US3882248A

US3882248A - Gallstone solubilizer

Info

Publication number: US3882248A
Application number: US437202A
Authority: US
Inventors: Hirotsune Igimi; Hiroyuki Ide
Original assignee: Hisamitsu Pharmaceutical Co Inc
Current assignee: Hisamitsu Pharmaceutical Co Inc
Priority date: 1972-03-12
Filing date: 1974-01-28
Publication date: 1975-05-06
Anticipated expiration: 1992-05-06

Abstract

A gallstone solubilizer containing a monoterpene, a sesquiterpene, an essential oil containing such a terpene or a mixture thereof as active ingredient.

Description

United States Patent lgimi et al. I I May 6, 1975 i i GALLSTONE SOLLBILIZER [58} Field of Search i. 424/l96 356 175] inventors: Hirntsune lgimi: Hirnyuki ide. both of Fukuoka. Japan References [73] Assignec: Hisamilsu Pharmaceutical OTHER, PUBLK ATIONS Company Inc" Tuswshi Japan Chcmlcal Abstracts. Mn. 50. 8899 I956).

[22} Filed: 1974 Primary Emmirwr-Frcdcrick E4 Wuddcil [2 y 431202 Almrney. Agent. or I"1'rmBr0\\'dy and Ncimnrk Related US. Application Data I57] ABSTRACT i 1 1 4 I63] My A guilsmnc soiubilizcr containing a monotcrpcnc n M sesquiierpcne. an essential oil containing such u ter [52] U 5 Cl 424/56 474/196 pone nr 1! mixture lhercuf as active ingredient. |5i I Int. Cl A6lk 27/00 2 Claims. N0 Drawings G A I, LSTON E SOLU BILIZER (ROSS REFERENCES TO RELATED APPLICATIONS The present application is a continuation in part of application Ser. No. 237.9]8 filed Mar. 12. I972. now abandoned. which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION Bile contains large amounts of organic and inorganic components which are easily crystallized. Such components in the bile are crystalli7ed into gallstone in some instances. The greater part of the crystal grows gradually on the wall of the gallbladder or bile duct. (iallstoncs in bile are \arious in size and number. They are in the form of sand grains. large lumps or relatively small grains [240 in number). The gallstones comprise various constituents which may be divided roughly into three groups of( l fatty acid calcium stones. 2) bilirubin stones and (3) cholesterol stones.

Chololithiasis without any subjective symptom causes no particular trouble and the stone in such a case is called a "silent stone. However. if a gallstone is caught at the outlet of the gallbladder thereby causing abnormal contraction of the gallbladder. or if the discharged gallstone is caught in the bile duct thereby causing bile duct convulsion. the patient feels acute pain.

For the treatment of chololithiasis. it is necessary to remove the gallstones completely. The removal of gallstones without surgery before subjective symptoms appear is the most preferable treatment. However. the method of such a treatment has not yet been developed. Although gallstones can be removed thoroughly by a surgical operation before subjective symptoms appear. this is not recommended generally. since the patient sometimes feels no pain throughout his life in spite of the presence of gallstones.

Usually. a patient having chololithiasis is subjected to cholangiography with a contrast medium. when he has subjective symptoms. to confirm the position of gallstones and then the gallstones are removed by a surgical operation. However. sometimes small stones in the bile duct are missed during the operation. Also. new gallstones are often again formed after the operation. Such cases are not rare and those stones are called residual stones." The greatest problem in the treatment of chololithiasis is the residual stone. At present. surgery must be repeated again if any residual stone is found.

THE PRIOR ART Chololithiasis treatments include internal treatment. surgical treatment and combined internal and surgical treatments.

The internal treatment includes the following meth' ods:

l. Lyon's method:

A duodenal sound is used. Magnesium sulfate is infused through the sound to react on the duodenal patilla whereby the sphincter of Oddi is loosed. Consequently. bile flows out thereby removing gallstones.

2. Treatment with cholagogues:

A cholagogue is reacted on parenchymal liver cells to increase secretion of bile thereby discharging the gallstones. As the cholagogues. there are used. for example. dchydrocholic acid. ursodesoxycholie acid.

a-oxy-a-(X-fluoranthcne) butyric acid. p-tolylmcthyl carbinol. l-phenylpropanol and Rowachol.

