WO2019022822A1

WO2019022822A1 - Water-soluble polysaccharides of improved palatability

Info

Publication number: WO2019022822A1
Application number: PCT/US2018/033819
Authority: WO
Inventors: Oliver Petermann
Original assignee: Dow Global Technologies Llc
Priority date: 2017-07-26
Filing date: 2018-05-22
Publication date: 2019-01-31

Abstract

A stable hydrogel is formed from an esterified cellulose ether and water by heat treatment and syneresis. The hydrogel, at a temperature of 21 °C, has a water content of from 15 to 91.0 weight percent, based on the total weight of the hydrogel. It additionally comprises a non-starch water-soluble polysaccharide which is different from the esterified cellulose ether. The esterified cellulose ether comprises aliphatic monovalent acyl groups and groups of the formula -C(O)-R-COOH, R being a divalent hydrocarbon group, wherein I) the degree of neutralization of the groups -C(O)-R-COOH is not more than 0.4 and II) the total degree of ester substitution is from 0.03 to 0.70.

Description

WATER-SOLUBLE POLYSACCHARIDES OF IMPROVED PALAT ABILITY

FIELD

This invention concerns water-soluble polysaccharides of improved palatability and a method of preparing them.

INTRODUCTION

Water-soluble polysaccharides have found a wide range of uses in food, food ingredients or food supplements.

One end-use is known as "dietary fiber". This term is often used to describe non- starch water-soluble polysaccharides which are not digested by enzymes of the upper intestinal tract. Dietary fibers can be used as slimming aid for obese and non-obese individuals and/or as a bulk laxative. Some dietary fibers, such as guar gum,

methylcellulose or hydroxypropyl methylcellulose, form viscous solutions in water and have been shown to be efficient at inducing satiety and/or at reducing caloric intake or causing weight loss in individuals.

International Patent Application WO 2005/020718 discloses the use of a large number of biopolymers for inducing satiety in a human or animal, such as non-starch

polysaccharides selected from alginates, pectins, carrageenans, amidated pectins, xanthans, gellans, furcellarans, karaya gum, rhamsan, welan, gum ghatti, and gum arabic. Of these, alginates are said to be especially preferred. Alternatively, neutral non-starch

polysaccharides selected from galactamannan, guar gum, locust bean gum, tara gum, ispaghula, P-glucans, konjacglucomannan, methylcellulose, gum tragacanth, detarium, or tamarind may be used.

International Patent Application WO 92/09212 discusses that one major disadvantage in the use of these types of polysaccharides is the difficulty in controlling their swelling behavior. The dry dietary fiber is usually dispersed in an aqueous medium, thus giving rise to a very rapid swelling through the binding of water molecules to the polysaccharide, i.e., the dissolution of the fiber takes place more or less instantaneously. The highly viscous dispersion which is then formed becomes difficult to ingest if not taken immediately and provides a slimy or tacky sensation in the mouth. To overcome this problem WO 92/09212 suggests a dietary fiber composition comprising a water-soluble, nonionic cellulose ether having a cloud point not higher than 35 °C, such as ethyl hydroxyethyl cellulose and a charged surfactant, such as alkyl ammonium compounds or alkyl ether sulphates, such as sodium dodecyl sulphate (SDS). SDS is used in large quantities in detergent compositions, but animal studies have suggested that SDS causes skin and eye irritation.

Grades of methylcellulose that gel in water and form quite strong gels at body temperature are disclosed in International Patent Applications WO2011/139763 and

WO2014/168915. These grades of methylcellulose are consumed as cold solutions in water, i.e., having room temperature or lower. Upon ingestion the aqueous solutions of methylcellulose warm up to body temperature and form a gel mass in the individual's body, which induces satiety. Unfortunately, the cold solutions in water of these grades of methylcellulose also tend to provide a slimy or tacky sensation and a bad taste in the mouth when they are ingested.

U.S. Patent No. 5,281,584 discloses that high viscosity cellulose ethers are effective for reducing serum cholesterol levels in humans. They are incorporated in bakable food compositions, such as cookies at an amount of 2 - 25 wt.%. The remaining part of the composition is composed of food ingredients, mainly butter, sugar, and flour, such as wheat flour. Unfortunately, the high viscosity cellulose ethers contribute to a grainy or gritty mouth feel. U.S. Patent No. 5,281,584 teaches that the palatability of the bakable food compositions can be improved by selecting a high viscosity cellulose ether of a certain particle size distribution. However, the consumption of the high viscosity cellulose ether in the form of cookies goes hand in hand with the consumption of calories inherent to the above-mentioned food ingredients. This is undesirable for managing the weight, reducing caloric intake or causing weight loss in individuals.

Accordingly, it would be desirable to find another way to improve the palatability of non-starch water-soluble polysaccharides. It would be particularly desirable to improve the palatability of non-starch water-soluble polysaccharides without making use of a charged monomeric surfactant.

Surprisingly, it has been found that such non-starch water-soluble polysaccharides, such as cellulose ethers, can be administered as chewable gels, also designated as gummies or pastilles, even when these water-soluble polysaccharides do not form thermostable gels. The new form of administering non-starch water-soluble polysaccharides does not lead to the gritty or sandy mouthfeel and/or to the additional caloric intake which is experienced when consuming cookies comprising such non-starch water-soluble polysaccharides.

Moreover, the new form of administering non-starch water-soluble polysaccharides does not provide the bad taste in the mouth which is experienced when consuming a liquid aqueous solution comprising such non-starch water-soluble polysaccharides.

Surprisingly, a process has been found that allows the production of gelatin-free hydrogels or gummies or pastilles that do not melt back to aqueous solutions at room temperature (21 °C) or refrigerator temperature (4 °C) and that comprise non-starch water- soluble polysaccharides, such as cellulose ethers.

In preferred embodiments the process even allows the production of gelatin- free hydrogels or gummies or pastilles that comprise non-starch water-soluble polysaccharides, such as cellulose ethers, which even maintain a substantially stable shape at room temperature or even at refrigerator temperature (4 °C).

SUMMARY

Accordingly, one aspect of the present invention is hydrogel which is formed from an esterified cellulose ether and water by heat treatment and syneresis and which additionally comprises a non-starch water-soluble polysaccharide that has a viscosity of at least 600 mPa-s, determined as a 2.0 % by weight solution in water at 20°C, and that is different from the esterified cellulose ether, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 15 to 91.0 weight percent, based on the total weight of the hydrogel, and the esterified cellulose ether comprises aliphatic monovalent acyl groups and groups of the formula - C(O) - R - COOH, R being a divalent hydrocarbon group, wherein I) the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4 and II) the total degree of ester substitution is from 0.03 to 0.70.

Another aspect of the present invention is a process for producing a hydrogel from an esterified cellulose ether and water and additionally incorporating in the hydrogel a non- starch water-soluble polysaccharide having a viscosity of at least 600 mPa-s, determined as a 2.0 % by weight solution in water at 20°C, and being different from the esterified cellulose, wherein the process comprises the steps of

a) preparing an aqueous solution comprising

i) at least 1.5 wt.-%, based on the total weight of the aqueous solution, of an esterified cellulose ether comprising aliphatic monovalent acyl groups and groups of the formula - C(O) - R - COOH, R being a divalent hydrocarbon group, wherein I) the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4 and II) the total degree of ester substitution is from 0.03 to 0.70, b) heating the aqueous solution of step a) to form a hydrogel from the aqueous solution and ii) a non-starch water-soluble polysaccharide having a viscosity of at least 600 mPa s, determined as a 2.0 % by weight solution in water at 20°C, and being different from the esterified cellulose ether,

c) maintaining the formed hydrogel at least at a temperature at which the hydrogel has been formed in step b) for a sufficient time period such that i) the remaining water content in the formed hydrogel is from 15 to 91.0 weight percent, based on the total weight of the hydrogel, and ii) at least 15 weight percent of water are liberated from the hydrogel, based on the water weight in the aqueous solution in step a), and

d) separating liberated water from the hydrogel and cooling the hydrogel to a temperature of 25 °C or less simultaneously or in any sequence.

