CA1167838A - Polymerizable phospholipids and a process for their preparation, polymeric phospholipids and a process for their preparation, and the use of the polymeric phospholipids - Google Patents
Polymerizable phospholipids and a process for their preparation, polymeric phospholipids and a process for their preparation, and the use of the polymeric phospholipidsInfo
- Publication number
- CA1167838A CA1167838A CA000373059A CA373059A CA1167838A CA 1167838 A CA1167838 A CA 1167838A CA 000373059 A CA000373059 A CA 000373059A CA 373059 A CA373059 A CA 373059A CA 1167838 A CA1167838 A CA 1167838A
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- Canada
- Prior art keywords
- radical
- phospholipid
- denotes
- glycerol
- benzyl
- 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.)
- Expired
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
- 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 System
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F30/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
- C08F30/02—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing phosphorus
Abstract
Abstract of the Disclosure Polymerizable phospholipids of the general formula I
(CH2 = ? - ? -)n - A I
in which n denotes an integer with a value from 1 to 6, R1 denotes a hydrogen atom or a methyl group and A denotes the radical, bonded via the polar or apolar region of the molecule, of a, phospholipid or phospholipid analogue of the general formula II
in which R represents the lipophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospho-lipid molecule, and a process for their preparation are described.
(CH2 = ? - ? -)n - A I
in which n denotes an integer with a value from 1 to 6, R1 denotes a hydrogen atom or a methyl group and A denotes the radical, bonded via the polar or apolar region of the molecule, of a, phospholipid or phospholipid analogue of the general formula II
in which R represents the lipophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospho-lipid molecule, and a process for their preparation are described.
Description
I ~ 6783~
The invention relates to polymerizable phospho-lipids and a process for their preparation1 and polymeric phospholipids which can be formed from these polymer-izable phospholipids, a process for tneir preparat.on and their use for the production of microcapsules.
It is already known that a large number of nat-urally occurring or synthetic materials can be used ~or the fcrmation of micro^apsules which can be used for en-capsulating an~ stabilizin~ med.cinal active cvmpounds or other active substances, such as enzymes, and for pro-te~ting these compounds unti] they are llsed ir. the inten-ded manner.
The m.aterials traditionally used for forming microcapsules are, for example, synthetic polymers, such as polyamides, or naturally occurring materiaJ~, such a_ gelatin. - However, these materials can~ot be comple~el~
satisfactory, since in some cases they necessitate multi-co~nponent systems, using organic solv~r~ts, for the for-~ mation of the microcapsules, do not have the required stability, cannot be biologically degraded or may display harmful side effects when they are to be employed for encapsulating medicinal active compounds.
The object of the present invention is thus to ~5 provide a material which is considerably more suitable for encapsulating active substances or otherwise immobil-izing them than the materials traditionally employed.
It has now been found, surprisingly, that poly-meric phospholipids which, because of their lipid charac-~`
.
" ~ : :
. ~
~ 1 ~7~,3~3 ter, are capable of forming spontaneously organized structures (vesicles, artificial liposomes) about U.05 to 100 um in size in an aqueous medium, can be formed from polymerizable phospholipids These particles are hollow spheres and are thus suitable for microencapsulat-ing water-soluble medicinal active compounds or other active compounds Furthermore, lipophilic substances can be concentrated in such microcapsules if, like chol-esterol, for example, they are soluble in the hydrophobic part of the polymers.
In particular, the invention relates to the poly-rnerizable phospholipids of the Eollowing general Eorrnula Rl O
,.
~CH2 = C - C -) - A (I) in which n denotes an integer with a value from 1 to 6, R denotes a hydrogen atoln or a methyl group and A de-notes the radical, bonded via the polar or apolar region of the molecule, of a phospholipid or phospholipid ana-logue of the general formula II
R - PO4H - Z (II) .. -. .
.
- "` 1 1 67~3~
in which R represents the lipophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospholipid molecule The radical ~ in the above general formula I pre-ferably represents the radical of a phospholipid which is isolated from naturally occurring material, such as egg yol~, soya bean or the like and which contains functional groups fr-om which derivatives can be formed, such as hydroxyl groups or amino groups, such as, for example, a cephalin, phosphatidylserine, phosphatidylglycerol, phos-phatidylinositol, cardiolipin, sphingomyelin or cerebro-side radieal or respeetive synthetie phospholipids of natural structure Aceording to a preferred embodiment of the inven-tion, the polymerizable phospholipids correspond to the following general formula III
O
R - P04H - Z - (- C - C = CH~)n . (III) in whieh n denotes an integer with a value from 1 to 6, Rl denotes a hydrogen atom or a methyl group and the radical R represents a radical seleeted from groups A) to K) defined below:
Group A comprises radieals of monohydrie alcohols, such as hexanol, decanol, hexadecanol, eicosanol and hexacosanol, and of cyclohexanol and corresponding com-'' - .
7~338 pounds which are halogenated, such as, for example, bromo-l-hexanol, 10-bromo-1-decanol and 16-bromo-1-hexadecanol, or unsaturated, such as g-octadecan-l-ol.
Group B comprises radicals of compounds which are formed by monosubstitution o~ allcanediols, with etherification or esterificatin, such as acetylglycol, ethylglycol, decanoylglycol, decylglycol, hexadecanoyl-glycol, hexadecylglycol~ eicosanoylglycol and eisosyl-glycol, and corresponding monoacyl or monoalkyl deriva-tives of 1,3-propanediol, ].,2-propanediol, 1,6-hexane-diol/ l,lU-decanediol and 1,16-hexadecanediol, which, like the glycol derivatives, can easily be prepared in a Known manner.
Group C comprises radicals of compounds which have likewise been built up from alicanediols but which contain ether groupings which are unstable to acid, such as, for example, the trityl or tetrahydropyranyl radical, such as l-tritylglycol, l-tetrahydropyranyl-glycol, l-trityl-1,3-propanediol, l-tetrahydropyranyl-1,6-hexanediol, l-trityl-l,10-decanediol, l-tetrahydro-pyranyl-l,10-decanediol, 1-trityl-1,16-hexadecanediol and l-tetrahydropyranyl-1~16-hexadecanediol. These compounds can also easily be prepared in a Icnown manner.
1 1 6~P)38 Group D likewise comprises radicals of com-pounds which are built up from alkanediols, but which contain either groups which can be removed again by cata-lytic hydrogenolysis, for exarnple benzyl ethers, such as l-benzylglycol, l-benzyl-1,3-propanediol, 1-benzyl-1,2-propanediol, l-benzyl-1,6-hexanediol, l-benzyl-l,10-dec-anediol and l-benzyl-1,16-hexadecanediol. These com-pounds can also easil~7 be prepared in a known manner.
Group E comprises radicals of compounds which are built up on the fur.dame~ltal glycerol skeleton and in which two alcohol groups are substituted as in the case of the radicals of group B, such as radicals oE
1,2-dimethylglycerol, 1,3-dimethylglycerol, 1,2-diacetyl-glycerol, l/3-diacetylglycerol, 1,2-diethylglycerol and 1,3-diethylglycerol and of corresponding esters with higher fatty acid radicals, such as capric acid, lauric acid, palmitic acid, arachic acid, oleic acid and lino-leic acid, or of ethers with higher alkyl radicals, such as decyl, hexadecyl and hexacosyl, and of mixed ester compounds, ether compounds or ester/ether compounds.
The corresponding starting materials can be prepared by known processes.
Group F comprises radicals of glycerol deriva-tives which contain groups which are unstable to acid, such as ditrityl radicals, such asl for example, 1,3-.:
'' ' ' ~ ~ ..
--6--ditritylglycerol or 1,2-isopropylideneglycerol.
Group G comprises radicals of compounds which are built up from glycerol but which, as in the case of the radicals of Group D, contain ether groupings which car be removed again by catalytic hydrogenolysis, for ex-ample benzyl ethers, such as l-benzyl-2-lauroyl-glycerol, l-lauroyl-2-benzyl-glycerol, 1-benzyl-2-palmitoyl-gly-cerol, l-palmitoyl-~-benzoyl-glycerol, 1-benzyl-2-arach-oyl-glycerol and l-arachoyl-2-benzyl-glycerol, and the corresponding alkyl ethers.
Group H comprises radicals of compounds of the type from which the radicals of groups B and E are der-ived, but with polyalcohols as the fundamental skeleton.
A n-polyol always contains n-l substituents and a free hydroxyl group, which can then be reacted by known pro-cesses to give the phosphoric acid diester (R-P04H-Z).
Examples of suitable polyols are erythritol, arabitol, xylitol, adonitol, mannitol, sorbitol and dulcitol.
Group I comprises radicals of compounds of the type from which the radicals Qf groups G and F are der-ived, these radicals being based on polyalcohols which are again unstable to acid. In a n-polyol, n-1 groups are protected, that is to say one free primary or secon-dary alcohol group is present, which again is available for reaction to give the phosphoric acid diester.
~ .
I 1 67~38 Group J comprises radicals of compounds of the type fran which the radicals of groups D and G are der-ived, these radicals con~aining ether groupings which can be removed again by catalytic hydrogenolysis.
Group K comprises the radicals of other biologi-cally and pharmaceutically interesting li~ophilic alco-hols which contain a primary or secondary hydroxyl group, such as, for example, of cholesterol, retinol, andro-sterone, ergosterol and other steroid alcohols, isopre-noid alcohols and carotenoid alcohols.
Group Z in the above general formula III repres-ents the polar portion of the molecule, which is bonded to the radical R via the phosphate group, and corres-ponds to one of the formulae 1) to 6) given below, the hetero-atom (O or N) on the right-hand side of the group-ing representing the bonding member to the polymerizable radical (acrylic acid radical or methacrylic acid radi-cal).
1) (CH2)a NH wherein a has a value from 2 to 10,
The invention relates to polymerizable phospho-lipids and a process for their preparation1 and polymeric phospholipids which can be formed from these polymer-izable phospholipids, a process for tneir preparat.on and their use for the production of microcapsules.
It is already known that a large number of nat-urally occurring or synthetic materials can be used ~or the fcrmation of micro^apsules which can be used for en-capsulating an~ stabilizin~ med.cinal active cvmpounds or other active substances, such as enzymes, and for pro-te~ting these compounds unti] they are llsed ir. the inten-ded manner.
