WO2019022819A1

WO2019022819A1 - Process for producing hydrogels based on esterified cellulose ethers of low molecular weight

Info

Publication number: WO2019022819A1
Application number: PCT/US2018/033808
Authority: WO
Inventors: Oliver Petermann
Original assignee: Dow Global Technologies LLC
Current assignee: Dow Global Technologies LLC
Priority date: 2017-07-26
Filing date: 2018-05-22
Publication date: 2019-01-31
Anticipated expiration: 2020-01-26

Abstract

A stable hydrogel can be formed from an esterified cellulose ether and water by heat treatment and syneresis, wherein the hydrogel, at a temperature of 21 C, has a water content of from 15 to 81.0 weight percent, based on the total weight of the hydrogel, and the esterified cellulose ether has a weight average molecular weight Mw of up to 80,000 Dalton and comprises groups of the formula - C(O) - R - COOH or a combination of aliphatic monovalent acyl groups and groups of the formula -C(O) - R - COOH, wherein R is a divalent hydrocarbon group, and wherein the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4.

Description

PROCESS FOR PRODUCING HYDROGELS BASED ON ESTERIFIED CELLULOSE ETHERS OF LOW MOLECULAR WEIGHT

FIELD

The present invention relates to novel hydrogels and a process for preparing them.

INTRODUCTION

Some esterified cellulose ethers are widely used and accepted in pharmaceutical applications, for example for the production of hard capsules or as tablet coatings. When the esterified cellulose ethers comprise ester groups which carry carboxylic groups, the solubility of the esterified cellulose ethers in aqueous liquids is typically dependent on the pH. For example, the solubility of hydroxypropyl methyl cellulose acetate succinate (HPMCAS) in aqueous liquids is pH-dependent due to the presence of succinate groups, also called succinyl groups or succinoyl groups. HPMCAS is known as enteric polymer for the production of hard capsules, tablet coatings or as a matrix polymer in tablets. In the acidic environment of the stomach HPMCAS is protonated and therefore insoluble.

HPMCAS undergoes deprotonation and becomes soluble in the small intestine, which is an environment of higher pH. Tablets coated with HPMCAS protect the drug from inactivation or degradation in the acidic environment of the stomach or prevent irritation of the stomach by the drug but release the drug in the small intestine. Moreover, esterified cellulose ethers, such as HPMCAS, are known for improving the solubility of poorly water-soluble drugs. The esterified cellulose ether is aimed at reducing the crystallinity of the drug, thereby minimizing the activation energy necessary for the dissolution of the drug, as well as establishing hydrophilic conditions around the drug molecules, thereby improving the solubility of the drug itself to increase its bioavailability, i.e., its in vivo absorption by an individual upon ingestion.

International patent applications WO2016/148976, WO2016/148977 and WO 2016/148973 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. This makes them very suitable for coating pharmaceutical dosage forms, such as tablets, or for producing capsule shells.

International patent application WO2017/099952 discloses that gels formed from aqueous solutions of such esterified cellulose ethers, such as HPMCAS, display expulsion of water from the gels at further increased temperatures, for example above 60 °C, or more typically at 70 °C or more. This phenomenon is known as "syneresis".

WO2017/099952 discloses that in applications where gel formation is desired at elevated temperature, such as the production of capsules shells wherein heated dipping pins are used, syneresis is undesired as it causes a breakdown of the gel structure. Adding a low viscosity cellulose ether, such as a viscosity hydroxypropyl methylcellulose, to the aqueous solutions of such esterified cellulose ethers, such as HPMCAS, is useful for reducing or preventing syneresis.

Although esterified cellulose ethers comprising ester groups which carry carboxylic groups, such as HPMCAS, are very useful and widely used as enteric polymer for the production of hard capsules, tablet coatings or as a matrix polymer in tablets, there is an urgent need to find new dosage forms for active ingredients. Some people have difficulties to swallow tablets or capsules, for example elderly people or children. The administration of tablets or capsules to pets or other animals is also difficult.

Therefore, chewable gels, also designated as gummies or pastilles, are also used as pharmaceutical or nutritional dosage forms. Chewable gels are particularly useful for administering nutritional supplements like vitamins or minerals or for applying

pharmaceuticals for the treatment of the oral cavity or throat, such as the treatment of sore throat or cough. Chewable gels are typically based on gelatin. Gelatin readily dissolves in hot water and sets to a gel on cooling. The most common materials for producing gelatin are pig skin, bovine hides or bones. Hence, there is great reluctance by many consumers to ingest such chewable capsules, e.g., for religious or other reasons, such as concerns about Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease.

Moreover, gelatin does not have enteric properties.

