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Title:
HYDROGELS BASED ON HYDROXYALKYL METHYLCELLULOSE
Document Type and Number:
WIPO Patent Application WO/2019/108266
Kind Code:
A1
Abstract:
A hydrogel is formed from a hydroxyalkyl methylcellulose and water by heat treatment and syneresis. The hydrogel also comprises an ion exchange resin and a pharmaceutical or nutritional ingredient. The hydroxyalkyl methylcellulose has i) a viscosity of at least 500 mPaos, when measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s-1, ii) an MS(hydroxyalkyl) of 0.05 to 1.00, and iii) hydroxy groups of anhydroglucose units being substituted with methyl groups such that [ s23/s26 - 0.2*MS(hydroxyalkyl) ] is 0.35 or less.

Inventors:
PETERMANN, Oliver (August-Wolff-Strasse 13, Bomlitz, Bomlitz, DE)
CURTIS-FISK, Jaime L. (3901 S. Saginaw Road, Building 212Midland, MI, 48640, US)
Application Number:
US2018/041739
Publication Date:
June 06, 2019
Filing Date:
July 12, 2018
Export Citation:
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Assignee:
DOW GLOBAL TECHNOLOGIES LLC (2040 Dow Center, Midland, MI, 48674, US)
International Classes:
C08L1/28; A23L29/262; A61K47/38; C08J3/075
Domestic Patent References:
WO1993017716A11993-09-16
WO2015047762A12015-04-02
WO2012051035A12012-04-19
WO2012173838A12012-12-20
WO2015047762A12015-04-02
WO2015009796A12015-01-22
Other References:
N. SARKAR: "Thermal Gelation Properties of Methyl and Hydroxypropyl Methylcellulose", JOURNAL OF APPLIED POLYMER SCIENCE, vol. 24, 1979, pages 1073 - 1087, XP009103302, DOI: doi:10.1002/app.1979.070240420
HAQUE, A; RICHARDSON, R.K.; MORRIS, E.R.; GIDLEY, M.J; CASWELL, D.C, CARBOHYDRATE POLYMERS, vol. 22, 1993, pages 175
HAQUE, A; MORRIS, E.R., CARBOHYDRATE POLYMERS, vol. 22, 1993, pages 161
ALMDAL, DYRE, J.; HVIDT, S.; KRAMER, 0.: "Towards a phenomological definition of the term 'gel", POLYMER AND GEL NETWORKS, vol. 1, 1993, pages 5 - 17, XP024175650, DOI: doi:10.1016/0966-7822(93)90020-I
G. BARTELMUS; R. KETTERER, Z. ANAL. CHEM., vol. 286, 1977, pages 161 - 190
BENGT LINDBERG; ULF LINDQUIST: "DISTRIBUTION OF SUBSTITUENTS IN O-ETHYL-O-(2-HYDROXYETHYL)CELLULOSE", vol. 176, 1988, ELSEVIER SCIENCE PUBLISHERS, article "Carbohydrate Research", pages: 137 - 144
R.G. ACKMAN, J. GAS CHROMATOGR., vol. 2, 1964, pages 173 - 179
R.F. ADDISON; R.G. ACKMAN, J. GAS CHROMATOGR., vol. 6, 1968, pages 135 - 138
D.P. SWEET; R.H. SHAPIRO; P. ALBERSHEIM, CARBOHYD. RES., vol. 40, 1975, pages 217 - 225
Attorney, Agent or Firm:
JOHNSON, Christopher (The Dow Chemical Company, Intellectual PropertyP.O. Box 196, Midland Michigan, 48641-1967, US)
Download PDF:
Claims:
Claims

1. A hydrogel formed from a hydroxyalkyl methylcellulose and water by heat treatment and syneresis and comprising an ion exchange resin and a pharmaceutical or nutritional ingredient, wherein the hydroxyalkyl methylcellulose has

i) a viscosity of at least 500 mPa»s, when measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s 1,

ii) an MS (hydroxyalkyl) of 0.05 to 1.00, and

iii) hydroxy groups of anhydroglucose units being substituted with methyl groups such that [ s23/s26 - 0.2*MS(hydroxyalkyl) ] is 0.35 or less, wherein s23 is the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 3-positions of the anhydroglucose unit are substituted with methyl groups and wherein s26 is the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups.