3. Treatment with cholecystokinetics:

A cholecystokinctics is used to loose the sphincter of Oddi and sometimes also to cause contraction of the wall of the gallbladder simultaneously. whereby bile is discharged. As the cholecystoltinetics. there are used. for example. cholccystokinin. pituitrin. atenin. butter. egg yolk. peptone. cows milk and magnesium sulfate.

The surgical treatments include the following methods:

l. Drainage of the biliary tract.

2. Anastomosis of the bile duct and duodenum.

3. Resection of liver.

In all of the above cases. the gallbladder is removed.

The combined internal and surgical treatments are carried out for removing residual stones after a surgical operation. The combined treatment comprises first infusing an organic solvent such as chloroform or chloroform/ether mixture through a drain inserted in ductus cholcdochus to solubili7e the residual stone lPribram. B.O.C. Lancet. I. [fill (I939) and Best. Arch. Surg. 67. 839 I953 I. This treatment may comprise infusion of a chelating agent such as a polyphosphate. for example sodium hexametaphosphate. to solubili/e the gallstone lHisatsugu. lgaku Kcnkyu (Acta Medical. 29. I773 (1959)]. In addition. some mechanical methods have been tried. for example. an elevating pressure has been added to the bile duct to discharge the gallstone adhering to the inner wall of the duct lDardik. Digestive Diseases. in. 33] (1971)].

Thus. various treatments have been tried for chololi thiasis. However. by the comcntional internal treat ments. permanent healing is almost impossible. though some gallstones can be removed By the surgical treatments. on the other hand. the problem of residual stones cannot be solved. though gallstones can be removed completely from the part of incision and. therefore. permanent healing cannot be attained by this method. Under the abo\e circumstances. combined internal and surgical treatments have been tried in which residual stones which remain after a surgical operation or which are formed thereafter are removed in various manners. However. if an organic solvent is used. a toxic effect is exhibited and. in addition. solubility ofthe gallstone in the solvent is poor. If a polyphosphatc is used. a disadvantage is that if the stone is a cholesterol stone it cannot be removed at all. though fatty acid calcium stones can be so removed. The method of increasing mechanically pressure in the bile duct is dangerous and. therefore. it cannot be carried out safely and easily. Although residual stones can be removed surgically. a search for the gallstone in the bile duct is particularly difficult and repetition of the surgical operation is extremely difficult and is sometimes impossible. since the first operation sometimes causes adhesion of the organs.

OBJECT OF THE INVENTION It is an object of the present invention to o\crcome the deficiencies of the prior art. such as indicated above.

Another object is to provide for improved gallstone removal.

Another object of the present invention is to provide a gallstone solubili7er which solubilives gallstones com pletely.

Another object of the in\ention is to proxide a gallstone solubilirer which is directly infused. after a surgical operation for chololithiasis. through a drain inserted in the bile duct to remove residual stones.

Still another object of the invention is to provide a gallstone solubili7cr which is directly infused through a drain inserted in the bile duct of a patient of chololithiasis to solubilize gallstones completely.

A further object ofthe invention is to provide a clear gallstone solubilizer which is stable for a long period of time.

These and other objects will he more apparent from the following detailed description of embodiments of the invention:

DESCRIPTION OF THE INVENTION The present invention relates to a gallstone solubi lizer comprising a member selected from the group consisting of monoterpcnes. sesquiterpenes. essential oils containing those terpenes and mixtures thereof. Particularly. the invention relates to a gallstone solubi lirer comprising a mixture of (a) a member of the group consisting of monoterpenes. sesquiterpenes. es sential oils containing those terpenes and mixtures thereof and (b) a member of the group consisting of nonionic surfactants and mixtures thereof. Preferably. the mixture also contains (c) a stabilizer selected from the group consisting of alcohols. amides. phospholip ids. esters. water and mixtures thereof.

The preferable solubilizcr in accordance with the present invention comprises 99.8 707: (W/V) of limonenc. 0.1 I592 (W V) sorbitan monolaurate. sorbi tan nionooleate or polyoxyethylenc sorbitan monoole ate having about moles of oxyethylene. and (H 1571 (W/Vl ethanol or water.

By using the gallstone solubilizers of the present invention. cholesterol stones which are difficult to solubilirc according to conventional methods can be solubilized completely within a short period of time. Of course. the gallstone solubilizers also solubilize bilirubin stones and fatty acid calcium stones and. therefore. if the gallstone solubilizers ofthe present invention are used after a surgical operation or directly. permanent healing of chololithiasis is possible.

