Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-10-21
2001-12-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S450000, C424S451000, C424S078080, C514S937000, C514S969000
Reexamination Certificate
active
06328988
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new hyperbranched colloidal polymers with micellar properties. The polymers comprise a mucic acid, alkyl chains and poly(ethylene glycol). Hydrophobic molecules encapsulated within these polymeric micelles are thermodynamically stable in aqueous solutions, suspensions, dispersions, emollients, lotions, creams, salves, balms and ointments at ambient, refrigerated and elevated temperatures. Further, these polymers have been found to stabilize liposomes and other lipid based structures used routinely in these types of formulations for extended periods of time such that precipitation is prevented and optical transparency is maintained. While the polymers of the present invention can be used to encapsulate and deliver any hydrophobic molecule, these colloids are particularly useful in delivery of hydrophobic drugs via various routes and in the topical delivery of hydrophobic molecules used routinely in cosmetics, toiletries, fragrances, perfumes, skin care products and beauty aids. Such hydrophobic molecules include, but are not limited to, dyes, proteins, vitamins and fragrances.
BACKGROUND OF THE INVENTION
Micelles are a class of surfactants that form organized structures, referred to as colloidal spheres, in aqueous media. The hydrophobic shell of micelles makes the entire assembly water-soluble while the lipophilic core solubilizes hydrophobic molecules. Attempts have been made to use micelles in drug delivery applications because the lipophilic core serves as a microcontainer for drugs, thereby segregating the drugs from the outer environment by the hydrophilic segments. Micelles or colloids encapsulate the drug, shielding the body from potentially toxic levels of drug while simultaneously protecting the drug from inactivating agents in the blood and lymphatic system. Thus, solubilization of water-insoluble drugs by micelles has long been investigated as a means for improving solubility for drug delivery, in particular for parenteral or oral administration, and also for ophthalmic, topical, rectal and nasal delivery (Florence, A. Techniques of Solubilization of Drugs, Ed. Yalkowsky, S. (New York: Marcel Dekker, 1981); Atwood, D. and Florence, A. T. Pharmaceutical Aspects of Solubilization, Surfactant Systems. Their Chemistry, Pharmacy and Biology, (London: Chapman Hall, 1983):293-387).
However, the formation of micelles is both temperature- and concentration-dependent. The concentration dependency is defined as the critical micelle concentration or CMC. Thus, after micelles are injected into the bloodstream, they begin to equilibrate between the micellar, colloidal structure and individual surfactant molecules. Because of the change in micellar structure and size, control over the release of drugs within the micellar microcontainer cannot be maintained for long periods. Typically drug is released over a period of hours and this release is often inconsistent over this period. Thus, the thermodynamic equilibrium between surfactant and micelles may ultimately cause serious toxicity problems due to potentially large fluctuations in drug concentrations accompanied by the breakdown in micellar structure into surfactant molecules. This dilution is particularly large after oral and intravenous administration and can cause unwanted precipitation of hydrophobic drugs.
Thus, while micelles are frequently evaluated for use as drug delivery systems, there are only a few products on the market that are considered practical. This is due to the eventual aggregation and/or precipitation of drugs resulting from equilibration of micelles back to the monomer and the solubilization capacity being too low to be of practical use.
Attempts have been made to design non-ionic surfactants such as poly(ethylene oxide) containing molecules with improved solubilization characteristics. An early approach involved the production of large micellar systems. However, despite the increased micelle size, solubilization decreased with the longer hydrophobic chains. This decrease was attributed to deleterious changes in the poly(ethylene oxide) chains nearest to the core, the main locus of solubilization for most drugs (Elworthy, P. and Patel, M. J. Pharm. Pharmacol. 1982 34:543).
Liu et al. (Polym. Preprint., 1997 38(2):582-583) report the synthesis of a single species of hyperbranched polymeric micelles for encapsulation of small hydrophobic organic molecules. This species contains no divalent amino acid moiety. Instead, this species comprises a 1,1,1-tris(hydroxyphenyl)ethane moiety and an acylated mucic acid moiety as the divalent dicarboxylic moiety. There remains a need for suitable delivery systems for the administration of hydrophobic molecules.
