3-PHOSPHATIDYL ESTERS FOR USE AS A LAXATIVE FOR RECTAL ADMINISTRATION

Abstract: One or more water-soluble 3-phosphatidyl esters of the formula (I), in which R1 and R2 are the same or different and each signifies the acyl group of a saturated or unsaturated fatty acid having 10-22 C-atoms, and R3 signifies the residue of a pentavalent or hexavalent alcohol, preferably in mixture with choline, for use as a rectally administrable laxative, process of preparing them, and medicinal compositions containing them.

Description: 3-PHOSPHATIDYL ESTERS FOR USE AS A LAXATIVE FOR RECTAL ADMINISTRATION The present invention relates to 3-phosphatidyl esters, preferably in mixture with choline, as a laxative for rectal administration. The invention also relates to a method for producing 3-phosphatidyl esters in mixture with choline. It is previously known that lecithin, also known as 3-phosphatidyl choline of the formula where R.. and R- each represent the acyl group of* a saturat¬ ed or unsaturated fatty acid having 10-20 carbon atoms, preferably 16-20 carbon atoms, in solution with ethyl alcohol splits off choline already at room temperature, and hence it is quite impossible to store such solutions. In order to modify lecithin so as to render it soluble in water and resorbable, which is a prerequisite with regard to its use as a pharmaceutical, it has been proposed to react the lecithin with a number of aliphatic polyalcohols, such as the pentitol arabitol, or the hexitols sorbitol and mannitol, in the presence of water (cf. DAS 12 27 191) . The advantage afforded by the reaction is said to be that the resultant compounds can be dissolved in water without the choline splitting off. The formation of choline is said to be disadvantageous, in view of the fact that it is said to be a venous poison. It has now been found that the reaction between lecithins and pentavalent or hexavalent alcohols of the aforesaid kind can be controlled towards a release of choline, if the lecithin is first dissolved in propylene glycol in the absence of water, and the resultant solution is then treated with the pentavalent or hexavalent alcohol. In the reaction, the propylene glycol serves both as a solvent for the lecithin and as an interesterification cata¬ lyst in the reaction with the pentavalent or hexavalent alcohol. Our own experiments have shown that the com¬ pound formed by the interesterification process has the formula I where R-. and R~ each have the aforesaid significance, and R-, represents the residue of the pentavalent or hexavalent alcohol. As far as is known, no compounds having this formula have been previously proposed as a pharmaceutical. It has now surprisingly been found that the water- soluble compounds of formula I have both surface active properties and are also able to affect the rectum or ali¬ mentary canal in a manner such as to soften the faeces present therein, so that the bowels can be emptied. It has also been found that the laxative effect of the compounds of formula I is enhanced synergistically, by the simultaneous precence of the choline released in the aforesaid interesterification reaction. As a result of particular enzymes in the body fluid, the choline is con- verted to acetyl choline, which in turn has a favourable effect on the intestines, so that any faeces present are caused to move therefrom, without causing discomfort. The lecithin rendered soluble in water through treat¬ ment under interesterification conditions can thus be used as a laxative, both as such, although preferably in mix¬ ture with choline. From the aspect of efficiency, it is usually preferred not to separate the choline released in the process of interesterification from the water-soluble compounds. Lecithin (3-phosphatidyl choline esters), occur to¬ gether with fat in both the plant and animal kingdoms, where it constitutes an important chemical ingredient of the plant and animal cells. Defatted lecithins, are used as starting material for the preparation of water-soluble compounds of formula I above. It is considered that in the majority of lecithins, one group of hydrocarbons in the acyl groups R... and R- above is saturated, while the other is unsaturated. In the hydrolysis of lecithin, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and arachidonic acid have been obtained. Lecithins occurring in nature are laevorotary. Lecithins are also found in egg yolks. On the basis of the above, the invention relates to one or more water-soluble 3-phosphatidyl esters of the formula I where R.. , R 2 and R.-, all have the aforesaid significance, preferably in ' mixture with choline, for use as a laxative for rectal administration. The invention also relates to a method for producing 3-phosphatidyl esters of the formula I, which is character- ized by reacting 3-phosphatidyl choline of formula II CH--0-R- f 2 2 R. O-CH (ID 1 I CH--0-P-OR . 