2. The hydrogel of claim 1, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 20 to 95 weight percent, based on the total weight of the hydrogel.

3. The hydrogel of claim 1 or 2, wherein the weight of the hydroxyalkyl methylcellulose is from 3.0 to 20 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 ion exchange resin is from 0.4 to 30 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 hydroxyalkyl methylcellulose and the ion exchange resins is from 3.5 to 50 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 viscosity of the hydroxyalkyl methylcellulose is from 1,000 to 150,000 mPa»s, when measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s-1.

8. The hydrogel of any one of claims 1 to 7, wherein the hydroxyalkyl methylcellulose is a hydroxypropyl methylcellulose having a DS(methyl) of 1.2 to 2.2 and [ s23/s26 - 0.2*MS(hydroxyalkyl) ] being 0.27 or less.

9. The hydrogel of any one of claims 1 to 8 having a gel fracture force

FGF(2l °C) of at least 8 N.

10. A process for producing a hydrogel from a hydroxyalkyl methylcellulose 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 2.0 wt.-% of a hydroxyalkyl methylcellulose, based on the total weight of the aqueous composition, the hydroxyalkyl methylcellulose having i) a viscosity of at least 500 mPa»s, when measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s 1, ii) an MS (hydroxyalkyl) of 0.05 to 1.00, and iii) hydroxy groups of anhydroglucose units being substituted with methyl groups such that [ s23/s26 - 0.2*MS(hydroxyalkyl) ] is 0.35 or less, wherein s23 is the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 3-positions of the anhydroglucose unit are substituted with methyl groups and wherein s26 is the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups,

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.

11. The process of claim 10, wherein in step a) an aqueous composition comprising at least 2.5 wt.-% of a hydroxyalkyl methylcellulose is prepared, based on the total weight of the aqueous composition.

12. The process of claim 10 or 11, 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.

13. The process of any one of claims 10 to 12, wherein in step b) the aqueous composition is heated to a temperature of at least 55 °C.

14. The process of any one of claims 10 to 13, 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.

15. The process of any one of claims 10 to 14, wherein in step c) at least 20 weight percent of water is liberated from the hydrogel, based on the water weight in the aqueous composition in step a).

Description:
HYDROGELS BASED ON HYDROXYALKYL METHYLCELLULOSE

FIELD

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

INTRODUCTION

Hydroxyalkyl methylcelluloses, such as hydroxypropyl methylcelluloses, are widely used and accepted in pharmaceutical applications, for example for the production of hard capsules, tablet coatings or as a matrix polymer in tablets. However, 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.

Therefore, there is an urgent need to provide gelatin-free gels. Unfortunately, hydroxyalkyl methylcelluloses, such as hydroxypropyl methylcelluloses, do not present themselves as alternatives to gelatin due to the unusual gelling behavior of hydroxyalkyl methylcelluloses, such as hydroxypropyl methylcelluloses. Hydroxyalkyl methylcelluloses, such as hydroxypropyl methylcelluloses, are known to exhibit reverse thermal gelation in water, in other words, aqueous hydroxypropyl methylcellulose materials are soluble at cooler temperatures and gel at warmer temperatures. The reverse thermal gelation in water is discussed in detail in the Article Thermal Gelation Properties of Methyl and Hydroxypropyl Methylcellulose by N. Sarkar, Journal of Applied Polymer Science, Vol. 24, 1073-1087 (1979). Described specifically, when an aqueous solution of hydroxypropyl methylcellulose is heated, de-hydration of the hydrophobic methoxyl groups localized in the molecule occurs and it turns into a hydrous gel. When the resulting gel is cooled, on the other hand, the hydrophobic methoxyl groups are re-hydrated, whereby the gel returns to the original aqueous solution. Hydroxyalkyl methylcelluloses are known to have a low storage modulus, compared to methyl cellulose. Hydroxyalkyl methylcelluloses which exhibit a low storage modulus do not form strong gels. High concentrations are needed to form even weak gels (Haque, A; Richardson, R.K.; Morris, E.R., Gidley, MJ and Caswell, D.C in Carbohydrate Polymers 22 (1993) p. 175; and Haque, A and Morris, E.R. in Carbohydrate Polymers 22 (1993) p. 161). For example, at the same concentration of 2 wt.-%, at elevated temperatures the maximum storage modulus of a METHOCEL™ K4M HPMC is typically less than about 100 Pa, whereas that of a METHOCEL™ A4M methylcellulose is typically above about 1000 Pa.

