Chemotherapeutic compositions

Details Chemotherapeutic compositions Chemotherapeutic compositions

1997-11-24

2004-04-20

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Specially adapted for ruminant animal

C424S405000, C424S409000, C424S410000, C424S418000, C424S423000, C424S426000, C424S430000, C424S433000, C424S436000, C424S442000, C424S484000, C424S488000, C424S449000, C424S078180, C424S078310, C424S078370, C514S557000, C514S558000, C514S675000, C514S693000

Reexamination Certificate

active

06723336

ABSTRACT:

TECHNICAL FIELD
The present invention relates to the treatment of gastrointestinal disease, and/or cancer, and a method of weight gain, via the ingestion of polymeric compositions in humans, animals or birds in need of said treatment.
BACKGROUND ART
Under the conditions of intensive pig-rearing, post-weaning colibacillosis is ubiquitous. For example, intensive pig-rearing is used throughout Europe, United States and Australia. For example, in the United States, post-weaning colibacillosis is the most common cause of mortality in the weaner pig (Leman et al., 1986). The disease is associated with the proliferation of
Escherichia coli
bacteria in the anterior small intestine after weaning, and gives rise to either death, or the young weaner failing to make normal weight-gains. Other microbiological diseases are common and often accompany colibacillosis in pigs as well as in other animals in intensive rearing conditions, especially poultry.
In the past, attempts have been made to control disease by the ingestion of antimicrobial compositions or by vaccination, neither of which has proved entirely effective.
The rationale behind the lack of success surrounding ingestion of antimicrobial compositions has been the fact that proteinaceous feedstuffs and the contents of the gastrointestinal tract present a reactive and hazardous environment to any chemotherapeutic agent and hence, an in vitro active antimicrobial agent will often not be effective when used in vivo within the gastrointestinal tract.
Further, to be antimicrobially effective in a practical way, there is often the restrictive demand that the gastrointestinal disease controlling agent should reasonably maintain the very low microbiological content in the duodenum, yet the very high content in the lower parts of the intestine.
As well, it does not follow that even in vivo effective antimicrobials will give weight-gains, since it is common that even a cocktail of several such commercially used antimicrobials only gives rise to variable, partial or even negative relative weight-gains over control animals.
Accordingly, there is a need for improvements in the prevention and/or treatment of disease via ingestion of antimicrobial compositions in humans and/or animals and/or birds in need of said treatment. Furthermore, there is the need for the attainment of weight gains of said humans and/or animals and/or birds undergoing said treatment.
The present invention provides polymers and/or copolymers preferably derived from acrolein and having the polymeric repeating unit:
wherein R is H or alkyl, usually C
1
to C
4
or this unit in hydrated, hemiacetal or acetal form and illustrated non-comprehensively of all possible structures, by the following formulae:
wherein n is one or more and R is as defined above; hereinafter referred to as the “Subject Polymers”, as broad spectrum in vivo antimicrobials and/or anti-cancer agents suitable for treatment by the oral route.
It is known that the rate of passage of molecules across membranes has an inverse relationship to their molecular weights. Thus, it is widely and generally accepted in the art that molecules taken by the oral route and having molecular weight <1000, will have their passage across the gut so restricted, and consequently any potential toxicity will be effectively minimised.
The Subject Polymers, being aldehydic, are especially reactive with protein. (In fact, in microbiological assays, the routine and facile method of quenching/destroying the activity of the Subject Polymers—is to add protein.) Hence, the Subject Polymers would not be expected to exhibit significant microbiological activity in the intestine, especially in the presence of proteinaceous feed.
Therefore, the present invention provides a method of prevention and/or treatment of gastrointestinal disease in humans, animals or birds resulting from the microbial infection of the gastrointestinal tract, and a method for increasing weight gain in humans, animals or birds having gastrointestinal disease and/or infection, comprising administering an effective amount to said humans, animals or birds of a pharmaceutical composition or feed additive, comprising an effective amount of the Subject Polymers together with a pharmaceutically or veterinarally acceptable carrier, diluent, adjuvant, excipient or controlled release system.
OBJECT OF THE INVENTION
It is an object of the present invention to provide methods for the prevention and treatment of dysfunctional/pathological states in a human, animal or bird, especially, those states within the gastrointestinal tract associated with colibacillosis, diarrhoea, mortality and/or reduced weight gains.
DISCLOSURE OF THE INVENTION
The present invention is based upon a series of discoveries herein:
Firstly, it has now been discovered that the Subject Polymers, being of high molecular weight are inhibited in passage through biological membranes, and have facilitated applications in the gastrointestinal tract, since passage through the gut and into the bloodstream to potentially cause toxicity is minimised. In particular, it has been discovered that the Subject Polymers have molecular weights >1000, and generally have molecular weights >2000, which effectively minimise their passage across the intestinal membranes and as a result, it has been found herein that whilst the Subject Polymers exhibit toxicity following intra-venous injection, they exhibit no toxicity when administered orally. Hence it has been discovered that the Subject Polymers have mimimised toxicities and that they have associated advantages when used for chemotherapeutic purposes, in any species having gut membranes, for example, humans, animals or birds.
Generally, the Subject Polymers formed by ionic initiation/catalysis are more hydrophilic than those formed by free radical initiation/catalysis, and hydrophilicity of the Subject Polymers may generally be increased by inclusion within them of hydrophilic groups, especially carboxyl groups, or of hydrophilic monomers, especially acrylic acid. Particularly, carefully heating the Subject Polymers formed by ionic initiation/catalysis with ample air from room temperature to up to 100° C., and preferably up to between 80-85° C., produces the Subject Polymers having 0.1-5 moles of carboxyl groups/kg, aqueous soluble at the pH of the duodenum especially, and preferred for the applications in gastrointestinal tracts described and envisaged herein.
The Subject Polymers have the following properties:
The Subject Polymers have an unusually broad in vivo antimicrobial profile, providing a method of treatment of gastrointestinal disease in humans, animal or birds.
It has been shown that the Subject Polymers provide increased weight gains in humans, animals or birds.
It has also been shown that the Subject Polymers are in vivo anti-cancer agents.
According to a first embodiment of the invention there is provided a method of in vivo cancer treatment in humans, animals or birds comprising administering to said humans, animals or birds an effective amount of a pharmaceutical or veterinary composition or feed additive, comprising an effective amount of polymers and/or copolymers having the repeating polymeric unit:
wherein R is H or alkyl, usually C
1
to C
4
, or this unit in hydrated, hemiacetal or acetal form and illustrated non-comprehensively of all possible structures, by the following formulae:
wherein n is one or more and R is as defined above; together with a pharmaceutically or veterinarally acceptable carrier, diluent, adjuvant, excipient and/or controlled release system.
According to a second embodiment of the invention there is provided a method for the treatment and/or prevention of gastrointestinal disease and/or infection and/or diarrhoea in humans, animals or birds resulting from a microbial infection of the gastrointestinal tract in said humans, animals or birds, comprising administering to said humans, animals or birds an effective amount of a pharmaceutical or veterinary composition or feed additive, comprising an effective amount of a polymer a

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