SUMMARY OF THE INVENTION
This need is met by the present invention. The present invention provides new hyperbranched polymer micelles that are useful for solubilizing hydrophobic molecules in water thus greatly simplifying the preparation of aqueous formulations for delivery of such molecules.
Therefore, according to one aspect of the present invention, a polymer is provided having a structure selected from:
R(—O—R
1
)
x
and R(—NH—R
1
)
x
,
wherein R(—O—)
x
, is a polyol moiety and R(—NH—)
x
, is a polyamine moiety, with x being between 2 and 10, inclusive, and each R
1
independently has the structure:
wherein
is a divalent amino acid moiety with R
2
being a covalent bond or having from 1 to 8 carbon atoms, and y and z are between 0 and 10, inclusive, provided that y and z are not both 0;
wherein
is a divalent dicarboxylic acid moiety in which R
3
is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms substituted with a total of from 1 to about 10 hydroxyl groups, with at least a portion of the hydroxyl groups being acylated with 3 to 24 carbon atom carboxylic acids; and
wherein R
4
is a poly(alkylene oxide) having the structure:
R
5
—(—R
6
—O—)
a
—R
6
—Q—
with R
5
being selected from 1 to 40 carbon atom alkyl groups, —OH, —OR
7
—, NH
2
, NHR
7
, NR
7
R
8
, —C—OH, —C—OR
7
, —C—O—C—R
7
, —C—NH
2
, C—NHR
7
, C—NR
7
, C—NR
7
R
8
;
R
6
, R
7
and R
8
being independently selected from 2 to 40 carbon atom, straight chain or branched alkylene groups; Q being a divalent linkage moiety; and a being between 2 and 110, inclusive;
with the proviso that when y is zero and R is a 1,1,1-tris(hydroxyphenyl)ethane moiety, the divalent dicarboxylic moiety is not an acylated mucic acid moiety.
The polymers of the present invention encapsulate a wide variety of hydrophobic molecules. The encapsulation is a physical encapsulation, and not a simple association of the hydrophobic molecule with the polymer. According to a preferred embodiment of the present invention, upon formation of the encapsulated hydrophobic molecule, the polymer is recovered and rinsed to remove any residue of non-encapsulated hydrophobic molecules.
Therefore, according to another aspect of the present invention, a hydrophobic molecule encapsulated in a polymer is provided, wherein the polymer has a structure selected from:
R(—O—R
1
)
x
, and R(—NH—R
1
)
x
wherein R(—O—)
x
is a polyol moiety and R(—NH—)
x
is a polyamine moiety, with x being between 2 and 10, inclusive, and each R
1
independently has the structure:
wherein
is a divalent amino acid moiety with R
2
being a covalent bond or having from 1 to 8 carbon atoms, and y and z are between 0 and 10, inclusive, provided that y and z are not both 0;
wherein
is a divalent dicarboxylic acid moiety in which R
3
is an alkylene or cycloalkylene group containing from 1 to about 15 carbon atoms substituted with a total of from 1 to about 10 hydroxyl groups, with at least a portion of the hydroxyl groups being acylated with 3 to 24 carbon atom carboxylic acids; and
wherein R
4
is a poly(alkylene oxide) having the structure:
R
5
—(—R
6
—O—)
a
—R
6
—Q—
with R
5
being selected from 1 to 40 carbon atom alkyl groups, —OH, —OR
7
, —NH
2
, —NHR
7
, —NR
7
R
8
, —C—OH, —C—OR
7
, —C—O—C—R
7
, —C—NH
2
, —C—NHR
7
and —C—NR
7
R
8
;
R
6
, R
7
and R
8
being in
Fubara Blessing
Page Thurman K.
Rutgers The State University of New Jersey
Schwegan, Lundberg, Woessner & Kluth, P.A.
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