CA2033509A1 - Therapeutic cholesterol gallstone dissolution method - Google Patents

Abstract

(57) Abstract A method and apparatus are disclosed for treating a patient having cholesterol calculi which involves infusing into the bil-ary tract of said patient a C5-C6 ester, ether or ketone having a boiling point in the range of 80°-140° C or a mixture thereof m an amount and at a flow rate effective to at least partially dissolve said calculi rapidly. The invention also encompasses dissolving cholesterol calculi by exposing such calculi to contact with effective quantities or those solvent compounds. The apparatus includes a high flow rate catheter pumping system for infusing a gallstone dissolution solvent into the gallbladder of a patient and aspiring the gallstone dissolution solvent from the gallbladder, and a unit measure container of the sol-vent. The preferred esters, ethers and ketones are n-propyl acetate, isopropyl acetate, ethyl propionate, ethyl isobutyrate, cyclopentanone, pentanone and methyl l-amyl ether. Contact flow rates are sufficiently high to insure fluid turbulence in the biliary tract region surrounding the calculi.

Description

WO90/12570 ~ PCT~S~/n~ ~ ~ a 9 1THERAPEUTIC CHOLESTEROL GAIISTONE DISSOLUTIOM ~ETHOD

4The application is a continuatisn~ part o~ application 5Serial No. 07/341,900, flled April 24, 1989.

8 ~
9 The in~ention herein relates to medical treatments of cholesterol calculi ~particularly gallstones) by c~ntact - 11 dissolution with organic ~olvent~. More particularly it 12 relates to therapeutic ~ethods using low v~scosity nsn-toxic 13 pumpable solvents.
14 2 Backqround of the Prior Art~
' 15 The contact dissolution of cholesterol gallstones by : 16 organic solvents in hu~an patients is a well recognized medical 17 procedure and may be favor~d over surgical procedures to remove 18 gallstones in patients at increased risk of surg~ry; see, f~r l9 instance, V.5. Pate~t No. 4,205,086. The dissolution procedures normally inv~lve infus~on of the solvent into the 21 biliary tract (includin~ the gallbladder and the b~le ducts) by 22 means of a T-tube, nasobiliary tube, percutaneous tran~hepatic 23 catheter or cholecyst~stomy tube by use of a constant infusion 24 pump or by gravity or by m~nual repeated inst~llation and withdrawal using a ~yringe; ~ee Palmer, et al~, 5~ 2, 196 26 (1986~. Often the stones f ragm~nt during the dissolution 27 procedure, which advantageou~ly increa~s the rate of 28 dissolution.
29 A number of different types of solvents have been used or suggested for the dissolution procedureO These include organic 31 solvents such as diethyl ether, chloroform or d-limonene as ~ 32 well as aqueous micellar solutions of bile salts. The 33 aforementisned U.S. Patent No. 4,205,086 also lists a large :.
, :
:

W09~/12570 ~ 0~ ~ ~ 0 9 - 2 ~
1 number of useful liquld fatty acids and the ~lcohol esters 2 thereof. A further solYent whi~h has received ~ubstantial 3 attention is monooctanoin, mentioned in V.S. Pa~ent No.

4 4,755,167 and several articles, such a~ Thistl~, et al., Gastroenterolo~y. j~ ~, 10l6 (1980). More recently methyl 6 t-butyl ether (MTBE) has been used as a cholesterol gallstone 7 solvent; see, e.g., Allen, et al., Gastroenteroloq~,~88, 1, 122 8 (1985); Thistle, et al., U.S. Patent N~. 4,758,596; and 9 Thistle, et al., N. Enql. J. Med.. 32~ 633 (~939).
While all of the~e ma~erials have shown s~me e~f~cacy in 11 in vivo andi/or J~L~L~ tests, all have some undesirable side 12 effects or physical properties. Monooctanoin, for instance, 13 has a relatively high viscosity and dissolves gallstones very 14 slowly. MTBE was ~elected by Thi~tle,, et al., becau~e it~
boiling point is above body temper~ture. However, if MTBE
16 escapes from the gallbladder into the small intestine, lt 17 causes sign~ of ~ystemic toxicity (seidaticn) , paln, nausea, 18 and by endoscopy, damage to the epithelium of the small 19 intestine. Entry o~ MTBE into the blood stre~m causes hemolysis, and one case o~ renal failure ~rever~ible) has been 21 reported. MTBE also has a relati~ely l~w boiling point (55~C), 22 not far above ordinary body t~mperature, which pose~ 80me 23 volatility problem~ in use because o~ it~ low flash point ~nd 24 strong, unpleasant odor. Those material~ ~uch a~ diethyl ether which have boiling points helow body temperature are hazardous 26 for clinical use because of rapid volatilization and marked 27 increase in volum~ in use.
28 Recently there has been dev~loped a novel infusion pump 29 which produces a high flow rate at low pressure. This pump has been described and claimed in U.S. Patent No. 4,902,276, issued 31 February 20, 1990, and U.S. Patent Application Ser. No.
32 07~482,194 (February 20, 1990~ by S. Zakko (the "Zakko pump").
3~ While this pump has proved very effective for ga1lstone ', .