DESCRIPTION OF EMBODIMENTS

According to the general understanding in the art "gel" refers to a soft, solid, or solidlike material which comprises at least two components, one of which is a liquid present in abundance (Almdal, Dyre, J., Hvidt, S., Kramer, O.; Towards a phenomological definition of the term 'gel'. Polymer and Gel Networks 1993, 1, 5-17). A hydrogel is a gel wherein water is the main liquid component.

The esterified cellulose ethers used for preparing the hydrogels of the present invention are disclosed in International patent applications WO2016/148976,

WO2016/148977 and WO 2016/148973. These WO publications disclose novel esterified cellulose ethers, such as HPMCAS, which are soluble in water at 2 °C or even at 20 °C although they have a low degree of neutralization. Aqueous solutions of many of these esterified cellulose ethers gel at slightly elevated temperature, typically at 30 to 55 °C. As discussed in WO2016/148976 and WO2016/148977, gelation of the disclosed aqueous solutions of esterified cellulose ethers, such as HPMCAS, is reversible. I.e., upon cooling of the gel to room temperature (about 20 °C) or less the gel transforms into a liquid aqueous solution. Surprisingly, the hydrogels of the present invention are not transformed into a liquid aqueous solution at room temperature. The esterified cellulose ether and the novel process used for preparing the hydrogel of the present invention are described in more detail below.

The esterified cellulose ether has a cellulose backbone having β-1,4 glycosidically bound D-glucopyranose repeating units, designated as anhydroglucose units in the context of this invention. The esterified cellulose ether preferably is an esterified alkyl cellulose, hydroxyalkyl cellulose or hydroxyalkyl alkylcellulose. This means that in the esterified cellulose ether at least a part of the hydroxyl groups of the anhydroglucose units are substituted by alkoxyl groups or hydroxyalkoxyl groups or a combination of alkoxyl and hydroxyalkoxyl groups. The hydroxyalkoxyl groups are typically hydroxymethoxyl, hydroxyethoxyl and/or hydroxypropoxyl groups. Hydroxyethoxyl and/or hydroxypropoxyl groups are preferred. Typically one or two kinds of hydroxyalkoxyl groups are present in the esterified cellulose ether. Preferably a single kind of hydroxyalkoxyl group, more preferably hydroxypropoxyl, is present. The alkoxyl groups are typically methoxyl, ethoxyl and/or propoxyl groups. Methoxyl groups are preferred. Illustrative of the above-defined esterified cellulose ether are esterified alkylcelluloses, such as esterified methylcelluloses, ethylcelluloses, and propylcelluloses; esterified hydroxyalkylcelluloses, such as esterified hydroxyethylcelluloses, hydroxypropylcelluloses, and hydroxybutylcelluloses; and esterified hydroxyalkyl alkylcelluloses, such as esterified hydroxyethyl methylcelluloses, hydroxymethyl ethylcelluloses, ethyl hydroxyethylcelluloses, hydroxypropyl

methylcelluloses, hydroxypropyl ethylcelluloses, hydroxybutyl methylcelluloses, and hydroxybutyl ethylcelluloses; and those having two or more hydroxyalkyl groups, such as esterified hydroxyethylhydroxypropyl methylcelluloses. Most preferably, the esterified cellulose ether is an esterified hydroxyalkyl methylcellulose, such as an esterified hydroxypropyl methylcellulose.

The degree of the substitution of hydroxyl groups of the anhydroglucose units by hydroxyalkoxyl groups is expressed by the molar substitution of hydroxyalkoxyl groups, the MS(hydroxyalkoxyl). The MS (hydroxyalkoxyl) is the average number of moles of hydroxyalkoxyl groups per anhydroglucose unit in the esterified cellulose ether. It is to be understood that during the hydroxyalkylation reaction the hydroxyl group of a

hydroxyalkoxyl group bound to the cellulose backbone can be further etherified by an alkylating agent, e.g. a methylating agent, and/or a hydroxyalkylating agent. Multiple subsequent hydroxyalkylation etherification reactions with respect to the same carbon atom position of an anhydroglucose unit yields a side chain, wherein multiple hydroxyalkoxyl groups are covalently bound to each other by ether bonds, each side chain as a whole forming a hydroxyalkoxyl substituent to the cellulose backbone.

The term "hydroxyalkoxyl groups" thus has to be interpreted in the context of the

MS(hydroxyalkoxyl) as referring to the hydroxyalkoxyl groups as the constituting units of hydroxyalkoxyl substituents, which either comprise a single hydroxyalkoxyl group or a side chain as outlined above, wherein two or more hydroxyalkoxyl units are covalently bound to each other by ether bonding. Within this definition it is not important whether the terminal hydroxyl group of a hydroxyalkoxyl substituent is further alkylated or not; both alkylated and non-alkylated hydroxyalkoxyl substituents are included for the determination of MS(hydroxyalkoxyl). The esterified cellulose ether generally has a molar substitution of hydroxyalkoxyl groups of at least 0.05, preferably at least 0.08, more preferably at least 0.12, and most preferably at least 0.15. The degree of molar substitution is generally not more than 1.00, preferably not more than 0.90, more preferably not more than 0.70, and most preferably not more than 0.50.

The average number of hydroxyl groups substituted by alkoxyl groups, such as methoxyl groups, per anhydroglucose unit, is designated as the degree of substitution of alkoxyl groups, DS(alkoxyl). In the above-given definition of DS, the term "hydroxyl groups substituted by alkoxyl groups" is to be construed within the present invention to include not only alkylated hydroxyl groups directly bound to the carbon atoms of the cellulose backbone, but also alkylated hydroxyl groups of hydroxyalkoxyl substituents bound to the cellulose backbone. The esterified cellulose ether preferably has a DS(alkoxyl) of at least 1.0, more preferably at least 1.1, even more preferably at least 1.2, most preferably at least 1.4, and particularly at least 1.6. The DS(alkoxyl) is preferably not more than 2.5, more preferably not more than 2.4, even more preferably not more than 2.2, and most not more than 2.05.

Most preferably the esterified cellulose ether is an esterified hydroxypropyl methylcellulose having a DS(methoxyl) within the ranges indicated above for DS(alkoxyl) and an MS(hydroxypropoxyl) within the ranges indicated above for MS (hydroxyalkoxyl).

The esterified cellulose ether comprises as ester groups the groups of the formula

- C(O) - R - COOH, wherein R is a divalent aliphatic or aromatic hydrocarbon group, such as - C(O) - CH₂ - CH₂ - COOH, - C(O) - CH = CH - COOH or - C(O) - C₆H₄ - COOH, and aliphatic monovalent acyl groups, such as acetyl, propionyl, or butyryl, such as n- butyryl or i-butyryl. Preferred groups of the formulas - C(O) - R - COOH are

- C(O) - CH₂ - CH₂ -COOH.

Specific examples of esterified cellulose ethers are hydroxypropyl methyl cellulose acetate phthalate (HPMCAP), hydroxypropyl methyl cellulose acetate maleate (HPMCAM) or hydroxypropyl methylcellulose acetate succinate (HPMCAS); hydroxypropyl cellulose acetate succinate (HPCAS), hydroxybutyl methyl cellulose propionate succinate

(HBMCPrS), hydroxyethyl hydroxypropyl cellulose propionate succinate (HEHPCPrS); or methyl cellulose acetate succinate (MCAS). Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is the most preferred esterified cellulose ether. In the esterified cellulose ether the degree of neutralization of the groups

- C(O) - R - COOH is not more than 0.4, preferably not more than 0.3, more preferably not more than 0.2, most preferably not more than 0.1, and particularly not more than 0.05 or even not more than 0.01. The degree of neutralization can even be essentially zero or only slightly above it, e.g. up to 10^"3 or even only up to 10^"4. The term "degree of neutralization" as used herein defines the ratio of deprotonated carboxylic groups over the sum of deprotonated and protonated carboxylic groups, i.e.,

Degree of neutralization = [-C(0)-R- COO^" ] / [-C(0)-R-COO^" + -C(0)-R-COOH]. If the groups - C(O) - R - COOH are partially neutralized, the cation preferably is an ammonium cation, such as NH₄ ⁺ or an alkali metal ion, such as the sodium or potassium ion, more preferably the sodium ion.