Active ingredients for solubilizing gallstones in the solubilizers of the invention are terpenes. particularly. monoterpenes and sesquiterpenes. They are used solely or in the form of mixture. Numerous essential oils may be used directly. since they contain large quantities of monoterpenes and sesquiterpenes. The essential oils may be used also in the form ofa mixture with a monotcrpene or sesquitcrpenc.

The monotcrpenes are. for example. myrccne. ocimenc. linalool. gcraniol. nerol. citronellol. artemisia ketonc. citral. citroncllal. linalyl acetate. limonenc. di pcntene. terpinolcnc. phellandrcne. terpinenc. sylvestrene. tcrpincol. pcrillaldchydc. carvonc. pulegonev piperitonc. menthonc. LX-cineole. l -l-cineole. sabin ene. pincnc and umbellulone. preferably limonenc.

Sesquiterpcncs are. for example. farnesol. nerolidol. bisabolenc and zingiberenc.

Though the abmc-mcntioned monoterpenes and ses quitcrpenes include their stcreoisomcrs and optical isomers. they may be used in the form of mixtures directly separated from natural materials without any further treatment. Of course. pure stcreoisomcrs and optical isomers may also be used.

Essential oils containing a monotcrpene or sesquiterpene are. for example. neroli oil. Kuromoji oil. opopanax oil. lemon-grass oil. pcrilla oil. car-away oil. star anise oil. lemon oil. lavender oil. turpentine oil, citronella oil. bergamot oil. eucalyptus oil. pennyroyal oil and ginger oil.

The monoterpenes, scsquiterpenes and essential oils containing those terpenes solubilize or directly break up gallstones at a surprisingly high speed. This is proved by the following experiments:

Gallstone Solubilization Test 1 (Preparation of cholesterol tablets) Cholesterol (special grade) in an amount of lOOmg/tablet was processed in a tablet-making machine to obtain tablets of diameter 7 mm and hardness 6-7 Kg/mm? The following tests were carried out by using the tablets as artificial cholesterol stones. (Solubilization test) Five milliliters of an essential oil or a terpene were charged in a 20 ml Erlenmeyer flask which were then mixed with the above mentioned cholesterol tablet and the whole was shaken in a water bath at 37C. Solubili zation time indicates a time required for the complete solubilization of the tablet.

Solubilization time is represented as follows:

Within minutes: l+

Within lZO minutes:

Within l minutes:

Longer than minutes:

Following tables l. 2 and 3 show the results of solubilization tests of monoterpenes. sesquiterpenes, essential oils and mixtures thereof on artificial cholesterol stones.

Table 1 No. Terpenc Solubility lv Myrccnc 2. Ocimene -l+ 3. Linalool -ll- 4. Geraniol Chain 5. Nero] H monoterpenc h. Citroncllol H 7. Artemisia ketone H. Citral H 9. Citronellal +lll), Linalyl acetate l l. Limonene -ili l2v Dipentene 4-H- 13, Terpinolene ++l Monocyclic l4, Phcllandrene H monotcrpcnc l 5 Terpincne -Hilo Sylyestrenc H l 7. Terpineol 4+ IX. Pcrillaldehytle H W Can one +i-l- Il Pulcgone -ll- Zl Piperitone 12. Mcnthonc 4-H Z3 lfl-(incolc +1+ 2-1 l.-1-(incole BlC \CllC Z5 Sabincnc monotcrpene 2o. Picnc H I? tnibellulone 28. Fitrltcsfll Scsquiterpcne I) l\crolitlol it) Bisabolcnc T l [.ingibercne Table 2 No. Essential Oil Solubility l. Patchouli oil Table Z-(ontinued Clear gallstone solubiliYer in the form of homogcne ous solution is obtained b heating the mixture to a temperature of IU ISUT. preferably 2()-7(]C. pref- No l-.sscntialt)il Solubilit) 2 Mum" nil H erably IMP-70C under stirring. 3. KUTL'I'HU]! oil H 5 The nonionic surfactants used in the present inven i- Nige ;:t tth tion are. for example. glyceryl monooleate, glyceryl if lfmi i ng rassoil H monostearate. sorbitan monolaurate. sorbitan mono- Z i'i ggfi j oleate. sorbitan monostearate. sorbitan trioleate. sorbi- (mum U tan monopalmitate. sorbitan tristearate. sorbitan ses Ill SIHHmi-W m quioleate, polyoxyethylene sorbitan monooleate such I 1 Cinnamon bark o|l t lcmmm W as Polysorbate 80 having moles of oxyethylene. 3 l mcntleroih H polyoxyethylene sorhitan monolaurate. polyoxyethyll x' l iz f 11 ene sorbitan monostearate. polyoxyethylene sorbitan 1a. Hergamut oil +-t+ trioleate. polyoxyethylene sorbitan monopalmitate. r 15 polyoxyethylene sorbitan tristcarate. polyosyethylene W (hngr 5} H stearate, polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil. preferably sorbitan mono- Tuhlc 3 laurate. sorbitan monooleate or Polysorbate tit).

