WO2019108264A1

WO2019108264A1 - Hydrogels based on esterified cellulose ethers

Info

Publication number: WO2019108264A1
Application number: PCT/US2018/041736
Authority: WO
Inventors: Jaime L. CURTIS-FISK; Oliver Petermann; Karen M. Balwinski
Original assignee: Dow Global Technologies Llc
Priority date: 2017-11-29
Filing date: 2018-07-12
Publication date: 2019-06-06

Abstract

A hydrogel is formed from an esterified cellulose ether and water by heat treatment and syneresis. The hydrogel also comprises an ion exchange resin and a pharmaceutical or nutritional ingredient. 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

HYDROGELS BASED ON ESTERIFIED CELLULOSE ETHERS 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 ingredients pharmaceutically active or nutritional 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 pharmaceutical or nutritional 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 pharmaceutical or nutritional ingredients are heat sensitive and should not be stored at elevated temperatures. Some pharmaceutical or nutritional 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 novel 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 novel 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). Pharmaceutical or nutritional ingredients are also incorporated in the novel hydrogels or gummies or pastilles based on esterified cellulose ethers. Surprisingly, it has been found that even ion exchange resins can be incorporated in the novel gelatin-free hydrogels or gummies or pastilles based on esterified cellulose ethers. Ion exchange resins are known for masking the taste of pharmaceutical or nutritional ingredients and for controlling their release.

Accordingly, one aspect of the present invention is a hydrogel formed from an esterified cellulose ether and water by heat treatment and syneresis and comprising an ion exchange resin and a pharmaceutical or nutritional ingredient, wherein 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 an ion exchange resin and a pharmaceutical or nutritional ingredient, wherein the process comprises the steps of

a) preparing an aqueous composition comprising i) at least 1.5 wt.-%, based on the total weight of the aqueous composition, 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, ii) an ion exchange resin and iii) a pharmaceutical or nutritional ingredient,

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

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 to liberate at least 15 weight percent of water from the hydrogel, based on the water weight in the aqueous composition 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.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 is a photographical representation of a hydrogel of the present invention. Figure 2 illustrates the controlled drug release from hydrogels of the present invention and of reference hydrogels.

DESCRIPTION OF EMBODIMENTS

According to the general understanding in the art "gel" refers to a soft, solid, or solid like material which comprises at least two components, one of which is a liquid (Aimdal, Dyre, I., Hvidt, S., Kramer, Q.; 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 b-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 10⁴. 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-COCr + -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

M(OCH₃) - M(OH)\

= 100 - ^%MeO *

M(OCH₃) j

%MeO %HPO

M(0CH₃) M(HPO)

DS(Me) = MS(HP) =

%cellulose backbone %cellulose backbone

M(AGU) M(AGU)

%Acetyl %Succinoyl

M (Acetyl) M(Succinoyl)

DS (Acetyl) = DS(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)-0H). 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.

M_w, 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 NahbPCb and 0.1 M NaNCL 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 composition comprising at least 1.5 wt.-% of the above-described esterified cellulose ether is prepared, based on the total weight of the aqueous composition. Preferably an aqueous composition 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 composition 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 composition. In step a) the esterified cellulose ether is dissolved in the aqueous composition.

The preferred concentration of esterified cellulose ether in the aqueous composition 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 composition 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 composition. When the esterified cellulose ether has a weight average molecular weight M_w of from 40,00 to 220,000 Dalton, it may be useful to prepare an aqueous composition 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 composition 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.

Ion exchange resins useful in the hydrogel and the process of the present invention include, but are not limited to, anionic exchange resins and cationic exchange resins.