The esterified cellulose ether has aliphatic monovalent acyl groups and groups of the formula - C(O) - R - COOH, such that the total degree of ester substitution is from 0.03 to 0.70. The sum of i) the degree of substitution of aliphatic monovalent acyl groups and ii) the degree of substitution of groups of formula -C(O) - R - COOH, of which the degree of neutralization is not more than 0.4, is an essential feature of the esterified cellulose ether. The total degree of ester substitution is at least 0.03, generally at least 0.07, preferably at least 0.10, more preferably at least 0.15, most preferably at least 0.20, and particularly at least 0.25. The total degree of ester substitution in the esterified cellulose ether is not more than 0.70, generally not more 0.65, preferably up to 0.60, more preferably up to 0.55, and most preferably or up to 0.50 or up to 0.45.

The esterified cellulose ether generally has a degree of substitution of aliphatic monovalent acyl groups, such as acetyl, propionyl, or butyryl groups, of at least 0.03 or 0.05, preferably at least 0.10, more preferably at least 0.15, most preferably at least 0.20, and particularly at least 0.25 or at least 0.30. The esterified cellulose ethers generally have a degree of substitution of aliphatic monovalent acyl groups of up to 0.69, preferably up to 0.60, more preferably up to 0.55, most preferably up to 0.50, and particularly up to 0.45 or even only up to 0.40.

The esterified cellulose ether generally has a degree of substitution of groups of formula -C(O) - R - COOH, such as succinoyl, of at least 0.01, preferably at least 0.02, more preferably at least 0.05, and most preferably at least 0.10. The esterified cellulose ether generally has a degree of substitution of groups of formula -C(O) - R - COOH of up to 0.65, preferably up to 0.60, more preferably up to 0.55, and most preferably up to 0.50 or up to 0.45. As indicated above, the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4.

Moreover, in the esterified cellulose ether the sum of i) the degree of substitution of aliphatic monovalent acyl groups and ii) the degree of substitution of groups of formula -C(O) - R - COOH and iii) the degree of substitution of alkoxyl groups, DS(alkoxyl), generally is not more than 2.60, preferably not more than 2.55, more preferably not more than 2.50, and most preferably not more than 2.45. The esterified cellulose ether generally has a sum of degrees of substitution of i) aliphatic monovalent acyl groups and ii) groups of formula -C(O) - R - COOH and iii) of alkoxyl groups of at least 1.7, preferably at least 1.9, and most preferably at least 2.1.

The content of the acetate and succinate ester groups is determined according to "Hypromellose Acetate Succinate", United States Pharmacopeia and National Formulary, NF 29, pp. 1548-1550. Reported values are corrected for volatiles (determined as described in section "loss on drying" in the above HPMCAS monograph). The method may be used in analogue manner to determine the content of propionyl, butyryl and other ester groups.

The content of ether groups in the esterified cellulose ether is determined in the same manner as described for "Hypromellose", United States Pharmacopeia and National Formulary, USP 35, pp 3467-3469.

The contents of ether and ester groups obtained by the above analyses are converted to DS and MS values of individual substituents according to the formulas below. The formulas may be used in analogue manner to determine the DS and MS of substituents of other cellulose ether esters.

% cellulose backbone

%MeO %HP0

M(0CH₃) M(HPO)

DS(Me) = MS(HP) =

%cellulose backbone %cellulose backbone

M(AGU) M(AGU) %Acetyl %Succinoyl

M (Acetyl) _ M(Succinoyl)

%cellulose backbone %cellulose backbone

M(AGU) M(AGU)

M(MeO) = M(OCH₃) = 31.03 Da M(HPO) = M(OCH₂CH(OH)CH₃) = 75.09 Da M (Acetyl) = M(COCH₃) = 43.04 Da M(Succinoyl) = M(C0C₂H₄C00H) = 101.08 Da M(AGU) = 162.14 Da M(OH) = 17.008 Da M(H) = 1.008 Da

By convention, the weight percent is an average weight percentage based on the total weight of the cellulose repeat unit, including all substituents. The content of the methoxyl group is reported based on the mass of the methoxyl group (i.e., -OCH3). The content of the hydroxyalkoxyl group is reported based on the mass of the hydroxyalkoxyl group (i.e., -O- alkylene-OH); such as hydroxypropoxyl (i.e., -0-CH2CH(CH3)-OH). The content of the aliphatic monovalent acyl groups is reported based on the mass of -C(O) - Ri wherein Ri is a monovalent aliphatic group, such as acetyl (-C(0)-CH3). The content of the group of formula -C(O) - R - COOH is reported based on the mass of this group, such as the mass of succinoyl groups (i.e., - C(O) - CH₂ - CH₂ - COOH).

The esterified cellulose ether is water-soluble, as disclosed in International patent applications WO2016/148976, WO2016/148977 and WO 2016/148973.

The esterified cellulose ether generally has a weight average molecular weight M_w of up to 500,000 Dalton, preferably up 450,000 Dalton, more preferably up to 400,000 Dalton, and most preferably up to 350,000 Dalton.

In one aspect of the invention the esterified cellulose ether only has a weight average molecular weight M_wof up to 80,000 Dalton, generally up to 70,000 Dalton, preferably up to 60,000 Dalton, and more preferably up to 50,000 Dalton or even up to 40,000 Dalton. This aspect of the invention is designated as "low molecular weight esterified cellulose ether".

The esterified cellulose ether generally has a weight average molecular weight M_w of at least 8,000 Dalton, preferably at least 12,000 Dalton, more preferably at least 15,000 Dalton, even more preferably at least 20,000 Dalton, and most preferably at least 25,000 Dalton.

In one aspect of the invention the esterified cellulose ether has a weight average molecular weight M_wof at least 40,000 Dalton, typically at least 80,000 Dalton, preferably at least 100,000 Dalton, more preferably at least 150,000 Dalton, even more preferably at least 220,000, and most preferably at least 300,000. This aspect of the invention is designated as "high molecular weight esterified cellulose ether".

The esterified cellulose ether generally has a number average molecular weight M_n of from 5000 to 300,000 Dalton, preferably from 8000 to 280,000 Dalton. Low molecular weight cellulose ethers preferably have a number average molecular weight M_n of from 5000 to 60,000 Dalton, more preferably from 8000 to 50,000 Dalton, and even more preferably from 10,000 to 40,000 Dalton. High molecular weight cellulose ethers preferably have a number average molecular weight M_n of from 50,000 to 300,000 Dalton, more preferably from 100,000 to 280,00 Dalton, even more preferably from 150,000 to 260,000 Dalton, and most preferably from 200,000 to 240,000 Dalton.

The esterified cellulose ether generally has a z- average molecular weight, M_z, of from 50,000 to 2,000,000 Dalton, preferably from 70,000 to 1,000,000 Dalton. Low molecular weight cellulose ethers preferably have a z-average molecular weight, M_z, of from 50,000 to 400,000 Dalton, more preferably from 70,000 to 300,000 Dalton. High molecular weight cellulose ethers preferably have a z-average molecular weight, M_z, of from 300,000 to 2,000,000 Dalton, more preferably from 400,000 to 1,000,000 Dalton.

Mw, M_n and M_z are measured according to Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 743 using a mixture of 40 parts by volume of acetonitrile and 60 parts by volume of aqueous buffer containing 50 mM NaH2P0₄ and 0.1 M NaN0₃ as mobile phase. The mobile phase is adjusted to a pH of 8.0. The measurement of M_w, M_n and M_z is described in more details in the Examples.

The production of the esterified cellulose ether is described in International patent applications WO2016/148976, WO2016/148977 and WO 2016/148973 and in the Examples Section.

In step a) of the process of the present invention an aqueous solution comprising at least 1.5 wt.-% of the above-described esterified cellulose ether is prepared, based on the total weight of the aqueous solution. Preferably an aqueous solution comprising at least 1.9 wt.-%, more preferably at least 2.0 wt.-%, even more preferably at least 2.5 wt.-%, and most preferably at least 2.8 wt.-% esterified cellulose ether is prepared. Typically an aqueous solution comprising up to 30 wt.-%, more typically up to 25 wt.-%, even more typically up to 20 wt.-%, and most typically up to 16 wt.-% of the above-described esterified cellulose ether is prepared, based on the total weight of the aqueous solution.

