Phosphatidyl oligoglycerols

Details Phosphatidyl oligoglycerols Phosphatidyl oligoglycerols

1998-11-20

2002-07-02

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C428S402200, C514S075000, C554S078000, C554S079000, C264S004100, C264S004300

Reexamination Certificate

active

06413543

ABSTRACT:

The invention relates to phosphatidyl compounds which contain a defined hydrophilic residue, and to long-circulating liposomes.
Conventional liposomes circulate in the serum for up to 5 hours. However, especially when liposomes are used as a means of drug delivery, it is desirable that they circulate in the bloodstream for as long as possible.
To this end, the so-called “stealth liposomes” were developed, which are not destroyed in the bloodstream so quickly. These “stealth liposomes” are built up on the basis of phosphatidyl compounds which have an extended polyethylene glycol residue. The polyethylene glycol residue proved to be most effective in producing the desired increase in liposome survival duration when the molecular weight was between 2000 and 3000. A serious disadvantage, however, of these “stealth-liposomes”, ie, of these phosphatidyl compounds with a polyethylene glycol residue, is that the compounds are not exactly defined, since the polyethylene glycol residues display different chain lengths.
Maruyama et al. (Int. J. Pharmac. 111 (1994), 103-107) suggested the use of dipalmitoyl phosphatidyl polyglycerols to lengthen the duration of liposome circulation. However, since technical-grade polyglycerols were used as starting material, no uniform products were obtained here either. Technical polyglycerols, which consist of a mixture of polyglycerols with different chain lengths and monoglycerol, and which are characterized by their average molecular weight, were phosphatidylated by means of phospholipase D. The resulting products only led to a small increase in the survival duration of liposomes in the blood.
The object of this invention was thus to provide compounds which increase the survival duration of liposomes and which are of exactly definable composition.
This objective is established according to the invention by means of a compound with the general formula (A)
where
R
1
and R
2
, independent of each other, stand for hydrogen or a saturated or unsaturated alkyl or acyl residue, which may be branched and/or substituted, R
3
stands for hydrogen or an alkyl residue,
n=0 or 1,
x is a whole number from 1 to 4 and
m is a whole number from 2 to 10 if n=0, or a whole number from 1 to 10 if n=1, or 1 if x is greater than 1,
and where, in the case that n=0, the compound is more than 90% uniform with respect to the value of m.
The stepwise synthesis—upon which this invention is based—of the hydrophilic residues of the phosphatidyl compounds of formula (A) makes it possible to obtain compounds of an exactly defined composition.
The compound of the invention, with the formula (A), is thus not a mixture of various molecules of indefinite composition and chain length, but can be synthesized to have precisely the desired structure. If, for example, the desired product is a triglycerol derivative, ie, x=1 and m=3 in formula (A), the content of monoglycerol, diglycerol, tetraglycerol and higher oligoglycerol derivatives will be low. It is preferable if a glycerol derivative of a certain chain length is obtained that is largely free of glycerol derivatives of other chain lengths. The content of monoglycerol derivatives, in particular, is low, amounting to less than 5%, preferably less than 1% or, even more preferably, less than 0.1% relative to the desired oligoglycerol derivative.
According to the invention, the compound of formula (A) is a uniform compound of defined structure. It is of advantage if, with respect to the value of m, the compound is greater than 95% uniform. It is to greater advantage if it is more than 99% uniform. It is even possible to provide a compound which is more than 99.9% uniform with respect to the value of m.
The compound is preferably an oligoglycerol derivative with 2 to 5 glycerol units, more preferably with 2 to 4 glycerol units. It is to advantage if these are 1.3-linked linear oligoglycerol residues.