Preferably, said resins are suitable for human and animal ingestion. The term "ion exchange resin", as used herein, means any water-insoluble polymer that can act as an ion exchanger. Ion exchange resins are characterized by their capacity to exchange ions. This is expressed as the "ion exchange capacity." For cation exchange resins the term used is "cation exchange capacity," and for anion exchange resins the term used is "anion exchange capacity." The ion exchange capacity is measured as the number equivalents of an ion that can be exchanged and can be expressed with reference to the mass of the polymer (herein abbreviated to "weight capacity") or its volume (often abbreviated to "volume capacity"). A frequently used unit for weight capacity is "milliequivalents of exchange capacity per gram of dry polymer." This is commonly abbreviated to "meq/g."

Ion exchange resins are manufactured in different forms. These forms can include spherical and non-spherical particles, typically with sizes in the range of 0.0001 mm to 2 mm. The non-spherical particles are frequently manufactured by grinding of the spherical particles. Products made in this way typically have particle size in the range 0.001 mm to 0.2 mm. The spherical particles are frequently known in the art as 'whole bead.' The non- spherical particles are frequently known in the art as 'powders.'

Preferred anionic exchange resins include, but are not limited to, styrenic strongly basic anion exchange resins with a quaternary amine functionality having a weight capacity of 0.1 to 15 meq/g, more preferably 0.1 to 12 meq/g, or styrenic weakly basic anion exchange resins with a primary, secondary, or, most preferably, a tertiary amine functionality having a weight capacity of 0.1 to 12 meq/g, or acrylic or methacrylic strongly basic anion exchange resins with a quaternary amine functionality having a weight capacity of 0.1 to 12 meq/g, more preferably of 0.1 to 10 meq/g, or acrylic or methacrylic weakly basic anion exchange resins with a primary, secondary, or most preferably, a tertiary amine functionality having a weight capacity of 0.1 to 12 meq/g, or allylic or vinylic weakly basic anion exchange resins with a primary, secondary, or tertiary amine functionality having a weight capacity of 0.1 to 24 meq/g.

Most preferred anionic exchange resins include, but are not limited to, styrenic strongly basic anion exchange resins with a quaternary amine functionality with weight capacity of 0.1 to 12 meq/g or acrylic anion exchange resins with a tertiary amine functionality with weight capacity of 0.1 to 12 meq/g.

Preferred cationic exchange resins include, but are not limited to, styrenic strongly acidic cation exchange resins with phosphonic acid or, preferably, sulfonic acid

functionalities having a weight capacity of 0.1 to 12 meq/g; or styrenic weakly acidic cation exchange resins with phenolic acid or, preferably, carboxylic acid functionalities having a weight capacity of 0.1 to 14 meq/g; or acrylic or methacrylic weakly acidic cation exchange resins with a phenolic acid or carboxylic acid functionality with a weight capacity of 0.1 to 14 meq/g.

Most preferred cationic exchange resins include, but are not limited to styrenic weakly acidic cation exchange resins or acrylic or methacrylic weakly acidic cation exchange resins with carboxylic acid functionalities having a weight capacity of 0.1 to 14 meq/g, preferably of 0.1 to 12 meq/g. Most preferably, the ion exchange resin comprised in the hydrogel of the present invention are weakly acidic cation exchange resins which have a copolymer of methacrylic acid and divinylbenzene as backbone and which have carboxylic acid functionalities having a weight capacity of 0.1 to 14 meq/g, preferably of 0.1 to 12 meq/g. A preferred example of such ion exchange resins is AMBERLITE™ IRP64 Pharmaceutical Grade Cation Exchange Resin which is commercially available from The Dow Chemical Company.

Ion exchange resins useful in this invention are in powder or whole bead form.

Strongly acidic and weakly acidic cation exchange resins useful in the practice of the present invention are in the acid form or salt form or partial salt form. Strongly basic anion exchange resins useful in this invention are in the salt form. Weakly basic anion exchange resins useful in this invention are in the free-base form or salt form or partial salt form.