, . . . . . ~ , . . , . , . . , . ; , . ... ,, . .. ~. .. . .. . .. , . ~ . " .. . . .. . . . . . .... . . . ..

WO90/12570 ; ~; P~/US90102212 2~33~0~

l dissolution, its satisfactory perfoxmance depends on being used 2 with relatively low viscosity solvents.
3 It would therefore be advantageou~ to have a therapeutic 4 procedure available in which cholesterol gallskones rould be easily, safely and rapidly dissolved by a solvent which would 6 be effective for dissolution of cholesterol gallstones, ea~y 7 and safe to handle for medical personnel ~nd capable of being 8 used in the most effective equipment such as the Zakko pu~p.
g BRIEF SUMM~RY OF THE INVENTION
ll In one aspect, the invention herein is a method for 12 treating a patient having cholestervl calculi, particularly 13 gallstones, which comprises infusing into th~ biliary tract of 14 said patient a C5-C~ ester, ether or ketone having a bo~ling point in the range of 80--l40'C or a mixture thereof i~ an 16 amount and at a flow rate effective to at least partially 17 dissolve ~aid calculi rapidly.
18 In another a6pect, the invention herein i~ a method for l9 dissolving cholestersl calcull (p~rticularly gallstones) which 23 comprises contacting said calculi with a C~-C~ ester, ether or 21 ~etone having a boiling point in the range sf 80--140-C or a 22 mixture thereof ~n an ~mount and at a flow rate ef~ectiYe to at 23 least partially di~olve said calculi rapidly.
24 Parti~ularly preferred among the Cs-C~ estexs, ethers and ketones ~re thos~ selected from the group çon~istlng of ~6 n-propyl acetate, isopropyl acetate, ethyl propionate, ethyl 27 isobutyrate, cyclopentanone, 3-pen~anone and methyl t-a~yl 28 ekher (methyl l,l-dimethylpropyl ether). These have all been 29 found to produce rapid dissolution of cholestérol gallstones (at a rate generally comparable to that of MTBE) without 31 problems of volatility or excessiv~ vis~osity.

~..

' ' .

WO90/12570 ~: PCT/USg0J022l2 - 4 - 2~3~
1 ~RIEF DESCRIPTION OF THE DRA~INGS
z The advantages of this invention may be better underst~od 3 by referring to the following description taken in conjunction 4 with the accompanying ~rawings in which:
Figure 1 depicts an embodiment of the invention using 6 peristaltic pumps.
7 Figure 2 depicts an embodiment of the catheter o~ the 8 inv~ntion. ~ ~
9 Figure 3 depicts an embodiment vf the reservoir of the invention containing a unit volum~ of solvent.
11 Figure 4 depicts an embodiment of the tubing of the 12 invention.
13 Figure 5 depicts an embodiment of a kit containi~g the 14 disposable portions of the invention.

16 DETAILED DES~IPTION AND PRE:FERRl~D EMBODIMII~aTS
17 The efficacy of the methods of this invention can be best 18 understood by csnsideration o~ the charact~ri~tics oP
19 cholestexol calculi and thc clai.med clas~ o~ 801vent8 usePul in the invention.
21 As used herein, the term "cholesterol c~lcul~" means tho~e 22 concretions which ~enerally develop in hollow organs or duct~
23 within humans and animals and which cont~in at least about ~0%
24 cholesterol. Well known common chol~terol calculi are cholesterol biliary duct ~tones and gallstones. Also, the term 26 ~Ibiliary tract" will be recogni~ed to encompa~s both th~
27 gallbladder and the bile ducts.
28 Consideration of the usual equatlons usPd to describe 29 dissolution of a sphere by a fluid under turbu~ent conditions indicate~ that not only equilibrium solubility but also 31 viscosity is important. This i6 because viscosity influences 32 the difPusion of cholesterol in the unstirred layer immediately 33 surrounding the stone (according to the Stokes-Einstein . ,.
.