2 i 4 OH where R. and R_ each have the aforesaid significance and R 4 represents the choline remainder, which - as is known - has the formula CH- I 2 OH in a non-aqueous solution of propylene glycol, with penta¬ valent or hexavalent alcohol under interesterifying con¬ ditions, whereupon the resultant mixture is used in its present form, or the resultant compounds of formula II are separated from the choline released during the inter- esterifying process. The reaction can be effected with, for example, de¬ fatted sojalecthin. Such sojalecthin is not readily dis¬ solved in ethyl alcohol, but can be dissolved in propylene glycol, with the application of heat. To effect the interesterifying reaction, the solution of lecithin in propylene glycol is preferably admixed with ethyl alcohol or isopropanol, and also with pentavalent or hexavalent alcohol in a quantity corresponding to at least two moles thereof, calculated on one mole of lecithin {3-phosphati- dyl choline) . The polyalcohol required for the inter¬ esterification reaction may suitably be dissolved in a small amount of water, whereafter the resultant solution is added to the solution of lecithin. The resultant mixture OMPI is then heated, whereupon the choline changes places with the polyalcohol in the lecithin, to form a water-soluble product, which can then be further processed, preferably in mixture with the released choline, into suitable pre- parations, optionally after being mixed with other sub¬ stances having the nature of promoting a particular effect. The surface-active compound of formula I formed by the interesterifying reaction, in combination with the released choline, is suitable for producing preparations, for example for use in the case of temporary constipation, or for emptying the bowels when wishing to examine the colon, for example with the aid of X-rays or visually with the use of special instruments herefor. The presence of faeces when making an examination of this nature can present such an obstacle as to render the result of the examination incorrect. To this end, it has been usual to introduce into the intestine minor quantities of con¬ centrated aqueous solutions of phosphate ("Fleet enema") or sorbitol ("Klyx"), icroenema ("Microlax") , which latter contains a small amount (5-15 ml) of a combination of trisodium nitrate and sorbitol. According to the in¬ vention, the present combination of water-soluble 3- phosphatidyl esters and choline can also be used in oper¬ ations of the aforesaid kind. In practice, microenemas of the kind which comprise a combination of trisodium.nitrate and sorbitol, always contain a certain percentage of a surfactant, whose pur¬ pose is to ensure that the enema fluid is spread rapidly in the intestine and, above all, that it penetrates the faeces more quickly, so that the active ingredients, in turn, are able to come into contact with the faece mass more rapidly. In this respect, the present mixture is able to replace the surface active substance, and the enema liquid is then complemented with additional ingre- dients which have a favourable effect on the bowel- emptying process, while retaining the ability of the OMPI solution to wet the bowel-contents at the same time. The intestine can also be emptied with the aid of suppositories comprising a core which contains a mixture capable of generating carbon dioxide when coming into contact with water (for example a mixture of sodium hydrogen carbonate and potassium hydrogen tartrate) , and a casing which surrounds the core and which comprises a lubricant facilitating insertion of the suppository into the rectum, which lubricant may comprise a suitable fat, such as cacao-fat for example. Such suppositories work by water present in the content of the intestine reacting with the substances in the suppository core, ' to form a carbon dioxide foam, which facilitates exit of the faeces from the intestine. It has now been found that a marked improvement can be obtained with such laxa¬ tives for rectal administration, when the casing which surrounds the gas-generating mixture comprises the com¬ pound or compounds of formula I, preferably in mixture with choline. It is then possible to incorporate in a single dosage-unit of laxative, additional ingredients which are active in conjunction with the emptying of the intestine. In addition to functioning as a protective means for shielding the moisture-sensible mixture, and as a lubricant for ease of insertion of the suppository into the rectum, the casing may also serve to release substanc¬ es which have a direct laxative effect. The invention will now be described more clearly, with reference to a number of examples. Example ~ 2 grams of lecithin, which are isolated soja-*-bean phospholipides enriched with respect to 3— hosphatidyl choline, were dissolved in 10 ml of propylene glycol while applying heat. The resultant solution was diluted with 10 ml of isopropyl alcohol. Heating was continued, wherewith part of the isopropyl alcohol boiled off. OMPI The concentrated solution of lecithin in propylene glykol was admixed with 0.5 gram mannitol, which was dissolved in its own weight of warm distilled water. A chemical reaction took place, which manifested itself in the form of a froth. Upon completion of this reaction, distilled water was added to the reaction mixture in portions, to a total volume of 50 ml. The resultant solution of 3-phosphatidyl mannitol ester and released choline was converted into unit-dosages of 20-100 ml, which were transferred to small containers