Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2000-06-29
2004-03-09
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001110, C424S009100
Reexamination Certificate
active
06702995
ABSTRACT:
The present invention relates to a delivery system. More particularly it relates to a method of packaging a water-insoluble substance, such as, for example, a drug or other therapeutic or diagnostic agent, to facilitate uptake into the human or animal body and to the so packaged substance. It also relates to the use of an amphiphilic polymer in the manufacture of a medicament.
Many substances, both natural and manmade, whilst having potential as drugs or other therapeutic or diagnostic agents are rejected in early studies because they are water-insoluble both in in-vitro cell culture and subsequent in-vivo phase I clinical studies.
Current attempts to deliver water-insoluble substances in medicaments mostly involve some form of encapsulation (not an ideal solution because of the complex chemistry involved in getting uniform release of the active substance), micelle or similar formation using lipid-like materials (not ideal because each active substance needs it own special formulation and the micelles are dynamic systems that open and close regularly so that the agent is lost prematurely) or use of a water-miscible solvent such as dimethyl sulphoxide (not a desired solution because of the need to inject or apply solvent into human metabolic systems).
It is an aim of the present invention to produce a water-solubilized form of a water-insoluble substance.
According to one aspect of the present invention there is provided a water-solubilized form of a water insoluble drug or other therapeutic or diagnostic agent characterised in that the water insoluble drug or other therapeutic or diagnostic agent is packaged in an amphiphilic polymer which is miscible with water.
The drug or other therapeutic or diagnostic agent is carried internally within a hydrophobic or lipophilic pocket or pockets defined by the conformation of said polymer in the aqueous environment.
Thus, in an aqueous system, the water-insoluble substance is carried in the hydrophobic or lipophilic pocket or pockets of the amphiphilic polymer, the latter (and therefore the whole system) being soluble in water. On reaching for example a cell membrane, the amphiphilic polymer cannot cross the membrane because of its size but it can undergo a conformational change to release its contents, namely the water-insoluble substance, to the cell wall.
The amphiphilic polymer is preferably a copolymer comprising hydrophilic monomers and hydrophobic monomers.
An advantage of the amphiphilic polymer is its ability per macromolecule to carry several molecules of the drug or other therapeutic or diagnostic agent (often about 5 to 20) internally within the hydrophobic or lipophilic pocket. This means less amphiphilic polymer is required per unit of drug or other therapeutic or diagnostic agent than other carriers.
A further advantage of the amphiphilic polymer is that it allows attachment of cell or tissue specific molecules such as, for example, antibodies. The attachment of such molecules provides a means of targeting drugs contained within the amphiphilic polymer. In addition, a major problem with therapeutic antibody targeting at present is that the relatively small number of antigenic sites on cells restricts the maximum concentration of drug or other therapeutic agent that can be delivered to the cell. By labeling the amphiphilic polymer it should be possible to deliver much higher concentrations of the drug or other therapeutic or diagnostic agent to the cell. By attaching the amphiphilic polymer to, for example, an antibody, it would be possible to target tumour or other cells with high concentrations of the water-insoluble drug by presenting them to the tumour or other cells using the amphiphilic polymer as a carrier.
Another characteristic of the amphiphilic polymers lie in their electronic charge, which means in solution they can flow under the influence of an electrical potential gradient. Thus, with the drug or other therapeutic or diagnostic agent carried within a pocket or pockets defined by the confirmation of said polymer in the aqueous environment the packaged drug or other therapeutic or diagnostic agent can be moved through a tissue under the influence of an electrical potential gradient. This ability would be advantageous in techniques in which molecules are transported from the surface of the skin to deeper layers by an electrical gradient.
Preferred amphiphilic polymers include: polymers comprising at least one hydrophilic group and at least one hydrophobic group, such that the ratio of hydrophilic groups to hydrophobic groups lies in the range from 1:10 to 10:1; preferably from 1:3 to 3:1.
More preferably the amphiphilic polymers will comprise regions which are hydrophobic and regions which are hydrophilic in nature. As a consequence of the polymer having regions of differing hydrophobicity/hydrophilicity the polymer takes up a confirmation in an aqueous environment in which the hydrophobic regions are generally presented internally and the hydrophilic regions are generally presented externally. This results in the formation of a hydrophobic or lipophilic pocket or pockets which can be used to carry water-insoluble drugs or other therapeutic or diagnostic agents.
The hydrophobic groups or regions interact with the water insoluble drug or other therapeutic or diagnostic agent through hydrophobic non-bonded interactions such as dispersion forces, Π—Π interactions, and/or charge transfer interactions, and/or Van der Waals interactions which stabilise the composition in a pocket or pockets while the hydrophilic groups of the polymer solubilise the composition. When acting by charge transfer interactions, an electron donor-acceptor complex is formed.
Preferred polymeric structures for solubilisation of a drug or other therapeutic or diagnostic agent include the following:
Structure of Formula I.
where A and B are selected from: CH
2
, NH, O, ketone, an ester linkage, an amide linkage (—CO—NR—), and an imine linkage (—CR═N—);
where n,m,p,r,s,t can independently be any whole number as long as (n+m+p)
v
+(r+s+t)
w
ranges from 1-1000, preferably from 1-500 and such that the ratio v/w varies between 0.1 and 1;
where the values of q and u, independently lie in the range from 1-10;
Each R, independently, can be selected from H, alkyl, haloalkyl, alkenyl, and alkynyl; preferably H or CH
3
;
R1 is selected from (partially) hydrophobic moieties containing aromatic hydrocarbon rings derived from compounds such as toluene, methyl styrene, stilbene, pyridine, naphthalene, anthracene, phenanthrene, phenyl, histidine, tryptophan, phenyl alanine, tyrosine, alkyl benzene, xylenes, carbazoles, xanthenes, acridines, purines, pyridazines and indoles;
R2 is selected to provide water-solubility and these substituents are therefore hydrophilic in nature such as —OH, hydroxylalkyl such as hydroxymethyl and hydroxyethyl; polyoxyethylene, hydroxyphenyl and derivatives thereof, moieties derived from pyrrolidine, pyridinre-N-oxide, N-oxide derivatives of histidine, tryptophan, phenyl alanine, tyrosine; phenyl sulphonate, naphthalene sulphonate, imidazole, water-soluble salt derivative of naphthalene, anthracene, phenanthrene, phenyl, carbazoles, xanthenes, acridines, purines, pyridazines, indoles, —COOH, —COOM, —SO
3
M where M is an alkali metal ion; —NR
2
, —NR
3
+
X
−
where X is a halide ion and R is independently selected from H, alkyl, and hydroxyalkyl;
R1 and R2, independently, can be substituents on the moieties A and B in the event that A and/or B are not an ether, ketone, amide, imine, or ester linkage.
Substituted polysaccharides of the unit structure
where C and D are oligosaccharide units and where oligosaccharide units comprise the product of polycondensation of monosaccharides by O-glycosidic linkage containing up to 10 such residues selected from hexose, pentose and deoxyhexose residues;
where the values of q and u, independently, lie in the range from 1 to 10;
where the substituent R1 is selected from (partially) hydrophobic moieties containing aromatic hydrocarbon rings derived
Figueiredo Thelmo Luis Coutinho
Johnstone Robert Alexander Walker
Sørensen Alexandra Maria
Warenius Hilmar Meek
Jones Dameron L.
Rothwell Figg Ernst & Manbeck
TheRyte, Ltd.
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