The gelation temperature of aqueous solutions of hydroxypropyl methylcellulose (HPMC) depends on the concentration and grade of HPMC. At a concentration of 1.5 weight percent, most HPMC grades gel at around 65 to 75 °C. Special grades of HPMC that gel at a concentration of 1.5 weight percent in water at a relatively low temperature, typically at 40 to 60 °C, are described in International patent applications WO 2012/051035 Al, WO2012/173838 Al and WO2015/047762 Al. Aqueous solutions of special grades of HPMC that even start to gel at lower temperatures, typically at 30 - 40 °C or even less, are disclosed in International patent application WO2015/009796. However, even when these HPMC gel at relatively low temperature, the gelation is reversible, i.e., the gels melt back to aqueous solutions when the gels cool down to room temperature or even refrigerator temperature. 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 hydroxyalkyl methylcelluloses gels at elevated temperatures to avoid their melt back and potentially even maintain the shape of the hydroxyalkyl methylcelluloses 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 a hydroxyalkyl methylcellulose 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 hydroxyalkyl methylcelluloses 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 a hydroxyalkyl methylcellulose. 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 a hydroxyalkyl methylcellulose. 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 a hydroxyalkyl methylcellulose and water by heat treatment and syneresis and comprising an ion exchange resin and a pharmaceutical or nutritional ingredient, wherein the hydroxyalkyl methylcellulose has i) a viscosity of at least 500 mPa»s, when measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s 1 , ii) an MS (hydroxyalkyl) of 0.05 to 1.00, and iii) hydroxy groups of anhydroglucose units being substituted with methyl groups such that [ s23/s26 - 0.2*MS(hydroxyalkyl) ] is 0.35 or less, wherein s23 is the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 3 -positions of the anhydroglucose unit are substituted with methyl groups and wherein s26 is the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 6- positions of the anhydroglucose unit are substituted with methyl groups.

Another aspect of the present invention is a process for producing a hydrogel from a hydroxyalkyl methylcellulose 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 2.0 wt.-% of the above-mentioned hydroxyalkyl methylcellulose, based on the total weight of the aqueous solution, 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 illustrates the controlled drug release from hydrogels of the present invention and of a reference hydrogel.

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 (Almdal, Dyre, I., Hvidt, S., Kramer, O.; Towards a phenomological definition of the term 'gel'. Polymer and Gel Networks 1993, I, 5-17). A hydrogel is a gel wherein water is the main liquid component.

The hydroxyalkyl methylcellulose used for preparing the hydrogel of the present invention comprises methyl groups and hydroxyalkyl groups, preferably hydroxy-Cio-alkyl groups, such as hydroxypropyl or hydroxy ethyl. Preferred hydroxyalkyl methylcelluloses are hydroxyethyl methylcelluloses and, more preferably, hydroxypropyl methylcelluloses.

An essential feature of the hydroxyalkyl methylcellulose is its unique distribution of methyl groups on the anhydroglucose units such that [ s23/s26 - 0.2*MS(hydroxyalkyl) ] is 0.35 or less, preferably 0.32 or less, more preferably 0.30 or less, most preferably 0.27 or less, particularly 0.25 or less, and especially 0.23 or less. Typically [ s23/s26 - 0.2*MS(hydroxyalkyl) ] is 0.07 or more, more typically 0.10 or more, and most typically 0.13 or more. More specifically, in the case of hydroxyethyl methylcelluloses the upper limit for [ s23/s26 - 0.2*MS(hydroxyalkyl) ] is 0.35; preferably 0.32, more preferably 0.30 and most preferably 0.27. In the case of hydroxypropyl methylcelluloses the preferred upper limit for [ s23/s26 - 0.2*MS(hydroxyalkyl) ] generally is 0.30, preferably 0.27; more preferably 0.25 and most preferably 0.23. As used herein, the symbol“ *“ represents the multiplication operator.