The m.aterials traditionally used for forming microcapsules are, for example, synthetic polymers, such as polyamides, or naturally occurring materiaJ~, such a_ gelatin. - However, these materials can~ot be comple~el~
satisfactory, since in some cases they necessitate multi-co~nponent systems, using organic solv~r~ts, for the for-~ mation of the microcapsules, do not have the required stability, cannot be biologically degraded or may display harmful side effects when they are to be employed for encapsulating medicinal active compounds.
The object of the present invention is thus to ~5 provide a material which is considerably more suitable for encapsulating active substances or otherwise immobil-izing them than the materials traditionally employed.
It has now been found, surprisingly, that poly-meric phospholipids which, because of their lipid charac-~`
.
" ~ : :
. ~
~ 1 ~7~,3~3 ter, are capable of forming spontaneously organized structures (vesicles, artificial liposomes) about U.05 to 100 um in size in an aqueous medium, can be formed from polymerizable phospholipids These particles are hollow spheres and are thus suitable for microencapsulat-ing water-soluble medicinal active compounds or other active compounds Furthermore, lipophilic substances can be concentrated in such microcapsules if, like chol-esterol, for example, they are soluble in the hydrophobic part of the polymers.
In particular, the invention relates to the poly-rnerizable phospholipids of the Eollowing general Eorrnula Rl O
,.
~CH2 = C - C -) - A (I) in which n denotes an integer with a value from 1 to 6, R denotes a hydrogen atoln or a methyl group and A de-notes the radical, bonded via the polar or apolar region of the molecule, of a phospholipid or phospholipid ana-logue of the general formula II
R - PO4H - Z (II) .. -. .
.
- "` 1 1 67~3~
in which R represents the lipophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospholipid molecule The radical ~ in the above general formula I pre-ferably represents the radical of a phospholipid which is isolated from naturally occurring material, such as egg yol~, soya bean or the like and which contains functional groups fr-om which derivatives can be formed, such as hydroxyl groups or amino groups, such as, for example, a cephalin, phosphatidylserine, phosphatidylglycerol, phos-phatidylinositol, cardiolipin, sphingomyelin or cerebro-side radieal or respeetive synthetie phospholipids of natural structure Aceording to a preferred embodiment of the inven-tion, the polymerizable phospholipids correspond to the following general formula III
O
R - P04H - Z - (- C - C = CH~)n . (III) in whieh n denotes an integer with a value from 1 to 6, Rl denotes a hydrogen atom or a methyl group and the radical R represents a radical seleeted from groups A) to K) defined below:
Group A comprises radieals of monohydrie alcohols, such as hexanol, decanol, hexadecanol, eicosanol and hexacosanol, and of cyclohexanol and corresponding com-'' - .
7~338 pounds which are halogenated, such as, for example, bromo-l-hexanol, 10-bromo-1-decanol and 16-bromo-1-hexadecanol, or unsaturated, such as g-octadecan-l-ol.
Group B comprises radicals of compounds which are formed by monosubstitution o~ allcanediols, with etherification or esterificatin, such as acetylglycol, ethylglycol, decanoylglycol, decylglycol, hexadecanoyl-glycol, hexadecylglycol~ eicosanoylglycol and eisosyl-glycol, and corresponding monoacyl or monoalkyl deriva-tives of 1,3-propanediol, ].,2-propanediol, 1,6-hexane-diol/ l,lU-decanediol and 1,16-hexadecanediol, which, like the glycol derivatives, can easily be prepared in a Known manner.
Group C comprises radicals of compounds which have likewise been built up from alicanediols but which contain ether groupings which are unstable to acid, such as, for example, the trityl or tetrahydropyranyl radical, such as l-tritylglycol, l-tetrahydropyranyl-glycol, l-trityl-1,3-propanediol, l-tetrahydropyranyl-1,6-hexanediol, l-trityl-l,10-decanediol, l-tetrahydro-pyranyl-l,10-decanediol, 1-trityl-1,16-hexadecanediol and l-tetrahydropyranyl-1~16-hexadecanediol. These compounds can also easily be prepared in a Icnown manner.
1 1 6~P)38 Group D likewise comprises radicals of com-pounds which are built up from alkanediols, but which contain either groups which can be removed again by cata-lytic hydrogenolysis, for exarnple benzyl ethers, such as l-benzylglycol, l-benzyl-1,3-propanediol, 1-benzyl-1,2-propanediol, l-benzyl-1,6-hexanediol, l-benzyl-l,10-dec-anediol and l-benzyl-1,16-hexadecanediol. These com-pounds can also easil~7 be prepared in a known manner.
Group E comprises radicals of compounds which are built up on the fur.dame~ltal glycerol skeleton and in which two alcohol groups are substituted as in the case of the radicals of group B, such as radicals oE
1,2-dimethylglycerol, 1,3-dimethylglycerol, 1,2-diacetyl-glycerol, l/3-diacetylglycerol, 1,2-diethylglycerol and 1,3-diethylglycerol and of corresponding esters with higher fatty acid radicals, such as capric acid, lauric acid, palmitic acid, arachic acid, oleic acid and lino-leic acid, or of ethers with higher alkyl radicals, such as decyl, hexadecyl and hexacosyl, and of mixed ester compounds, ether compounds or ester/ether compounds.
The corresponding starting materials can be prepared by known processes.
Group F comprises radicals of glycerol deriva-tives which contain groups which are unstable to acid, such as ditrityl radicals, such asl for example, 1,3-.:
'' ' ' ~ ~ ..
--6--ditritylglycerol or 1,2-isopropylideneglycerol.
Group G comprises radicals of compounds which are built up from glycerol but which, as in the case of the radicals of Group D, contain ether groupings which car be removed again by catalytic hydrogenolysis, for ex-ample benzyl ethers, such as l-benzyl-2-lauroyl-glycerol, l-lauroyl-2-benzyl-glycerol, 1-benzyl-2-palmitoyl-gly-cerol, l-palmitoyl-~-benzoyl-glycerol, 1-benzyl-2-arach-oyl-glycerol and l-arachoyl-2-benzyl-glycerol, and the corresponding alkyl ethers.
Group H comprises radicals of compounds of the type from which the radicals of groups B and E are der-ived, but with polyalcohols as the fundamental skeleton.
A n-polyol always contains n-l substituents and a free hydroxyl group, which can then be reacted by known pro-cesses to give the phosphoric acid diester (R-P04H-Z).
Examples of suitable polyols are erythritol, arabitol, xylitol, adonitol, mannitol, sorbitol and dulcitol.
Group I comprises radicals of compounds of the type from which the radicals Qf groups G and F are der-ived, these radicals being based on polyalcohols which are again unstable to acid. In a n-polyol, n-1 groups are protected, that is to say one free primary or secon-dary alcohol group is present, which again is available for reaction to give the phosphoric acid diester.
~ .
I 1 67~38 Group J comprises radicals of compounds of the type fran which the radicals of groups D and G are der-ived, these radicals con~aining ether groupings which can be removed again by catalytic hydrogenolysis.
Group K comprises the radicals of other biologi-cally and pharmaceutically interesting li~ophilic alco-hols which contain a primary or secondary hydroxyl group, such as, for example, of cholesterol, retinol, andro-sterone, ergosterol and other steroid alcohols, isopre-noid alcohols and carotenoid alcohols.
Group Z in the above general formula III repres-ents the polar portion of the molecule, which is bonded to the radical R via the phosphate group, and corres-ponds to one of the formulae 1) to 6) given below, the hetero-atom (O or N) on the right-hand side of the group-ing representing the bonding member to the polymerizable radical (acrylic acid radical or methacrylic acid radi-cal).
1) (CH2)a NH wherein a has a value from 2 to 10,
2) -(CH2)b-- wherein b has a value from 2 to 10,
3) -(CH2)-(CHOH)c-CH2-o- wherein c has a value from 1 to
4) -(CH2)x-l~+-(CH2)y~0~ wherein x and y independently CH3 of one another can assume val-ues from 2 to 10, '.
~ . .
~ J ~7~3~
~ . .
~ J ~7~3~
5 ) -CH2-C-i~H
COOH
or CH3
COOH
or CH3
6) -(CH2)X-l~+-(CH~)y~i~H~ wherein x and y independently CH3 of one another can assume val-ues from 2 to 10.
However, it is also possible for several hydroxyl groups or amino groups in the molecular radical Z to be linked to the polymerizable radical. Crosslinked poly-mers, which can be used as filter materials, for ex-ample as tobacco filters, can.thereby be formed.
According to another embodiment of the inven~on, the polymerizable phospholipids correspond to the follow-ing general formula IV
Rl O
~, (CH2 = C - C ~ )n ~ R - PO4H - Z (IV) wherein, ln this case, the polymerizable group is bonded in the apolar region of the r.lolecule. In this general formula IV, the symbols Rl and n have the abovementioned meanings, whilst ~
A) represents an alkyl radical which is at least bifunc-tional and has 6 to 22, preferably 12 to 22, carbon atoms, such as, for example, an alkanediol, amino alcohol or alkanediamine radical;
b) represents the radical of a monosubstituted alkane-, ~ 1 67~33~
diol, amino alcohol or al~anediamine which has 2 to 6carbon atoms, which carry a substituent which has 6 to 22, preferably 12 to 22, carbon atoms and an ester, ether or amide lin~age, and which contains at least one additional amino or alcohol group;
C) represents the radical of a monosubstituted or di-substituted ylycerol derivative which carries substitu-ents as mentioned under ~); or ~) re~resents the radical of a monosubstituted or poly-substituted (nOH-l) polyol which carries substituents as mentioned under B), and Z represents a group of one of the following general formulae 1) to 10) or a hydrogen atom:
1) (CH2)a NH2 wherein a has a value from 2 to 10, 2) -(CH2)b-OH wherein b has a value from 2 to 1~, 3) -(CH2)-(CHOH)c-CH2-OH wherein c has a value from 1 ,CH3 to 4, 4) ~(CH2)X~N~~(CH2)y~OH wherein x and y independently CH3 of one another can assume val-H ues from 2 to 10, 5) -CH2-C-I~H2 COOH
~,~, .~
I ~ ~7~,3~
6) -(CH2)X-N~-(cH2)y NH2 wherein x and y independently CH3 of one another can assume val-ues from 2 to 10, +
However, it is also possible for several hydroxyl groups or amino groups in the molecular radical Z to be linked to the polymerizable radical. Crosslinked poly-mers, which can be used as filter materials, for ex-ample as tobacco filters, can.thereby be formed.