In step a) of the process of the present invention the ion exchange resin is generally incorporated in the aqueous composition at an amount of at least 0.2 wt.-%, preferably at least 0.5 wt.-%, more preferably at least 1 wt.-%, even more preferably at least 2 wt.-%, and most preferably at least 5 wt.-%, based on the total weight of the aqueous composition. In step a) of the process of the present invention the ion exchange resin is generally incorporated in the aqueous composition at an amount of up to 30 wt.-%, typically up to 25 wt-%, more typically up to 20 wt.-%, even more typically up to 15 wt.-%, and most typically up to 12 wt.-%, based on the total weight of the aqueous composition.

The above described esterified cellulose ether and ion exchange resin are generally incorporated in such amount in the aqueous composition in step a) that the weight ratio between the above described esterified cellulose and the ion exchange resin is from 10 : 1 to 1 : 20, typically from 5 : 1 to 1 : 15, preferably from 2 : 1 to 1 : 10, more preferably from 1 : 1 to 1 : 5, and most preferably from 1 : 2 to 1 : 4.

In step a) of the process of the present invention one or more pharmaceutical or nutritional ingredients are incorporated in the aqueous composition. Pharmaceutical or nutritional ingredients useful in the practice of the present invention include, but are not limited to, pharmaceutically active ingredients, vitamins, flavors, herbals, mineral supplements, and nutrients. One or more pharmaceutical ingredients, one or more nutritional ingredients or one or more pharmaceutical and nutritional ingredients can be incorporated in the aqueous composition. Preferably the pharmaceutical or nutritional ingredients have acidic or basic ionizable groups.

Pharmaceutically active ingredients useful in the practice of this invention include, but are not limited to, drugs, such as indomethacin, salicylic acid, ibuprofen, sulindac, diclofenac, piroxicam, naproxen, timolol, pilocarpine, acetylcholine, dibucaine, thorazine, promazine, chlorpromazine, acepromazine, aminopromazine, perazine, prochlorperazine, trifluoroperazine, thioproperazine, reserpine, deserpine, chlorprothixene, tiotixene, haloperidol, moperone, trifluorperidol, timiperone, droperidol, pimozide, sulpiride, tiapride, hydroxyzine, chlordiazepoxide, diazepam, propanolol, metoprolol, pindolol, imipramine, amitryptyline, mianserine, phenelzine, iproniazid, amphetamines, dexamphetamines, fenproporex, phentermine, amfepramone, pemoline, clofenciclan, cyprodenate, aminorex, mazindol, progabide, codergoctine, dihydroergocristine, vincamone, citicoline,

physostigmine, pyritinol, meclofenoxate, lansoprazole, nifedipine, risperidone,

clarithromycin, cisapride, nelfinavir, midazolam, lorazepam, nicotine, prozac, erythromycin, ciprofloxacin, quinapril, isotretinoin, valcyclovir, acyclovir, delavirdin, famciclovir, lamivudine, zalcitabine, osteltamivir, abacavir, prilosec, or theophylline.

Nutritional ingredients useful in the practice of this invention include, but are not limited to, flavors or nutritional supplements, such as vitamins or minerals. Vitamins useful in the practice of the present invention include, but are not limited to, A, C, E, and K.

Flavors useful in the practice of the present invention include, but are not limited to, 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; salicylate, thymol, acesulfame, or saccharin.

The amount of the pharmaceutical or nutritional ingredient generally is from 0.1 to 30 percent, preferably from 0.2 to 25 percent, more preferably from 0.5 to 20 percent, and most preferably from 1 to 15 percent, based on the total weight of the aqueous composition. Preferably, the loading of the pharmaceutical or nutritional ingredient is 1 to 100% of the ion exchange capacity of the resin, more preferably it is 5 to 95% of the ion exchange capacity of the ion exchange resin, most preferably it is 10 to 90% of the ion exchange capacity of the ion exchange resin.

Water or an aqueous composition comprising the esterified cellulose ether and/or the ion exchange resin and/or the pharmaceutical or nutritional ingredient 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.

In step a) of the process of the present invention optional ingredients can be incorporated in the aqueous composition, such as coloring agents, pigments, opacifiers, inorganic salts, such as sodium chloride, potassium chloride, calcium chloride, or magnesium chloride; or combinations thereof. The amount of these optional 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 composition. The optional ingredients are preferably

pharmaceutically acceptable.