: `l `' W090/12570 ( PCT/US~0/02212 2~3~
l relationship). In addition, low viscosity is important ~ince 2 catheters used for thls purpose must have a small bore (usually 3 less khan 8 French), with a hi~h flow-low pre~sure pumping 4 system such as that of the Za~ko Pu~p. The pressure need~d to obtain a qiven flow varies inversely as the 4th power of the ; . 6 radius, and directly with the viscosity of the fluid being ` 7 pumpedO Thus for a small bore tube, the lower the YisCoSity, : ~ the greater i8 the solvent flow for a given pressure.
9 There are two addition~l requirements for a satisfactory solvent. It must be relatively non-toxic in ~everal aspects.
ll First, the solvent must not damage the gallbladder mucosa 12 significantly during a sev~ral hour exposure of the mucosa to 13 the anhydrous solvent. Second, the solvent must not damage he : 14 mucosa of the biliary duct ~ystem ox the ~mall ~n~estine if the solvent leaks out of the gallbladder. The ~ol~ent ~hould cause 16 little he~olysi~ if mixed with ~lood, should not ~ause release 17 of toxic cytokines such as platélet activating factor, and 18 should not be toxic if it escapes into the peritoneal ca~ity.
19 In addition, the solvent should have a pleasant odor 60 that if absorbed it do~s not induce nausea. Further, th~ solvent should 21 be rapidly metabolized by digestive ~nzymes if it ~6~apes lnto 22 the gastrointestinal tract, an~ the resultant digestive 23 products should be known to be sa~e.
24 Lastly, there are ~af@ty c~n~iderations in handling the solvent. I~ spilled, it should not cause danger to exposed 26 employees. It ~hould be a non-explosive and have a relatiYely 27 high ~lash point. It should have a stabl~ shel~ life and not 28 form peroxides or othe~ explosive by-pro~uc~s.
29 viscosity is known to vary directly with the number of carbon atoms in a molecule. It varies inversely approximately 31 exponentially with temperature. Boiling point and flash point 32 also vary directly with the total number of carbon atoms, but 33 the relationship is not as slmple. Cholesterol solubi}i~y in ,, .

' WOg0~12570 ~ PCT~S90tO2212 2 ~

1 solvents can be predicted to some ext~nt by solubility2 parameter consideration~O
3 The determination of solvents suitable for ef fective 4 contact dissolution of cholesterol gallstones thuR involves multiple considerations. In addition, there are ~olute 6 considerations. Cholesterol gallstones are compoqed of 7 cholestervl monohydrate (and other insoluble salts); see 8 Whiting, et ~1., Clin. Sci.. 68, s89 (1985). If gallstones are 9 stored in the dry state, the water ~ay evaporate ~o that the cholest2rol monohydrate becomes anhydrou~ cholesterol.
11 Thereore testing of solvents is best done on freshly harvested 12 human gallstones which have been Xept wet.
; 13 Based on these considerations, our research has led to the . 1~ discovery that ef~ctive solvents are those having 5-6 carbon . 15 atoms per molecule and being selected fro~ the group consisting 16 of ethers, esters and ketones with a boiling point in the range 17 of 80 -140-C and mixtures thereof. We have al~o discovered 18 that within this cl~ss tho~e compounds which are particularly ~9 preferred solvent~, due to their most closely mee~ng the :~ 20 desirable .criteria discussed above, are n-propyl acetat~, 21 i~opropyl acetate, ethyl propisnate, ethyl i60butyrats, 22 cyclopentanone, 3-pentanone and methyl t-amyl ether ~çthyl 23 l,l-dimethylpropyl ether). All o~ these are known compounds and 24 need not be defined f~rther here; their physlcal and chemlcal properties are well described in the chemical llterature.
26 Their ef~icacy and the techniques of the pre~ent invention 27 may be ~een from the ~ollowing data. In the tests describ~d in 28 ~able I below, fresh human aceted cholesterol gallstones ~kept 29 in distilled water) were dissolved in vitro and the times were recorded for the total dissolution, using a model gall~ladder 31 at a high flow rate achieved by a metering pumpO "High flow : 32 rate" as used herein will mean rates of flow in the range which .. 33 can be anticipated to result in fluid turbulence for the , `:
..
, ;
., ~