The preferred concentration of esterified cellulose ether in the aqueous solution that is produced in step a) of the process of the present invention is dependent on the weight average molecular weight M_w of the esterified cellulose ether. When the esterified cellulose ether has a weight average molecular weight M_w of up to 40,000, the aqueous solution that is produced in step a) preferably comprises from 7.5 to 30 wt.-%, more preferably from 8 to 25 wt.-%, even more preferably from 10 to 20 wt.-%, and most preferably from 12 to 18 wt.-% of the above-described esterified cellulose ether, based on the total weight of the aqueous solution. When the esterified cellulose ether has a weight average molecular weight Mw of from 40,00 to 220,000 Dalton, it may be useful to prepare an aqueous solution that comprises from 2.5 to 15 wt.-%, more preferably from 2.8 to 10 wt.-%, and most preferably from 3.5 to 8 wt.-% esterified cellulose ether. When the esterified cellulose ether has a weight average molecular weight M_w of at least 220,000 Dalton, an aqueous solution is prepared that preferably comprises from 1.5 to 7.0 wt.-%, more preferably from 1.9 to 6.0 wt.-%, and most preferably from 2.5 to 4.5 wt.-% esterified cellulose ether.

The non-starch water-soluble polysaccharide which is useful in the process and the hydrogel of the present invention is different from an esterified cellulose ether described above. Advantageously, the non-starch water-soluble polysaccharide is not an esterified cellulose ether. The non-starch water-soluble polysaccharide has a solubility of at least 1 gram, more preferably at least 2 grams in distilled water at 25 °C and 1 atmosphere. The viscosity of the non-starch water-soluble polysaccharide, preferably a cellulose ether, more preferably an alkylcellulose or a hydroxyalkyl alkylcellulose, and most preferably a methylcellulose or a hydroxypropyl methylcellulose, is at least 600 mPa s, generally at least 1000 mPa-s, preferably at least 10,000 mPa-s, more preferably from 25,000 to 2,000,000 mPa-s, even more preferably from 50,000 to 800,000 mPa-s, and most preferably from 100,000 to 500,000, determined as a 2.0 % by weight solution in water at 20°C ± 0.1 °C by a Brookfield viscosity measurement as described in the US Pharmacopeia (USP 40) on Hypromellose.

Examples of non-starch polysaccharides include natural gums comprising a polysaccharide hydrocolloid containing mannose repeating units, carrageenans, pectins, amidated pectins, xanthan gum, gum karaya, gum tragacanth, alginates, gellan gum, guar derivatives, xanthan derivatives, furcellarans, rhamsan, cellulose derivatives, or mixture of two or more of such polysaccharides.

Hydrocolloids are well known to the person skilled in the art and polysaccharide hydrocolloids are polysaccharide-based compositions that form colloidal dispersions (also referred to as "colloidal solutions") in water. In preferred embodiments the polysaccharide hydrocolloid is selected from glucomannan, galactomannan, and mixtures thereof. Typically, the natural gum is a vegetable gum such as konjac gum, fenugreek gum, guar gum, tara gum, locust bean gum (carob gum), or a mixture of at least two of them.

Carrageenans are polysaccharides made of repeating units of galactose and 3,6- anhydrogalactose (3, 6- AG), both sulfated and nonsulfated. The units are joined by alternating la→3 and 1β→4 glycosidic linkages.

Guar derivatives and xanthan derivatives are described in more detail in European patent EP 0 504 870 B, page 3, lines 25-56 and page 4, lines 1-30. Useful guar derivatives are, for example, carboxymethyl guar, hydroxypropyl guar, carboxymethyl hydroxypropyl guar or cationized guar. Preferred hydroxypropyl guars and the production thereof are described in U.S patent No. 4,645,812, columns 4-6.

Preferred non-starch water-soluble polysaccharides are water-soluble cellulose ethers, more preferably alkyl celluloses, hydroxyalkyl celluloses or hydroxyalkyl alkylcelluloses, such as Ci-C3-alkyl celluloses, Ci-C3-alkyl hydroxy-Ci-3-alkyl celluloses, hydroxy-Ci-3-alkyl celluloses, mixed hydroxy-Ci-C3-alkyl celluloses, or mixed Ci-C3-alkyl celluloses. Typically one or two kinds of hydroxyalkoxyl groups are present in the cellulose ether. Preferably a single kind of hydroxyalkoxyl group, more preferably hydroxypropoxyl, is present.

Preferred alkyl hydroxyalkyl celluloses including mixed alkyl hydroxyalkyl celluloses are hydroxyalkyl methylcelluloses, such as hydroxyethyl methylcelluloses, hydroxypropyl methylcelluloses or hydroxybutyl methylcelluloses; or hydroxyalkyl ethyl celluloses, such as hydroxypropyl ethylcelluloses, ethyl hydroxyethyl celluloses, ethyl hydroxypropyl celluloses or ethyl hydroxybutyl celluloses; or ethyl hydroxypropyl methylcelluloses, ethyl hydroxyethyl methylcelluloses, hydroxyethyl hydroxypropyl methylcelluloses or alkoxy hydroxyethyl hydroxypropyl celluloses, the alkoxy group being straight-chain or branched and containing 2 to 8 carbon atoms. Preferred hydroxyalkyl celluloses are hydroxyethyl celluloses, hydroxypropyl celluloses or hydroxybutyl celluloses; or mixed hydroxylkyl celluloses, such as hydroxyethyl hydroxypropyl celluloses.

Preferred are hydroxyalkyl alkylcelluloses, more preferred are hydroxyalkyl methylcelluloses and most preferred are hydroxypropyl methylcelluloses, preferably those which have an MS(hydroxyalkoxyl) and a DS(alkoxyl) described below. The degree of the substitution of hydroxyl groups of the anhydroglucose units by hydroxyalkoxyl groups is expressed by the molar substitution of hydroxyalkoxyl groups, the MS (hydroxyalkoxyl). The MS (hydroxyalkoxyl) is the average number of moles of hydroxyalkoxyl groups per anhydroglucose unit in the cellulose ether. It is to be understood that during the hydroxyalkylation reaction the hydroxyl group of a hydroxyalkoxyl group bound to the cellulose backbone can be further etherified by an alkylation agent, e.g. a methylation agent, and/or a hydroxyalkylation agent. Multiple subsequent hydroxyalkylation etherification reactions with respect to the same carbon atom position of an anhydroglucose unit yields a side chain, wherein multiple hydroxyalkoxyl groups are covalently bound to each other by ether bonds, each side chain as a whole forming a hydroxyalkoxyl substituent to the cellulose backbone. The term "hydroxyalkoxyl groups" thus has to be interpreted in the context of the MS(hydroxyalkoxyl) as referring to the hydroxyalkoxyl groups as the constituting units of hydroxyalkoxyl substituents, which either comprise a single hydroxyalkoxyl group or a side chain as outlined above, wherein two or more

hydroxyalkoxy units are covalently bound to each other by ether bonding. Within this definition it is not important whether the terminal hydroxyl group of a hydroxyalkoxyl substituent is further alkylated, e.g. methylated, or not; both alkylated and non-alkylated hydroxyalkoxyl substituents are included for the determination of MS (hydroxyalkoxyl). The hydroxyalkyl alkylcelluloses of the invention generally has a molar substitution of hydroxyalkoxyl groups in the range of 0.05 to 1.00, preferably 0.08 to 0.70, more preferably 0.10 to 0.50, even more preferably 0.10 to 0.40, and most preferably 0.10 to 0.35.