According to another embodiment of the inven~on, the polymerizable phospholipids correspond to the follow-ing general formula IV
Rl O
~, (CH2 = C - C ~ )n ~ R - PO4H - Z (IV) wherein, ln this case, the polymerizable group is bonded in the apolar region of the r.lolecule. In this general formula IV, the symbols Rl and n have the abovementioned meanings, whilst ~
A) represents an alkyl radical which is at least bifunc-tional and has 6 to 22, preferably 12 to 22, carbon atoms, such as, for example, an alkanediol, amino alcohol or alkanediamine radical;
b) represents the radical of a monosubstituted alkane-, ~ 1 67~33~
diol, amino alcohol or al~anediamine which has 2 to 6carbon atoms, which carry a substituent which has 6 to 22, preferably 12 to 22, carbon atoms and an ester, ether or amide lin~age, and which contains at least one additional amino or alcohol group;
C) represents the radical of a monosubstituted or di-substituted ylycerol derivative which carries substitu-ents as mentioned under ~); or ~) re~resents the radical of a monosubstituted or poly-substituted (nOH-l) polyol which carries substituents as mentioned under B), and Z represents a group of one of the following general formulae 1) to 10) or a hydrogen atom:
1) (CH2)a NH2 wherein a has a value from 2 to 10, 2) -(CH2)b-OH wherein b has a value from 2 to 1~, 3) -(CH2)-(CHOH)c-CH2-OH wherein c has a value from 1 ,CH3 to 4, 4) ~(CH2)X~N~~(CH2)y~OH wherein x and y independently CH3 of one another can assume val-H ues from 2 to 10, 5) -CH2-C-I~H2 COOH
~,~, .~
I ~ ~7~,3~
6) -(CH2)X-N~-(cH2)y NH2 wherein x and y independently CH3 of one another can assume val-ues from 2 to 10, +
7) -(CH2)d-NCH3~2 wherein d denotes an integer from 2 to 10~
8) -(CH )3-N(CH3)2H wherein e denotes an integer from 2 to 10, g) (cH2)f N( 3)3 whereir.-f denotes an integer . from 2 to 10, or 10) ~CH2)g~H wherein g denotes an integer from 2 to 10.
The polymerizable phospholipids aecordiny to the invention can be prepared by introdueing the polymer-izable acrylie aeid or methaerylie acid radieals into the phospholipid or the phospholipid analogue via the partieular aeid ehloride or with the aid of the custom-ary condensation methods, with the formation of the corresponding ~onomeric estes or amides.
This procedure eomprises subjeeting a reaeting acrylic aeid derivative of the following general formula R O
CH2 = C - C - X (V) t 1 ~7~338 in which X represents a halogen atom, a hydroxyl group or another easily replaceable molecular group and Rl re-presents a hydrogen atom or a methyl group, to a conden-sation reaction with a phospholipid of the followi.ng gen-eral formula II
R P04H X ~II) in which R and Z have the abovementioned meanings, in a manner which is known per se.
The condensation reactlon can be carried out in a manner such that the polymerizable functional group is located either in the polar region or in the apolar region of the molecule of the phospholipid or of the phospholipid analogue, resulting in cornpounds of the general formulae III and IV described above.
The polmerizable phospholipids according to the invention can be polymerized by homopolymerization or by copolymerization, with the aid of customary polymeriza-tion inhibitors, such as a,a' azobisisobutyronl;trile, di-benzoyl peroxide, ri.boflavin, a peroxydisulfate and the li~e, to give polyrneric phospholipids of the following general formula VI
- -(R )m ~ (CH2-c )n tR )p - (CH2-C ~ (R )q - (VI) C=O C=O
A A -~ .
I 1 67~338 to which the invention likewise relates. In the above general formula VI, n, Rl and A have the abovementioned meanings, whilst R2 represents the radical of an identi-cal or different copolymerizable monomer and m, p and q independently of one another denote integers with values from U to 6. The radical R2 preferably represents the radical of a copolymerizable acrylor vinyl compound, such as acryIic acid, methacrylic acid, al~yl acrylates or methacrylates with in each case 1 to 22 carbon atoms in the alkyl group, vinyl chloride, vinyl fluoride, vinyl bromide or vinyl esters or vinyl ethers with in each case 1 to 22 carbon atoms in the al~yl group. The degree of polymerization of these polymeric phospholip-ids according to the invention is greater than 10, which corresponds to a lower limit for a molecular weight of about 8,000.
The homopol-ylnerization or copolymerization of the polymerizable phospnolipids according to the inven-tion, with formation or the polymeric phospholipids of the general formula VI described above, can be carried out a) in the absence of solvents (in bul~), b) in homo-geneous solution (solution polymerization) or c) in aqueous emulsion (emulsion polymerization), with the aid of the polymelization initiators described above, and using customary procedures. ~loc~ copolymerization is preferably effected.
I ~ ~783~
~ ecause of their lipid character, the polymeric phospholipids, according to the lnvention, of the gen-eral formula VI described above are capable of forming spontaneously organized structures (vesicles or arti-ficial liposomes) about ~.-05 to 10~ um in size in an aqueous medium. These particles are hollow spheres and are therefore suitable for microencapsulating water-soluble pharmaceutical active compounds or other active compounds Lipophilic substances can lilcewise be con-centrated in such microcapsules if, like cholesterol, for example, they are solubl'e in the hydrophobic part of the polymer.
The inventio~ thus also relates to the use of polymeric phospholipids of the general formula I des-cribed above for the preparation of microcapsules.
From the method point of view, microencapsulat-ion is achieved by polymerization of the polymerizable phospholip.ids of..'che general formula I or III and IV
according to the invention in the presence of the sub-stance to be encapsulated. Methods such as dialysis, centrifugation and column chromatography have proved suitable for purification and isolation of the.loaded microcapsules, ,~ ., ,"~, " :
- .
;: :
I 1 6~33~3 The advantage of the microcapsules of the poly-meric phospholipid of the present invention, which are formed using the polymerizable phospholipids according to the invention, compared with aetificial liposomes of simple lipids is the higher stability of the polymeric phospholipids according to the invention.
The advantage compared with microcapsules of traditional polymeric materials, such as polyamides, lies 1) in the milder method of encapsulation, which takes place in an aqueous medium, so that no two-compollent system with an organic solvent is necessary, and 2) in the fact that the polymeric phospholipids accord-in~ to the invention are very similar to the naturally occurring membrane components, that is to say substan-tial biological degradability is ensured and immunolog-ical indifference is to be expected.
Since the boundary conditions (temperature of less than 60C aqueous rnediurn) can be very gentle, en-capsulation of very sensitive substances, such as en-zymes, is also possible according to the invention.
This results in the possibility of immobilizing enzymes without these having ~o be fixed via covalent bonding.
I 1 67~38 The polymeric phospholipids according to the in-vention are an immobilized lipid matrix and can there-rore be used as adsorbents for lipophilic compounds, for example as a base material for affinity chromatograp.hy or as a stabilizer for lipophilic proteins.
The polymeric phospholipids accordng to the in-vention can also be formed by polymerization in the pre-sence of customary crosslin~ing agents, crosslinked poly-mers being obtained. It is also possible for polymer-iæable phospholipids which have the abovementioned gen-eral formula I ana contain two unsaturated groups suit-able for polymerixation to be employed as crosslinicing agents.
rrhe following examples serve to illustrate the invention further.
Examples 1 to 9 relate to the synthesis of poly-merizable~phospholipids which contain one or more poly-merizable functional groups in the polar molecular reg-ionr Examples 10 to 12 relate to the synthesis of poly-merizable phospholipids which contain one or more poly-merizable functional groups in the apolar mQlecular reg-ion, Examples 13 to 18 relate to the preparation of the polymeric phospholipids according to the invention and Example 19 relates to their use for the preparation of microcapsules.
::
~ 338 Example 1 The polymerizable phospholipids containing acryl-amide groups are obtained by applying the procedure given below.
N-~ethacrylamido-(1,2-dimyristoyl-rac-glycerol-3-phospho-r l)-ethanolamine Y
2 g (2 x 10 2 moles~ of triethylamine are added to 5.4 g (10 2 mole) of 1,2-dimyristoyl-rac-glycerol-3-phosphoryl-ethanolamine in 100 ml of trichloroethylene.
A solution of 2.1 g (1.5 x 10 2 moles) of methacryl chloride in 50 ml of chloroform is added dropwise, whilst cooling with ice and stirring. After the drop-wise addition, stirring of the reaction mixture is con-tinued at room temperature for a further hour; ~there-after the triethylammonium hydrochloride which has pre-cipitated is filtered off and the filtrate is concen-trated to dryness (oil) at 25C in a rotary evaporator.
The residue is treated with 150 ml of saturated aqueous sodium chloride solution and the product is extracted with chloroform. The chloroforrn extract is dried over sodium sulfate and concentrated to 10 ml and the concentrate is discharged onto a silica gel column (Merclc HR 60). Solvent systems CHC13;CH30H;H~O: 1)200:
, .
~ .
15;1; 2) 100:15:1; 3) 65;15:1 (V/V). The purification by column chromatography gives 5.5 g (78~ of theory) of a colorless substance which is still just solid at room temperature.
Example 2 The preparation of the polymerizable phospholip-ids according to the invention which contain acrylate groups is carried out by applying the following proce-dure: ~
Octadecyl-phosphorylqlycerol l!~ono-methacrylate 4.5 g (10 2 mole) of actadecyl-phosphorylglycer-ol are dissolved in 50 ml of trichloroethylenet 2 g (2 x 10 2 moles) of triethylamine are added and the mixture is added dropwise to a solution of 2.1 g (1.5 x 10 2 moles) of methacrylyl chloride ln 50 ml of trichloro-ethylene in the course of 20 minutes, whilst stirring and cooling with ice. After 2 hours, the triethyl-ammonium hydro~chloride formed is filtered off and the filtrate is concentrated to dryness at 30C under a waterpump vacuum in a rotary evaporator. For hydroly-sis, the residue is treated with 200 ml of saturated sodium chloride solution, after which the product is ex-tracted with chloroform. The chloroform phase is dried over sodium sulfate and concentrated , after which the product is purified by column chromatography (silica ~1 , .