0 In the SOlUlHlWL'tIUOH ofgallstone in a human bodt, the N0 Mmun. [M mm) Solubility gallstone solubilizer of the present invention containing a nonionic surfactant is easily emulsified together with 5:32? bile and thereby brought into contact with the stone to Tcrpinnc; 5 solubilize the stone at a surprisingly high velocity. This 1 Sufis N is apparent from the following emulsification test on l i 5 W bile and gallstone solubilization test. 4. Turpentine oil: 70 Table 4 shows the results of the emulsifieation test of 5 if p H mixtures ofa terpene or an essential oil and a nonionie Lavendcroil' 7o surfactant on artificial bile or human bile. Table 5 H m shows the results ofthe test of solubilization of artificial i cholesterol stones with the gallstone solubiliyers.

If a monoterpene. a sesquiterpene or an essential oil I containing such a tcrpene is brought into contact with hmulsmciltlm gall$mncit Snlubillzcs gallsmnc quickly Seven parts of a gallstone solubili/er of the present evergallstones in the hllmlm gilllblllddcl' bile duct invention are added to three parts of human bile or isoare rounded by a fairly large quantity of bile. tonic sodium chloride solution (as artificial bile]. The In the Solublllllllion gilllsmnss in hllmlm y whole is shaken vigorously and allowed to stand for five with a monmcrpcncscsqultcl'pcflc an essential minutes. Phase separation of the mixture was e\am containing such a terpene. bile must be discharged m r from the body or it must be washed away therefrom 4t) into the intestines before infusion of the solubilizer in The results Shmvn mum: order to facilitate the contact thereof with the stone Nfm'scpilmmlm H and thereby to facilitate the solubilizationt Though the F pm-mum: solubilization can be carried out by direct infusion of (Ons'dcmhlc Scpumtmn: the solubilizer without effecting such a pretreatment; g solubilization time is prolonged in such a case. since Gullsmnc sllublhmtmn bile is a hindrance IO the SOlllhiliMlU-On Solubilizing powers ofthe gallstone solubilizers ofthe According to the Prescm lm'cmmm gllllsmm in bile present invention for artificial cholesterol stones mixed n be soluhililcd ill a Surprisingly high Wluclty y with human bile were examined. l5 Milliliters of a mix- Using monmcrpcnc scsqultcrpcnc 1m csscmiulull 5o ture comprising 5-9 parts of the solubilizer and l-S containing sucha terpene incorporated with a nonionic parts f h u Wcm Charged in a 30 m| Er|cn surfactant. meyer flask. An artificial cholesterol stone was added The gullsmnc Wluhlllzcr of ms Present imcmkm is to the mixture and the whole was shaken in a water p p y mixing 99-84459! (w/v) member of bath at 37C. Soluhilization time indicates a time rethe group C(mslstlng of mfmmcrpcncs- Scsqullcrpcnc5- quired for complete disappearance of the whole artific essential oils containing those terpcnes and mixtures m] m thercofwith 0. 1-157! (W/V) ofa member ofthe group sniuhflizmion timc; consisting ofnonionic surfactants and mixtures thereof. wi 3 minutcs: u Preferred amount of the nonionic surfactant is in the within minutes: i range of 0.25.()71 (W/Vl. (to Longer than (it) minutes1 Table 4 Miscibilit with l'erpene or isotonic \tith No Essential oil Surfactant (J l sodium human L'hlUTltlL bile solution I. (arawat oil (il \cer \l monoleate (t5 I limonene Sorbitan monolauratc ll 5 H+ 3. Caraway oil Sorbitan monolauratc U3 -li According to the present imention. it is possible to soluhiliie gallstone readily by using monoterpenes. ses' quite rpenes and essential oils containing those terpenes mixed with one or more nonionic surfactants in the are stable and readily miscible with bile and that they have excellent gallstone solubilizing effects.