The average number of hydroxyl groups substituted by alkoxyl groups, such as methoxyl groups, per anhydroglucose unit, is designated as the degree of substitution of alkoxyl groups, DS(alkoxyl). In the above-given definition of DS, the term "hydroxyl groups substituted by alkoxyl groups" is to be construed within the present invention to include not only alkylated hydroxyl groups directly bound to the carbon atoms of the cellulose backbone, but also alkylated hydroxyl groups of hydroxyalkoxyl substituents bound to the cellulose backbone. The hydroxyalkyl alkylcelluloses according to this invention preferably have a DS(alkoxyl) in the range of 1.0 to 2.5, more preferably 1.1 to

2.2, and most preferably 1.25 to 2.10. Most preferably the cellulose ether is a hydroxypropyl methylcellulose or hydroxy ethyl methylcellulose having a DS (methoxyl) within the ranges indicated above for DS(alkoxyl) and an MS(hydroxypropoxyl) or an MS (hydroxy ethoxyl) within the ranges indicated above for MS (hydroxyalkoxyl). The degree of substitution of alkoxyl groups and the molar substitution of hydroxyalkoxyl groups can be determined by Zeisel cleavage of the cellulose ether with hydrogen iodide and subsequent quantitative gas chromatographic analysis (G. Bartelmus and R. Ketterer, Z. Anal. Chem., 286 (1977) 161- 190). When the hydroxyalkyl alkylcellulose is a hydroxypropyl methylcellulose, the determination of the % methoxyl and % hydroxypropoxyl in HPMC is carried out according to the United States Pharmacopeia (USP 40). The values obtained are % methoxyl and % hydroxypropoxyl. These are subsequently converted into degree of substitution (DS) for methyl substituents and molar substitution (MS) for hydroxypropyl substituents.

Also preferred are methylcelluloses. Methylcellulose are cellulose derivatives wherein the hydroxyl groups of the anhydroglucose units in the cellulose backbone are not substituted with other groups than methyl groups. Methylcellulose can be characterized by the weight percent of methoxyl groups. By convention, the weight percent is an average weight percentage based on the total weight of the cellulose repeat unit, including all substituents. The content of the methoxyl group is reported based on the mass of the methoxyl group (i.e.,— OCH3). The determination of the % methoxyl in methylcellulose (MC) polymer is carried out according to the United States Pharmacopeia (USP 37, "Methylcellulose", pages 3776-3778). The % methoxyl can be converted into degree of substitution (DS) for methyl substituents, DS(methyl). DS(methyl), also designated as DS(methoxyl), of a methylcellulose is the average number of OH groups substituted with methyl groups per anhydroglucose unit. Preferably, the methylcellulose has % methoxyl of 18% or more; more preferably 25% or more. Preferably, the methylcellulose has % methoxyl of 40% or less; more preferably 35% or less. Even more preferably,

methylcellulose has a DS(methyl) of 1.55 or higher; more preferably 1.65 or higher; and most preferably 1.70 or higher. DS(methyl) is preferably 2.25 or lower; more preferably 2.20 or lower; and most preferably 2.10 or lower. Most preferred methylcelluloses are those that gel in water at a relatively low temperature, such as 38 to 44 °C or even lower. Such methylcelluloses are disclosed in US Patent No. 6,235,893 and in International Patent Applications WO2011/139763 and WO2014/168915.

The above described non-starch water-soluble polysaccharide is generally incorporated in such amount in the aqueous solution in step a) that the weight ratio between the above described esterified cellulose and the non-starch water-soluble polysaccharide is from 50 : 1 to 1 : 1, typically from 35 : 1 to 2 : 1, preferably from 25 : 1 to 4 : 1, more preferably from 20 : 1 to 6 : 1, even more preferably from 15 : 1 to 7 : 1, and most preferably from 12 : 1 to 8 : 1.

Water or the aqueous solution of the esterified cellulose ether and/or the non-starch water-soluble polysaccharide may be mixed with a minor amount of one or more organic liquids which are preferably physiologically acceptable, such as ethanol or one or more animal or vegetable oils, but the total amount of organic liquids is preferably not more than 10 percent, more preferably not more than 5 percent, even more preferably not more than 2 percent, based on the total weight of water and organic liquid. Most preferably, the aqueous liquid is not mixed with an organic liquid.

The aqueous solution prepared in step a) may comprise one or more active ingredients, such as fertilizers, herbicides or pesticides, or biologically active ingredients, such as vitamins, herbals and mineral supplements or drugs. The term "drug" is conventional, denoting a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially humans. The amount of the active ingredients generally is not more than 15 percent, preferably not more than 10 percent, more preferably not more than 5 percent, and most preferably not more than 2 percent, based on the total weight of the aqueous solution.

Other optional ingredients in the aqueous solution prepared in step a) are additives, such as coloring agents, pigments, opacifiers, flavoring agents, antioxidants, preservatives, salts, preferably inorganic salts, such as sodium chloride, potassium chloride, calcium chloride, or magnesium chloride; or combinations thereof. Examples of flavoring agents are sugars, artificial sweeteners, varying types of cocoa, pure vanilla or artificial flavor, such as vanillin, ethyl vanillin, chocolate, malt, and mint, extracts or spices, such as cinnamon, nutmeg and ginger; antioxidants, The amount of these additives is generally not more than 15 percent, preferably not more than 10 percent, more preferably not more than 5 percent, and most preferably not more than 2 percent, based on the total weight of the aqueous solution.

The optional ingredients are preferably pharmaceutically acceptable. The optional ingredients like active ingredients or additives may be added to the esterified cellulose ether and/or the non-starch water-soluble polysaccharide, to water and/or to the aqueous solution before or during the process for producing the aqueous solution of esterified cellulose ether and/or the non-starch water-soluble polysaccharide as described above. Alternatively, optional ingredients may be added after the preparation of the aqueous solution.

In step a) of the process, wherein an aqueous solution of an esterified cellulose ether is prepared, the above described esterified cellulose ether is typically utilized in ground and dried form. The esterified cellulose ether and the non- starch water-soluble polysaccharide are generally mixed with water while cooling the aqueous mixture to a temperature of not higher than 10 °C, preferably not higher than 8 °C, more preferably not higher than 6.5 °C, even more preferably not higher than 5 °C, and particularly from 0.5 to 2 °C.

Generally the aqueous solution prepared in step a) of the present invention is gelatin- free. Other than the esterified cellulose ether and/or the non-starch water-soluble polysaccharide described above, the aqueous solution prepared in step a) of the present invention preferably does not comprise a significant amount of ingredients, such as thickeners or gelling agents, that are able to increase the gel strength of the produced hydrogel at room temperature (21 °C) or at a lower temperature. The non- starch water- soluble polysaccharide such as a water-soluble cellulose ether, preferably a hydroxypropyl methylcellulose, typically does not form a gel at room temperature or lower. Many of the non-starch water-soluble polysaccharides form gels at 50 - 60 °C or higher, depending on their concentration in water, but melt back to liquid aqueous solutions at room temperature.

The sum of the esterified cellulose ether and water is generally at least 70 percent, preferably at least 80 percent, more preferably at least 90 percent, and most preferably at least 95 percent, based on the total weight of the aqueous solution prepared in step a).

In step b) of the process of the present invention, the aqueous solution of step a) is heated to form a hydrogel from the aqueous solution. It is known that aqueous solutions of the esterified cellulose ether described in more details above can gel at a temperature as low as about 30 °C. Increasing the concentration of the esterified cellulose ether or incorporating active ingredients or optional additives, such as tonicity-adjusting agents in the aqueous solution in step a) of the process of the present invention lowers the gelation temperature of the aqueous solution. For practical reasons the aqueous solution of step a) is generally heated to a temperature of at least 55 °C, preferably at least 65 °C, more preferably at least 70 °C, even more preferably at least 75 °C, and most preferably at least 80 °C to form a hydrogel from the aqueous solution. Generally the aqueous solution is heated to a temperature of up to 95 °C, typically up to 90 °C, and more typically up to 87 °C.

In step c) of the process of the present invention, the formed hydrogel is maintained at least at a temperature at which the hydrogel has been formed in step b) for a sufficient time period to liberate at least 15 weight percent of water from the hydrogel, based on the weight of water in the aqueous solution in step a). Generally at least 30 wt.-%, preferably at least 40 wt.-%, even more preferably at least 45 wt.-%, and most preferably even at least 50 weight percent of water is liberated from the hydrogel. In the most preferred embodiments of the process even at least 55 wt.-% of water is liberated from the hydrogel. Generally up to 90 wt.-%, preferably up to 85 wt.-%, more preferably up to 80 wt.-%, even more preferably up to 75 wt.-%, and most preferably up to 70 wt.-% , and in some embodiments up to 60 wt.-% of water is liberated from the hydrogel, based on the weight of water in the aqueous solution in step a). In any event a sufficient amount of water is liberated from the hydrogel such that the remaining water content in the hydrogel is from 15 to 91.0 weight percent, based on the total weight of the hydrogel. The remaining water content of the hydrogel is preferably up to 88.0 wt.-%, more preferably up to 86.0 wt.-%, even more preferably at least 84.0 wt.-%, and most preferably up to 82.0 weight percent, based on the total weight of the hydrogel. In some embodiments of the invention the remaining water content of the hydrogel is only up to 80.0 wt.-% or even only up to 75.0 wt.-%, based on the total weight of the hydrogel. The remaining water content of the hydrogel is preferably at least 30 wt.-%, more preferably at least 40 wt.-%, even more preferably at least 50 wt.-%, and most preferably at least 60 weight percent, based on the total weight of the hydrogel. In some embodiments of the invention the remaining water content of the hydrogel is even at least 65 wt.-%, based on the total weight of the hydrogel.