'
The polymerizable phospholipids aecordiny to the invention can be prepared by introdueing the polymer-izable acrylie aeid or methaerylie acid radieals into the phospholipid or the phospholipid analogue via the partieular aeid ehloride or with the aid of the custom-ary condensation methods, with the formation of the corresponding ~onomeric estes or amides.
This procedure eomprises subjeeting a reaeting acrylic aeid derivative of the following general formula R O
CH2 = C - C - X (V) t 1 ~7~338 in which X represents a halogen atom, a hydroxyl group or another easily replaceable molecular group and Rl re-presents a hydrogen atom or a methyl group, to a conden-sation reaction with a phospholipid of the followi.ng gen-eral formula II
R P04H X ~II) in which R and Z have the abovementioned meanings, in a manner which is known per se.
The condensation reactlon can be carried out in a manner such that the polymerizable functional group is located either in the polar region or in the apolar region of the molecule of the phospholipid or of the phospholipid analogue, resulting in cornpounds of the general formulae III and IV described above.
The polmerizable phospholipids according to the invention can be polymerized by homopolymerization or by copolymerization, with the aid of customary polymeriza-tion inhibitors, such as a,a' azobisisobutyronl;trile, di-benzoyl peroxide, ri.boflavin, a peroxydisulfate and the li~e, to give polyrneric phospholipids of the following general formula VI
- -(R )m ~ (CH2-c )n tR )p - (CH2-C ~ (R )q - (VI) C=O C=O
A A -~ .
I 1 67~338 to which the invention likewise relates. In the above general formula VI, n, Rl and A have the abovementioned meanings, whilst R2 represents the radical of an identi-cal or different copolymerizable monomer and m, p and q independently of one another denote integers with values from U to 6. The radical R2 preferably represents the radical of a copolymerizable acrylor vinyl compound, such as acryIic acid, methacrylic acid, al~yl acrylates or methacrylates with in each case 1 to 22 carbon atoms in the alkyl group, vinyl chloride, vinyl fluoride, vinyl bromide or vinyl esters or vinyl ethers with in each case 1 to 22 carbon atoms in the al~yl group. The degree of polymerization of these polymeric phospholip-ids according to the invention is greater than 10, which corresponds to a lower limit for a molecular weight of about 8,000.
The homopol-ylnerization or copolymerization of the polymerizable phospnolipids according to the inven-tion, with formation or the polymeric phospholipids of the general formula VI described above, can be carried out a) in the absence of solvents (in bul~), b) in homo-geneous solution (solution polymerization) or c) in aqueous emulsion (emulsion polymerization), with the aid of the polymelization initiators described above, and using customary procedures. ~loc~ copolymerization is preferably effected.
I ~ ~783~
~ ecause of their lipid character, the polymeric phospholipids, according to the lnvention, of the gen-eral formula VI described above are capable of forming spontaneously organized structures (vesicles or arti-ficial liposomes) about ~.-05 to 10~ um in size in an aqueous medium. These particles are hollow spheres and are therefore suitable for microencapsulating water-soluble pharmaceutical active compounds or other active compounds Lipophilic substances can lilcewise be con-centrated in such microcapsules if, like cholesterol, for example, they are solubl'e in the hydrophobic part of the polymer.
The inventio~ thus also relates to the use of polymeric phospholipids of the general formula I des-cribed above for the preparation of microcapsules.
From the method point of view, microencapsulat-ion is achieved by polymerization of the polymerizable phospholip.ids of..'che general formula I or III and IV
according to the invention in the presence of the sub-stance to be encapsulated. Methods such as dialysis, centrifugation and column chromatography have proved suitable for purification and isolation of the.loaded microcapsules, ,~ ., ,"~, " :
- .
;: :
I 1 6~33~3 The advantage of the microcapsules of the poly-meric phospholipid of the present invention, which are formed using the polymerizable phospholipids according to the invention, compared with aetificial liposomes of simple lipids is the higher stability of the polymeric phospholipids according to the invention.
The advantage compared with microcapsules of traditional polymeric materials, such as polyamides, lies 1) in the milder method of encapsulation, which takes place in an aqueous medium, so that no two-compollent system with an organic solvent is necessary, and 2) in the fact that the polymeric phospholipids accord-in~ to the invention are very similar to the naturally occurring membrane components, that is to say substan-tial biological degradability is ensured and immunolog-ical indifference is to be expected.
Since the boundary conditions (temperature of less than 60C aqueous rnediurn) can be very gentle, en-capsulation of very sensitive substances, such as en-zymes, is also possible according to the invention.
This results in the possibility of immobilizing enzymes without these having ~o be fixed via covalent bonding.
I 1 67~38 The polymeric phospholipids according to the in-vention are an immobilized lipid matrix and can there-rore be used as adsorbents for lipophilic compounds, for example as a base material for affinity chromatograp.hy or as a stabilizer for lipophilic proteins.
The polymeric phospholipids accordng to the in-vention can also be formed by polymerization in the pre-sence of customary crosslin~ing agents, crosslinked poly-mers being obtained. It is also possible for polymer-iæable phospholipids which have the abovementioned gen-eral formula I ana contain two unsaturated groups suit-able for polymerixation to be employed as crosslinicing agents.
rrhe following examples serve to illustrate the invention further.
Examples 1 to 9 relate to the synthesis of poly-merizable~phospholipids which contain one or more poly-merizable functional groups in the polar molecular reg-ionr Examples 10 to 12 relate to the synthesis of poly-merizable phospholipids which contain one or more poly-merizable functional groups in the apolar mQlecular reg-ion, Examples 13 to 18 relate to the preparation of the polymeric phospholipids according to the invention and Example 19 relates to their use for the preparation of microcapsules.
::
~ 338 Example 1 The polymerizable phospholipids containing acryl-amide groups are obtained by applying the procedure given below.
N-~ethacrylamido-(1,2-dimyristoyl-rac-glycerol-3-phospho-r l)-ethanolamine Y
2 g (2 x 10 2 moles~ of triethylamine are added to 5.4 g (10 2 mole) of 1,2-dimyristoyl-rac-glycerol-3-phosphoryl-ethanolamine in 100 ml of trichloroethylene.
A solution of 2.1 g (1.5 x 10 2 moles) of methacryl chloride in 50 ml of chloroform is added dropwise, whilst cooling with ice and stirring. After the drop-wise addition, stirring of the reaction mixture is con-tinued at room temperature for a further hour; ~there-after the triethylammonium hydrochloride which has pre-cipitated is filtered off and the filtrate is concen-trated to dryness (oil) at 25C in a rotary evaporator.
The residue is treated with 150 ml of saturated aqueous sodium chloride solution and the product is extracted with chloroform. The chloroforrn extract is dried over sodium sulfate and concentrated to 10 ml and the concentrate is discharged onto a silica gel column (Merclc HR 60). Solvent systems CHC13;CH30H;H~O: 1)200:
, .
~ .
15;1; 2) 100:15:1; 3) 65;15:1 (V/V). The purification by column chromatography gives 5.5 g (78~ of theory) of a colorless substance which is still just solid at room temperature.
Example 2 The preparation of the polymerizable phospholip-ids according to the invention which contain acrylate groups is carried out by applying the following proce-dure: ~
Octadecyl-phosphorylqlycerol l!~ono-methacrylate 4.5 g (10 2 mole) of actadecyl-phosphorylglycer-ol are dissolved in 50 ml of trichloroethylenet 2 g (2 x 10 2 moles) of triethylamine are added and the mixture is added dropwise to a solution of 2.1 g (1.5 x 10 2 moles) of methacrylyl chloride ln 50 ml of trichloro-ethylene in the course of 20 minutes, whilst stirring and cooling with ice. After 2 hours, the triethyl-ammonium hydro~chloride formed is filtered off and the filtrate is concentrated to dryness at 30C under a waterpump vacuum in a rotary evaporator. For hydroly-sis, the residue is treated with 200 ml of saturated sodium chloride solution, after which the product is ex-tracted with chloroform. The chloroform phase is dried over sodium sulfate and concentrated , after which the product is purified by column chromatography (silica ~1 , .
'
9 J ~7~3~
gel Merck HR 60; solvent system CHC13:CH3OH:H2O: 100:
15:1 tV/V). 3.5 g (68% of theory) of a colorless oil which is highly viscous at room temperature are obtained.
Analysis: Octadecyl-phosphorylglycerol mono-methacryl-ate C25H~8~a 7P; MW 514-60 C~ H~ P~
calculated: 58.35 9.40 6.02 found: 58.29 9.30 5.79 Example 3 Octadecyl-phosphoryl-N-methacrylamino-ethanolamine This compound is formed by the procedure of Ex-ample 1, by reacting octadecylphosphorylethanolamine with methacrylyl chloride. The compound is identi-fied by thin layer chromatography.
Er,lpirical formu1a: C24H47NNa O5e; ~W: 483-54 Example 4 1,2-Dipentadecylmethylidene-glycerol-3-phosphoryl-N-acrylamido-ethanolamine The title compound is formed by reacting 1,2-dipentadecylmethylidene-glycerol-3-phosphroyl-ethanol-amine with acrylyl chloride by the procedure in Example 1. .
Empirical formula: C39H75NNaO7P; MS: 723.97 I J 67~33~
C% H~ N% P~
calculated:~4.70 10.44 1.93 4.2~
found: 65.10 10.28 1.89 4.14 Example 5 N-Acrylamido-cephalin The title compound is formed by the procedure of Example 1, by reacting cephalin isolated from eggs with acrylyl chloride. The compound is identified by thin layer chromatography.
Example 6 Octadecylphosphoryl-1,3-propanediol methacrylate The title cornpound is forrned by the procedure of Example 2~ by reacting octadecylphosphoryl-1,3-propane-diol with methacrylyl chloride, Emp rical formula: C25H4~NaO6P; MW; 498.60 C% H% P%
calculated: 60.22 9.70 6.21 found: 58.97 9.4~ 6.02 Example 7 Palmitoyl-1,3-propanediol-phosphoryl-N,N-dimethyl-N-acryloyl)-ethyl~ -ethanolamine The title compound is formed by the procedure of Example 2, and the compound is identified by thin layer chromatography.