WO 90/12570 !~ PCr~US90/02212 - 7 - 21D33~9 1 solvent in the region ~f the biliary tract surrounding the 2 calculi (gallstones). While "high" rat2s will vary ~ccording 3 to solvent type and viscosity and with indiv~dual patients~ it 4 will be expected that appropriate flow rates will be at least about 20 ml/min, preferably at least about 100 ml/min, and more 6 preferably at least about 150 ml/min. For comparison purposes 7 a parallel test with MTBE is also shown. The second column 8 shows the weight of stone treated, of which 90~ by weight can g b~ considered to he cholesterol.
l 0 TABLE
12 Boiling Stone Dissolution 13 Point, Weight, Ti~e, Rate, 14 Solvent C ma min. mq/min.
16 n-propyl acetate 102 150 10 14 17 isopropyl acetate89 147 14 9 18 ethyl propionate 99 140 10 13 ethyl isobutyrate112 132 15 8 cyclopentanone 131 125 10 11 21 3-pentanone 101 142 9 14 22 methyl t-a~yl ether85 131 8 15 23 methyl t-butyl ether 55 175 8 2 It will be evident ~rom t~ese data that the C5-Cb ether, 26 ester and ketone solYent of this ~nvention are essen~ially 27 similar to the known MTBE in their abil~ty to rapidly dissolve 23 cholesterol gallstones, while yet having substantially higher 29 boiling point~ than MTBE and thus substantially less potenti~l for problems w~th volatility.
31 Toxicological considerations indicate that the first six 32 solvents have a low order o~ toxicity, although only limited 33 informa~ion is available on cyclopentanone. The toxicity of 34 methyl t-amyl ether has not been studied, but should be similar to that of MTBE; see Savolainen, et al., A~ge~_~sL~
36 285 (1985).
37 In another series of experim~nts, the Pfectiveness of 38 propyl acetate, isopropyl acetate, ethyl propionate and ethyl ! ~
.` .

:.
. :~

WO90tl2570 ( ' (' ~Cr/US90~02212 - 8 ~ 3 ~ ~ ~
1 isobutyrate esters ver~u~ MTBE in dissolving cholesterol 2 gallstones was determined in ~itro. For this study stones from 3 five cholecystectomy patients were matched. All stones were 4 visually jud~ed to be primarily cholesterol. The mean stone weight ~or the ~est sets (five stones each) ranged ~rom 79-340 6 mg. The test protocol utilized a 30 ml polyethylene bag a~ a 7 model gallbladder. One stone wa~ dissolved at a time. For 8 each stone a re~ervoir containing lS0 ~1 of solYent was u~ed.
9 Flow to the bag was maintained at 1~0 ml/min. ~ closed loop pumping system was employed to deliver the ~olvent to th~
11 iexperimental stone within the polyethylen~ bag. A Medical 12 Disposable~ ~nternational subclavian catheter ~#1900115A) was 13 used to deliver and withdraw tihe ~olvent and monitor pressure 14 which controlled the pump. This catheter consisted o~ two 18 gage lumens and a ~ingle 16 gage lumen. ~h~ larger lumens were 16 used to aspirate and infuse the sol~ent and the smaller lumen 17 was used to monitor pressure within the model gallbladd~r. ~he 18 termination of each lumen was a ~ingle port. ~he feed back 19 f rom the pressure triansducer was used to control the pumps to 20 delivery 180 ml/min within a predetermined intralumen pressure.
21 A ~low of 180 ml/min was used to assure high turbulence and 22 o~tain optimum àissolution rates due to high rate~ of masi~
23 transfer . ComplQte di~solut~ on wai~ def lned as the 24 disappearance of all d~brls in the model gallbladd~r. The data 25 are summarized in Table II.
2 6 TABL;13 I I

28 Mean TimeOverall Rate 29 min. mg/min.
31 Ethyl Propionate - 14 12.22 32 MTBE 19 7.69 33 I~opropyl Acetate 26 5. 48 34 Ethyl Isobutyrate 33 4 . 55 3 5 Propyl Acetate 3 5 4 . 4 5 37 This comparison shows the esters tested to be woso~12s7o ( ~ ~ . PC~/VS90/022l2 2~33~
_ 9 _ 1 substantially eguivalent to MT~E. The variation in ra~es is 2 well within experimental expecta~ions, sinse great differences 3 exist from stone to stone for each solvent and the surface area 4 per unit volume increases as the stone diameter (weigh~) decreases for similar materials and for similar geometries. It 6 is also expected that the chemical differences ~rom stone to 7 stone may cause one solvent to perform appreciably different 8 than the next.
g Met~bolic consideration~ lndicate th~t the ester~
lo (n-propyl ~cetate, isopropyl ~cetate, ethyl propionate and 11 ethyl isobutyrate~ are likely to be hydrolyzed by digestive 12 esterases and quickly converted to the corr sponding alXanol 13 and aliphatic acid (which will ionize). The hydrolysis 14 product~ -- ethanol, n-propanol and isopropanol and the acetate, propionate and butyrate ion~ -- all have a low degr~e 16 of toxicity. The ~etones will be reduced in the liver to the 17 equivalent alcohols, which are generally non-toxic.
18 We believe that it is likely that ~ mixture the solvents 19 will have less toxicity (expressed per un~t volume of ~olvent) than any o~ the solvents alone because each of ~he olv2nt~
21 undergoes a dif~erent metabolic pathway.
22 Any suitable technique of infusion o~ the described 23 solvents into a patient in the method of this invention can be 24 used; normally the one chosen will be a~ that described in the prior art for other solvents,, including monooctanoin ~nd MT~E.
26 The solvents are normally used in undiluted liquid form, but if 27 desired may also be used as part of mixtures with inert liquid 28 carriers. Since dissolution is a contact phenomenon it will be 29 recognized that dilution in such mixtures will normally slow the rate of dissolution and extend the time needed to achieve 31 the desired degree of gallstone dissolution.
32 Another aspect of the invention is the in vivo dissolution 33 of gallstones using the Cs-C6 ester, ether and k~tone class of ,, .
;