For practical reasons the formed hydrogel is generally maintained at a temperature of at least 55 °C, preferably at least 65 °C, more preferably at least 70 °C, even more preferably at least 75 °C, and most preferably at least 80 °C. Generally the temperature in step c) is up to 95 °C, typically up to 90 °C, and more typically up to 87 °C. Generally maintaining the formed hydrogel at an above-mentioned temperature for at least 1 hour, preferably at least 1.5 hours, more preferably for at least 2 hours, and most preferably at least 3 hours is sufficient for expelling or liberating an amount of water as described above. During the heating of the hydrogel for an extended time period as described above, syneresis takes place and water is expelled or liberated from the hydrogel. Water is typically liberated from the hydrogel in its liquid state, however a portion of the expelled or liberated water can evaporate. In some embodiments of the invention even most or all of the expelled or liberated water can directly evaporate, e.g., by placing the formed hydrogel on a sieve or in or on another device that facilitates water evaporation. The preferred time periods to liberate an amount of water and to achieve a remaining water content as described above depends on the temperature and on the concentration of the esterified cellulose ether in the aqueous solution. The higher the chosen temperature and the concentration of the esterified cellulose ether, the less time period is generally needed to expel the desired amount of water.

Generally the formed hydrogel is maintained at an above-mentioned temperature for a time period of up to 12 hours, typically up to 10 hours, more typically up to 8 hours and in preferred embodiments up to 6 hours. Syneresis of hydrogels formed from the esterified cellulose ether and water is known. However, it is important in the present invention to cause sufficient syneresis by heating to liberate an amount of as described above. In step d) liberated water is separated from the hydrogel and the hydrogel is cooled to a temperature of 25 °C or less or to 23 °C or less or to 21 °C or less simultaneously or in any sequence. Typically the hydrogel is cooled to a temperature of 0 °C or more, more typically of 4 ° or more. Preferably liberated water is separated from the hydrogel before, while or shortly after the hydrogel is cooled to a temperature of 25 °C or less. It is preferred to separate liberated water from the hydrogel within 24 hours, preferably within 12 hours, and more preferably within 3 hours upon completion of step c). Generally at least 80 percent, preferably at least more 85 percent, more preferably at least 90 percent, most preferably at least 95 percent, and particularly at least 98 percent of the liberated water is separated from the hydrogel, for example by draining or contacting the hydrogel with a cloth or another article that is able to remove liberated water from the hydrogel. If desired, in step d) the hydrogel can even be cooled to a temperature of 0 °C or less, e.g., to a temperature of 0 °C to - 20 °C, more typically of 0 °C to - 10 °C. It is advisable to separate liberated water from the hydrogel before cooling the hydrogel to such a low temperature. For practical reasons the hydrogel is preferably cooled to a temperature of 23 °C to 4 °C.

Surprisingly, it has been found that the produced hydrogel does not display any melt back, remains a gel and keeps its shape even when it is stored for hours or days at a temperature of 25 °C or less, such as 23 °C to 4 °C.

Preferred embodiments of the produced hydrogel have a gel fracture force FG_F(21 °C) of at least 10 N, more preferably at least 12 N, even more preferably at least 14 N and in the most preferred embodiments even at least 16 N. Typically the produced hydrogels have a gel fracture force FG_F(21 °C) of up to 90 N, more typically up to 85 N, and most typically up to 80 N. How to determine the gel fracture force FGF(21 °C) is described in the Examples section.

Another aspect of the present invention is a hydrogel that has been formed from an esterified cellulose ether and water by heat treatment and syneresis and that additionally comprises a non-starch water-soluble polysaccharide being different from the n esterified cellulose ether, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 15 to 91.0 weight percent, based on the total weight of the hydrogel. The esterified cellulose ether and the non-starch water-soluble polysaccharide in the hydrogel are as described in detail above. The water content of the hydrogel is preferably up to 88.0 wt.-%, more preferably up to 86.0 wt.-%, even more preferably up to 84.0 wt.-% and most preferably up to 82.0 weight percent, based on the total weight of the hydrogel. In some embodiments of the invention the water content of the hydrogel is only up to 80.0 wt.-% or even only up to 75.0 wt.-%, based on the total weight of the hydrogel. The water content of the hydrogel is preferably at least 30 wt.-%, more preferably at least 40 wt.-%, even more preferably at least 50 wt.-% and most preferably at least 60 weight percent, based on the total weight of the hydrogel. In some embodiments of the invention the water content of the hydrogel is even at least 65 wt.-%, based on the total weight of the hydrogel.

The term "formed by heat treatment and syneresis" as used herein means that heat treatment is sufficient to liberate at least 15 weight percent of water from the hydrogel, based on the weight of water used to form the hydrogel. The term "formed by heat treatment and syneresis" preferably means that heat treatment is sufficient to liberate at least 15 wt.-%, preferably at least 30 wt.-%, more preferably at least 40 wt.-%, even more preferably at least 45 wt.-%, most preferably even at least 50 wt.-% of water and in the most preferred embodiments even at least 55 weight percent of water from the hydrogel, based on the weight of water used to form the hydrogel. In the hydrogel formed from the esterified cellulose ether and the non-starch water-soluble polysaccharide by heat treatment and syneresis generally up to 90 wt.-%, preferably up to 85 wt.-%, more preferably up to 80 wt.-%, even more preferably up to 75 wt.-%, and most preferably up to 70 wt.-% and in some embodiments up to 60 wt.-% of water has been liberated from the hydrogel, based on the weight of water used to form the hydrogel. Ways to conduct the heat treatment are described further above.

The hydrogel of the present invention preferably has a gel fracture force FG_F( 1 °C) of at least 10 N, more preferably at least 12 N, even more preferably at least 14 N and in the most preferred embodiments even at least 16 N. Typically the hydrogel has a gel fracture force FGF(21 °C) of up to 30 N, more typically of up to 22 N. How to determine the gel fracture force FGF(21 °C) is described in the Examples section.

The hydrogel of the present invention may comprise a minor amount of one or more organic liquids which are preferably physiologically acceptable, such as ethanol or one or more animal or vegetable oils, but the total amount of organic liquids is preferably not more than 10 percent, more preferably not more than 5 percent, even more preferably not more than 2 percent, based on the total weight of water and organic liquid in the hydrogel at a temperature of 21 °C. Most preferably, the hydrogel does not comprise an organic liquid.

The hydrogel of the present invention may comprise one or more active ingredients, such as fertilizers, herbicides or pesticides, or biologically active ingredients, such as vitamins, herbals and mineral supplements or drugs. The amount of the active ingredients generally is not more than 15 percent, preferably not more than 10 percent, more preferably not more than 5 percent, and most preferably not more than 2 percent, based on the total weight of the hydrogel at a temperature of 21 °C.

Other optional ingredients are additives, such as coloring agents, pigments, opacifiers, flavoring agents, antioxidants, preservatives, salts, such as sodium chloride, or combinations thereof. Examples of flavoring agents are sugars, artificial sweeteners, varying types of cocoa, pure vanilla or artificial flavor, such as vanillin, ethyl vanillin, chocolate, malt, and mint, extracts or spices, such as cinnamon, nutmeg and ginger; antioxidants, Optional ingredients are preferably pharmaceutically acceptable. The amount of these additives is generally not more than 15 percent, preferably not more than 10 percent, more preferably not more than 5 percent, and most preferably not more than 2 percent, based on the total weight of the hydrogel at a temperature of 21 °C.