of soft, flexible plastics material, with a connecting tube for insertion into the rectum. The unit dosages were administered to the intestine, through the rectum, by squeezing the outer wall of the plastics container with the fingers. The mixture gave a gentle and mild laxative effect. Example 2 ' The experiment of Example 1 was repeated, but with the difference that the hexavalent alcohol inositol was used instead of mannitol. The resultant solution of 3-phosphatidyl inositol ester and choline gave the same advantageous laxative effect as the mixture in Example 1. Example 3 200 grams of the same enriched phosphatidyl choline as that used in Example 1 were dissolved in 1000 ml of propylene glycol, whereafter 10Q0 ml of absolute ethyl alcohol were added to the solution. The solution was heated under refluxing conditions for three hours, and was then admixed with 100 grams of mannitol in the form of a solution in 1Q0 ml of distilled water, thereby to cause an interesterification to take place, which lead to the release of choline and the insertion of a residue of mannitol in the choline-site of the 3-phosphatidyl- molecule. OM?I 1 kg of cacao fat was added to the resultant solution, and the resultant mixture was heated to melt the fat. 500 grams of talc were then added, to form a suspension. The suspension was then distributed between 2000 suppository cases produced in a tablet-forming machine and containing a mixture of sodium hydrogen car¬ bonate and potassium hydrogen tartrate, this mixture being able to generate carbon dioxide under the influence of water. The coated bodies obtained were tested as supposito¬ ries against constipation, and were found to have an amplified effect in comparison with suppositories having an inert casing of solely cacao fat. Example 4 100 grams of lecithin similar to that used in the previous examples were dissolved in 500 ml propylene alcohol while applying heat. The resultant solution was admixed with 500 ml of absolute ethanol and was partially concentrated. The concentrated solution of lecithin in propylene glycol was admixed with 100 ml of 70-% sorbitol- solution in water, and the mixture was heated to release choline, through interesterification. In order to produce a solution suitable for a so- called microenema, the reaction product obtained in accordance with the aforegoing and containing 3-phospati- dyl sorbitol ester and choline was admixed with 500 grams of trisodium citrate dissolved in 1000 ml of heated water. A 70-% solution of sorbitol in water was then added to- the resultant solution, until a total volume of 10,000 ml was reached. 1000 so-called microenemae, each containing 10 ml of solution, were produced from the terminal solu¬ tion obtained. Each such dosage was transferred to a suitable con¬ tainer having means for administering the fluid to the rectum, and was tested as a preparation capable of being administered rectally, for emptying the bowel. The results obtained were superior to those obtained with a solution of trisodium citrate and sorbitol and a sur¬ factant whose sole effect is to wet the faeces in the bowel.

Claims: C L A I M S 1. One or more water-soluble 3-phosphatidyl esters of the formula I in which R- and R 2 are the same or different and each signify the acyl group of a saturated or unsaturated fatty acid having 10-22 carbon atoms, and R., signifies the residue of a pentavalent or hexavalent alcohol, pre¬ ferably in mixture with choline, for use as a laxative intended for rectal administration. 2. A method for producing a mixture of 3-phos- phatidyl esters of the formula I in which R.. , R 2 , R_, each have the significance recited in Claim 1 , and choline according to Claim 1, c h a r a c ¬ t e r i z e d b y causing 3-phosphatidyl choline of the formula II in which R. signifies the residue of choline, which has the formula in a non-aqueous solution of 1 ,2-propandiol, to react with a pentavalent or hexavalent alcohol of the formula R 3 OH in which R-, has the aforesaid significance, under inter¬ esterifying conditions, whereupon the resultant reaction mixture is used in its present form, or the obtained compound or compounds having formula I is, or are, separated from the choline released during interesterifi¬ cation in a non-aqueous environment. 3. A method according to Claim 2, c h a r a c - t e r i z e d i n that the interesterification pro¬ cess is effected in the presence of propylene glycol as an interesterifying catalyst and solvent for the lecithin. 4. A rectally administrable preparation for empty¬ ing the bowels, c h a r a c t e r i z e d i n that it comprises an aqueous solution which contains one or more compounds of the formula I, and preferably also choline. 5. A rectally administrable preparation for empty¬ ing the bowels, c h a r a c t e r i z e d i n that it comprises a body which can be inserted into the rectum and which includes a core of a gas-generating mixture and a casing comprising a mixture of one or more compounds of the formula I, and preferably also choline.

Inventors: EMBRING PAUL GUNNAR, EMBRING, PAUL, GUNNAR
Applicants: PHARMACIA AB, PHARMACIA AKTIEBOLAG
Application year: 1984
Main classification: C07F9
IPC codes: A61K31, C07F9