wall. 
A drug solution with a concentration of 0.5 to 1.0% by weight is 
appropriate for clinically effective iontophoretic delivery rates. 
The above mentioned improvements achievable by the method of this invention 
are particularly important not only from a purely economical point of view 
but also, and more importantly, from the point of view of the patient's 
comfort and safety. 
The following examples are intended as purely illustrative of the various 
possible embodiments of the present inventive method without limiting in 
any way the scope of this invention.

EXAMPLE 1 
Lidocaine and Mepivacaine (Positively Charged Drug Ion) 
In this example, two commonly used local anesthetic agents, lidocaine and 
mepivacaine have been used. 
Twenty eight urological patients having urines with a pH below 6.5 had 100 
ml solutions of mepivacaine or lidocaine with epinephrine (a 
vasoconstrictor) infused into their bladders, prior to endoscopic 
operative procedures by using a catheter with an active anode of silver. 
Twenty two of these patients received currents of 10-30 mA for 10-20 
minutes with the anode in the bladder and six patients (controls) either 
had no current applied or had current applied with the cathode in the 
bladder. 
The twenty two experimental subjects tolerated operative procedures with up 
to 25 grams of bladder tissue removed by cautery. The six control subjects 
required supplemental intravenous anesthesia or abandonment of the 
operative procedure. 
EXAMPLE 2 
Netilmycin Antibiotic (Positively Charged Drug Ion) 
A 65 year old male with severe Parkinson's disease had an indwelling 
bladder catheter for more than 5 years. As almost always occurs, the urine 
became infected and then the bladder (infective cystitis). Antibiotics 
were given orally, intramuscularly and directly into the bladder 
(locally). Susceptible strains of bacteria were eliminated and more 
resistant strains appeared in their place until, finally, there were 
present Pseudomonas and Enterobacter bacteria. These two species resisted 
all attempts at eradication by all appropriate antibiotics administered by 
all logical routes. 
The patient whose urine showed a pH above 7.0 units has received 
Netilmycin, 900 mg in 100 ml of water, by instillation into the bladder. 
Iontophoresis using 15 mA over 15 minutes and a gold (inert) electrode was 
applied. Both Pseudomonas and Enterobacter were eliminated and were 
replaced by another bacteria, Escherichia Coli. This was an excellent 
result for the patient because the E. Coli was sensitive to a number of 
common antibiotics and was eliminated in turn by a course of antibiotics 
taken by mouth.