In the ratio s23/s26, s23 is the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 3-positions of the anhydroglucose unit are substituted with methyl groups and s26 is the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups. For determining the s23, the term“the molar fraction of

anhydroglucose units wherein only the two hydroxy groups in the 2- and 3 -positions of the anhydroglucose unit are substituted with methyl groups” means that the 6-positions are not substituted with methyl; for example, they can be unsubstituted hydroxy groups or they can be substituted with hydroxyalkyl groups or methylated hydroxyalkyl groups. For determining the s26, the term“the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups” means that the 3-positions are not substituted with methyl; for example, they can be unsubstituted hydroxy groups or they can be substituted with hydroxyalkyl groups or methylated hydroxyalkyl groups.

Formula I below illustrates the numbering of the hydroxy groups in anhydroglucose units. Formula I is only used for illustrative purposes and does not represent the cellulose ethers of the invention; the substitution with hydroxyalkyl groups is not shown in Formula I.

Formula I

The hydroxyalkyl methylcellulose preferably has a DS(methyl) of from 1.2 to 2.2, more preferably from 1.25 to 2.10, and most preferably from 1.40 to 2.05. The degree of the methyl substitution, DS(methyl), of a hydroxyalkyl methylcellulose is the average number of OH groups substituted with methyl groups per anhydroglucose unit. For determining the DS(methyl), the term“OH groups substituted with methyl groups” does not only include the methylated OH groups at the polymer backbone, i.e., that are directly a part of the anhydroglucose unit, but also methylated OH groups that have been formed after hydroxyalkylation.

The hydroxyalkyl methylcellulose has an MS(hydroxyalkyl) of from 05 to 1.00, preferably from 0.07 to 0.80, more preferably from 0.08 to 0.70, most preferably from 0.10 to 0.60, and particularly from 0.10 to 0.50. The degree of the hydroxyalkyl substitution is described by the MS (molar substitution). The MS (hydroxyalkyl) is the average number of hydroxyalkyl groups which are bound by an ether bond per mole of anhydroglucose unit. During the hydroxyalkylation, multiple substitutions can result in side chains.

The hydroxyalkyl methylcellulose preferably has a preferred DS(methyl) and a preferred MS (hydroxyalkyl) in combination.

The determination of the % methoxyl and % hydroxypropoxyl in hydroxypropyl methylcellulose is carried out according to the United States Pharmacopeia (USP 40).

The values obtained are % methoxyl and % hydroxypropoxyl. These are subsequently converted into degree of substitution (DS) for methyl substituents and molar substitution (MS) for hydroxypropyl substituents. Residual amounts of salt are taken into account in the conversion. The DS(methyl) and MS(hydroxyethyl) in hydroxyethyl methylcellulose is effected by Zeisel cleavage with hydrogen iodide followed by gas chromatography. (G. Bartelmus and R. Ketterer, Z. Anal. Chem. 286 (1977) 161-190).

The viscosity of the hydroxyalkyl methylcellulose that is used in the process and the hydrogel of the present invention is important. The hydroxyalkyl methylcelluloses that are utilized in the present invention typically gel at lower temperatures than standard grades of hydroxyalkyl methylcelluloses. Therefore, the viscosity of the hydroxyalkyl methylcellulose that is used in the process and the hydrogel of the present invention is measured as a 2 wt.- % solution in water at 5 °C at a shear rate of 10 s 1 to obtain accurate results. The hydroxyalkyl methylcellulose utilized in the present invention has a viscosity of at least 500 mPa»s, preferably at least 1000 mPa»s, more preferably at least 2000 mPa»s, even more preferably at least 3000 mPa»s, and most preferably at least 4000 mPa»s. Generally, the hydroxyalkyl methylcellulose has a viscosity of up to 150,000 mPa»s. Preferably, the hydroxyalkyl methylcellulose has a viscosity of up to 100,000 mPa»s, more preferably up to 50,000 mPa»s, even more preferably up to 20,000 mPa»s, and most preferably up to 8000 mPa»s. All these viscosities are measured as a 2 wt.-% solution in water at 5 °C at a shear rate of 10 s 1 .

