Note: Descriptions are shown in the official language in which they were submitted.
WO90/12570 ~ PCT~S~/n~ ~ ~ a 9
-- 1 --
1THERAPEUTIC CHOLESTEROL GAIISTONE DISSOLUTIOM ~ETHOD
3CROSS-REFERENCE TO RELATED APPLICATION
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~
- 3 -
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.
32
33
~..
' '
.
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 ~
- 6 -
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
24
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
27
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
36
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 ~
-- 13 --
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:
. .