1 ~ 67838 --~o--Empirical formula C28H54N8P; i~lW: 563-69 Exarnple 3 1,2-Dimyristolyl-sn-glycerol-3-phosphoryl-1,3-propane-diol methacrylate - The title compound is formed by the procedure of Example 1, by reacting 1,2-diMyristoyl-sn-glycerol-3-phosphoryl-1,3-propanediol with r,lethacrylyl chloride.
The compound is identified by thin layer chromatography.
Empirical formula: C38H70NaO10 ;
Example 9 1,2-Dimyristoyl-sn-glycerol-3-phosphorylglycerol mono-methacrylate The title cornpound is formed by the procedure of Example 2, by reacting 1,2-diMyristoyl-sn-glycerol-3-phosphoryl-glycerol with methacrylyl chloride.
`Empirical formula: C38H70NaOll ;
C% H~ P%
calculated: 60.29 9.32 4.09 found: 59.73 9.22 ~.12 In the following Examples 10 to 12, the polymer-izable radical is introduced into the phospholipid com-pound of the phospholipid analogue by a procedure anala-gous to the procedures given in the above exa~ples, after removal of the protective group (n) by appropriate reactions (hydrogenolysis, acid splitting).
I ~ 6~3~
Example 10 (16-0-Acryloyl)-hexadecanoyl-1,3-propanediol-phosphoryl-choline This compound is formed by reacting 16-hydroxy-hexadecanoyl-1,3-propanediol-phosphorylcholine with acrylyl chloride.
Ernpirical formula: C27Hs2No8o~l~2o; ~ ; 567-69 C%H% N% P%
calculated: 57.129.59 2.47 5.46 found~ 56.92 9.33 - 2.32 S.23 Example 11 1,2-Di-(16-0-acryloyl)-hexadecanoyl-rac-glycerol-3-phos-phorylcholine The title compound is formed by reacting 1,2-di-(16-hydroxy)-hexadecanoyl-rac-glycerol-3-phosphorylchol-ine with acrylyl chloride. The compound is identified by thin layer chrornatography.
Empirical formula: C44H84N012P.H20;
Example 12 (12-l~Jethacryloyl)-octadecanoyl-1,3-propanediol-phosphor-ylcholine The title compound is formed by reacting 12-hydroxystearoyl-1,3-propanediol--phosphorylcholine with methacrylyl chloride. The compound is identified by thin layer chromatography.
.~
~ J 6~38 Empirical formula: C30H58No8o-H2o;
The following Examples 13 to 18 illustrate the preparation of the polymeric phospholipids according to Example 13 B10CK polymerization The general procedure comprises adding 10 to 20 mg (1 to 2% by weight~ of dibenzoy7 peroxide or an equal amount of ~ azoiso~utyronitrile to 1 g of the rnolten monomer (the acryl or methacryl compounds with an alkyl chain are present as highly viscous oils at room ternpera-ture, whilst the compounds with two long-chain alkyl radicals melt in the range between 20 and 50C), whilst stirring. This mixture is then polymerized in a closed reaction vessel under a nitrogen atmosphere at 50 to 60C for 12 to 24 hours. The solid product is comrninuted, and boiled up several times with a chloro-~orm/methanol mixture (1/1, V/V), until no further mono-mer can be detected in the supernatant liquid by thin layer chromatography. The yields are 50 to 95~ of theory, depending on the polymerization temperature and reaction time.
In the abovementioned general procedure, at a polymerization teinperature of 60C and with a polymer-ization time of 30 seconds, using dibenzoyl peroxide as the initiator, poly-(palmitoyl-2,2-dimethyl- 1,3-propane-1 1 67~
diol-phosphorylethanolamino)-methacrylamide is formed in a yield of 87% of theory.
Empirical formula: (C27H51NNaP)p; MW: p. (555 65) C%H~ N% P~
calculated: 5~.25 9.42 2.52 5.56 found: 58.46 8.75 2.20 4.75 Example 14 Solution polymerization Solution polymerization is generally carried out by a procedure in which 1 g of the monomer is dissolved either in 10 ml of dioxane or in 10 ml of ethyl acetete, and 10 mg (1% by weight) of dibenzoyl ~eroxide (or al-ternatively ~,~-azobisisobutyronitrile) are added. The honogeneous solution is then heated to 50C in a closed vessel under a nitrogen atmosphere for 24 hours. The resulting highly viscous solution is then poured into 150 ml of acetone, whereupon the polymeric product is precipitated, and the precipitate is filtered off and dried in a vacuum desiccator. The yields are 70 to 90% of theory.
Poly-(octadecyl-phosphorylglycerol) methacrylate is formed by applying the procedure described above.
Empirical formula: (C25H49O7P);; MW: p. (4~2.64) 1 1 B783~
-2~-C% H% P%
calculated;60.95 10.08b . 25 found: 60,02 9.55 6.23 Example 15 Poly-(1,2-dipalmitoyl-rac-glycerol-3-phosphoryl-1,3-pro~anediol)methacrylate The title compound is formed by the procedure of Example 14.
Empirical formula: ~C42H78NaOl~P) ; ~ p.(797.0) C% H~ P%
calculated: 63.2Y 9.86 3.87 found: 62.57 9.62 3.79 Example 16 Poly-(palmitoyl-2,2-dimethyl-1,3-propanediol-phosphoryl-ethanolaMino)-methacrylamide The title compound is formed by the procedure of Example 14.
Empirical formula: (C27H51NNaO7P)p; MW: p.(555.65) C% H% W% P~
calculated:58.25 9.42 2.52 5,56 found: 57.41 9.06 2.33 4.72 58.88 9.95 4.17 5.61 Example 17 Poly-(1,2-dimyristoyl-sn-glycerol-3-phosphorylethanol-amino)-acrylamide ~`!
..
I J 67~338 The title compound is formed by the procedure of Example 14.
Empirical formula: (C36H67Ni~aO9P~p; ~w p.(712.87) C~ H~ N~ p%
calculated: 60.65 9.62 1.96 4.35 found: 59.99 9.25 2.7S 4.03 Example 18 Emulsion polymerization A) Emulsion polymerization triggered off by heat 5 x 10 4 moles of the monomer are emulsified in 100 ml of aqueous buffer solution (~hosphate buffer with a pH value of 7.0), whilst sha~ing vigorously in a nitrogen atmosphere. 10 to 20 mg of potassium peroxy-disulfate are then added to the emulsion and the flask is flushed again with a vigorous stream of nitrogen and, after being closed, is heated to a temperature of 60C
in a shaking watérbath for 12 to 1~ hours. The pro-gress of the polymerization reaction is followed by thin layer chromatography (solvent system chloroforin/methanol/
25% strength aqueous ammonia (65/15/1)). Chloroform extracts of samples of the aqueous reaction mixture are used for this. The conversion is estimated from the thin layer chromatogram.
~ ~ `
~ 1 67~3fl B) Emulsion polymeri~ation triggered off photochemic-ally 5 x 10 4 moles of the monomer are emulsified in
gel Merck HR 60; solvent system CHC13:CH3OH:H2O: 100:
15:1 tV/V). 3.5 g (68% of theory) of a colorless oil which is highly viscous at room temperature are obtained.
Analysis: Octadecyl-phosphorylglycerol mono-methacryl-ate C25H~8~a 7P; MW 514-60 C~ H~ P~
calculated: 58.35 9.40 6.02 found: 58.29 9.30 5.79 Example 3 Octadecyl-phosphoryl-N-methacrylamino-ethanolamine This compound is formed by the procedure of Ex-ample 1, by reacting octadecylphosphorylethanolamine with methacrylyl chloride. The compound is identi-fied by thin layer chromatography.
Er,lpirical formu1a: C24H47NNa O5e; ~W: 483-54 Example 4 1,2-Dipentadecylmethylidene-glycerol-3-phosphoryl-N-acrylamido-ethanolamine The title compound is formed by reacting 1,2-dipentadecylmethylidene-glycerol-3-phosphroyl-ethanol-amine with acrylyl chloride by the procedure in Example 1. .
Empirical formula: C39H75NNaO7P; MS: 723.97 I J 67~33~
C% H~ N% P~
calculated:~4.70 10.44 1.93 4.2~
found: 65.10 10.28 1.89 4.14 Example 5 N-Acrylamido-cephalin The title compound is formed by the procedure of Example 1, by reacting cephalin isolated from eggs with acrylyl chloride. The compound is identified by thin layer chromatography.
Example 6 Octadecylphosphoryl-1,3-propanediol methacrylate The title cornpound is forrned by the procedure of Example 2~ by reacting octadecylphosphoryl-1,3-propane-diol with methacrylyl chloride, Emp rical formula: C25H4~NaO6P; MW; 498.60 C% H% P%
calculated: 60.22 9.70 6.21 found: 58.97 9.4~ 6.02 Example 7 Palmitoyl-1,3-propanediol-phosphoryl-N,N-dimethyl-N-acryloyl)-ethyl~ -ethanolamine The title compound is formed by the procedure of Example 2, and the compound is identified by thin layer chromatography.
1 ~ 67838 --~o--Empirical formula C28H54N8P; i~lW: 563-69 Exarnple 3 1,2-Dimyristolyl-sn-glycerol-3-phosphoryl-1,3-propane-diol methacrylate - The title compound is formed by the procedure of Example 1, by reacting 1,2-diMyristoyl-sn-glycerol-3-phosphoryl-1,3-propanediol with r,lethacrylyl chloride.
The compound is identified by thin layer chromatography.
Empirical formula: C38H70NaO10 ;
Example 9 1,2-Dimyristoyl-sn-glycerol-3-phosphorylglycerol mono-methacrylate The title cornpound is formed by the procedure of Example 2, by reacting 1,2-diMyristoyl-sn-glycerol-3-phosphoryl-glycerol with methacrylyl chloride.
`Empirical formula: C38H70NaOll ;
C% H~ P%
calculated: 60.29 9.32 4.09 found: 59.73 9.22 ~.12 In the following Examples 10 to 12, the polymer-izable radical is introduced into the phospholipid com-pound of the phospholipid analogue by a procedure anala-gous to the procedures given in the above exa~ples, after removal of the protective group (n) by appropriate reactions (hydrogenolysis, acid splitting).