Processes for producing the hydroxyalkyl methylcellulose utilized in the process and in the hydrogel of the present invention are described in International Patent Applications WO 2012/051035 Al, pages 10 - 13 and 21 - 25; and WO 2012/173838 Al, pages 7 - 12, and the teachings of which is incorporated herein by reference.

In step a) of the process of the present invention an aqueous composition comprising at least 2.0 wt.-% of the above-described hydroxyalkyl methylcellulose is prepared, based on the total weight of the aqueous composition. Preferably an aqueous composition comprising at least 2.5 wt.-%, more preferably at least 3.0 wt.-%, and most preferably at least 3.3 wt .-% hydroxyalkyl methylcellulose is prepared. Typically an aqueous composition comprising up to 15 wt.-%, more typically up to 10 wt.-%, even more typically up to 7.5 wt-%, and most typically up to 5 wt.-% of the above-described hydroxyalkyl methylcellulose is prepared, based on the total weight of the aqueous composition.

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 0.3 wt.-%, more preferably at least 0.5 wt.-%, even more preferably at least 1 wt.-%, and most preferably at least 2 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 20 wt-%, more typically up to 15 wt.-%, even more typically up to 10 wt.-%, and most typically up to 5 wt.-%, based on the total weight of the aqueous composition.

The above described 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 hydroxyalkyl methylcellulose and the ion exchange resin is from 10 : 1 to 1 : 20, preferably from 10 : 1 to 1 : 10, more preferably from 9 : 1 to 1 : 5, and most preferably from 5 : 1 to 1 : 2.

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 hydroxyalkyl methylcellulose 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 hydroxyalkyl methylcellulose, 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 hydroxyalkyl methylcellulose, 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 hydroxyalkyl

methylcellulose is prepared, the above described hydroxyalkyl methylcellulose is typically utilized in ground and dried form. The hydroxyalkyl methylcellulose 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 hydroxyalkyl methylcellulose 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 hydroxyalkyl methylcellulose described above, 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, 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 hydroxyalkyl methylcellulose described above is the only thickener or gelling agent in the aqueous composition. The sum of the hydroxyalkyl methylcellulose, 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 compositions of the hydroxyalkyl methylcellulose described in more details above can gel at a temperature as low as 30 °C. Increasing the concentration of the hydroxyalkyl methylcellulose 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 20 wt.-%, preferably at least 25 wt.-%, more preferably at least 30 wt.-%, and most preferably at least 35 weight percent of water is liberated from the hydrogel. Generally up to 90 wt.-%, preferably up to 80 wt.-%, more preferably up to 70 wt.-%, even more preferably up to 65 wt.-%, and most preferably up to 60 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 95 wt. preferably up to 93 wt.-%, more preferably up to 91 wt.-%, and most preferably up to 85 weight percent, based on the total weight of the hydrogel. The remaining water content of the hydrogel is generally at least 20 wt.-%, preferably at least 40 wt.-%, more preferably at least 60 wt.-%, and most preferably at least 75 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. 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 hydroxyalkyl methylcellulose in the aqueous composition. The higher the chosen temperature and the concentration of the hydroxyalkyl methylcellulose, 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 hydroxyalkyl methylcellulose 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 °C 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 F GF (2l °C) of at least 8 N, more preferably at least 10 N. Typically the produced hydrogels have a gel fracture force FQ Y( 2 \ °C) of up to 25 N, more typically up to 20 N. How to determine the gel fracture force F GF (2l °C) is described in the Examples section.

Another aspect of the present invention is a hydrogel formed from a hydroxyalkyl methylcellulose and water by heat treatment and syneresis and comprising an ion exchange resin and a pharmaceutical or nutritional ingredient. The hydroxyalkyl methylcellulose, the ion exchange resin and the pharmaceutical or nutritional ingredient in the hydrogel are as described in detail above.

The weight of the hydroxyalkyl methylcellulose is preferably at least 3.0 wt.-%, more preferably at least 4.0 wt.-%, and most preferably at least 5.0 wt.-%, based on the total weight of the hydrogel. The weight of the hydroxyalkyl methylcellulose is preferably up to 20 wt.-%, more preferably up to 15 wt.-%, and most preferably up to 10 wt.-%, based on the total weight of the hydrogel.