The hydrogel of the present invention is formed from the esterified cellulose ether and water. This means that no other gelling agents than the above described esterified cellulose ether are needed for gel formation at room temperature (21 °C) or lower. Generally the hydrogel of the present invention is gelatin-free. Other than the esterified cellulose ether and the non-starch water-soluble polysaccharide (B) described above, the hydrogel preferably does not comprise a significant amount of ingredients, such as thickeners or gelling agents that are able to increase the gel strength of the hydrogel at room temperature (21 °C) or at a lower temperature. The non-starch water-soluble polysaccharide, such as a water-soluble cellulose ether, preferably a hydroxypropyl methylcellulose, typically does not form a gel at room temperature or lower. Many of the above-mentioned non-starch water-soluble polysaccharides form gels at 50 - 60 °C or higher, depending on their concentration in water, but melt back to liquid aqueous solutions at room temperature.

The sum of the esterified cellulose ether and water is generally at least 70 percent, preferably at least 80 percent, more preferably at least 90 percent, and most preferably at least 95 percent, based on the total weight of the hydrogel.

Some embodiments of the invention will now be described in detail in the following Examples. EXAMPLES

Unless otherwise mentioned, all parts and percentages are by weight. In the

Examples the following test procedures are used. Content of ether and ester groups of Hydroxypropyl Methylcellulose Acetate

Succinate (HPMCAS)

The ester substitution with acetyl groups (-CO-CH3) and the ester substitution with succinoyl groups (-CO-CH2-CH2-COOH) are determined according to Hypromellose Acetate Succinate, United States Pharmacopeia and National Formulary, NF 29, pp. 1548- 1550". Reported values for ester substitution are corrected for volatiles (determined as described in section "loss on drying" in the above HPMCAS monograph).

Determination of M_w, M_n and M_z

Mw, Mn and M_z are measured according to Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 743 unless stated otherwise. The mobile phase is a mixture of 40 parts by volume of acetonitrile and 60 parts by volume of aqueous buffer containing 50 mM

NaH2P0₄ and 0.1 M NaNCh. The mobile phase is adjusted to a pH of 8.0. Solutions of the cellulose ether esters are filtered into a HPLC vial through a syringe filter of 0.45 μιη pore size. The exact details of measuring M_w and M_n are disclosed in the International Patent Application No. WO 2014/137777 in the section "Examples" under the title "Determination

Determination of the Gel Fracture Forces G_F(21 °C) and G_F(4 °C) of the Hydrogel The gel fracture forces GF(21 °C) and GF(4 °C) are measured with a Texture Analyzer (model TA.XTPlus; Stable Micro Systems, 5-Kg load cell) at 21°C. The gels are compressed between a steel plate (90mmxl00mmx9mm with a filter paper0110mm

"2294" from Whatman and then a filter vlies 0110mm "0980/1" from Whatman on the top of the plate) and a Teflon cylinder (diameter: 50mm, height: 20mm) with the following parameters: speed until first sample contact: 1.5mm sec, speed of compression: 1.00 mm sec, trigger force: 0.005N, maximum distance: 20 mm). The plate displacement [mm] and compression force [N] is measured at selected time intervals (400 points/s) until the gel collapses. The maximum compressional force is the maximum height of the peak during gel collapse. It is identified as G_F(21 °C) or G_F(4 °C), depending on the temperature at which the gel fracture force is measured. Production of HPMCAS-I

19.9 g of acetic anhydride are stirred in 176 g of glacial acetic acid. 3.2 g of succinic anhydride, 57 g of sodium acetate (water free) and 67 g of hydroxypropyl methyl cellulose (HPMC, water free) are added under stirring. The amount of HPMC is calculated on a dried basis. The HPMC has a methoxyl substitution (DS_M) of 1.92 and hydroxypropoxyl substitution (MS_HP) of 0.24 and a viscosity of 3.2 mPa-s, measured as a 2 % solution in water at 20 °C according to ASTM D2363 - 79 (Reapproved 2006). The HPMC is commercially available from The Dow Chemical Company as Methocel E3 cellulose ether.

Then the reaction mixture is heated up to and allowed to react for 3 hours. Then the crude product is precipitated by adding 4 L of hot water (temperature about 95 °C).

Subsequently the precipitated product is separated from the mixture by filtration. The separated product is washed several times by re-suspension under high-shear with hot water, each time followed by filtration. Then the product is dried at 55°C overnight.

The HPMCAS-I has these properties:

Methoxyl groups: 26.7 %; hydroxypropoxyl groups: 8.0 %; acetyl groups: 5.5%; and succinoyl groups; 3.6%. This corresponds to a

DS_M = DS(methoxyl): degree of substitution with methoxyl groups: 1.92;

MS_HP = MS (hydroxypropoxyl): molar subst. with hydroxypropoxyl groups: 0.24;

DSAC = degree of substitution of acetyl groups: 0.28; and

DSs = degree of substitution of succinoyl groups: 0.08.

M_n: 20,000 Dalton; M_w: 31,000 Dalton; and M_z: 106,000 Dalton.

Production of HPMCAS-II

90 g of acetic anhydride are stirred in 1000 g of glacial acetic acid. 20 g of succinic anhydride, 25 g of sodium acetate (water free) and 50 g of hydroxypropyl methyl cellulose (HPMC, water free) are added under stirring. The amount of HPMC is calculated on a dried basis. The HPMC has a methoxyl substitution (DSM) of 1.92 and hydroxypropoxyl substitution (MSHP) of 0.25 and a viscosity of 4,100 mPa-s, measured as a 2 % solution in water at 20 °C according to ASTM D2363 - 79 (Reapproved 2006). The HPMC is commercially available from The Dow Chemical Company as Methocel E4M cellulose ether. Then the reaction mixture is heated up, allowed to react and processed as described above for HPMCAS-I.

The HPMCAS-II has these properties: Methoxyl groups: 26.4 %; hydroxypropoxyl groups: 8.5 %; acetyl groups: 4.5%; and succinoyl groups; 5.9 %. This corresponds to a

DSM = DS(methoxyl): degree of substitution with methoxyl groups: 1.94;

MSHP = MS (hydroxypropoxyl): molar subst. with hydroxypropoxyl groups: 0.26;

DSA_C = degree of substitution of acetyl groups: 0.24; and

DSs = degree of substitution of succinoyl groups: 0.13.

M_n: 232,000 Dalton; M_w: 339,000 Dalton; and M_z: 543,000 Dalton.

Reference Example I (Not Prior Art)

HPMCAS-I is used that has been produced as described above and that has the properties as described above. 30.0 g of an aqueous HPMCAS-I solution having a

HPMCAS-I concentration as listed in Table 1 below is prepared in a glass container by stirring at 1000 rpm in an ice bath for 6 hours and storage overnight in a refrigerator. Then the solution is centrifuged (Sorvall Lynx 4000 centrifuge at 4000 rpm at 10°C) until the solutions are free of air bubbles.

The aqueous solution is then heated to 85 °C and kept at 85 °C for the time period listed in Table 1 below. The temperature of 85 °C is held by placing the glass container in an oven maintained at 85 °C. Alternatively, the glass container can be placed in a water bath of corresponding temperature. The aqueous solution gels at 85 °C. During the heat treatments the hydrogel undergoes syneresis wherein the entire amount of HPMCAS-I remains in the hydrogel and a large portion of the water originally present in the aqueous solution is expelled from the hydrogel. The hydrogel is removed from the liberated water, mechanically dried with a tissue and weighed while the gel is still hot. The % liberated water after the heat treatment is calculated according to the formula:

[1 - (g gel - g HPMCAS in aq. sol.) / (g aq. solution - g HPMCAS in aq. solution)] x 100. The remaining water content of the produced hydrogel after heating is calculated from the weight of the hydrogel and the HPMCAS weight of the starting aqueous solution, which corresponds to the HPMCAS weight in the hydrogel.

The produced hydrogel is placed on a glass plate without delay and allowed to cool to room temperature. The texture of the hydrogel is assessed immediately after heat treatment, removal of expelled water and cooling to room temperature, but before storage in a refrigerator. The produced hydrogel is then placed in a bag and stored at 4 °C for 3 days. The consistency of the hydrogel is assessed after this time period. The results are listed in Table 1 below. Examples 1 and 2

The experiments are carried out as described for Reference Example I, except that a blend of HPMCAS-I and hydroxypropyl methylcellulose (HPMC) at a weight ratio of 9 : 1 is dissolved in water. The HPMCAS-I has the properties described further above.