Therefore, there is an urgent need to provide gelatin-free gels. There is another urgent need to provide gels that are based on polymers that are able to improve the solubility of poorly water-soluble drugs and/or display enteric properties. Unfortunately, esterified cellulose ethers comprising ester groups which carry carboxylic groups, such as HPMCAS, do not present themselves as an alternative to gelatin due to their gelling behavior. 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 (20 °C) or less the gel transforms into a liquid aqueous solution. Gels that melt back to aqueous solutions when the gels cool down to room temperature or even refrigerator temperature are normally unsuitable as dosage forms for active ingredients, such as drugs. Producing, transporting and storing HPMCAS gels at temperatures of more than 30 °C to avoid their melt back and potentially even maintain the shape of the HPMCAS gels is energy consuming and inconvenient. Moreover, many active ingredients are heat sensitive and should not be stored at elevated temperatures. Some active ingredients should even be stored in a refrigerator.

Therefore, the urgent need remains to provide gelatin- free gels, more specifically gelatin-free hydrogels. SUMMARY

Surprisingly, a process has been found that allows the production of gelatin-free hydrogels or gummies or pastilles based on esterified cellulose ethers that do not melt back to aqueous solutions at room temperature (21 °C) or refrigerator temperature (4 °C). In preferred embodiments the process even allows the production of gelatin-free hydrogels or gummies or pastilles based on esterified cellulose ethers that even maintain a substantially stable shape at room temperature or even at refrigerator temperature (4 °C).

Accordingly, one aspect of the present invention is a process for producing a hydrogel from an esterified cellulose and water, which comprises the steps of a) preparing an aqueous solution of at least 7.5 wt.-% of an esterified cellulose ether having a weight average molecular weight M_w of up to 80,000 Dalton and comprising groups of the formula

- C(O) - R - COOH or a combination of aliphatic monovalent acyl groups and groups of the formula -C(O) - R - COOH, wherein R is a divalent hydrocarbon group, and wherein the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4;

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 81.0 weight percent, based on the total weight of the hydrogel, and ii) at least 30 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.

Another aspect of the present invention is a hydrogel formed from an esterified cellulose ether and water by heat treatment and syneresis, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 15 to 81.0 weight percent, based on the total weight of the hydrogel, and the esterified cellulose ether has a weight average molecular weight M_w of up to 80,000 Dalton and comprises groups of the formula

- C(O) - R - COOH or a combination of aliphatic monovalent acyl groups and groups of the formula -C(O) - R - COOH, wherein R is a divalent hydrocarbon group, and wherein the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4.

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 ether used for preparing the hydrogel of the present invention has a weight average molecular weight M_w of up to 80,000 Dalton and comprises groups of the formula - C(O) - R - COOH or a combination of aliphatic monovalent acyl groups and groups of the formula -C(O) - R - COOH, wherein R is a divalent hydrocarbon group, and wherein the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4.

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 hydroxy methoxyl, 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 ethers 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 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 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 preferably 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 optionally 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 methyl cellulose phthalate (HPMCP); 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 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 0.07. The esterified cellulose ether generally has a degree of substitution of groups of formula -C(O) - R - COOH of up to 0.90, preferably up to 0.65, more preferably up to 0.55, and most preferably up to 0.45 or even only up to 0.30.

The esterified cellulose ether generally has a degree of substitution of aliphatic monovalent acyl groups, such as acetyl, propionyl, or butyryl groups, of 0 or at least 0.03 or at least 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. The esterified cellulose ether generally has a degree of substitution of aliphatic monovalent acyl groups of up to 0.95, typically up to 0.80, preferably up to 0.69, more preferably up to 0.60, most preferably up to 0.50, and particularly up to 0.45 or even only up to 0.40.

The total degree of ester substitution is generally at least 0.03, typically 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 is generally not more than 1.0, typically not more than 0.90, preferably not more than 0.70, more preferably not more than 0.60, and most preferably up to 0.50, or even up to 0.45.

The content of the acetate and succinate ester groups is determined according to "Hypromellose Acetate Succinate, United States Pharmacopia 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, phthalyl 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

M(C0C₂H₄C00H)

— I % Succinoyl *

M(C0C₂H₄C00H)

%MeO %HP0

M(0CH₃) M(HPO)

DS(Me) = ^3J

%cellulose backb one MS (HP) %cellulose backb one

M(AGU) M(AGU)

%Acetyl % Succinoyl

M (Acetyl) M (Succinoyl)

one %cellulose backb one

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 has a weight average molecular weight M_w of 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 up to 40,000 Dalton. Generally it 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.