~ ' .
., .

WO90~12570 ~ ~ PCJ/U590/02212 - lo ~33~13~
1 solvent~ provided herein as the solvent in a high flow ra~e 2 pumping system, in particular a continuous pumping sy~tem 3 controlled by gallbladder pressure feedback and employing a 4 delivery system consisting of a catheter, a continuous ~low pumping system, a controller and a tubing set; see aforesaid 6 U.S. Patent Application No. 07/482,194, filed February 20, 7 1990, to S. Zakko, incorporated her~in by reference.
8 In general, the system shown in that application and see 9 Figure 1 hereinl is capable of operating continuously at a hiyh flow rate to produce continuous turbulence in the gallbladder 11 while as~uring that the i.ntra-luminal gallbladder pres~ure does 12 not exceed the critical leakage pressure, thereby preventing 13 solvent ~rom en~ering the intestine through the ~ystic and 14 common bile ducts. Such a pumping system, in combination with the low viscosity solvent provided herein, has the capability 16 of emptying the gallbladder many time~ faster than the rate of 17 normal gallbladder contraction, to prevent solve~t from 18 emptying into the intestine should such a gallbladder 19 contractlon occur during perfusion. The system is however designed to permit internal pressure ~ransients due to patient 21 coughing, laughing, movement and the like without interrupting 22 the solvent flow.
23 The ~ystem will accept flow calibra~ions of both lnfusion 24 and aspiration pumps and operate those pumps at substantially equal flow rates to minimize the control modulation ~nd 26 maximize ~he overall ~low rate. The controller oP the sy~t~m 27 can, for example, accept, upon command, flow rate, set 28 pressure, lower pressure limit, upper pressure limit and alarm 29 conditions and permit the operation at flow rates of the solvent from ~lose to zero to 250 ml/min, with normal perfusion 31 occurring at 1OW rates preferably above about 150 ml/min. As 32 previously mentioned, the present solvents, due to their low 33 viscosities, are intrinsically efficient in contact dissolution ;

r.;,j ~
WO 90tl~570 "'; i PCr/US91)/0221Z
3~f39 l due to enhanced mass transfer per~ormance; furthermore, he 2 high flow rates and attendant turbulence permitted by the low viscosity will enhance the dissolution e~ect.
The pump infuses solvent into the gallbladder of the patient through a catheter, shown in Figure 2, and more fully 6 in the aforesaid U.S. Patent Application Serial No. 07/482,194.
7 The catheter is constructed to permi~ the aspiration and 8 ~nfusion of the disclosed low viscosity clas~ of e~tsrs, ethers 9 and ketones at flow rates up to 250 ml/min while requiring no more than an 8 french catheter ~ize. Such a cathet~r includes ll an infusion lumen, an aspiration lumen and a pressure sensing 12 lumen to permit the continuous remote monitoring of 13 intra-gallbladder pressure with a column of physiolo~ical 14 saline. The catheter also includes a retention device to secure the catheter within the gallbladder intra- and post-16 operatively.
17 The cathet~r 76 is s~pplied wlth solvent by a tubing set 18 and reservoir which are provided as a dispo~able kit, as l9 discussed below. The tubing, catheter and reservoir are constructed of materials compatible with the select2d solv~nt.
21 The tubing must be strong enough to be u~ed in a peristaltic 22 pump in which ~olvent is being infused or aspirated at ~low 23 rates up to 250 ml/min. and y~t not limit flow or permlt 24 elastic dePormation under positive or negative pressure whlch would adversely reduce the frequency response of the pump to 26 control gallbladder pressure. Additionally, the reservoir 27 allows ~or the yravity separation o~ bile and solvent, thereby 28 permitting aspirated solvent to be reinfused.
29 In more detail, the pumping system portrayed in Figure l comprises a peristaltic infusion pump 14 and a peristaltic 31 aspiration pump 18. These pumps are driven by separate, 32 reversible DC motors which are controlled by a programmable 33 controller 90. The infusion pump draws the solvent from , ~

