Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
2001-05-08
2002-10-15
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C424S078270, C424S078290, C424SDIG001, C424S405000, C525S540000
Reexamination Certificate
active
06464971
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to inhibition of microbial and parasitic agents, and in particular it relates to the use of dendrimers as inhibitors of infection of human and non-human animal patients by pathogens such as bacteria, fungi or parasites.
BACKGROUND OF THE INVENTION
Dendrimers are 3-dimensional polymeric materials of low polydispersity which are characterised by a large number of surface terminal groups. In addition, the manner in which these materials are prepared allows tight control over the size, shape, and number and type of surface groups. Dendritic materials have several features that are useful for use as therapeutic materials: fixed shape which presents a large and defined surface with which to interact with biological surfaces and receptors; and the large number of terminal groups allow for multiple interactions with the biological targets.
International Patent Applications No. PCT/AU95/00350 (WO 95/34595) and PCT/AU97100447 (WO 98/03573) disclose dendrimers such as a polyamidoamine or polylysine dendrimers having a plurality of terminal groups, wherein at least one of the terminal groups has an anionic- or cationic-containing moiety bonded or linked thereto. The contents of these published International patent applications are incorporated herein by reference.
The present invention provides the use of dendritic polymers in the inhibition of microbial agents including bacterial and fungal pathogens, and parasitic agents.
SUMMARY OF THE INVENTION
According to the present invention, there is provided a method of prophylactic or therapeutic inhibition of a microbial or parasitic agent in a human or non-human animal patient, which comprises administration to the patient of an effective amount of a dendrimer having a plurality of terminal groups wherein at least one of said terminal groups has an anionic- or cationic-containing moiety bonded or linked thereto.
Particularly preferred compounds for use in the method of the present invention are dendrimers having sulfonic acid-containing moieties, carboxylic acid-containing moieties, phosphoric or phosphonic acid-containing moieties, boronic acid-containing moieties, neuraminic or sialic acid-containing moieties or moieties containing neuraminic or sialic acid; primary, secondary, tertiary or quaternary amino-containing moieties, pyridinium-containing moieties; guanidinium-containing moieties; amidinium-containing moieties; phenol-containing moieties; heterocycles possessing acidic or basic hydrogens; zwitterionic-containing moieties; or mixtures of the above moieties, linked to terminal groups thereof.
The compounds used in the method of this invention are referred to herein as polyionic dendrimers, and this term is used throughout this specification to include not only the dendrimers per se, but also their pharmaceutically or veterinarily acceptable salts, for example the alkaline metal or alkaline earth metal salts such as the sodium, potassium or calcium salts as well as pharmaceutically acceptable anions such as fluoride, chloride, bromide, iodide, citrate, acetate, p-toluene sulfonate and the like.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds used in accordance with the present invention include polyionic dendrimers of the general formula I:
wherein: I is an initiator core;
Z is an interior branching unit;
n is an integer which represents the number of generations of the dendrimer; and
A is an anionic- or cationic-containing moiety which may be linked to interior branching unit Z through an optional linking group X.
Dendrimers are macromolecular highly branched compounds formed by reiterative reaction sequences starting from an initial core molecule with successive layers or stages being added in successive “generations” to build up a three-dimensional, highly ordered polymeric compound. Dendrimers are characterised by the following features: I an initator core (I) which may have one or more reactive sites and be point-like or of significant size so as to effect the final topology of the dendrimer; ii layers of branched repeating units (Z) attached to the initiator core; iii functional terminal groups (such as moieties A) attached to the surface of the dendrimer, optionally through linking groups (such as linking groups X). The present invention uses dendritic structures as frameworks for the attachment of ionic moieties; the invention is not limited to the spherical dendrimers described in detail herein but can be based on any dendritic structure. The variety of dendrimers in both shape and constitution are well known to persons skilled in the art.
The preparation of dendrimers is well known, and is described by way of example in U.S. Pat. Nos. 4,289,872 and 4,410,688 (describing dendrimers based on layers of lysine units), as well as U.S. Pat. Nos. 4,507,466, 4,558,120, 4,568,737 and 4,587,329 (describing dendrimers based on other units including polyamidoamine or PAMAM dendrimers). The dendrimers disclosed in these U.S. patents are described as being suitable for uses such as surface modifying agents, as metal chelating agents, as demulsifiers or oil/water emulsions, wet strength agents in the manufacture of paper, and as agents for modifying viscosity in aqueous formulations such as paints. It is also suggested in U.S. Pat. Nos. 4,289,872 and 4,410,688 that the dendrimers based on lysine units can be used as substrates for the preparation of pharmaceutical dosages.
International Patent Publications Nos. WO 88/01178, WO 88/01179 and WO 88/01180 disclose conjugates in which a dendrimer is conjugated or associated with another material such as a carried pharmaceutical or agricultural material. In addition, International Patent Publication No. WO 95/24221 discloses dendritic polymer conjugates composed of at least one dendrimer in association with a carrier material which can be a biological response modifier, and optionally a target director. These patent publications together with the U.S. patents mentioned above contain a broad disclosure of various dendrimers and processes for the preparation thereof, and the disclosure of each of these publications is incorporated herein by reference.
The term “dendrimer” as used herein is to be understood in its broadest sense, and to include within its scope all forms and compositions of these dendrimers as disclosed in Patent Publications Nos. WO 88/01178, WO 88/01179 and WO 88/01180. The term also includes linked or bridged dendrimers as disclosed in these patent publications.
The preferred dendrimers of the present invention comprise a polyvalent core covalently bonded to at least two dendritic branches, and preferably extend through at least two generations. Particularly preferred dendrimers are polyamidoamine (PAMAM) dendrimers, PAMAM (EDA) dendrimers, poly(Propyleneimine) (PPI) dendrimers and polylysine dendrimers.
In accordance with the present invention, at least one, and preferably a substantial number, of the terminal groups on the surface of the dendrimer has an anionic- or cationic-containing moiety covalently bonded thereto. The branches of the dendrimer may terminate in amino groups or other functional reactive groups such as OH, SH, or the like, which subsequently can be reacted with the anionic or cationic moieties. Where the terminal groups of the dendrimer are amine groups, the anionic- or cationic-containing moiety may be linked to the dendrimer by a variety of functional groups including amide and thiourea linkages. Preferred anionic- or cationic-containing moieties which may be bonded to the terminal groups of the dendrimer include sulfonic acid-containing moieties, carboxylic acid-containing moieties (including neuraminic and sialic acid-containing moieties and modified neuraminic and sialic acid-containing moieties), boronic acid-containing moieties, phosphoric and phosphonic acid-containing moieties (including esterified phosphoric and phosphonic acid-containing moieties) and primary, secondary, tertiary or quaternary amino-containing moieties, pyridinium-containing moieties; guanidinium-containing moieties; amidi
Holan George
Matthews Barry Ross
Nguyen Helen
Starpharma Limited
Webman Edward J.
LandOfFree
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