Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Polymer from ethylenic monomers only
Reexamination Certificate
1999-04-23
2002-04-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Polymer from ethylenic monomers only
C424S078350, C424S078370, C424S045000, C424S451000, C424S443000, C424S464000, C424S434000, C424S449000, C424S489000, C514S772400, C514S772600
Reexamination Certificate
active
06365146
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the encapsulation of hydrophobic molecules within polymeric micelles, and, in particular, to the encapsulation of materials such as biologically or pharmaceutically active hydrophobic molecules. The present invention further relates to pharmaceutical dosage forms comprised of thermodynamically stable aqueous solutions, suspensions or dispersions of the polymeric micelle encapsulated, biologically or pharmaceutically active, hydrophobic molecules. The present invention also relates to treatment methods employing the pharmaceutical dosage forms of the present invention.
SUMMARY OF THE INVENTION
The efficacy of pharmaceuticals is strongly affected by the way they are administered. There are many problems associated with the introduction of free drugs into the bloodstream. first, many drugs are deactivated when delivered in the free form. Although deactivation mechanisms can be quite complicated, interactions between drugs and components in the bloodstream (e.g., proteins and enzymes, as well as water) are the most common factors. Second, free drugs frequently have short circulation times (i.e., minutes) and are quickly excreted from the body. Third, free drugs are often distributed randomly among organs and tissues. The inability of most drugs to discriminate between normal and diseased cells contributes to drug toxicity, especially for anti-tumor drugs.
Another problem associated with drug delivery is water solubility; most drugs are too hydrophobic to be water-soluble. This water-insolubility limits both the applicable administration methods as well as dosage levels. Over the years, drug delivery system have been devised to overcome all or some of the problems described above, such as enhancing solubility and efficacy, prolonging circulation time, achieving controlled release, and providing site-specific delivery. Delivery systems range from the use of starch as an additive to form tablets, to the use of capsules to achieve slow release, to more complex devices consisting of hydrogels, polymers, liposomes and various surfactants.
The use of surfactants is one of the promising answers for drug delivery. The use of polymeric surfactants as drug delivery devices has been reviewed extensively, and several successful examples have been demonstrated. For example, micelles have a hydrophobic core that can solubilize hydrophobic materials, such as drugs, as well as a hydrophilic outer shell that makes the assembly water-soluble. Polymeric surfactants have been favored over smaller organic surfactants because they usually have much lower critical micelle concentrations, or cmc's (about 10
−5
M), compared to smaller organic surfactants (about 10
−2
M). Site-specific drug delivery has been shown possible by controlling the size or the surface properties of the polymeric surfactants. However, the thermodynamic instability that is both concentration and temperature dependent of these conventional micelles limits their use in drug delivery. The reversal of micelle to surfactant causes a flux of drug concentration which can cause serious toxicity problems.
One way to overcome the thermodynamic instability of conventional micelles is to construct an assembly that topologically resembles the micelle architecture but with all components covalently bound together. These assemblies are polymers consisting of both hydrophobic (usually aliphatic) and hydrophilic (ionic or non-ionic) components. Most examples of such materials are dendrimers with hydrophilic end functional groups based on amine or carboxylate groups. In a few systems, guest molecules have been entrapped within the structures. Jansen et al.,
JACS,
117, 4417-4418 (1995) demonstrated that different entrapped guest molecules could be liberated by selective chemical removal of the outer shell components. In general, unimolecular micelles showed either dynamic encapsulation (See, Newkome, et al.,
Angew. Chem. Int. Ed. Engl.,
30, 1178-1180 (1991)) or physical entrapment (Jansen et al.) of guest molecules depending on the steric compactness of the structures. The guest molecules either escape from the unimolecular micelles too soon (in the case of dynamic encapsulation) or do not diffuse at all (in the case of physical entrapment) unless the micellar structures are physically disrupted.
Liu et al.,
Polym. Preprint.,
38(2), 582-583 (1997) report the synthesis of hyper-branched polymeric micelles for encapsulation of small hydrophobic organic molecules. There remains a need for suitable delivery systems for the administration of hydrophobic drugs.
SUMMARY OF THE INVENTION
This need is met by the present invention. The present invention provides new polymeric micelles that are useful for solubilizing a variety of hydrophobic materials in water, particularly hydrophobic materials with biological or pharmaceutic activity, which greatly simplifies the preparation of aqueous dosage forms of biologically or pharmaceutically active hydrophobic materials.
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;
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
R
4
is a poly(alkylene oxide) having the structure:
R
5
—(—R
6
—O—)
a
—R
6
—Q—
with R
5
selected from 1 to 40 carbon atom alkyl groups, —O—, OR
7
—, —NH—, —NHR7, 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
are independently selected from 2 to 40 carbon atom, straight chain or branched alkylene groups; Q is a divalent linkage moiety; and a is between 2 and 110, inclusive;
provided 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;
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
R
4
is a poly(alkylene oxide) having the structure:
R
5
—(—R
6
—O—)
a
—R
6
—Q—
with R
5
selected from 1 to 40 carbon atom alkyl groups, —O—, —OR
7
, —NH—, —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
are independently selected from 2 to 40 carbon atom, straight chain or branched alkylene groups; Q
Howard S.
Page Thurman K.
Rutgers The State University of New Jersey
Schwegman Lundberg Woessner & Kluth P.A.
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