WO90/l2570 ( f~ PC~/US90/02212 i - 12 - 2~
1 reservoir lO by means of conduit 12 and discharges the solvent 2 into infusion lumen 54 of catheter 76. Th a~piration pump 3 draws the ~olvent from the gallbladder by means of the 4 aspiration lumen 50 of cathe~ex 76 ~nd conduit 25 and discharges it to reservoir 10.
6 The pressure in the gallbladder is sensed by transducer 24 7 by means of a ~itatic liquid column 27. The analog pressure 8 signal is convert~id to a digital signal by an analog to digital 9 converter 94 and supplied to the micro-procesiior 9~ through bus 98.
11 In the normal operation mode, the microprocessor 96, 12 responding tD a pressure si~nal ~rom transducer 24, operates 13 the infusion pump 14 at the desired flow rate. The aspiration 14 pump is driven at varying speeds when the pressure is above or below the desired pressure, and at a constant speed when the 16 pressure is in the vicinity of the desired pressura, to keep 17 the gallbl~dder pressure within khe upper And lower pressure limits.
19 Further, should the pressure remaln above (as may occur with the beginning of a qallbladder contraction) or below the 21 upper and lower pre6sure limits in excess of empirically 22 determined delays, or above or below thei upper and lower 23 pressure alarms, for the associated delays, the controllQir 24 cauges the system to enter into an alarm mode in which both ~S pumps operate in ~he aspiration directiQn at maximum flow rate 26 to remove the 1PW viscosity solvent.
27 The catheter, shown in Figure 2, includes three fluid 23 lumens 50, 52, 54 and a pigtail retention device.75. As shown 29 in Figure 2, a separate lumen 70 in provided for the pigtail retention. The aspiration lumen SO is made largQr than the 31 infusion lumen 54 to provide for the fact that thP pressure 32 drop in the aspiration mode is limited to the difference 33 between atmospheric pressure and the solvent's vapor pressure.

.

. ~
.

WO 90J12570 Is ~ P~/US90/OZ;i~12 2 ~

Additionally, under aspiration, the lumen tends to c:ollapse, 2 further redusing flow. In the infusion mode, the pressure 3 within the infusion lumen ~an ~xceed 6 atmospheres: the 4 catheter is constructed of a material which can endure this type of pressure. The pressure sensing lum~n 52 need only be 6 .020 inch ln diameter to obtain excellent respon6e.
7 The ports 71 to the aspiration lumen 50 and the ports (not 8 shown~ to the infusion lumen 54 direct flow of the low viscosity solvent perpendicular to the plane of the pigtail.
1~ Each lumen 50, 52 and 54 terminates in a plurality o~ ports, 11 each having a cross-sectional are~ less than the respeckive 12 lumen with which it is in communication. This size ratio is 13 desirable to reduce the possibility of lumen blockage. Each 14 lumen terminates at the proximal and of the catheter in one of a series of polar~zed luer fittings 80, 82, 84, 86 for 16 connection to the ~ystem tubing.
17 Referring to Fig. 3, the ~olvent i~ preferably prepackàged 18 in a disposable gravity-separation reservoir 1~ containing A
19 unit measure o~ the solvent 102, and spe~ial ~eatures enabl~ng use in the continuous, high flow rate, Za~ko pumping system.
21 The reservoir 10 has a total volume ~arger than the volume of 22 solvent 102 contained, for example 200 ml of solvent in a 250 23 ~1 container. The reservoir 10 include~ a~ integral intake 24 tube 104 and an integral return tube 114. One end 108 of the intake tube 104 terminates below the solvent-a~r meniscus 106, 26 while the other end 110 o~ the intake tube 104 ls constructed 27 to mate only with the tubing from the infusion pump. Similarly, 28 one end 112 of the return tube 114 extends ~urther into the 29 reservoir 10 than does the inta~e ~.be 104 in order to expel the solvent/bile mixture removed from t~ patient closer to the 31 bottom of the reservoir 10. This ~s done to prevent the 32 aspiration sf wa~te bile by the intake tube 104. The other end 33 116 of the re~urn tube 1.'' is also cons~ructed with a connector :

