EP0139697A1 - 3-phosphatidyl esters for use as a laxative for rectal administration - Google Patents

3-phosphatidyl esters for use as a laxative for rectal administration

Info

Publication number
EP0139697A1
EP0139697A1 EP19840901452 EP84901452A EP0139697A1 EP 0139697 A1 EP0139697 A1 EP 0139697A1 EP 19840901452 EP19840901452 EP 19840901452 EP 84901452 A EP84901452 A EP 84901452A EP 0139697 A1 EP0139697 A1 EP 0139697A1
Authority
EP
European Patent Office
Prior art keywords
choline
formula
mixture
phosphatidyl
compounds
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP19840901452
Other languages
German (de)
English (en)
French (fr)
Inventor
Paul Gunnar Embring
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Health AB
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 EP0139697A1 publication Critical patent/EP0139697A1/en
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (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)
EP19840901452 1983-03-24 1984-03-23 3-phosphatidyl esters for use as a laxative for rectal administration Withdrawn EP0139697A1 (en)

Applications Claiming Priority (2)

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
SE8301639 1983-03-24

Publications (1)

Publication Number Publication Date
EP0139697A1 true EP0139697A1 (en) 1985-05-08

Family

ID=20350519

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19840901452 Withdrawn EP0139697A1 (en) 1983-03-24 1984-03-23 3-phosphatidyl esters for use as a laxative for rectal administration

Country Status (3)

Country Link
EP (1) EP0139697A1 (sv)
SE (1) SE452466B (sv)
WO (1) WO1984003704A1 (sv)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3476770D1 (en) * 1983-04-11 1989-03-23 Meito Sangyo Kk Production of primary or secondary alcohol derivatives of phospholipids by the enzymatic technique
IT1249063B (it) * 1991-05-28 1995-02-11 Fidia Spa Impiego di derivati fosfolipidici per la preparazione di composizioni farmaceutiche aventi attivita' immunosoppressiva

Family Cites Families (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
GB2045612B (en) * 1979-03-27 1983-04-20 Nippon Shoji Kaisha Ltd Pharmaceutical compositions containing phosphatidic acids for the treatment of disorders of consciousness perception and movement
EP0092121B1 (en) * 1982-04-12 1987-12-16 Board Of Regents, The University Of Texas System Methods and compositions for treating gastro-intestinal ulcer diesease
DE3239817A1 (de) * 1982-07-06 1984-01-12 Max Planck Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen Neue glycerinderivate zur synthese von phospholipiden
DE3239858A1 (de) * 1982-07-06 1984-01-12 Max Planck Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen Neue d-mannitderivate als ausgangsprodukte zur synthese von phospholipiden

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8403704A1 *

Also Published As

Publication number Publication date
SE8301639L (sv) 1984-09-25
SE452466B (sv) 1987-11-30
WO1984003704A1 (en) 1984-09-27
SE8301639D0 (sv) 1983-03-24

Similar Documents

Publication Publication Date Title
US5190748A (en) Absorption enhancement of antibiotics
US5049552A (en) Compositions containing hexadecylphosphocholine and use thereof
US3288824A (en) Esterification of triglyceride with polyethylene glycols and products
JP2804081B2 (ja) 非イオン界面活性剤の製造方法、皮膚手入れおよび化粧用調製品、塗料および木材防腐剤
EP0265702A2 (en) A transparent or semitransparent jelly-like cosmetic composition
EP0028456B1 (en) Branched fatty acid cholesterol ester and a cosmetic composition containing the same
DE2961917D1 (en) Herbicidal active unsaturated esters of 4- (3',5'-dihalogenpyridyl-(2')-oxy)-alpha-phenoxy propionic acids, process for their preparation, herbicidal compositions containing them and their use
GB1563302A (en) Oral pharmaceutical preparation with anabolic activity containing a 17 -ester of nandrolone
JPH0215248B2 (sv)
GB1595873A (en) Medicaments to be applied externally and process for the preparation of such medicaments
US4600539A (en) O/W Emulsifiers for cosmetic purposes
US4842865A (en) Use of glycofurol for the liquidization of pharmaceutical preparations to be filled into soft gelatine capsules
US4366151A (en) Oxyalkylated fatty acids and their use as solubilizers
EP0139697A1 (en) 3-phosphatidyl esters for use as a laxative for rectal administration
US2055063A (en) Suppository medication
JPH0517918B2 (sv)
WELLS The fat metabolism of lipomas
US2056208A (en) Acetyl-salicylic acid composition
US4150125A (en) Triglyceride ester of phosphonoacetic acid having antiviral activity
JP4526120B2 (ja) Ｌ−メントール水中油型乳剤
US5137820A (en) Superoxide dismutase derivatives, a method of producing the same and medicinal uses of the same
JPS6241202B2 (sv)
US4209451A (en) Process for the manufacture of mixed esters from hydroxycarboxylic acids and partial glycerides of fatty acids
US4510070A (en) Emulsifying composition
EP0102410B1 (en) Topical preparation for treating herpes simplex virus

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19850228

RIN1 Information on inventor provided before grant (corrected)

Inventor name: EMBRING, PAUL, GUNNAR