The HPMC has a methoxyl content of 23 % and a hydroxypropoxyl content of 9 %, corresponding to a DS(methoxyl) of 1.45 and an MS (hydroxypropoxyl) of 0.24. The determination of the % methoxyl and % hydroxypropoxyl in HPMC is carried out according to the United States Pharmacopeia (USP 40). The values obtained are % methoxyl and % hydroxypropoxyl. The HPMC has a viscosity of about 245,000 mPa»s, determined as a 2.0 % by weight solution in water at 20°C ± 0.1 °C by an Brookfield viscosity

measurement, as described in the US Pharmacopeia (USP 40) on Hypromellose.

Aqueous solutions are prepared which have a total polymer content of 10 wt.-% or 15 wt.-%, respectively. A 10 wt.-% aqueous solution contains 9.0 wt.-% HPMCAS-I and 1.0 wt.-% HPMC. A 15 wt.-% aqueous solution contains 13.5 wt.-% HPMCAS-I and 1.5 wt-% HPMC. The results are listed in Table 1 below.

Examples 1 and 2 illustrate that reasonably high concentrations of HPMC can be incorporated in the gels to consume the prescribed amount of dietary fiber, such as HPMC, in sufficient quantities without consuming excessive quantities of the hydrogel and without consuming a substantial amount of calories.

Table 1

Reference Examples II - VIII and Comparative Examples A - E (Not Prior Art)

The same procedure as for Reference Example 1 is carried out except that aqueous HPMCAS-II solutions are prepared and gelled under the conditions as listed in Table 4 below. The Reference Examples and Comparative Examples illustrate that stable hydrogels from water and HPMCAS-II that do not melt back at room temperature or even at 4 °C can also be produced at lower concentrations than in Reference Example I and Examples 1 and 2. Reference Example IX and Comparative Example F (Not Prior Art)

In both experiments a 2 wt.-% aqueous solution of HPMCAS-II is prepared as described for Reference Example I. The solution is heated to a temperature for the time period as listed in Table 2 below. Both aqueous solutions gel. Water is expelled during the heat treatment at different degrees. The degree of expelled water (syneresis water) is only qualitatively assessed. A large amount of water is expelled during the heat treatment of

Reference Example IX; a very low amount of water is expelled during the heat treatment of Comparative Example F. The expelled water is separated from the hydrogels. The hydrogels are mechanically dried with a tissue. The produced hydrogels are then stored at 4 °C for several weeks. The gel of Comparative Example F melts after 3 hours. The gel of Reference Example IX does not melt even after storage at 4 °C for several weeks.

Table 2

The Reference Examples do not comprise a non-starch water-soluble polysaccharide. The Reference Examples are incorporated herein to illustrate that in steps b) and c) of the process of the present invention heating to a certain temperature during a certain time period is needed, as described in the general description, to be able to prepare a thermostable hydrogel from the esterified cellulose ether and water that does not melt back when cooled to room temperature or even to 4 °C. Reference Examples X- XII and Comparative Examples G and H (Not Prior Art) The experiments are carried out as described for Reference Example I applying the conditions listed in Table 3 below. The gel fracture forces _GF(21 °C) of the produced hydrogels are determined after having stored the gels overnight at the temperature listed in Table 3 below. Table 3 below provides a rough correlation between the results of the visually inspected gels and the measured gel fraction forces.

Table 3

not measurable

Table 4

Claims

1. A hydrogel formed from an esterified cellulose ether and water by heat treatment and syneresis and additionally comprising a non-starch water-soluble

polysaccharide having a viscosity of at least 600 mPa-s, determined as a 2.0 % by weight solution in water at 20°C, and being different from the esterified cellulose ether wherein the hydrogel, at a temperature of 21 °C, has a water content of from 15 to 91.0 weight percent, based on the total weight of the hydrogel, and

the esterified cellulose ether comprises aliphatic monovalent acyl groups and groups of the formula - C(O) - R - COOH, R being a divalent hydrocarbon group, wherein I) the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4 and II) the total degree of ester substitution is from 0.03 to 0.70.

2. The hydrogel of claim 1, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 30 to 88 weight percent, based on the total weight of the hydrogel.

3. The hydrogel of claim 1 or 2, wherein the esterified cellulose ether is a hydroxypropyl methylcellulose acetate succinate.

4. The hydrogel of any one of claims 1 to 3, wherein the non-starch water- soluble polysaccharide is a water-soluble cellulose ether.

5. The hydrogel of claim 4, wherein the non-starch water-soluble

polysaccharide is a water-soluble Ci-C3-alkyl cellulose, Ci-C3-alkyl hydroxy-Ci-3-alkyl cellulose, hydroxy-Ci-3-alkyl cellulose, mixed hydroxy-Ci-C3-alkyl cellulose, or mixed Ci- C3-alkyl cellulose.

6. The hydrogel of claim 5, wherein the non-starch water-soluble

polysaccharide is a hydroxypropyl methylcellulose.

7. The hydrogel of any one of claims 1 to 6, wherein the non-starch water- soluble polysaccharide has a viscosity of at least 1000 mPa-s, determined as a 2.0 % by weight solution in water at 20°C.

8. The hydrogel of any one of claims 1 to 7, wherein the weight ratio between the esterified cellulose ether and the non-starch water-soluble polysaccharide is from 50 : 1 to 1 : 1.

9. The hydrogel of any one of claims 1 to 8, wherein additionally one or more active ingredients and/or one or more additives selected from coloring agents, pigments, opacifiers, flavoring agents, antioxidants, preservatives and salts are incorporated.

10. The hydrogel of any one of claims 1 to 9 having a gel fracture force

GF(21 °C) of at least IO N.

11. A process for producing a hydrogel from an esterified cellulose ether and water and additionally incorporating in the hydrogel a non- starch water-soluble

polysaccharide having a viscosity of at least 600 mPa-s, determined as a 2.0 % by weight solution in water at 20°C, and being different from the esterified cellulose, wherein the process comprises the steps of

a) preparing an aqueous solution comprising

i) at least 1.5 wt.-%, based on the total weight of the aqueous solution, of an esterified cellulose ether comprising aliphatic monovalent acyl groups and groups of the formula

- C(O) - R - COOH, R being a divalent hydrocarbon group, wherein I) the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4 and II) the total degree of ester substitution is from 0.03 to 0.70, and

ii) a non-starch water-soluble polysaccharide having a viscosity of at least 600 mPa-s, determined as a 2.0 % by weight solution in water at 20°C, and being different from the esterified cellulose ether,

b) heating the aqueous solution of step a) to form a hydrogel from the aqueous solution,

c) maintaining the formed hydrogel at least at a temperature at which the hydrogel has been formed in step b) for a sufficient time period such that i) the remaining water content in the formed hydrogel is from 15 to 91.0 weight percent, based on the total weight of the hydrogel, and ii) at least 15 weight percent of water are liberated from the hydrogel, based on the water weight in the aqueous solution in step a), and d) separating liberated water from the hydrogel and cooling the hydrogel to a temperature of 25 °C or less simultaneously or in any sequence.

12. The process of claim 11, wherein in step b) the aqueous solution is heated to a temperature of at least 55 °C and in step c) the formed hydrogel is maintained for a time period of at least 1 hour at a temperature of at least 55 °C.

13. The process of claim 11 or 12, wherein in step a) an aqueous solution comprising from 7.5 to 30 wt.-% of the esterified cellulose ether is prepared, when the esterified cellulose ether has a weight average molecular weight M_w of up to 40,000 Dalton.

14. The process of claim 11 or 12, wherein in step a) an aqueous solution comprising from 2.5 to 15 wt.-% of the esterified cellulose ether is prepared, when the esterified cellulose ether has a weight average molecular weight M_w of from 40,000 to 220,000 Dalton.

15. The process of claim 11 or 12, wherein in step a) an aqueous solution comprising from 1.5 to 7.0 wt.-% of the esterified cellulose ether is prepared, when the esterified cellulose ether has a weight average molecular weight M_w of at least 220,000 Dalton.