WO90/l2570 ~ ' PCl'/VS90/~2212 - 14 - 2~33~t~
. 1 which permits it to mate on1y with the tubing from the : 2 aspiratlon pump.
3Referring also to Figure 4, the tubing assemblies 12, 25 4comprise the perlstaltic tubing 128, 146 for the infusion and 5aspiratlon pumps respectively, catheter tubing 120, 152 for 6fluid flow between the-~perista1tic tubing 128, 146 and She 7catheter connectors 80, 82 and reservoir tubing 132, 142 for i 8f1uid flow between the peri~ta1~ic tubing 128, 146 and the 9reservoir intake 110 and return tubes 114.
10The tubing assemblies 12, 25 are spec1fic for use w1th the 11infusion pump 14 and the aspiration pump 18, respectively. One , 12end 134 o~ the reservolr tubing 132 terminates in a connec~or : 13which wi11 only mate with the connector 110 on the integral 14intake tube 104 from the reservoir 10. Similarly, one end 140 of the reservoir tu~ing 142 terminates in a connector which 16 will only mate with the connector 116 on the integra1 return 17tube 114 from the reservoir 10. The oth~r end 130, 144 of the 18reservoir tubing 132, 142 has a connector which w~11 mate with 19the peristaltic tubing 128, 146 respective1y. The catheter 20tubing 120, 152 also have connector~ at one and 124, 150 which 21connect to the perista1tic tubing 128, 146 respective1y. The 22other ends 122, 154 of the catheter tubing are constructed to 23 mate only with the respectivs connector~ on the catheter 80, 24 82. For example, the reservoir tubing may be constructed o~
.125" i.d./.210" o.d. polyethylen~ wh~le the perista1~ic pump 26 tubing may be 5/16" i.d./7/16" o.d. "Tygo~han~" tubing. It is 27 also pos6ible to construct each tubing as a sing1e unit.
- 28 Additionally the pressure sensing lumen 52 communicates 29 with the pressure transducer 24 through a pressure tube 27.
Pressur~ tube 27 has a fitting lS6 at one end for connection to .. 31 the transducer 24 and a fitting at the other end 160 which 32 permits its connection on1y to the proper catheter connector 33 84. Additionally, since transducer assemblies typically have ;

., ,. ~ ." .. , .; ~ . ., .. . . .... , ., .. ,, . ., . , , . , .. , . .. , , .. . , . .. . . ~, . .. , . . .. , . , ." . ,, .; .. . . .

WO90/12570 (~ ~ PCT/US90/02212 - 15 - 2~5(~
l a filling/aspiration port to permit thelr beiny filled with 2 physiological saline, an additional tube 164 i~ needed w~th a 3 fitting 162 for connection to the filling port of the 4 transducer 163 and a fitting 166 for connection to a three-way syringe valve l65. The tubing ll9 discussed is disposable and 6 is typically replaced each time the reservoir lO in replaced.
7 Referring to Figure 5, the tubing ll9, r~servoir lO and 8 solvent 106 are most conveniently provided as a single unit kit 9 180 in a tray 182. The catheter 76 may be included in the kit or may be supplied separately since although the catheter 76 is ll disposable, typically only one catheter is used ~n one 12 procedure with a single patient, while the reservoir lO and the 13 tuhing ll9 will be replaced ~everal times in a procedure. The 14 catheter 76, tubing ll9 and reservoir lO are provided pre-sterilized.
l6 As suggested by dashed line the unit measure of solvent or 17 an additional unit measure of ~olvent may be 6uppl ied in an 18 additional container, to be emptied into the reservoir at the l9 point of use.
I~ will be understood by those skilled in the ~rt ~hat 2l there are numerous other embodimants which are not described 22 above but which are clearly within the ~cope and ~pirit of the 23 invention. The description ahove is therefore intended to be 24 exemplary only and the ~cope o~ the invention is to be llmited 25 solely by the appended claims.
26 We claim:

. .

Claims (34)

1. A method for dissolving cholesterol calculi which comprises contacting said calculi with a solvent comprising a C5-C6 ester, ether or ketone having a boiling point in the range of 80°-140°C or a mixture thereof in an amount and at a flow rate effective to at least partially dissolve said calculi rapidly.

2. A method as in Claim 1 wherein said ester, ether or ketone is n-propyl acetate, isopropyl acetate, ethyl propionate, ethyl isobutyrate, cyclopentanone, 3-pentanone or methyl t-amyl ether.

3. A method as in Claim 1 wherein said solvent is used in an undiluted form.

4. A method as in Claim 1 wherein said solvent is used in a form in which it is mixed with and diluted by an inert carrier liquid.