The pharmaceutical or nutritional ingredients and optional ingredients may be added to the esterified cellulose ether, to the ion exchange resin, to water and/or to the aqueous composition before or during the process for producing the aqueous composition comprising the esterified cellulose ether, the ion exchange resin and the pharmaceutical or nutritional ingredient. Alternatively, optional ingredients may be added after the preparation of the aqueous composition.

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. Conveniently the ion exchange resin, the pharmaceutical or nutritional ingredient and optional ingredients are also mixed with water at a temperature in the above-mentioned ranges. When the ion exchange resin, the pharmaceutical or nutritional ingredient and optional ingredients are added after the aqueous solution of the esterified cellulose ether has been prepared, these ingredients can be added at higher temperatures, e.g., at room temperature or up to 30 °C.

Generally the aqueous composition prepared in step a) of the present invention is gelatin-free. Other than the esterified cellulose ether, the aqueous composition prepared in step a) of the present invention preferably does not comprise a significant amount of ingredients, such as thickeners or gelling agents, which are able to increase the gel strength of the produced hydrogel at room temperature (21 °C) or at a lower temperature.

The sum of the esterified cellulose ether, the ion exchange resin, the pharmaceutical or nutritional ingredient and water is generally at least 70 percent, preferably at least 80 percent, more preferably at least 90 percent, most preferably at least 95 percent, and up to 100 percent, based on the total weight of the aqueous composition prepared in step a).

In step b) of the process of the present invention, the aqueous composition of step a) is heated to form a hydrogel from the aqueous composition. 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 pharmaceutical or nutritional ingredients or optional additives, such as tonicity-adjusting agents in the aqueous composition in step a) of the process of the present invention lowers the gelation temperature of the aqueous composition. For practical reasons the aqueous composition 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 composition.

Generally the aqueous composition 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 composition in step a). Generally at least 30 wt.-%, preferably at least 50 wt.-%, even more preferably at least 65 wt.-%, and most preferably even at least 80 weight percent of water is liberated from the hydrogel. In most cases up to 95 wt.-%, typically up to 92 wt.-%, and in some embodiments up to 90 wt.-% of water is liberated from the hydrogel, based on the weight of water in the aqueous composition in step a).

Generally a sufficient amount of water is liberated from the hydrogel such that the remaining water content of the hydrogel is up to 89 wt.-%, preferably up to 84 wt.-%, more preferably up to 80 wt.-%, and most preferably up to 75 weight percent, based on the total weight of the hydrogel. The remaining water content of the hydrogel is generally at least 15 wt.-%, preferably at least 25 wt.-%, more preferably at least 35 wt.-%, and even more preferably at least 40 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, 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 composition. 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 10 hours, typically up to 8 hours, more typically up to 6 hours and in preferred embodiments up to 4 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 Fc_F(2l °C) of at least 10 N, more preferably at least 15 N, even more preferably at least 20 N and in the most preferred embodiments even at least 25 N or even at least 30 N. Typically the produced hydrogels have a gel fracture force Fc_F(2l °C) of up to 40 N, more typically up to 35 N. How to determine the gel fracture force Fc_F(2l °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 and comprising an ion exchange resin and a pharmaceutical or nutritional ingredient, wherein 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.

The esterified cellulose ether, the ion exchange resin and the pharmaceutical or nutritional ingredient in the hydrogel are as described in detail above.

The weight of the esterified cellulose ether is preferably at least 5 wt.-%, more preferably at least 7 wt.-%, and most preferably at least 10 wt.-%, based on the total weight of the hydrogel. The weight of the esterified cellulose ether is preferably up to 40 wt.-%, more preferably up to 30 wt.-%, and most preferably up to 25 wt.-%, based on the total weight of the hydrogel.

