WO1984003704A1 - Esters de 3-phosphatidyl utilises comme laxatifs pour administration rectale - Google Patents

Esters de 3-phosphatidyl utilises comme laxatifs pour administration rectale Download PDF

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Publication number
WO1984003704A1
WO1984003704A1 PCT/SE1984/000105 SE8400105W WO8403704A1 WO 1984003704 A1 WO1984003704 A1 WO 1984003704A1 SE 8400105 W SE8400105 W SE 8400105W WO 8403704 A1 WO8403704 A1 WO 8403704A1
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WO
WIPO (PCT)
Prior art keywords
choline
formula
mixture
phosphatidyl
compounds
Prior art date
Application number
PCT/SE1984/000105
Other languages
English (en)
Inventor
Paul Gunnar Embring
Original Assignee
Pharmacia Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia Ab filed Critical Pharmacia Ab
Publication of WO1984003704A1 publication Critical patent/WO1984003704A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/10—Phosphatides, e.g. lecithin

Definitions

  • 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.
  • lecithin also known as 3-phosphatidyl choline of the formula
  • 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.
  • a number of aliphatic polyalcohols such as the pentitol arabitol, or the hexitols sorbitol and mannitol, in the presence of water (cf.
  • 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.
  • 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
  • R-. and R ⁇ each have the aforesaid significance, and R-, represents the residue of the pentavalent or hexavalent alcohol.
  • 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.
  • Lecithins occurring in nature are laevorotary. Lecithins are also found in egg yolks.
  • the invention relates to one or more water-soluble 3-phosphatidyl esters of the formula I
  • 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. and R_ each have the aforesaid significance and R 4 represents the choline remainder, which - as is known - has the formula
  • the reaction can be effected with, for example, de ⁇ fatted sojalecthin.
  • sojalecthin is not readily dis ⁇ solved in ethyl alcohol, but can be dissolved in propylene glycol, with the application of heat.
  • 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.
  • 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.
  • 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.
  • the present mixture is able to replace the surface active substance, and the enema liquid is then complemented with additional ingre- dominant effect on the bowel- emptying process, while retaining the ability of the
  • 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.
  • 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.
  • 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.
  • the casing may also serve to release substanc ⁇ es which have a direct laxative effect.
  • 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 1 The experiment of Example 1 was repeated, but with the difference that the hexavalent alcohol inositol was used instead of mannitol.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Un ou plusieurs esters de 3-phosphatidyl solubles dans l'eau de formule (I) où R1 et R2 sont semblables ou différents et représentent chacun le groupe acyle d'un acide gras saturé ou non saturé possédant entre 10 et 22 atomes de carbone, et où R3 représente le résidu d'un alcool pentavalent ou hexavalent, de préférence mélangé avec de la choline, utilisés comme laxatifs administrables rectalement, leur procédé de préparation et les compositions médicales qui les contiennent.
PCT/SE1984/000105 1983-03-24 1984-03-23 Esters de 3-phosphatidyl utilises comme laxatifs pour administration rectale WO1984003704A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
SE8301639A SE452466B (sv) 1983-03-24 1983-03-24 Blandning av vattenlosliga 3-fosfatidylestrar och kolin, sett att framstella denna och ett rektalt administrerbart preparat for tomning av grovtarm

Publications (1)

Publication Number Publication Date
WO1984003704A1 true WO1984003704A1 (fr) 1984-09-27

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PCT/SE1984/000105 WO1984003704A1 (fr) 1983-03-24 1984-03-23 Esters de 3-phosphatidyl utilises comme laxatifs pour administration rectale

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EP (1) EP0139697A1 (fr)
SE (1) SE452466B (fr)
WO (1) WO1984003704A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0122151A2 (fr) * 1983-04-11 1984-10-17 Meito Sangyo Kabushiki Kaisha Production de dérivés phospholipidiques d'alcools primaires ou secondaires par la technique enzymatique
EP0516034A1 (fr) * 1991-05-28 1992-12-02 FIDIA S.p.A. Compositions pharmaceutiques à capacité immunosuppressive

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1227191B (de) * 1960-07-01 1966-10-20 Propharma Lab Verfahren zur Herstellung von fluessigen Lecithinpraeparaten
DE2659048A1 (de) * 1976-12-27 1978-07-06 Nattermann A & Cie Neue inositphosphatid-derivate und verfahren zur herstellung dieser verbindungen
DE2717547A1 (de) * 1977-04-20 1978-11-02 Max Planck Gesellschaft Verfahren zur umesterung von phospholipiden mit phospholipase d
FR2452286A1 (fr) * 1979-03-27 1980-10-24 Nippon Shoji Kaisha Ltd Acides phosphatidiques utilisables pour le traitement des desordres de la conscience et des desordres de la perception et des mouvements
EP0092121A1 (fr) * 1982-04-12 1983-10-26 Board Of Regents, The University Of Texas System Méthodes et compositions pour traiter les ulcères gastro-intestinaux
WO1984000367A1 (fr) * 1982-07-06 1984-02-02 Max Planck Gesellschaft Nouveaux derives de la glycerine pour la synthese de phospholipides
WO1984000362A2 (fr) * 1982-07-06 1984-02-02 Max Planck Gesellschaft Nouveaux derives de d-mannite comme produits de depart pour la synthese de phospholipides

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1227191B (de) * 1960-07-01 1966-10-20 Propharma Lab Verfahren zur Herstellung von fluessigen Lecithinpraeparaten
DE2659048A1 (de) * 1976-12-27 1978-07-06 Nattermann A & Cie Neue inositphosphatid-derivate und verfahren zur herstellung dieser verbindungen
DE2717547A1 (de) * 1977-04-20 1978-11-02 Max Planck Gesellschaft Verfahren zur umesterung von phospholipiden mit phospholipase d
FR2452286A1 (fr) * 1979-03-27 1980-10-24 Nippon Shoji Kaisha Ltd Acides phosphatidiques utilisables pour le traitement des desordres de la conscience et des desordres de la perception et des mouvements
EP0092121A1 (fr) * 1982-04-12 1983-10-26 Board Of Regents, The University Of Texas System Méthodes et compositions pour traiter les ulcères gastro-intestinaux
WO1984000367A1 (fr) * 1982-07-06 1984-02-02 Max Planck Gesellschaft Nouveaux derives de la glycerine pour la synthese de phospholipides
WO1984000362A2 (fr) * 1982-07-06 1984-02-02 Max Planck Gesellschaft Nouveaux derives de d-mannite comme produits de depart pour la synthese de phospholipides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, Vol 86 No 5, February 1982, Columbus, Ohio (US), V M KLIMOVICH: "Spectroscopic study of lipidcarbohydrate complexes of phospatidyl-choline in a nonpolar medium", see page 233, column 2, abstract 30357w, VINITI 388-81, 1k pp. (SU), Deposited Doc 1981. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0122151A2 (fr) * 1983-04-11 1984-10-17 Meito Sangyo Kabushiki Kaisha Production de dérivés phospholipidiques d'alcools primaires ou secondaires par la technique enzymatique
EP0122151A3 (en) * 1983-04-11 1986-03-26 Meito Sangyo Kabushiki Kaisha Production of primary or secondary alcohol derivatives of phospholipids by the enzymatic technique
EP0516034A1 (fr) * 1991-05-28 1992-12-02 FIDIA S.p.A. Compositions pharmaceutiques à capacité immunosuppressive

Also Published As

Publication number Publication date
SE8301639D0 (sv) 1983-03-24
EP0139697A1 (fr) 1985-05-08
SE452466B (sv) 1987-11-30
SE8301639L (sv) 1984-09-25

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