The esterified cellulose ether generally has a polydispersity M_w/M_n, i.e., a ratio of weight average molecular weight M_w to number average molecular weight M_n, of not more than 2.6, preferably not more than 2.1, more preferably not more than 2.0, most preferably not more than 1.8, and in some embodiments even not more thanl.6. The polydispersity Mw/Mn generally is at least 1.1, typically at least 1.2 or at least 1.3.

The esterified cellulose ether generally has a z- average molecular weight, M_z, of from 50,000 to 400,000 Dalton, more preferably from 70,000 to 200,000 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 7.5 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 8.0 wt.-%, more preferably at least 8.5 wt.-%, even more preferably at least 9.0 wt.-%, and most preferably at least 9.5 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 or 15 wt.-%, and in some embodiments up to 12 wt.-% of the above-described esterified cellulose ether is prepared, based on the total weight 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 is 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.

Water or the aqueous solution of the esterified cellulose ether 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 of the esterified cellulose ether.

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 of the esterified cellulose ether.

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

Generally the aqueous solution prepared in step a) of the present invention is gelatin- free. Other than the esterified cellulose ether 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. More preferably, the esterified cellulose ether described above is the only thickener or gelling agent in the aqueous solution. 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 of the above-described esterified cellulose ether.

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 30 weight percent of water from the hydrogel, based on the weight of water in the aqueous solution in step a). Generally at least 40 wt.-%, preferably at least 50 wt.-%, more preferably at least 55 wt.-%, even more preferably at least 60 wt.-%, and most preferably even at least 65 weight percent of water is liberated from the hydrogel. Generally up to 90 wt.-%, typically up to 85 wt.-%, and more typically up to 80 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 provided that the remaining water content in the hydrogel is from 15 to 81.0 weight percent, based on the total weight of the hydrogel. The remaining water content of the hydrogel is preferably up to 80.0 wt.-%, more preferably up to 79.0 wt.-%, and most preferably up to 78.0 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 76.0 wt.-%, even only up to 74.0 wt.-% or even only up to 70.0 wt.-%, based on the total weight of the hydrogel. The remaining water content of the hydrogel is preferably at least 20 wt.-%, more preferably at least 30 wt.-%, even more preferably at least 40 wt.-%, and most preferably at least 50 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 60 wt.-% or 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 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.

The produced hydrogel generally have a gel fracture force G_F(21 °C) of at least 10 N. Preferred embodiments of the produced hydrogel have a gel fracture force GF(21 °C) of at least 20 N, more preferably at least 30 N, even more preferably at least 40 N. Typically the produced hydrogels have a gel fracture force G_F(21 °C) of up to 150 N, more typically up to 120 N, and most typically up to 100 N or up to 90 N. How to determine the gel fracture force G_F(21 °C) is described in the Examples section.

Another aspect of the present invention is a hydrogel formed from an esterified cellulose ether and water by heat treatment and syneresis, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 15 to 81.0 weight percent, based on the total weight of the hydrogel, and the esterified cellulose ether is as described in detail above.

The water content of the hydrogel is preferably up to 80.0 wt.-%, more preferably up to 79.0 wt.-%, and most preferably up to 78.0 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 76.0 wt.-%, even only up to 74.0 wt.-% or even only up to 70.0 wt.-%, based on the total weight of the hydrogel. The water content of the hydrogel is preferably at least 20 wt.-%, more preferably at least 30 wt.-%, even more preferably at least 40 wt.-%, and most preferably at least 50 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 60 wt.-% or 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 30 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 40 wt.- %, preferably at least 50 wt.-%, more preferably at least 55 wt.-%, even more preferably at least 60 wt.-%, and most preferably even at least 65 weight percent of water from the hydrogel, based on the weight of water used to form the hydrogel. In the hydrogel formed from an esterified cellulose ether and water by heat treatment and syneresis preferably up to 90 wt.-%, more preferably up to 85 wt.-%, and most preferably up to 80 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.

Preferred embodiments of the esterified cellulose ether are described above. The hydrogel of the present invention generally has a gel fracture force GF(21 °C) of at least 10 N. Preferred embodiments of the hydrogel have a gel fracture force G_F(21 °C) of at least 20 N, more preferably at least 30 N, even more preferably at least 40 N. Typically the produced hydrogels have a gel fracture force GF(21 °C) of up to 150 N, more typically up to 120 N, and most typically up to 100 N or up to 90 N. How to determine the gel fracture force G_F(21 °C) is described in the Examples section.

How to determine the gel fracture force G_F(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, 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, 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 an 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 at a lower temperature. Generally the hydrogel of the present invention is gelatin-free. Other than the esterified cellulose ether 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. 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, M_n 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 force G_F(21 °C) of the hydrogel

The gel fracture force G_F(21 °C) is 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). The results of two replicates are averaged and the average results reported in units of Newton.