The weight of the ion exchange resin is preferably at least 5 wt.-%, more preferably at least 8 wt.-%, and most preferably at least 10 wt.-%, based on the total weight of the hydrogel. The weight of the ion exchange resin is preferably up to 70 wt.-%, more preferably up to 55 wt.-%, and most preferably up to 40 wt.-%, based on the total weight of the hydrogel.

The total weight of the esterified cellulose ether and the ion exchange resin is preferably at least 10 wt.-%, more preferably at least 20 wt.-%, even more preferably at least 25 wt.-%, and most preferably at least 30 wt.-%, based on the total weight of the hydrogel. The total weight of the esterified cellulose ether and the ion exchange resin is preferably up to 84 wt.-%, more preferably up to 80 wt.-%, even more preferably up to 75 wt-%, and most preferably up to 70 wt.-%, based on the total weight of the hydrogel.

The weight of the pharmaceutical or nutritional ingredient is preferably at least 0.2 wt-%, more preferably at least 1 wt.-%, and most preferably at least 3 wt.-%, based on the total weight of the hydrogel. The weight of the pharmaceutical or nutritional ingredient is preferably up to 40 wt.-%, more preferably up to 30 wt.-%, and most preferably up to 20 wt-%, based on the total weight of the hydrogel.

The water content of the hydrogel is generally up to 89 wt.-%, preferably up to 84 wt.- %, more preferably up to 80 wt.-%, and most preferably up to 75 weight percent, based on the total weight of the hydrogel. The water content of the hydrogel is generally at least 15 wt.-%, preferably at least 25 wt.-%, more preferably at least 35 wt.-%, and even more preferably at least 40 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, preferably at least 30 wt.-%, more preferably at least 50 wt-%, even more preferably at least 65 wt.-%, and most preferably even at least 80 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” typically means that heat treatment is sufficient to liberate up to 95 wt.-%, more typically up to 92 wt.-%, and in some

embodiments up to 90 wt.-% of water, 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 Fc_F(2l °C) of at least 10 N, more preferably at least 15 N, even more preferably at least 20 N and in the most preferred embodiments even at least 25 N or even at least 30 N. Typically the hydrogel has a gel fracture force Fc_F(2l °C) of up to 40 N, more typically of up to 35 N. How to determine the gel fracture force Fc_F(2l °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 optional ingredients as disclosed above. The amount of the optional ingredients 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, the hydrogel preferably does not comprise a significant amount of ingredients, such as thickeners or gelling agents, which are able to increase the gel strength of the hydrogel at room temperature (21 °C) or at a lower temperature.

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

M_w, 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 NaNOs. 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 pm 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 of M_w, M_n and M_z”.

Determination of the Gel Fracture Forces FGF(2! °C) of the Hydrogel

The gel fracture forces F_GF(2! °C) are measured with a Texture Analyzer (model

TA.XTPlus; Stable Micro Systems, 30-Kg load cell) at 21 °C. The gels are compressed between a steel plate (90mm l00mmx9mm with a filter paper 0 llOmm "2294" from Whatman and then a filter vlies 0 1 lOmm "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: l.5mm/sec, speed of compression: 1.00 mm/sec, trigger force: 0.05N, maximum distance: 30 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. The gel collapse is observed visually. It is identified as Fc_F(2l °C).

Drug dissolution test

The rate of drug release over 24 hours is assessed. The hydrogel samples are dissolved in 0.5M phosphate 5.8 +/- 0.5 pH buffer (900 mL) at 37° C ± 0.5° C. Samples are automatically drawn from each vessel through a 70 micron tip filter at specified time intervals and returned to the vessel after passing through a flow cell. Quantification of the amount of drug released is accomplished by UV detection. The dissolutions are performed on a Distek 2100 dissolution unit equipped with an HP Diode Array Spectrophotometer with a deuterium (wavelength range 190 nm - 800 nm) lamp. The measurements are taken at 289 for propranolol HC1. Hydrogel sample placement follows USP II guidelines at 50 rpm with tablets in stationary hanging baskets (10 mesh).