I ~ 6~3~
Example 10 (16-0-Acryloyl)-hexadecanoyl-1,3-propanediol-phosphoryl-choline This compound is formed by reacting 16-hydroxy-hexadecanoyl-1,3-propanediol-phosphorylcholine with acrylyl chloride.
Ernpirical formula: C27Hs2No8o~l~2o; ~ ; 567-69 C%H% N% P%
calculated: 57.129.59 2.47 5.46 found~ 56.92 9.33 - 2.32 S.23 Example 11 1,2-Di-(16-0-acryloyl)-hexadecanoyl-rac-glycerol-3-phos-phorylcholine The title compound is formed by reacting 1,2-di-(16-hydroxy)-hexadecanoyl-rac-glycerol-3-phosphorylchol-ine with acrylyl chloride. The compound is identified by thin layer chrornatography.
Empirical formula: C44H84N012P.H20;
Example 12 (12-l~Jethacryloyl)-octadecanoyl-1,3-propanediol-phosphor-ylcholine The title compound is formed by reacting 12-hydroxystearoyl-1,3-propanediol--phosphorylcholine with methacrylyl chloride. The compound is identified by thin layer chromatography.
.~
~ J 6~38 Empirical formula: C30H58No8o-H2o;
The following Examples 13 to 18 illustrate the preparation of the polymeric phospholipids according to Example 13 B10CK polymerization The general procedure comprises adding 10 to 20 mg (1 to 2% by weight~ of dibenzoy7 peroxide or an equal amount of ~ azoiso~utyronitrile to 1 g of the rnolten monomer (the acryl or methacryl compounds with an alkyl chain are present as highly viscous oils at room ternpera-ture, whilst the compounds with two long-chain alkyl radicals melt in the range between 20 and 50C), whilst stirring. This mixture is then polymerized in a closed reaction vessel under a nitrogen atmosphere at 50 to 60C for 12 to 24 hours. The solid product is comrninuted, and boiled up several times with a chloro-~orm/methanol mixture (1/1, V/V), until no further mono-mer can be detected in the supernatant liquid by thin layer chromatography. The yields are 50 to 95~ of theory, depending on the polymerization temperature and reaction time.
In the abovementioned general procedure, at a polymerization teinperature of 60C and with a polymer-ization time of 30 seconds, using dibenzoyl peroxide as the initiator, poly-(palmitoyl-2,2-dimethyl- 1,3-propane-1 1 67~
diol-phosphorylethanolamino)-methacrylamide is formed in a yield of 87% of theory.
Empirical formula: (C27H51NNaP)p; MW: p. (555 65) C%H~ N% P~
calculated: 5~.25 9.42 2.52 5.56 found: 58.46 8.75 2.20 4.75 Example 14 Solution polymerization Solution polymerization is generally carried out by a procedure in which 1 g of the monomer is dissolved either in 10 ml of dioxane or in 10 ml of ethyl acetete, and 10 mg (1% by weight) of dibenzoyl ~eroxide (or al-ternatively ~,~-azobisisobutyronitrile) are added. The honogeneous solution is then heated to 50C in a closed vessel under a nitrogen atmosphere for 24 hours. The resulting highly viscous solution is then poured into 150 ml of acetone, whereupon the polymeric product is precipitated, and the precipitate is filtered off and dried in a vacuum desiccator. The yields are 70 to 90% of theory.
Poly-(octadecyl-phosphorylglycerol) methacrylate is formed by applying the procedure described above.
Empirical formula: (C25H49O7P);; MW: p. (4~2.64) 1 1 B783~
-2~-C% H% P%
calculated;60.95 10.08b . 25 found: 60,02 9.55 6.23 Example 15 Poly-(1,2-dipalmitoyl-rac-glycerol-3-phosphoryl-1,3-pro~anediol)methacrylate The title compound is formed by the procedure of Example 14.
Empirical formula: ~C42H78NaOl~P) ; ~ p.(797.0) C% H~ P%
calculated: 63.2Y 9.86 3.87 found: 62.57 9.62 3.79 Example 16 Poly-(palmitoyl-2,2-dimethyl-1,3-propanediol-phosphoryl-ethanolaMino)-methacrylamide The title compound is formed by the procedure of Example 14.
Empirical formula: (C27H51NNaO7P)p; MW: p.(555.65) C% H% W% P~
calculated:58.25 9.42 2.52 5,56 found: 57.41 9.06 2.33 4.72 58.88 9.95 4.17 5.61 Example 17 Poly-(1,2-dimyristoyl-sn-glycerol-3-phosphorylethanol-amino)-acrylamide ~`!
..
I J 67~338 The title compound is formed by the procedure of Example 14.
Empirical formula: (C36H67Ni~aO9P~p; ~w p.(712.87) C~ H~ N~ p%
calculated: 60.65 9.62 1.96 4.35 found: 59.99 9.25 2.7S 4.03 Example 18 Emulsion polymerization A) Emulsion polymerization triggered off by heat 5 x 10 4 moles of the monomer are emulsified in 100 ml of aqueous buffer solution (~hosphate buffer with a pH value of 7.0), whilst sha~ing vigorously in a nitrogen atmosphere. 10 to 20 mg of potassium peroxy-disulfate are then added to the emulsion and the flask is flushed again with a vigorous stream of nitrogen and, after being closed, is heated to a temperature of 60C
in a shaking watérbath for 12 to 1~ hours. The pro-gress of the polymerization reaction is followed by thin layer chromatography (solvent system chloroforin/methanol/
25% strength aqueous ammonia (65/15/1)). Chloroform extracts of samples of the aqueous reaction mixture are used for this. The conversion is estimated from the thin layer chromatogram.
~ ~ `
~ 1 67~3fl B) Emulsion polymeri~ation triggered off photochemic-ally 5 x 10 4 moles of the monomer are emulsified in
10~ ml of a 5 x 10 3~ strength aqueous solution of the di-~a salt of riboflavin. The flask containing the emulsion is temperature-controlled by water flowing round it. The emulsion is then irradiated with a 1000 W
daylight lamp for 30 minutes. During this period, about 80% of the monomer polymer~i~es. The conversion is monitored by thin layer chromatography. The choice of reaction temperature plays an important part in this emulsion polymerization triggered off photochemically.
Using the procedures described above and the monorners given in Examples 14 to 17, the corresponding polymers can be formed.
Example 19 Poly-~octadecylphosphoryl-glycerol) methacrylate micro-capsules containing fluorescein.
2.5 g (~ x 10 3 moles) of octadecylphosphoryl-glycerol mono-methacrylate are dissolved in 100 ml of chlorororm and the material is evaporated to dryness at room temperature under a waterpump vacuum such that the inside of the 1 1 round-bottomed flask is covered with a ~,~
1 ~ ~7838 uniform layer of the monomer. The flasl~ is then char-ged with 500 ml of a 0.1 M sodium chloride solution which contains 165 mg (5 x 10 4 moles) of fluorescein and has been adjusted to a pH value of 7-8 with sodium hydroxide. After adding 50 ml of potassium peroxy-disulfate as an initiator of free radical polymerization (the initiator being employed in an amount of ~%, rela-tive to the monomer) and flushing the flasK with a vigor-ous stream of nitrogen, ~he ~lask is closed tight and the reaction mixture is heated to 60C in a shaking waterbath for ~ hours. 3U ml of the resulting reaction mixture are then transferred, in order to remove the fluorescein which has not been encapsulated, to a dialy-sis tube of regenerated cellulose (which is permeable to substances with a molecular weight of more than 15,000) and the material is dialyzed against four portions of 1 :
1 of 0.1 M sodiu~n chloride solution for 48 hours. The microcapsules obtained in this manner are filled with fluorescein. Their size can be deterTnined by fluores-cent microscopy and by electron microscopy. The diam-eter of these microcapsules is ~.05 to 10 um. It is possible to separate these r,licrocapsules into various size classes by chromatography.
~1 1 1 67~338 -2~-From the above example, it can be clearly seen that, with the aid of the procedure according to the in-vention, it is possible to form stable microcapsules under very mild conditions, so that even sensitive sub-stances, such as enzymes, can be encapsula~ed under gentle conditions, which was not possible with the aid of the hitherto customary formation of microcapsules by interfacial polymerization of polyamides.
, . ' - ' .
daylight lamp for 30 minutes. During this period, about 80% of the monomer polymer~i~es. The conversion is monitored by thin layer chromatography. The choice of reaction temperature plays an important part in this emulsion polymerization triggered off photochemically.
Using the procedures described above and the monorners given in Examples 14 to 17, the corresponding polymers can be formed.
Example 19 Poly-~octadecylphosphoryl-glycerol) methacrylate micro-capsules containing fluorescein.
2.5 g (~ x 10 3 moles) of octadecylphosphoryl-glycerol mono-methacrylate are dissolved in 100 ml of chlorororm and the material is evaporated to dryness at room temperature under a waterpump vacuum such that the inside of the 1 1 round-bottomed flask is covered with a ~,~
1 ~ ~7838 uniform layer of the monomer. The flasl~ is then char-ged with 500 ml of a 0.1 M sodium chloride solution which contains 165 mg (5 x 10 4 moles) of fluorescein and has been adjusted to a pH value of 7-8 with sodium hydroxide. After adding 50 ml of potassium peroxy-disulfate as an initiator of free radical polymerization (the initiator being employed in an amount of ~%, rela-tive to the monomer) and flushing the flasK with a vigor-ous stream of nitrogen, ~he ~lask is closed tight and the reaction mixture is heated to 60C in a shaking waterbath for ~ hours. 3U ml of the resulting reaction mixture are then transferred, in order to remove the fluorescein which has not been encapsulated, to a dialy-sis tube of regenerated cellulose (which is permeable to substances with a molecular weight of more than 15,000) and the material is dialyzed against four portions of 1 :
1 of 0.1 M sodiu~n chloride solution for 48 hours. The microcapsules obtained in this manner are filled with fluorescein. Their size can be deterTnined by fluores-cent microscopy and by electron microscopy. The diam-eter of these microcapsules is ~.05 to 10 um. It is possible to separate these r,licrocapsules into various size classes by chromatography.
~1 1 1 67~338 -2~-From the above example, it can be clearly seen that, with the aid of the procedure according to the in-vention, it is possible to form stable microcapsules under very mild conditions, so that even sensitive sub-stances, such as enzymes, can be encapsula~ed under gentle conditions, which was not possible with the aid of the hitherto customary formation of microcapsules by interfacial polymerization of polyamides.
