Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2001-06-08
2004-02-24
Nguyen, Dave T. (Department: 1632)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C548S413000, C514S023000, C514S025000, C514S04400A, C536S117000, C536S018700, C549S006000
Reexamination Certificate
active
06696081
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to lipid compositions. More particularly, the present invention relates to lipid compositions comprising a carbohydrate backbone, and to supramolecular structures comprising the same. In a preferred embodiment, the lipid composition further comprises a phospholipid.
Table of Abbreviations
Å
angstrom(s)
aq
aqueous
CF
carboxyfluorescein
CBZ
carbobenzoxy group
CH
2
Cl
2
methylene chloride
cm
centimeter(s)
13
C-NMR
carbon 13-
nuclear magnetic resonance
COPD
chronic obstruction pulmonary
disease
COSY
correlation spectroscopy
DAPC
methyl-2,3-di-O-arachadonyl-b-D-
5-phosphocholine
DARPC
methyl-2,3-di-O-arachadonyl-b-D-
ribo-5-phosphocholine
DCC
dicyclohexylcarbodiimide
dd
double deionzied
dev
deviation
DI
deionized
DLPA
dilauroyl phosphatidic acid
DLPC
1,2-dilauroyl-sn-glycero-3-
phosphocholine
DLR-Lys
1-methoxy-2,3-dilauroyl-ribo-5
lysine
DLRPA
bis-(2,3-lauroyl)-1-methoxy-5-ribo-
phosphatidic acid
DLRPC
methyl-2,3-di-O-lauroyl-b-D-ribo-5-
phosphocholine
DMAP
dimethylaminopyridine
DMF
dimethyl furan
DMPC
dimyristyl phosphocholine
DMRPC
methyl-2,3-di-O-myristoyl-b-D-ribo-
5-phosphocholine
DPPC
dipalmitoylphosphatidyl-choline
DPTS
4-dimethylaminopyridium-p-
toluenesulfate
EtAc
ethyl acetate
g
gram
h or hr or hrs
hour(s)
hex
hexane
HMQC
Heteronuclear Multiple-Quantum
Correlation
1
H-NMR
hydrogen 1-
nuclear magnetic resonance
Hz
Hertz
ILD
interstitial lung disease
J
Joule
kcal
kilocalorie(s)
L
&agr;
liquid crystalline
L
&bgr;
lamellar gel
M
Molar
m
meter
MeOH
methyl alcohol
MDSC
modulated differential scanning
calorimetry
MHz
Megahertz
Min
minute
Mg
milligram(s)
mL
milliliter(s)
mm
millimeter(s)
mmol
millimolar
mol %
mole percent
MRI
magnetic resonance imaging
MS
mass spectroscopy
N
Normal
nm
nanometer(s)
P
&bgr;
rippled gel
PBS
phosphate buffered saline
PEG
polyethylene glycol
PET
positron emission tomography
PLA
2
phospholipase A
2
31
P-NMR
phosphorus 31-
nuclear magnetic resonance
ppm
parts per million
PSI
pounds per square inch
Pyr
pyrimidine
Rpm
revolutions per minute
std
standard
t
time
THF
tetrahydro furan
TLC
thin layer chromatography
T
m
phase-transition temperature
TrCl
trityl chloride
BACKGROUND ART
A lipid compound, including particularly a phospholipid compound, typically comprises a hydrophilic head group, a lipophilic tail group, a backbone, and linker moieties between the head group and backbone and tail group and backbone, respectively. The most common backbone for a phospholipid, including particularly naturally occurring phospholipids, is a glycerol backbone.
In the art, many different variations of phospholipids have been synthesized by changing linkers, head groups and tail groups. See e.g. U.S. Pat. No. 4,426,330 to Sears; Thomas, B. N.; et al.,
J. Am. Chem. Soc.
1998, 120, 12178-12186; Srisiri, W.; et al.,
J. Am. Chem. Soc.
1996, 118, 11327-11328. The glycerol backbone of a phospholipid compound has also been modified. Two major classes of non-glycerol-based synthetic phospholipids exist in the art, the phosphonolipids and the cyclopentane-based phospholipids. See e.g. Engel, R.
Chem. Rev.
1977, 77, 349-367; Bittman, R. Chemical Synthesis of glycerophospholipds and their analogs; Bittman, R., Ed.; CRC Press: Boca Raton, Fla., United States of America, 1999, pp 185-207. These modified phospholipids exhibit different physical properties from their glycerol-based analogs, indicating the importance of backbone on bilayer structure. Thus, the preparation and characterization of lipids having modified backbones represents an ongoing need and effort in the art.