Production of HPMCAS

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 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 HPMC AS has these properties:

Methoxyl groups: 26.4 %; hydroxypropoxyl groups: 8.5 %; acetyl groups: 4.5%; and succinoyl groups; 5.9 %. This corresponds to a

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

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

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

DS_s = degree of substitution of succinoyl groups: 0.13.

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

Examples 1 - 3 and Reference Example A

The HPMCAS as described above, an ion exchange resin (IER) and an active pharmaceutical ingredient (API) are mixed with water as described below to prepare an aqueous composition. The amounts of the HPMCAS, IER, API and of water are listed in Table 1 below.

The ion exchange resin (IER) is an AMBERLITE™ IRP64 Pharmaceutical Grade Cation Exchange Resin which is commercially available from The Dow Chemical

Company. This ion exchange resin is a weakly acidic cation exchange resin which has a copolymer of methacrylic acid and divinylbenzene as backbone and which has carboxylic acid functionalities having a weight capacity of not less than 10.0 meq/g.

The API is Propranolol HC1.

HPMCAS is mixed with water in a glass container by stirring at 400 rpm at 0°C overnight. Then the API is incorporated in the aqueous HPMCAS solution. The amounts of water, HPMCAS and API are as listed in Table 1 below. Finally the ion exchange resin (IER) is mixed with the aqueous HPMCAS solution comprising the API in the amounts listed in Table 1 below. Shortly after addition of the ion exchange resin, the resulting liquid aqueous composition is heated in the glass container to 85 °C until the composition gels. The gel is then removed from the glass container and heated on a metal pan at 85 °C. The total heating period at 85 °C is 2 hours. During the heat treatment the hydrogel undergoes syneresis wherein the entire amount of HPMCAS, of the ion exchange resin, if present, and API associated with the IER, if present, remains in the hydrogel and a large portion of the water originally present in the liquid aqueous composition is expelled from the hydrogel. Most of the expelled water is evaporated.

The hydrogel is removed from the liberated water, mechanically dried with a tissue and weighed after the gel has cooled to room temperature. Table 2 below lists the weighed amount of the hydrogel and the liquid loss. The liquid loss corresponds to the weight of the liquid aqueous composition before gelling minus the weight of the hydrogel. The HPMCAS content and the IER content are calculated based on the amounts of the HPMCAS and the IER in the liquid aqueous composition before gelling and the weight of the hydrogel.

In all Examples 1 - 3 a hydrogel of stable shape is obtained that maintains its shape when the hydrogel is cooled to room temperature and stored at room temperature.

Reference Example A is used for reference purposes but does not represent prior art.

Table 1

Table 2

Examples 4 and 5 and Reference Examples B and C

The same procedure is carried out as in Examples 1 - 3 and Reference Example A, except that the prepared compositions comprising water, HPMCAS, API and IER (in Examples 4 and 5 only) are heated in a glass container to 80 °C and maintained at 80 °C for 1 hour. The resulting hydrogels are then removed from the glass container and heated on a metal pan at 80 °C for 1 hour. The amounts of HPMCAS, API, IER and water are listed in Table 3 below.

Fig. 1 is a photographical representation of the hydrogel of Example 5.

Table 3

The produced hydrogels are then stored at room temperature for at least 24 hours prior to further analysis. The release of the API Propranolol HC1 is tested in an USP phosphate buffer having a pH 5.8 in an USP dissolution tester as described above. The % Propranolol HC1 that is dissolved over time, based on the total amount of Propranolol HC1 released during the experiment, is determined and plotted in Fig. 2. Figure 2 illustrates the controlled release of Propranolol HC1 over time from the hydrogels of Examples 4 and 5 and

Reference Examples B and C. The extended release of Propranolol HC1 from the hydrogels of Examples 4 and 5 and Reference Examples B and C is compared with a Control, which is a sample of Propranolol HC1 placed in an immediate release capsule, where the Propranolol HC1 is filled in a K-Caps capsule made of HPMC (hydroxypropyl methylcellulose) as the film-forming polymer and designed for immediate release of the contents in an USP phosphate buffer having a pH 5.8.