, . ' - ' .
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a polymerizable phospholipid of the general formula I
(CH2 = ? - ? -) n - A I
wherein n denotes an integer with a value from 1 to 6, R1 denotes a hydrogen atom or a methyl group and A
denotes the radical, bonded via the polar or apolar region of the molecule, of a phospholipid or phospholipid analogue of the general formula II
wherein R represents the liphophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospholipid molecule, in which a reacting acrylic acid derivative of the general formula V
CH2 = ? - ? - X IV
wherein X represents a halogen atom, a hydroxyl group or another easily replaceable molecular group and represents a hydrogen atom or a methyl group, is subjected to a condensation reaction with a phospholipid of the general formula II
in which R and Z are as defined above.
(CH2 = ? - ? -) n - A I
wherein n denotes an integer with a value from 1 to 6, R1 denotes a hydrogen atom or a methyl group and A
denotes the radical, bonded via the polar or apolar region of the molecule, of a phospholipid or phospholipid analogue of the general formula II
wherein R represents the liphophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospholipid molecule, in which a reacting acrylic acid derivative of the general formula V
CH2 = ? - ? - X IV
wherein X represents a halogen atom, a hydroxyl group or another easily replaceable molecular group and represents a hydrogen atom or a methyl group, is subjected to a condensation reaction with a phospholipid of the general formula II
in which R and Z are as defined above.
2. A polymerizable phospholipid as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
3. A process as claimed in claim 1 for the preparation of a polymerizable phospholipid of the formula I as set forth in claim 1 wherein n and R1 are as defined in claim 1 and A represents the radical of a phospholipid which is isolated from naturally occurring material and contains functional groups from which derivatives can be formed (alcohol groups or amino groups).
4. A polymerizable phospholipid of the formula I
as set forth in claim 1 wherein n and R1 are as defined in claim 1 and A is as defined in claim 3, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.
as set forth in claim 1 wherein n and R1 are as defined in claim 1 and A is as defined in claim 3, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 wherein the polymerizable group is bonded in the polar region Z of the phospholipid molecule, of the general formula III
R - P04H - Z - (- ? - ? = CH2)n III
in which R
A) represents the radical of a monohydric, optionally halogenated and/or unsaturated alcohol;
B) represents the radical of a compound formed by monosubstitution of alkanediols, with etherification or esterification;
C) represents the radical of a compound which contains ether groups which are unstable to acid and is formed by monosubstitution of alkanediols, with etherification;
D) represents the radical of a compound which contains ether groups which can be split off by catalytic hydrogenolysis and is formed by monosubstitution of alkanediols, with etherification;
E) represents the radical of a glycerol derivative with two etherified and/or esterified alcohol groups;
F) represents the radical of a glycerol derivative which has two ether groups which are unstable to acid;
G) represents the radical of a glycerol derivative which contains ether groups which can be split off by catalytic hydrogenolysis and, if appropriate, alkyl ether groups;
H) represents the radical of a phenol of which the free hydroxyl groups are etherified or esterified;
I) represents the radical of a phenol of which the free hydroxyl groups have been converted into ether groups which are unstable to acid;
J) represents the radical of a polyol of which the free hydroxyl groups have been converted into ether groups which can be split off by catalytic hydrogenolysis;
or K) represents the radical of a lipophilic alcohol, and Z
denotes a group of the general formula 1) -(CH2)a-NH- in which a has a value from 2 to 10 2) -(CH2)b-O- in which b has a value from 2 to 10 3) -(CH2)-(CHOH)c-CH2-O- in which c has a value from 1 to 4, in which x and y 4) -(CH2)X-?+-(cH2)y-O- independently of one another can assume values from 2 to 10 5) -CH2-?-NH-or in which x and y 6) independently of one another can assume values from 2 to 10 n denotes an integer with a value from 1 to 6 and denotes, a hydrogen atom or a methyl group.
R - P04H - Z - (- ? - ? = CH2)n III
in which R
A) represents the radical of a monohydric, optionally halogenated and/or unsaturated alcohol;
B) represents the radical of a compound formed by monosubstitution of alkanediols, with etherification or esterification;
C) represents the radical of a compound which contains ether groups which are unstable to acid and is formed by monosubstitution of alkanediols, with etherification;
D) represents the radical of a compound which contains ether groups which can be split off by catalytic hydrogenolysis and is formed by monosubstitution of alkanediols, with etherification;
E) represents the radical of a glycerol derivative with two etherified and/or esterified alcohol groups;
F) represents the radical of a glycerol derivative which has two ether groups which are unstable to acid;
G) represents the radical of a glycerol derivative which contains ether groups which can be split off by catalytic hydrogenolysis and, if appropriate, alkyl ether groups;
H) represents the radical of a phenol of which the free hydroxyl groups are etherified or esterified;
I) represents the radical of a phenol of which the free hydroxyl groups have been converted into ether groups which are unstable to acid;
J) represents the radical of a polyol of which the free hydroxyl groups have been converted into ether groups which can be split off by catalytic hydrogenolysis;
or K) represents the radical of a lipophilic alcohol, and Z
denotes a group of the general formula 1) -(CH2)a-NH- in which a has a value from 2 to 10 2) -(CH2)b-O- in which b has a value from 2 to 10 3) -(CH2)-(CHOH)c-CH2-O- in which c has a value from 1 to 4, in which x and y 4) -(CH2)X-?+-(cH2)y-O- independently of one another can assume values from 2 to 10 5) -CH2-?-NH-or in which x and y 6) independently of one another can assume values from 2 to 10 n denotes an integer with a value from 1 to 6 and denotes, a hydrogen atom or a methyl group.
6. A polymerizable phospholipid of the formula I
as defined in claim 1, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
as defined in claim 1, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
7. A process as claimed in claim 5 wherein R
A) represents the radical of hexanol, decanol, hexa-decanol, eicosanol, hexacosanol, cyclohexanol, bromo-l-hexanol, 10-bromo-1-decanol, 16-bromo-1-hexa-decanol or 9-octadecen-1-ol;
B) represents the radical of acetylglycol, ethylglycol, decanoylglycol, decylglycol, hexadecanoylglycol, hexadecylglycol, eicosanoylglycol or eicosylglycol or of a monoacyl or monoalkyl derivative of l,3-propane-diol, 1,2-propanediol, 1,6-hexanediol, l,10-decane-diol or l,16-hexadecanediol, the acyl and alkyl groups of the monoacyl or monoalkyl derivatives each containing 1 to 22 carbon atoms;
C) represents the radical of l-tritylglycol, l-tetra-hydropryanylglycol, l-trityl-1,3-propanediol, 1-K) represents the radical of cholesterol, retinol, and rosterone, ergosterol, a steroid alcohol, an isoprenoid alcohol or a carotenoid alcohol.
A) represents the radical of hexanol, decanol, hexa-decanol, eicosanol, hexacosanol, cyclohexanol, bromo-l-hexanol, 10-bromo-1-decanol, 16-bromo-1-hexa-decanol or 9-octadecen-1-ol;
B) represents the radical of acetylglycol, ethylglycol, decanoylglycol, decylglycol, hexadecanoylglycol, hexadecylglycol, eicosanoylglycol or eicosylglycol or of a monoacyl or monoalkyl derivative of l,3-propane-diol, 1,2-propanediol, 1,6-hexanediol, l,10-decane-diol or l,16-hexadecanediol, the acyl and alkyl groups of the monoacyl or monoalkyl derivatives each containing 1 to 22 carbon atoms;
C) represents the radical of l-tritylglycol, l-tetra-hydropryanylglycol, l-trityl-1,3-propanediol, 1-K) represents the radical of cholesterol, retinol, and rosterone, ergosterol, a steroid alcohol, an isoprenoid alcohol or a carotenoid alcohol.
8. A polymerizable phospholipid of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.
9. A process as claimed in claim 1 for the preparation of a polymerizable phospholipid in which the polymerizable group is bonded in the apolar region R of the molecule, of the general formula IV
(CH2 = ? - ? - )n - R P04H-z IV
in which R
A) represents an alkyl radical which is at least bifunctional and has 6 to 22 carbon atoms;
B) represents the radical of a monosubstituted alkane-diol, amino alcohol or alkanediamine which has 2 to 6 carbon atoms, which carry a substituent which has 6 to 22 carbon atoms and an ester, ether or amide linkage, and which contains at least one additional amino or alcohol group;
C) represents the radical of a monosubstituted or disubstituted glycerol derivative which carries tetrahydropyranyl-1,3-propanediol, 1-trityl-1,6-hexanediol, 1-tetrahydropyranyl-1,6-hexanediol, 1-trityl-l,10-decanediol, l-tetrahydropyranyl-1,10-decanediol, 1-trityl-1,16-hexadecanol or 1-tetra-hydropyranyl-1,16-hexadecanol;
D) represents the radical of 1 benzylglycol, 1-benzyl-1,3-propanediol, 1-benzyl-1,2 propanediol, 1-benzyl-1,6-hexanediol, 1-benzyl-1,10-decanediol or 1-benzyl-1,16-hexadecanediol;
E) represents the radical of 1,2-dimethylglycerol, 1,3-dimethylglycerol, l,2-diacetylglycerol, 1,3-diacetyl-glycerol, 1,2-diethylglycerol or 1,3-diethylglycerol or of the corresponding esters with higher fatty acids, of the corresponding ethers with higher alkyl radicals, or of the corresponding mixed esters, mixed ethers or mixed ester/ether compounds;
F) represents the radical of 1,3-ditritylglycerol or 1,2-isopropylideneglycerol;
G) represents the radical of l-benzyl-2-lauroyl-glycerol, 1-lauroyl-2-benzyl-glycerol, 1-benzyl-2-palmitoyl-glycerol, 1-palmitoyl-2-benzyl-glycerol, 1-benzyl-2-arachoyl-glycerol or 1-arachoyl-2-benzyl-glycerol, or of the corresponding alkyl ethers with low-molecular alkyl groups;
H) represents the radical of erythritol, arabitol, xylitol, adonitol, mannitol, sorbitol or dulcitol;
or substituents as mentioned under B); or D) represents the radical of a monosubstituted or polysubstituted (nOH-l) pvlyol which carries substituents as mentioned under B), and Z denotes a group of the general formula 1) -(CH2)a-NH2 in which a has a value from 2 to 10, 2) -(CH2)b-OH in which b has a value from 2 to 10 3) -(CH2)-(CHOH)c-CH2-OH in which c has a value from 1 to 4, in which x and y 4) -(CH2)x-?+-(CH2)y-OH independently of one another can assume values from 2 to 10, 5) -CH2-1?-HN2 in which x and y 6) -(CH2)X-?+-(CH2)y-NH independently of one another can assume values from 2 to 10, 7) -(CH2)d-?CH3H2 in which d denotes an integer from 2 to 10, 8) -(CH2)e-?(CH3)2H in which e denotes an integer from 2 to 10, 9) -(CH2)f-?(CH3)3 in which f denotes an integer from 2 to 10, 10) -(CH2)g-H in which g denotes an integer from 2 10 10, or 11) a hydrogen atom, n denotes an integer with a value from 1 to 6 and R1 denotes a hydrogen atom or a methyl group.