The weight of the ion exchange resin is preferably at least 0.4 wt.-%, more preferably at least 0.5 wt.-%, and most preferably at least 0.8 wt.-%, based on the total weight of the hydrogel. The weight of the ion exchange resin is preferably up to 30 wt.-%, more preferably up to 20 wt.-%, and most preferably up to 10 wt.-%, based on the total weight of the hydrogel.

The total weight of the hydroxyalkyl methylcellulose and the ion exchange resin is preferably at least 3.5 wt.-%, more preferably at least 5 wt.-%, even more preferably at least 6.5 wt.-%, and most preferably at least 8 wt.-%, based on the total weight of the hydrogel. The total weight of the hydroxyalkyl methylcellulose and the ion exchange resin is preferably up to 50 wt.-%, more preferably up to 30 wt.-%, even more preferably up to 20 wt-%, and most preferably up to 15 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 2.5 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 95 wt -%, preferably up to 93 wt-%, more preferably up to 91 wt-%, and most preferably up to 85 weight percent, based on the total weight of the hydrogel. The water content of the hydrogel is generally at least 20 wt-%, preferably at least 40 wt-%, more preferably at least 60 wt-%, and most preferably at least 75 weight percent, 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, generally at least 20 wt.-%, preferably at least 25 wt.-%, more preferably at least 30 wt.-%, and most preferably even at least 35 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 90 wt.-%, more typically up to 80 wt.-%, even more typically up to 70 wt.-%, and most typically up to 65 wt .-% or only up to 60 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,r(2 \ °C) of at least 8 N, more preferably at least 10 N. Typically the hydrogel has a gel fracture force Fc,r(2 \ °C) of up to 25 N, more typically of up to 20 N. How to determine the gel fracture force F GF (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 a hydroxyalkyl methylcellulose and water. This means that no other gelling agents than the above described hydroxyalkyl methylcellulose 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 hydroxyalkyl methylcellulose described above, 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. Determination of the viscosity, % methoxyl and % hydroxypropoxyl in

hydroxypropyl methylcellulose (HPMC)

To achieve homogenous solutions, 3 g of the cellulose ether powder (under consideration of the water content of the cellulose ether) is suspended in 197 g water at 70°C with an overhead laboratory stirrer at 700 rpm for 10 min. These solutions are then cooled to a temperature of 2 °C for 5 hours to complete the dissolution process. During these 5 hours the solutions are stirred at 500 - 1000 rpm and lost water due to evaporation is replaced. These solutions are then stored in a refrigerator overnight. Prior to the analysis the cold solutions are stirred for 15 min at 100 rpm.

The steady-shear-flow viscosity h(5 °C, 10 s -1 , 2 wt.% HPMC) of an aqueous 2-wt.% HPMC solution is measured at 5 °C at a shear rate of 10 s 1 with an Anton Paar Physica MCR 501 rheometer and cone-and-plate sample fixtures (CP-50/1, 50-mm diameters).

The determination of the % methoxyl and % hydroxypropoxyl in HPMC is carried out according to the United States Pharmacopeia (USP 40). The values obtained are % methoxyl and % hydroxypropoxyl. These are subsequently converted into degree of substitution (DS) for methyl substituents and molar substitution (MS) for hydroxypropyl substituents. Residual amounts of salt have been taken into account in the conversion.

Determination of s23/s26

The determination of ether substituents in cellulose ethers is generally known and e.g., described in Carbohydrate Research, 176 (1988) 137-144, Elsevier Science Publishers B.V., Amsterdam, DISTRIBUTION OF SUBSTITUENTS IN 0-ETHYL-0-(2- HYDROXYETHYL)CELLULOSE by Bengt Lindberg, Ulf Lindquist, and

Olle Stenberg.