5. A method as in Claim 1 wherein said contacting comprises pumping said solvent past said calculi.

6. A method as in Claim 5 wherein said pumping is conducted at a high solvent flow rate.

7. A method as in Claim 6 wherein said pumping is conducted at a high solvent flow rate at low pressure.

8. A method as in Claim 6 wherein said high solvent flow rate is on the order of at least 20 ml/min.

9. A method as in Claim 8 wherein said high solvent flow rate is on the order of at least 100 ml/min.

10. A method as in Claim 9 wherein said high solvent flow rate is on the order of at least 150 ml/min.

11. A method as in Claim 6 wherein said pumping 1 conducted with a constant circulation pump.
..

12. A method as in Claim 2 wherein said ester is n-pxopyl acetate.

13. A method as in Claim 2 wherein said ester is isopropyl acetate.

14. A method as in Claim 2 wherein said ester is ethyl propionate.

15. A method as in Claim 2 wherein said ester is ethyl isobutyrate.

16. A method as in Claim l wherein the rate of dissolution of said calculi is on the order of at least 8 mg/min.

17. A method as in Claim 16 wherein the rate of dissolution of said calculi is on the order of 8-14 mg/min.

18. A method for treating a patient having cholesterol calculi in the biliary tract which comprises infusing into the biliary tract of said patient a solvent comprising a C5-C6 ester, ether or ketone having a boiling point in the range of 80°-l40°C or a mixture thereof in an amount and at a flow rate effective to at least partially dissolve said calculi rapidly.

19. A method as in Claim 18 wherein said ester, ether or ketone is n-propyl acetate, isopropyl acetate, ethyl propionate, ethyl isobutyrate, cyclopentanone, 3-pentanone or methyl t-amyl ether.

20. A method as in Claim 18 wherein said infusion comprises pumping said solvent through said patient biliary tract. f-

21. A method of gallstone dissolution using a high flow rate catheter pumping system for infusing a gallstone dissolution solvent into the gallbladder of a patient, and aspirating the gallstone dissolution solvent from the gallbladder characterized in which the solvent comprises a C5-C6 ester, ether or ketone having a boiling point in the range of 80°-140°C or a mixture thereof in an amount characterized in that said infusing and aspirating is at a flow rate effective to at least partially dissolve said calculi rapidly.

22. A method as is Claim 21 wherein said flow is continuous and at a rate sufficient to cause sustained turbulence within the gallbladder.

23. A method as in Claim 22 wherein said solvent is infused at a rate about 150 ml/min.

24. A container product for use with a gallstone dissolution apparatus including a high flow rate catheter pumping system for infusing a gallstone dissolution solvent into the gallbladder of a patient, and aspirating the gallstone dissolution solvent from the gallbladder, said container product comprising a unit measure of a solvent comprising C5-C6 ester, ether or ketone having a boiling point in the range of 80°-140°C or a mixture thereof.

25. A product as in Claim 24 wherein said unit measure of solvent is packaged in a disposable kit including a disposable reservoir for holding the solvent, said reservoir including an inlet line constructed to be connected with an inlet line of said high flow rate pumping system to supply solvent to said system.

26. A product as in Claim 25 wherein said solvent is prepackaged within said reservoir.

27. A product as in Claim 25 wherein said kit includes a disposable tubing set constructed to connect said reservoir with said high flow rate pumping system.

28. A product as in Claim 27 wherein said high flow rate pumping system is a continuous flow system which includes peristaltic infusion and aspiration pumps and said tubing includes sections of peristaltic tubing for said aspiration and infusion pumps and sections of connecting tubing connecting said peristaltic tubing with said reservoir and a catheter.

29. A product as in Claim 25 wherein said disposable reservoir includes a return line for connection with an outlet of said high flow rate pumping system to receive said solvent and bile aspirated from said system and the volume of said reservoir being greater than the volume of pre-filled solvent supplied to permit accumulation of bile and debris.

30. A product as in Claim 25 wherein said high flow rate pumping system with which said kit is to be used includes a control means responsive to intra gallbladder pressure for controlling the high flow rate pumping and said disposable tubing set includes a length of tubing for connecting a respective lumen of the catheter used with said system to said control means.

31. A product as in Claim 25 wherein said unit measure is of the order of 200 ml of said solvent.

32. A gallstone dissolution apparatus including a high flow rate catheter pumping system for infusing a gallstone dissolution solvent into the gallbladder of a patient, and aspirating the gallstone dissolution solvent from the gallbladder, characterized in that the solvent comprises a C5-C6 ester, ether or ketone having a boiling point in the range of 80'-140°C or a mixture thereof in an amount and at a flow rate effective to at least partially dissolve said calculi rapidly.

33. Apparatus as in Claim 32 wherein said high flow rate catheter pumping system is a continuous flow system capable of simultaneous infusion and aspiration, said high flow rate catheter pumping system further including a reservoir for providing said solvent infused into and for receiving said solvent aspirated from said gallbladder.

34. Apparatus as in Claim 33 wherein said reservoir comprises a disposable unit package pre-filled with said solvent, the total volume of said reservoir is greater than the volume of pre-filled solvent supplied to permit the accumulation of bile and debris and said reservoir is constructed to enable separation of bile and debris from the solvent aspirated from the gallbladder.