Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1987-08-03
1990-09-04
Griffin, Ronald W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
514 54, 536 11, 536 41, 536123, C08B 3718, A61K 31715
Patent
active
049546228
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the preparation and identification of individual polymorphic crystalline forms of inulin, immunotherapeutic preparations containing inulin and to a method of antitumour treatment by the administration of those preparations in which inulin is in an insoluble or particulate form.
"Inulin" is a simple, inert polysaccharide comprising a family of linear .beta.-D-(2.fwdarw.1) polyfructofuranosyl .alpha.-D-glucoses, in which an unbranched chain of up to 100 fructose moieties is linked to a single terminal glucose, the end fructose-glucose pair incidentally being identical to sucrose; there are no other components. Inulin preparations are therefore molecularly polydisperse (mol. wts up to 16,000), neutral polysaccharides of simple, known composition. Inulin is the storage carbohydrate of Compositae and is cheaply available from dahlia tubers. It has a relatively hydrophobic, polyoxyethylene-like backbone, and this unusual structure plus its non-ionised nature allows recrystallisation and easy preparation in a very pure state.
Although the molecular composition of inulin is well-known, the reported determinations of its solubility are conflicting. For example, the Merck Index describes inulin as "slightly soluble in cold water, soluble in hot", whereas a quantitative study (Biochem. J., 1965, 95, 41-47) suggests that two distinct forms of inulin exist--the first obtained by precipitation from water, the second by precipitation from ethanol--both of which are substantially soluble in water at 37.degree. C. It is also known that suspensions of inulin become less soluble on standing. The form obtained from precipitation from water is referred to as alpha-inulin, and the form obtained by precipitation from ethanol is known as beta-inulin. However, the conformational differences between the two forms have not been determined, nor has a method been established which can distinguish between the various polymorphic forms of inulin.
In developing a method for distinguishing the various forms of inulin, a third, hitherto unknown, polymorph has been discovered and isolated.
This third polymorph, hereinafter referred to as gamma-inulin, is virtually insoluble in water at 37.degree. C., but is soluble at temperatures in the range of 70.degree.-80.degree. C., as are the alpha and beta forms. The series of polymorphic forms in which inulin crystallises may be characterised by their different solubility rates in aqueous media ranging from one instantly soluble at 23.degree. C. (beta .sub.23.sup.0 inulin) through a form soluble at 37.degree. C. with a half-time of 8 minutes (alpha .sub.37.sup.8 inulin) to a form virtually insoluble at 37.degree. C. (gamma inulin). All forms are interconvertible, the more soluble and unstable progressing on standing to less soluble and more stable forms, only reversible by complete solution followed by recystallisation. The end product is the stable gamma inulin.
According to the present invention, there is provided, a composition comprising particles of inulin or an inulin derivative in the gamma polymorphic form, characterised in that said particles have a low rate of solution in aqueous media above 30.degree. C.
The active components which may be used in accordance with this invention include not only inulin, .beta.-D-[2-1]-polyfructofuranosyl .alpha.-D-glucose, but also derivatives thereof including .beta.-D-[2-1] polyfructose which may be obtained by enzymatic removal of the end glucose from inulin, for example using an invertase or inulase enzyme capable of removing this end glucose. Other derivatives included within the ambit of this invention are derivatives of inulin in which the free hydroxyl groups have been etherified or esterified, for example by chemical substitution with alkyl, aryl or acyl groups by known methods.
The active component is preferably of molecular weight greater than about 3000, more preferably, greater than about 8000.
According to one preferred aspect of the present invention, the composition comprises particles of gamma inulin, which is cha
REFERENCES:
Cooper, "The Anti-Melanoma Activity of Inulin in Mice"; Molecular Immunology, vol. 23, No. 8, pp. 903-908, 1986.
Cooper, Anti-Complementary Action of Polymorphic "Solubility Forms" of Particulate Inulin, Mol. Immun., vol. 23, No. 8, pp. 895-901, 1986.
The Australian National University, Provisional Specification, "Immunotherapeutic Preparation for Treatment of Cancer".
Phelps; Biochem. J. 95:41-47 (1965).
Sommerman et al.; Biochem. Biophys. Res. Comm. 122(1):319-324 (1984).
Cooper et al.; Int. J. Cancer 33:683-684 (1984).
Cooper; Advances in Immunity and Cancer Therapy, pp. 125-166 (1985).
Cooper et al.; Molecular Immunology 23(3):895-901 , 903-908 (1986).
Carson Nancy S.
Griffin Ronald W.
The Australian National University
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