Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1999-11-29
2001-11-27
Levy, Neil S. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S078020, C424S078050, C424S078060, C424S078070, C424S195170, C424S400000, C424S409000, C424S485000, C424S488000, C536S114000, C514S024000, C514S064000, C514S054000
Reexamination Certificate
active
06322814
ABSTRACT:
This invention relates to methods of making agars with very low gel strengths, and the discovery of uses for these materials.
According to the US Pharmocopeia, agar is a hydrophilic colloid which can be extracted from certain seaweeds of the Rhodophyceae. Its characteristic property is that it is insoluble in cold water, and if 1.5% parts by weight are dissolved in hot water, on cooling it forms a firm gel. Agar is generally considered to be a mixture of agarose and agaropectin. Idealised agarose is a polymer with alternating 3-linked &bgr;-D-galactosyl residues and 4-linked &agr;-3,6-anhydro-L-galactosyl residues, which can also be thought of as polyagarobiose, and gelation is generally held to arise through the formation of double helices between agarobiose units (Rees, 1969). Agar generally contains a number of agarose precursor units, where the 4-linked residues contain L-galactose-6-sulphate. These 6-sulphated residues cannot form double helices, and hence when these units arise in agar, it is generally held that helix formation terminates, the strands branch, and may form further double helices when strands with appropriate agarobiosyl units can meet. The resultant gel is, accordingly, a large interwoven network. If there are too many L-galactose-6-sulphate units, the amount of double helix structure is too small, and the gel strength weakens. Since L-galactose-6-sulphate units can be converted to anhydrogalactosyl units by treatment with alkali, alkali treatment of agar, or agar bearing seaweeds, is commonly practised in order to improve gel strength (Armisen 1987).
Alkali treatment of agar to improve gel strength is well known to those familiar with the art, and the literature contains a number of procedures. For the purposes of this invention, we define an alkali treatment as “rigorous” if if a repeat of the treatment or of a standard alternative alkali treatment to the resultant agar leads to no significant decrease in level of sulphate ester.
Agar is generally used industrially because of its rather unusual gelling properties, and the gel strength of an industrial agar of 1.5% concentration generally lies between 600-1100 g/cm
2
. An important feature of an agar gel is the property of syneresis, whereby when pressure is applied to it, water is squeezed from the gel. Accordingly in some cases when a weaker binding force is required and the option of using less agar might lead to excess syneresis, an agar which has had its gel strength reduced might be used as increasing the agar content reduces the tendency towards syneresis. The manufacture of a partially hydrolysed agar for this purpose has been proposed (Kojima et al 1993). Of particular interest regarding this material is the proposed means of dehydratng the gel, as shown by the following quote: “when an agar of low gel strength is interposed between dehydrating cloths and pressurized, clogging occurs in the cloths and dehydration is not performed desirably. On the other hand, in the case of employing the freezing/denaturing process, an agar gel of a low gel strength does not have an orderly spongy structure, and it is caused to flow out with water.” Accordingly these workers proposed to prepare a low gel strength agar and isolate it by evaporating off water, with the option of alcohol precipitation from concentrated solutions.
It is generally held to be not possible to make an idealized agarose, as there is always some residual sulphate ester, but it becomes clear from the above theory that if sufficient sulphate ester is removed, and sufficient hydrolysis is performed to shorten the polyagarobiose molecules, strands of shorter double helices may be formed with no defects in their structure. Although the constituent analyses may be little different from a low gel strength agar, significant differences in properties of the material should be expected, since on the molecular level, there will be a minimum of interstrand connectivity, and the molecules will consist of rods of double helix. The purpose of this invention is to show that these expectations can be met, although this invention is not intended to be dependent on the validity of the theory outlined above.
What we have found is that provided there is sufficiently low levels of anionic content arising from sulphate ester, and if the hydrolysis is carried out for a sufficient length of time, what is obtained is a material which behaves in solution like a thick paste. While normal agar, after freeze-thawing, is recovered as leathery spongy-like lumps corresponding to the original lumps of agar, and weak gel-strength agar does not denature at all well, leaving a material with insufficient strength to enable it to be easily recovered, if the product of this invention is freeze-thawed, the polyagarobiose units, assumed to be in the rod-like configuration, form a coarse fibre-like precipitate which can be recovered by straining the water through a gauze. The fibrous material is able to be further dewatered by squeezing it for a few minutes in a filter cloth and the precipiate is sufficiently firm that clogging does not occur. Although the material of this invention does not have to be purified this way, it is characteristic of the material of this invention that it can undergo such a freeze-thawing process. This clearly differentiates it from the weak-gelling agar in the prior art, for which the freeze-thawing process is unavailable.
Gel strengths are usually recorded in terms of the ability of a gel to support a force for 20 seconds. This material has zero rigidity, hence such a measurement would give a result of zero. We have, however, found it possible to differentiate between such virtually zero strength gels according to their resistance to flow, by placing the gel on a balance pan and penetrating the material with a 1 cm
2
plunger within a period of approximately 1 second. The maximum reading from the balance is recorded as a dynamic gel strength, and while it is somewhat arbitrary, it does separate very weak gels into two classes, namely those with such a dynamic gel strength of less than 10 g/cm
2
, which are essentially thick flowing liquids, and those greater than 10 g/cm
2
by this method, in which some gel-like structure is progressively retained as the dynamic gel strength increases so that on stirring some gel-like lumps are retained.
A number of other agar bearing seaweeds give low gel strengths when extracted, but when treated with alkali following methods known to those practised in the art, give an agar with a higher gel strength. These initial weak gels tend to rupture, and in the limit of weakness flow as a sloppy gel. These initial weak gels generally consist of agar molecules which have high levels of anionic substitution, for example, sulphate ester, and the preparation of such materials are not the subject of this invention.
If, however, the agars from such seaweeds are treated according to the methods of this invention, that is they are subjected to rigorous alkali treatment followed by controlled acid hydrolysis, the resultant gels have a rather unusual creamy texture and with unusual water retention properties. The best gels for some of the purposes of this invention are gels which have a low gel strength specifically because of the lower molecular weight, and paradoxically are best prepared from high gel strength agars. The material of this patent is a low molecular weight agar with negligible amounts of 4-linked residues in any form other than as anhydrogalactosyl. It is characterized by forming an ultraweak gel with a very low gel strength, but which, on freeze-thawing, forms a readily collectible coarse fibre-like precipitate. Of special note is the absence in the 13CNMR spectrum of any significant signal at 67.9 ppm or at 101.3 ppm which would be due to L-galactose-6-sulphate.
There are already a number of thickeners and gels on the market which have a number of uses, particularly in the food industry, and the uses are generally based on water retention properties, gelling ability, emulsifying properties, and stabilizing properti
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