According to the invention, the residues R
1
and R
2
, independent of each other, stand for hydrogen, a saturated or unsaturated C
1
-C
24
alkyl or C
1
-C
24
acyl residue, preferably hydrogen or a saturated or unsaturated C
8
-C
24
alkyl or C
8
-C
24
acyl residue, it being beneficial if it at least one of the residues R
1
and R
2
is an acyl residue.
The residue R
3
is preferably hydrogen or an alkyl residue with 1 to 4 carbon atoms.
The compound of formula (A) can be a racemic compound which contains a phospho-rac-(1 or 3)-oligoglycerol linkage, or it can be in the form of a stereospecific isomer. The stereoisomers can have a phospho-sn-1-oligoglycerol linkage or a phospho-sn-3-oligoglycerol linkage. The formation of the stereospecific linkage can be carried out in a manner analogous to those described in the literature (DE 31 30 867 A1; H. Eibl et al., Chem. Phys. Lipids, 28 (1981), 1-5, 41 (1986), 53-63 and 47 (1988, 47-53).
The subject matter of the invention also includes liposomes which contain phospholipids and/or alkyl phospholipids, maybe cholesterol, and 1 to 50 mol % of a compound with the general formula (A),
or salts thereof, where the cholesterol, the phospholipids, the alkyl phospholipids and the compound of formula (A) together make up 100 mol %, and R
1
and R2, independent of each other, stand for hydrogen, a saturated or unsaturated alkyl or acyl residue which may be branched and/or substituted,
R
3
stands for hydrogen or an alkyl residue,
n=0 or 1,
x is a whole number from 1 to 4 and
m is a whole number from 2 to 10 if n=0, or a whole number from 1 to 10 if n=1, or 1 if x is greater than 1, and where, in the case that n=0, the compound (A) is more than 90% uniform in respect of the value of m.
The liposomes of the invention have a half-life in serum of up to 18 to 20 hours. Surprisingly, the liposome concentration in blood was found to decrease linearly.
It is beneficial according to the invention if compound (A) displays a uniformity of more than 95% or, even better, more than 99% with respect to the value of m. It is also possible, however, to use compound (A) in practically pure form, ie, more than 99.9% uniform with respect to the value of m.
The liposomes preferably contain a compound of formula (A), in which x=1 and m is a whole number from 2 to 5; it is even more preferable if m is a whole number from 2 to 4.
The residues R
1
and R
2
of the compound of formula (A) contained in the liposomes can stand, independent of each other, for hydrogen or a saturated or unsaturated C
1
-C
24
alkyl or C
1
-C
24
acyl residue, preferably hydrogen or a saturated or unsaturated C
8
-C
24
alkyl or C
8
-C
24
acyl residue. The substituent is a residue which does not interfere during the preparation. R
3
is preferably hydrogen or a C
1
-C
4
alkyl residue.
The compound of formula (A) can be present in the liposomes as a racemic mixture, ie, with a phospho-rac-(1 or 3)-oligoglycerol linkage. It is preferable if it is present in stereospecific form with a phospho-sn-1-oligoglycerol linkage or a phospho-sn-3-oligoglycerol linkage.
It is to advantage if at least one of the residues R
1
and R
2
of formula (A) is an acyl group.
It is beneficial if liposomes containing the compound of formula (A) with n=0 exhibit an excess negative charge. However, liposomes can also be prepared from compounds of formula (A) in which n=1. In this case, it is better if the liposomes exhibit no excess charge or a positive one.
Besides a compound of formula (A), the liposomes contain phospholipids and/or alkyl phospholipids and maybe cholesterol. It is preferable to use the compound of formula (A) in an amount of 5 to 15 mol %. If the liposomes do not display an excess charge, a composition of 0 to 70 mol % cholesterol, 1 to 50 mol % of a compound of formula (A), and phospholipids and/or alkyl phospholipids is preferred. If there is a negative excess charge, a preferred liposome composition consists of 0 to 70 mol % cholesterol, 1 to 15 mol % of a compound of formula (A), and phospholipids and/or alkyl phospholipids. A higher proportion of compounds of fo

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