Phospholipid structure plays an important role in determining the supramolecular structures formed in solution. Israelachvili, J. N.
Intermolecular and Surface Forces
; Academic Press Inc.: San Diego, 1992. Specifically, the hydrophilic charged head and hydrophobic tail(s) groups influence the supramolecular and bilayer structure formed, as well as the physical and mechanical properties of these bilayers. For example, the properties of negatively charged phospholipids and their corresponding supramolecular structures can also be dependent upon environmental conditions such as pH and cation concentration. Van Dijck, P. W. M.; et al.,
Biochim. Biophys. Acta.
1978, 512, 84-96. Bilayer structures formed from anionic phospholipids are also dependent on the chemical constituents of the amphiphilic compound as demonstrated by anionic phospholipids containing a cyclopentane or a dipenta-decylmethylidene backbone instead of glycerol. Ahmad, T. Y.; et al.,
Chem. Phys. Lipids
1990, 55, 231-243; Blume, A.; Eibl, H.
Biochim. Biophys. Acta.
1981, 640, 609-618.
Three conformational changes occur in a bilayer membrane at the critical gel-liquid crystalline phase-transition temperature (T
m
): rotational isomers from all-trans to multiple gauche in the tails of the molecule, rapid lateral diffusion within the bilayer membrane, and bilayer area expansion. All three of these factors are important in establishing the phase-transition temperature. For example, electrostatic interactions affect bilayer area. With an increase in phospholipid charge, inter-phospholipid repulsions increase, yielding an increase in bilayer area, and a decrease in T
m
. Trauble, H.; Eibl, H.
Proc. Nat Acad. Sci. USA
1974, 71, 214-219. Variations in pH are also known to alter the T
m
, and this effect is particularly significant in those pH regions similar to the pKa's of the head group. Sensitivity to the aqueous solution in which the bilayer resides is important physiologically, since changes in pH and ion concentration alter bilayer physical properties. Van Dijck, P. W. M.; et al.,
J. Biochim. Biophys. Acta.
1978, 512, 84-96. The manipulation of these and other characteristics and variables in a supramolecular structure composition comprising a phospholipid thus represents an ongoing research effort and unsolved problem in the art.
This present invention pertains to a unique class of lipids where the glycerol backbone is replaced with a carbohydrate. In a series of preferred embodiments, zwitterionic, anionic, and cationic carbohydrate-based phospholipids were synthesized and characterized, and novel functionalities were observed. Thus, the present invention meets a long-felt and continuing need in the art for a novel lipid compound, a novel supramolecular structure comprising the same, and for methods of making and using the same.
SUMMARY OF THE INVENTION
A lipid compound comprising:
Formula (I),
where each carbon of C
n+1
and C
1
to C
n
is a stereochemical center; each carbon of C
1
to C
n
is a member of a heterocyclic ring containing M; n=4, 5, 6 or 7; R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are the same or different, and are selected from the group consisting of H, OH, amine, thiol, methoxy, straight or branched chain ester of 6-50 carbon atoms, straight or branched chain silane of 6-50 carbon atoms, straight or branched chain amide of 6-50 carbon atoms, straight or branched chain urea of 6-50 carbon atoms, straight or branched chain urethane of 6-50 carbon atoms, straight or branched chain carbonate of 6-50 carbon atoms, straight or branched chain sulfate of 6-50 carbon atoms, straight or branched chain thiol-urethane of 6-50 carbon atoms, straight or branched chain phosphate of 6-50 carbon atoms, straight or branched chain amine of 6-50 carbon atoms, straight or branched chain thio-urea of 6-50 carbon atoms, straight or branched chain thio-ether of 6-50 carbon atoms, straight or branched chain thio-ester of 6-50 carbon atoms, straight or branched chain ether of 6-50 carbon atoms, and any combination thereof, wherein the chain is fully saturated, fully unsaturated or any combination thereof; M and X
1
the same or different and are O, S, or N—R
7
, wherein R
7
is H, a lower alkane, a chain as recited for R
1
, R
2
, R
3
, Se or any isoelectronic species of oxygen and a=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; X
2
is phosphonate, phosphate, boronophosphate, thiophosphate, or selenophosphate and b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; X
3
=m
Grinstaff Mark W.
Hird Geoffrey S.
Duke University
Jenkins & Wilson & Taylor, P.A.
Nguyen Dave T.
Schnizer Richard
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