Tests for Effect of Stabilizer form of a mixture. However. the gallstone solubilizer 5 (Method of stabilization test) 1- ,1 i i gl f l i lf l l 'l The SUlLlhlllZCl'S were allowed to stand in a relngeraf f ga f i 9" tor at C for 12 hours. then filtered. again allowed to 111 1 m l L g r l stand for an add|tional 72 hours and stahihty was examduring a long period storage or due to climatic change.

These dis'idv'mtl es have been eliminated by incor m f I l i The stabilities are shown as follows: poratmg a stabilizer m the gallstone solubiliier. The sums, s abilizer is selected from the rou consistin I of a 7- l I p Substantially stable: hols. amides. phospholipnls. esters. water and mixtures Unsnhkv thereof. The stabilizers are. for example. cctyl alcohol. lauryl alcohol. myristyl alcohol. stearyl alcohol. glyc- (Method of emulsification of bile) *rol. ethanol. iso ro l llCUhOl. eth 'lene l 'col. o I I t l pi I Seven parts of a solubllizer were added to three parts ene *co. "n "eo.me "osow. u--

I i g l 3 I t f 1 of human bile or isotonic sodium chloride solutIon (as t H V v a 2 T L g T l artificial bile). The whole was shaken \'lUlCnll tor one :1) .ig,. t i N m l l L l L hopmp-v m minute. After allowing to stand tor toe minutes. the demynstate. benzyl ben'mate. ethvl lactate. water and gree ol separation was examined. mixtures thereof. and preferablv ethanol or water.

g r The results are shown as tollows: I Theclear. stable gallstone solubllizers oi the present Nomscpumtim]; invention thus comprise Nil-707i (W/V) of a member s m scpdmlinn; selected from the group consisting of monoterpenes. N (nnsidcmhlc scpdmtiun; sesquiterpenes. essential oils containing those terpenes scpumtiom or mixtures thereof. (Ll-% (W/V] of a member selected from the group consisting of nonionie surfac- (Mcllmd gilllsmnc *luhllmlllfm mms and mlxlurcs thcnmf and (ll-157 (w/V) In an Erlenmeyer flask. ml of a mixture compris smhlllzcr The Stilhlllzcr 15 prcfclllbll' 11 q y m 3 ing 5-9 parts of a gallstone solubiliyer and l-5 parts of the "Inge (W/Vlhuman bile were charged. Artificial cholesterol stone Thus resulting mixture is heated to l(ll5llC. prefwas added to the mixture and the whole was shaken in erably 2(l7l)C under stirring to obtain homogeneous a water bath at 37C. Solubililation time indicates a solution. Thus. clear. stable gallstone solubilizer is obtime required for complete disappearance of the whole tained. Tests were carried out on the effects obtainable artificial cholesterol stone. by the solubilizers. Table 6 shows the results of emulsi- Solubilization time: fication tests for bile and also the results of tests on sol- Within 30 minutes: +1 ubilization of gallstone. It is apparent from the results Within 60 minutes: that the gallstone soluhilizers of the present invention Longer than 60 minutes:

Table (1 Emulsilicalion Test for test for bile dissolution Miscibilit ol gallstone Terpcne or Soluhilirxv Sla- \\ith lerpenehwr No Essential oil Surl'actantl l lion stabibilisotonic \\ith essential lizcr ('3; il sodium human oil): bile chloride bile Il 7 3 l l solution l (anone (ilyccryl monoolcatc (l5 Ethanol 5 l- -v- Z (l 5 lsoprop \l alcohol 5 H H l 3 (L5 (etanol I -l l.4-(ineolc Sorbitan monopalmitate (L5 Ethanol 3 A 5 (L5 (ctanolt ll 2 lithanok l l (1 l'erpincne Sorbitan monostearate U5 Ethanol 5 w 7 (t5 (ctanok l I 5 Ethanolt 4] X lcrpinolene Sorbitantristearate H5 l-lthanol 5 -l+ 1-4 9 U5 (etanoll l l 5 H lithanolt-l) lll Limoncne Sorbitanmonoolcntc l.ll lithanol 5 H H H l l limonene Sorbitan monooleatc ll 5 lsoprop l i H H l alcohol 11 (I5 ('etanol H I] Dipentenc Sorbilan scsquioleate (L5 litlianol 5 4* l +l I-l Dipentcnc l5 ('etanol l +-l I. (araoat oll Sorbitan trioleate (l5 lalhanol 3 l+ lo (lf (ctanol l -l+ H v 4 l able h (ontinued ltmulslficatiori lest for test for bile dissolution Miscibilit of gallstone lerpene or SoIubili/m Stawith lerpenetor .No lzssenual oil Surlaclanti'l l lion stlihibilisotonle with essential li/er i |t soillum human oil)- s chloride hile H 711 ll solution h? Menihone Sorhitan monolauratc I l ('etanolt (I. l)