(CH2 = ? - ? - )n - R P04H-z IV
in which R
A) represents an alkyl radical which is at least bifunctional and has 6 to 22 carbon atoms;
B) represents the radical of a monosubstituted alkane-diol, amino alcohol or alkanediamine which has 2 to 6 carbon atoms, which carry a substituent which has 6 to 22 carbon atoms and an ester, ether or amide linkage, and which contains at least one additional amino or alcohol group;
C) represents the radical of a monosubstituted or disubstituted glycerol derivative which carries tetrahydropyranyl-1,3-propanediol, 1-trityl-1,6-hexanediol, 1-tetrahydropyranyl-1,6-hexanediol, 1-trityl-l,10-decanediol, l-tetrahydropyranyl-1,10-decanediol, 1-trityl-1,16-hexadecanol or 1-tetra-hydropyranyl-1,16-hexadecanol;
D) represents the radical of 1 benzylglycol, 1-benzyl-1,3-propanediol, 1-benzyl-1,2 propanediol, 1-benzyl-1,6-hexanediol, 1-benzyl-1,10-decanediol or 1-benzyl-1,16-hexadecanediol;
E) represents the radical of 1,2-dimethylglycerol, 1,3-dimethylglycerol, l,2-diacetylglycerol, 1,3-diacetyl-glycerol, 1,2-diethylglycerol or 1,3-diethylglycerol or of the corresponding esters with higher fatty acids, of the corresponding ethers with higher alkyl radicals, or of the corresponding mixed esters, mixed ethers or mixed ester/ether compounds;
F) represents the radical of 1,3-ditritylglycerol or 1,2-isopropylideneglycerol;
G) represents the radical of l-benzyl-2-lauroyl-glycerol, 1-lauroyl-2-benzyl-glycerol, 1-benzyl-2-palmitoyl-glycerol, 1-palmitoyl-2-benzyl-glycerol, 1-benzyl-2-arachoyl-glycerol or 1-arachoyl-2-benzyl-glycerol, or of the corresponding alkyl ethers with low-molecular alkyl groups;
H) represents the radical of erythritol, arabitol, xylitol, adonitol, mannitol, sorbitol or dulcitol;
or substituents as mentioned under B); or D) represents the radical of a monosubstituted or polysubstituted (nOH-l) pvlyol which carries substituents as mentioned under B), and Z denotes a group of the general formula 1) -(CH2)a-NH2 in which a has a value from 2 to 10, 2) -(CH2)b-OH in which b has a value from 2 to 10 3) -(CH2)-(CHOH)c-CH2-OH in which c has a value from 1 to 4, in which x and y 4) -(CH2)x-?+-(CH2)y-OH independently of one another can assume values from 2 to 10, 5) -CH2-1?-HN2 in which x and y 6) -(CH2)X-?+-(CH2)y-NH independently of one another can assume values from 2 to 10, 7) -(CH2)d-?CH3H2 in which d denotes an integer from 2 to 10, 8) -(CH2)e-?(CH3)2H in which e denotes an integer from 2 to 10, 9) -(CH2)f-?(CH3)3 in which f denotes an integer from 2 to 10, 10) -(CH2)g-H in which g denotes an integer from 2 10 10, or 11) a hydrogen atom, n denotes an integer with a value from 1 to 6 and R1 denotes a hydrogen atom or a methyl group.
10. A polymerizable phospholipid of the formula I
as defined in claim 1, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.
as defined in claim 1, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803010185 DE3010185A1 (en) | 1980-03-17 | 1980-03-17 | POLYMERIZABLE PHOSPHOLIPIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR THE PRODUCTION OF POLYMER PHOSPHOLIPIDS |
| DEP3010185.0 | 1980-03-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1167838A true CA1167838A (en) | 1984-05-22 |
Family
ID=6097444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000373059A Expired CA1167838A (en) | 1980-03-17 | 1981-03-16 | Polymerizable phospholipids and a process for their preparation, polymeric phospholipids and a process for their preparation, and the use of the polymeric phospholipids |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0036155A3 (en) |
| JP (1) | JPS56152816A (en) |
| CA (1) | CA1167838A (en) |
| DE (1) | DE3010185A1 (en) |
| ES (2) | ES500259A0 (en) |
| IL (1) | IL62369A0 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5648442A (en) * | 1991-07-05 | 1997-07-15 | Biocompatibles Limited | Polymeric surface coatings |
| US6090901A (en) * | 1991-07-05 | 2000-07-18 | Biocompatibles Limited | Polymeric surface coatings |
| US6420453B1 (en) | 1990-10-29 | 2002-07-16 | Biocompatibles Limited | Contact lens material |
| US6743878B2 (en) | 1991-07-05 | 2004-06-01 | Biocompatibles Uk Limited | Polymeric surface coatings |
| CN103917548A (en) * | 2011-06-24 | 2014-07-09 | 生物相互作用有限公司 | Biocompatible, biomimetic ampholyte materials |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60179408A (en) * | 1984-02-24 | 1985-09-13 | Oki Electric Ind Co Ltd | Compound having phospholipid-like structure and its polymer and production thereof |
| JPS61155336A (en) * | 1984-12-28 | 1986-07-15 | Terumo Corp | Medical carrier |
| AU559292B2 (en) * | 1984-12-28 | 1987-03-05 | Terumo Kabushiki Kaisha | Polymerisable liposome-forming lipids |
| US4736051A (en) * | 1985-03-20 | 1988-04-05 | Kao Corporation | Process for the preparation of an alkali metal salt of a diester phosphoric acid |
| JPS61215398A (en) * | 1985-03-20 | 1986-09-25 | Kao Corp | Phosphoric ester |
| DE3623068A1 (en) * | 1985-07-12 | 1987-01-22 | Kao Corp | POLYMERS AND COPOLYMERS CONTAINING A PHOSPHATE GROUP AND PROCESS FOR THEIR MANUFACTURING |
| JPS638391A (en) * | 1986-06-27 | 1988-01-14 | Terumo Corp | Polymerizable beta-glycerophospholipid and production thereof |
| JPS63222185A (en) * | 1987-03-11 | 1988-09-16 | Oki Electric Ind Co Ltd | Compound having phospholipid analogous structure, polymer and production thereof |
| JPS6386704A (en) * | 1987-05-21 | 1988-04-18 | Oki Electric Ind Co Ltd | Polymer from compound having phospholipid-like structure |
| JPH04283207A (en) * | 1991-03-13 | 1992-10-08 | Kao Corp | Vesicle and polymer vesicle |
| US5466853A (en) * | 1992-07-23 | 1995-11-14 | Nof Corporation | Diester monomer, its polymer, water-containing soft contact lens, and processing solution for contact lens |
| GB9301701D0 (en) * | 1993-01-28 | 1993-03-17 | Biocompatibles Ltd | New zwitterionic materials |
| FR2717427B1 (en) * | 1994-03-17 | 1996-04-19 | Renault | Motor vehicle air conditioning system. |
| WO2021107141A1 (en) * | 2019-11-29 | 2021-06-03 | 国立大学法人徳島大学 | Zwitterion compound and production method and use for same |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6021599B2 (en) * | 1977-10-28 | 1985-05-28 | 株式会社クラレ | 2-methacryloxyethylphosphorylcholine |
-
1980
- 1980-03-17 DE DE19803010185 patent/DE3010185A1/en not_active Withdrawn
-
1981
- 1981-03-07 EP EP81101675A patent/EP0036155A3/en not_active Withdrawn
- 1981-03-11 ES ES500259A patent/ES500259A0/en active Granted
- 1981-03-11 ES ES500256A patent/ES500256A0/en active Granted
- 1981-03-15 IL IL62369A patent/IL62369A0/en unknown
- 1981-03-16 CA CA000373059A patent/CA1167838A/en not_active Expired
- 1981-03-17 JP JP3736481A patent/JPS56152816A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6420453B1 (en) | 1990-10-29 | 2002-07-16 | Biocompatibles Limited | Contact lens material |
| US6423761B1 (en) | 1990-10-29 | 2002-07-23 | Biocompatibles Limited | Contact lens material |
| US5648442A (en) * | 1991-07-05 | 1997-07-15 | Biocompatibles Limited | Polymeric surface coatings |
| US5783650A (en) * | 1991-07-05 | 1998-07-21 | Biocompatibles Limited | Polymeric surface coatings |
| US6090901A (en) * | 1991-07-05 | 2000-07-18 | Biocompatibles Limited | Polymeric surface coatings |
| US6743878B2 (en) | 1991-07-05 | 2004-06-01 | Biocompatibles Uk Limited | Polymeric surface coatings |
| US7160953B2 (en) | 1991-07-05 | 2007-01-09 | Biocompatibles Uk Limited | Polymeric surface coatings |
| CN103917548A (en) * | 2011-06-24 | 2014-07-09 | 生物相互作用有限公司 | Biocompatible, biomimetic ampholyte materials |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0036155A2 (en) | 1981-09-23 |
| IL62369A0 (en) | 1981-05-20 |
| ES8201590A1 (en) | 1981-12-16 |
| DE3010185A1 (en) | 1981-09-24 |
| ES8201591A1 (en) | 1981-12-16 |
| ES500256A0 (en) | 1981-12-16 |
| JPS56152816A (en) | 1981-11-26 |
| EP0036155A3 (en) | 1982-01-20 |
| ES500259A0 (en) | 1981-12-16 |
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