Production of HPMCAS

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 (DSM) 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 has these properties:

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

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

MSHP = 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. Examples 1 to 3 and Comparative Examples A to C

A HPMCAS is used that has been produced as described above and that has the properties as described above.

In all experiments an amount of an aqueous HPMCAS solution 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 solutions are centrifuged (Sorvall Lynx 4000 centrifuge at 4000 rpm at 10°C) until the solutions are free of air bubbles.

The HPMCAS concentration, based on the total weight of the aqueous solution, is as listed in Table 1 below. The aqueous solutions are then heated to 85 °C and kept at 85 °C for 3 hours. 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. All aqueous solutions gel at 85 °C. During the heat treatments the hydrogels undergo syneresis wherein the entire amount of HPMCAS remains in the hydrogel and the major portion of the water originally present in the aqueous solution is expelled from the hydrogel. The hydrogels are 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 hydrogels are then placed in separate bags and stored at 4 °C for 2 days. The consistency of the hydrogels is assessed after this time period. The results are listed in Table 1 below.

The hydrogel of Example 3 has such a high strength that the gel fracture force G_F(21 °C) is difficult to measure according to the method described above. Hence, the hydrogel of Example 3 is compared by visual and haptic assessment with the gels of Examples 9 - 13 in the copending US Provisional Patent Application No. 62/537011, dated 26 July 2017, filed on the same date as the present patent application and having the title "PROCESS FOR PRODUCING HYDROGELS BASED ON ESTERIFIED CELLULOSE ETHERS". The hydrogel of Example 3 of the present patent application has a significantly higher gel strength than all of Examples 9 - 13 of the copending US Provisional Patent Application No. 62/537011 , which have gel fracture forces of _GF(21 °C)_of 56 N - 78 N.

Table 1

Claims

1. A process for producing a hydrogel from an esterified cellulose and water, comprising the steps of

a) preparing an aqueous solution of at least 7.5 wt.-% of an esterified cellulose ether having a weight average molecular weight M_w of up to 80,000 Dalton and comprising groups of the formula - C(O) - R - COOH or a combination of aliphatic monovalent acyl groups and groups of the formula -C(O) - R - COOH, wherein R is a divalent hydrocarbon group, and wherein the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4,

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 81.0 weight percent, based on the total weight of the hydrogel, and ii) at least 30 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.

2. The process of claim 1 wherein the esterified cellulose ether has a total degree of ester substitution of from 0.03 to 1.0.

3. The process of claim 1 or 2, wherein the remaining water content in the hydrogel formed in step c) is from 30 to 79.0 weight percent, based on the total weight of the hydrogel.

4. The process of any one of claims 1 to 3 wherein the esterified cellulose ether has a weight average molecular weight M_w of from 8,000 to 70,000 Dalton and in step a) an aqueous solution is prepared comprising from 7.5 to 30 wt.-% of an esterified cellulose ether, based on the total weight of the aqueous solution.

5. The process of any one of claims 1 to 4 wherein in step b) the aqueous solution is heated to a temperature of at least 55 °C.

6. The process of any one of claims 1 to 5, wherein in step c) the formed hydrogel is maintained for a time period of at least 1 hour.

7. The process of any one of claims 1 to 6, wherein in step c) at least 50 weight percent of water are liberated from the hydrogel, based on the water weight in the aqueous solution in step a).

8. The process of any one of claims 1 to 7, wherein the esterified cellulose ether is hydroxypropyl methylcellulose acetate succinate.

9. The process of any one of claims 1 to 8, wherein in step a) 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 in the aqueous solution.

10. A hydrogel formed from an esterified cellulose ether and water by heat treatment and syneresis, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 15 to 81.0 weight percent, based on the total weight of the hydrogel, and the esterified cellulose ether has a weight average molecular weight M_w of up to 80,000 Dalton and comprises groups of the formula - C(O) - R - COOH or a combination of aliphatic monovalent acyl groups and groups of the formula -C(O) - R - COOH, wherein R is a divalent hydrocarbon group, and wherein the degree of neutralization of the groups - C(O) - R - COOH is not more than 0.4.

11. The hydrogel of claim 10 wherein the esterified cellulose ether has a total degree of ester substitution of from 0.03 to 1.0.

12. The hydrogel of claim 10 or 11 wherein the esterified cellulose ether is hydroxypropyl methylcellulose acetate succinate.

13. The hydrogel of any one of claims 10 to 12 having at a temperature of 21°C a water content of from 30 to 79.0 weight percent, based on the total weight of the hydrogel.

14. The hydrogel of any one of claims 10 to 13 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.

15. The hydrogel of any one of claims 10 to 14 having a gel fracture force GF(21 °C) of at least IO N.