lsoprupy 5 l H a -+i i lideiie gl ceroll 5.0) (18 Bergamot oil Pill: sorhitan tristearule 5 Water U5 H -i+t o I imonene P11 l sorhilan HIOnUOlCLIk 5 Water (L5 H- -ii+- -+l- W ('anouc I (ll -Mrhilan triuleale Water U5 H 71 l.-l-('incole P.().l-.. eastor oil 5 Water 3 H +'r+' +4+ V TI lerpinene Sorhitan monooleate (ILIllUL. 3.3 Water l.2 1-i- +l+ -llisorhitan palmiiatet U] 7, lerpinolene Sorhitan monoolente (0.0] l,! Water [3.3 H +-H l P l. hlll1 lUllitlUll easlur oilltlfil 74 Dipentenc l ()l. sorhitan 5 Water 0.5 H i++ tristearate PUI ln-lu netluleoe The gallstone solubilizers of the present invention are used by directly infusing them into the human body through a drain inserted in the bile duct and. after the Then. the gallstone solubilizers of the present invention were tested by using pigs. It was confirmed that the gallstones are dissolved completely.

so solubiliration of the gallstone. the soluhilizers are ex E A I l creted into the duodenum. Therefore. ifthe solubilizers xpt'nmcmb 5 were to show any toxicity. a serious problem would A pig in the experiments weighing 50 kg was suboecur in the human body. Tosicities of representative je ted to median in i ion under general a th i terpenes and nonionic surfactants used in the gallstone a Normality of the internal organs in the abdo i l (jay. soluhilizers were examined. The results of the test are ity was confirmed. The liver was pushed aside to expose shown in Tables 7 and 8. the gallbladder. Upon effecting a small incisional cut, Tmiu T at a large human cholesterol stone (2.1 g) was placed in r the gall bladder. A Nelatone s tube was inserted therein Test samples were given perorally to mice and rats. 4 d fixed th t d l to h peritoneum. N

leakage of the bile through the Nelatone's tube was Tlhlc 7 confirmed and the tube was buried within the abdominal wall. The abdominal wall was sutured to complete No l'erpenc UL. (ml/kg P OJ h operation 1 limhm' 39 45 One week after the operation a small incisional cut 2. Meantime th of the skin was effected and the buried Nelatone's tube 1 1.44" 2.4 4 ir s 4 4 was exposed. A solubilizer of Example 6 mfra was in- S. (some 5.1 fused through the tube once a day for two days in a Ma a" quantity of 60 cc. each.

CL 5' r. H l "ck-WC i4 5 g A day after the completion of the infusion disappearance of the gallstone. which had been buried in the gall Table 8 No Surfactant l.D mg/kg or Animal mlfkg l (il cer \l monoolcate 87 ml mouse 3 (il eer \l monostearatc 9 ml 3 Sorbitan monolaurate 20 ml rat 4. Sorhitan monooleate Ill ml 5. Sorhitan monostearate Milli! mg Sorhitan trioleate ltLtItlU mg 7. Sorhitan monopalmitate HHIUU mg X Sorhitan trislearate ltLtlUU m 9 Sorhitan sesquioleate IUJIUU mg lll P01 sorhiian monooleate 25.000 mg mouse ll PU P sorhitan monolaurate 33.8 ml rat l: .().l:. sorhitan monostearate (all) ml l1 PO F sorhitan trioleate 30.4 ml l4 PI) surllkui monopalmitate 3-1.2 ml l P0,} \orhitaii tristcarate llHl ml to P0 lstearate ItLtltlU mg 17 P (l l. ezistor oil 71m nil IN P l'. hulrogenated eastor oil Tllllll mg mouse enous iniection) bladder. was confirmed. Nothing unusual was obser ed in the biliary tract system. li er and other tissues in histoehemically.