Fig. 2 illustrates the controlled release of the API from the hydrogels of Examples 4 and 5 and of Reference Examples B and C. Reference Examples B and C are used for reference purposes to illustrate the API release from hydrogels without IER. However, Reference Examples B and C do not represent the prior art.

Examples 6 - 7

In all experiments 30.0 g of an aqueous solution of the HPMCAS (28.74 g deionized water, l.05g HPMCAS) is prepared in a glass container by stirring at 1000 rpm in an ice bath for 6 hours and storage overnight in a refrigerator followed by the addition of 0.l05g of propranolol.HCl and 0.l05g of Amberlite IRP 65 ion exchange resin. Then the solutions are centrifuged (Sorvall Lynx 4000 centrifuge at 4000 rpm at l0°C) until the solutions are free of air bubbles.

The aqueous solutions are then heated to 85 °C and kept at 85 °C for a time period of 6 hours. The temperature of 85 °C is held by placing the glass container in an oven maintained at 85 °C.

All aqueous solutions gel at 85 °C. During the heat treatments the hydrogels undergo syneresis to a very large degree 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 and mechanically dried with a tissue.

The produced hydrogels are placed on a glass container without delay and allowed to cool to room temperature.

The gel fracture forces FGF(21 °C) of the produced hydrogels are determined after having stored the gels over night at a temperature of 21 °C. The gel fracture forces FGF(21 °C) are as follows:

Example 6: 32.8 N;

Example 7: 30.7 N.

Claims

1. A hydrogel formed from an esterified cellulose ether and water by heat treatment and syneresis and comprising an ion exchange resin and pharmaceutical or nutritional ingredient, wherein

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 15 to 89 weight percent, based on the total weight of the hydrogel.

3. The hydrogel of claim 2, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 25 to 84 weight percent, based on the total weight of the hydrogel.

4. The hydrogel of any one of claims 1 to 3, wherein the weight of the esterified cellulose ether is from 5 to 40 weight percent, based on the total weight of the hydrogel.

5. The hydrogel of any one of claims 1 to 4, wherein the total weight of the esterified cellulose ether and the ion exchange resins is from 10 to 84 weight percent, based on the total weight of the hydrogel.

6. The hydrogel of any one of claims 1 to 5, wherein the weight of the pharmaceutical or nutritional ingredient is from 0.2 to 40 weight percent, based on the total weight of the hydrogel.

7. The hydrogel of any one of claims 1 to 6, wherein the esterified cellulose ether is a hydroxypropyl methylcellulose acetate succinate.

8. The hydrogel of any one of claims 1 to 7, having a gel fracture force Fc_F(2l °C) of at least 10 N.

9. A process for producing a hydrogel from an esterified cellulose ether and water and additionally incorporating in the hydrogel an ion exchange resin and a pharmaceutical or nutritional ingredient, wherein the process comprises the steps of

a) preparing an aqueous composition comprising

i) at least 1.5 wt.-%, based on the total weight of the aqueous composition, 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, ii) an ion exchange resin and

iii) a pharmaceutical or nutritional ingredient,

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 to liberate at least 15 weight percent of water from the hydrogel, based on the water weight in the aqueous composition 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.

10. The process of claim 9, wherein in step b) the aqueous composition is heated to a temperature of at least 55 °C.

11. The process of claim 9 or 10, wherein 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.

12. The process of any one of claims 9 to 11, wherein in step a) an aqueous composition 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.

13. The process of any one of claims 9 to 11, wherein in step a) an aqueous composition 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.

14. The process of any one of claims 9 to 11, wherein in step a) an aqueous composition 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.

15. The process of any one of claims 9 to 14, wherein in step a) an aqueous composition comprising from 0.2 to 30 wt.-% of an ion exchange resin is prepared, based on the total weight of the aqueous composition.