EXAMPLE l ln an Erlenmeyer flask. 70 ml of terpinolene and 30 ml of human bile were charged and temperature was controlled to 37C in a water bath. About 700 mg of human cholesterol stone were added to the mixture and the whole was shaken violently in the water bath. Though terpinolene did not give homogeneous mixture with the bile. disappearance ofthe human gallstone was recognized within 120 minutes.

In the same manner. disappearance of human gall stones within 120 minutes was recognized when terpin olene was replaced with other monoterpenes including terpinene. menthone. l.4-cineole. car onc. limonene. l,8cineole. piperitone. terpineol. dipentcne. citronellal and ncrol.

EXAMPLE 2 ln an Erlenmeyer flask. 70 ml. of farnesol and 30 ml of human bile were charged and temperature was controlled to 37C in a water bath. About 700 mg of human cholesterol stone were added to the mixture and the whole was shaken \iolently in the water hath. Though farnesol did not give homogeneous mixture with the bile. disappearance of the human gallstone was recognized within 180 minutes.

In the same manner. disappearance of human gallstones within 180 minutes was recognized when farnesol was replaced with other sesquiterpenes such as nerolidol. bisabolene or zingiberene.

EXAMPLE 3 ln an Erlenmeyer flask. 70 ml ofcaraway oil and 30 ml of human bile were charged and the temperature was controlled to 37C in a water hath. About 700 mg of human cholesterol stone were added to the mixture and the whole was shaken violently in the water bath. Though car-away oil did not give homogeneous mixture with the bile. disappearance ofthe human gallstone was recognized within l minutes.

In the same manner. disappearance of human gallstones within [20 minutes was recognized when caraway oil was replaced with lemongrass oil. lemon oil. lavender oil. turpentine oil. citronella oil. bargamot oil. eucalyptus oil or ginger oil.

EXAMPLE 4 Twenty milliliters of menthone were added to l.5 g or sorbitan monooleate and the whole blended thor oughly in a water bath at 50C. Menthone was added to make the whole quantity 100 ml. After allowing the solution to stand at 5C for 12 hours. the solution was such as sorbitan monolaurate. glyceryl monostearate. sorbitan monopalmitate. polyoxyethylene sorbitan monooleate, polyoxyethylene castor oil or polyoxyethvtene tristearate.

EXAMPLE. 5

Twenty milliliters of dipentcne were added to 0.3 g of sorbitan monooleate and 0.1 g of polyoxyethylene sorbitan stearate and the whole was blended thoroughly in a water bath at 50C. Dipentene was added to make the total 100 ml. After the same procedures as in Example 4. similar effects were obtained.

EXAMPLE (w 0.5 g or polyoxyethylene stearage and 5 g ofethanol were mixed together thoroughly in a water bath at 50C to obtain solution. Then. limonene was added to the solution under stirring to make the total 100 ml. After allowing the mixture to stand at 5C for l] hours. the solution was filtered. The resulting filtrate was thoroughly miscible with human bile. Afterallowing the solution to stand at 5C for 72 hours. neither separation nor change in appearance occured. The solubilizer exhilr ited a strong solubilizing effect on human cholesterol stone in bile and solubilization time was within min- EXAMPLE 7 Five g of isopropylidene glycerol were added to 1.0 g of sorbitan monolanrate and 0.l g of cetanol and the whole was blended thoroughly in a water bath at 50C to obtain homogeneous mixture. Menthone as added under stirring to make the total I00 ml. After allowing the solution at 5C for 12 hours. the solution was fil tered. Thereafter. the same procedures as in Example 6 were repeated to obtain the similar effects.

EXAMPLE 8 Five g of ethanol were added to 0.5 g of polyoxyethylene castor oil and 0.5 g of sorbitan monopalmitate and the whole was blended thoroughly in a water bath at 50C to obtain a homogeneous mixture. 'lhereafter. terpinolene was added to the mixture under stirring to make the total l00 ml. After allowing the solution at 5C for l2 hours. the solution was filtered. Thereafter. the same procedures as in Example (1 were repeated to obtain similar effects.

EXAMPLE 9 Five g of ethanol were added to 0.5 g of polyoxyethylene sorbitan monooleate and 0.5 g of sorbitan sesquioleate. Then bergamot oil was added to the mixture to make the total ml. Thereafter. the same procedures as in Example 6 were repeated to obtain the similar effects.

EXAMPLE l0 0.5 g of lecithin and 5 g ofethanol were added to 0.5 g of polyoxyethylene sorbitan monolaurate and 0.5 g of glyceryl monostearate. Then eucalyptus oil was added to the mixture to make the total 100 ml. Thereafter. the same procedures as in Example 6 were repeated to obtain similar effects.

EXAMPLE ll 50 milliliters of l.4-cineole were added to 5.0 g of polyoxyethylene castor oil and 3.0 g of water and the whole was blended thoroughly in a water bath at 35C to obtain homogeneous mixture. Thereafter. 1.4 cineolc was added again to the mixture to make the total lUU ml. After allowing the solution at C for IE hours. the solution was filtered and the filtrate was allowed to stand at 5C for 78 hours. It was stable and no phase separation occurred. The thus obtained gallstone shlUhillYCf was shaken together with isotonic sodium chloride solution (as artificial bile) or human bile in a flask to obtain homogeneous mixturesv After five min utes. no separation was observed. The product exhibited a strong solubiliring effect on human gallstones in bile and solubili7ation time thereof was within 6U minutes.

EXAMPLE 12 Zn milliliters of terpinolcne were added to a mixture of 0.6 g of sorbitan monooleate. U5 g of polyoityethyl ene hydrogenated castor oil and (1.] g of water and the whole was blended thoroughly in a water bath at 50C to obtain homogeneous mixture. Thereafter, terpinolene was added to the mixture to make the total 100 ml. Thereafter. the same procedures as in Example 1 l were repeated to obtain similar effects.

It will be understood that the invention is not limited to the embodiments disclosed abme. which are offered illustratively. and that modifications may be made without departing from the invention.

EXAMPLE [3 U2 g of water were added to 2.8 g of polyoxyethylene sorbitan monooleate having about moles of oxyeth- \lene (Polysorbate 80] and the both was blended thoroughl at room temperature for it) minutes. Then. 50 ml of limonene was added to the mixture and the whole was blended at room temperature for [5 minutes. An

adequate amount of limonene was added to the solu tion to make the total volume to 100 ml and the whole was blended at room temperature for 15 minutes.

Thereafter. the same procedures as in Example ll was repeated to obtain similar effects.

EXAMPLE 14 0.5 g of ethanol were added to 2.5 g of polyoxyethyl ene sorbitan monooleate having about 20 moles of oxyethylene (Polysorbate and the both was blended thoroughly at room temperature for 10 minutes. Then. 5t) ml of limonene was added to the mixture and the whole was blended at room temperature for IS min utes. An adequate amount of limonene was added to the solution to make the total volume to ml and the whole was blended at room temperature for IS minutes.

Thereafter. the same procedures as in Example 1] were repeated to obtain similar effects.

What we claim is:

l. A gallstone solubilizer for dissolving cholesteroltype gallstones by direct injection into the affected parts of the patient through a medical eathether. comprising:

a. 99.8 70% (W/V) of limonene;

b. 0.] 15% (W/V) of a member selected from the group consisting of sorbitan monnlaurate. sorbitan monooleate and polyoxyethylene sorbitan monooleate having about 20 oxyethylene units; and

c. 0.1 lSVr (W/V) of a member selected from the group consisting of ethanol and water.

2. A method of eliminating cholesterol-type gallstones comprising infusing into the bile duct of the patient the gallstone solubilizer of claim 1 in an amount sufficient to eliminate the cholesteroftype gallstones.

Claims

1. A GALLSTONE SOLUBILIZER FOR DISSOLVING CHOLESTEROL-TYPE GALLSTONES BY DIRECT INJECTION INTO THE AFFECTED PARTS OF THE PATIENT THROUGH A MEDICAL CATHETHER, COMPRISING: A. 99.8 - 70% (W/V) OF A MEMBER SELECTED FROM THE GROUP B. 0.1 - 15% (W/V) OF A MEMBER SELECTED FROM THE GOUP CONSISTING OF SORBITAN MONOLAURATE, SORRBITAN MONOOLEATE AND POLYOXETHYLENE SORBITAN MONOOLEATE HAVING ABOUT 20 OXYETHYLENE UNITS; AND C. 0.01 - 15% (W/V) OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF ETHANOL AND WATER.

2. A method of eliminating cholesterol-type gallstones comprising infusing into the bile duct of the patient the gallstone solubilizer of claim 1 in an amount sufficient to eliminate the cholesterol-type gallstones.