Specifically, determination of s23/s26 is conducted as follows:

10-12 mg of the cellulose ether are dissolved in 4.0 mL of dry analytical grade dimethyl sulfoxide (DMSO) (Merck, Darmstadt, Germany, stored over 0.3nm molecular sieve beads) at about 90 °C under stirring and then cooled down to room temperature again. The solution is left stirring at room temperature overnight to ensure complete solubilization. The entire reaction including the solubilization of the cellulose ether is performed using a dry nitrogen atmosphere in a 4 mL screw cap vial. After solubilization the dissolved cellulose ether is transferred to a 22 mL screw cap vial. Powdered sodium hydroxide (freshly pestled, analytical grade, Merck, Darmstadt, Germany) and ethyl iodide (for synthesis, stabilized with silver, Merck-Schuchardt, Hohenbrunn, Germany) in a thirty fold molar excess of the reagents sodium hydroxide and ethyl iodide per hydroxyl group of the anhydroglucose unit are added and the solution is vigorously stirred under nitrogen in the dark for three days at ambient temperature. The perethylation is repeated with addition of the threefold amount of the reagents sodium hydroxide and ethyl iodide compared to the first reagent addition and further stirring at room temperature for additional two days. Optionally the reaction mixture can be diluted with up to 1.5 mL DMSO to ensure good mixing during the course of the reaction. 5 mL of 5 % aqueous sodium thiosulfate solution is poured into the reaction mixture and the obtained solution is then extracted three times with 4 mL of

dichloromethane. The combined extracts are washed three times with 2 mL of water. The organic phase is dried with anhydrous sodium sulfate (ca. lg). After filtration the solvent is removed in a gentle stream of nitrogen and the sample is stored at 4 °C until further sample preparation.

Hydrolysis of about 5 mg of the perethylated samples is performed under nitrogen in a 2 mL screw cap vial with 1 mL of 90 % aqueous formic acid under stirring at 100 °C for 1 hour. The acid is removed in a stream of nitrogen at 35-40 °C and the hydrolysis is repeated with 1 mL of 2M aqueous trifluoroacetic acid for 3 hours at 120 °C in an inert nitrogen atmosphere under stirring. After completion the acid is removed to dryness in a stream of nitrogen at ambient temperature using ca. 1 mL of toluene for co-distillation.

The residues of the hydrolysis are reduced with 0.5 mL of 0.5 M sodium

borodeuteride in 2N aqueous ammonia solution (freshly prepared) for 3 hours at room temperature under stirring. The excess reagent is destroyed by drop wise addition of ca. 200 pL of concentrated acetic acid. The resulting solution is evaporated to dryness in a stream of nitrogen at ca. 35-40 °C and subsequently dried in vacuum for 15 min at room temperature. The viscous residue is dissolved in 0.5 mL of 15 % acetic acid in methanol and evaporated to dryness at room temperature. This is done five times and repeated four times with pure methanol. After the final evaporation the sample is dried in vacuum overnight at room temperature.

The residue of the reduction is acetylated with 600 pL of acetic anhydride and 150 pL of pyridine for 3 hrs at 90 °C. After cooling the sample vial is filled with toluene and evaporated to dryness in a stream of nitrogen at room temperature. The residue is dissolved in 4 mL of dichloromethane and poured into 2 mL of water and extracted with 2 mL of dichloromethane. The extraction is repeated three times. The combined extracts are washed three times with 4 mL of water and dried with anhydrous sodium sulfate. The dried dichloromethane extract is subsequently submitted to GC analysis. Depending on the sensitivity of the GC system, a further dilution of the extract can be necessary.

Gas-liquid (GLC) chromatographic analyses are performed with Hewlett Packard 5890A and 5890A Series II type of gas chromatographs equipped with J&W capillary columns DB5, 30 m, 0.25 mm ID, 0.25 mhi phase layer thickness operated with 1.5 bar helium carrier gas. The gas chromatograph is programmed with a temperature profile that holds constant at 60 °C for 1 min, heats up at a rate of 20 °C / min to 200 °C, heats further up with a rate of 4 °C / min to 250 °C, heats further up with a rate of 20 °C / min to 310 °C where it is held constant for another 10 min. The injector temperature is set to 280 °C and the temperature of the flame ionization detector (FID) is set to 300 °C. 1 pL of the samples is injected in the splitless mode at 0.5 min valve time. Data are acquired and processed with a LabSystems Atlas work station.

Quantitative monomer composition data are obtained from the peak areas measured by GLC with FID detection. Molar responses of the monomers are calculated in line with the effective carbon number (ECN) concept but modified as described in the table below. The effective carbon number (ECN) concept has been described by Ackman (R.G. Ackman, J. Gas Chromatogr., 2 (1964) 173-179 and R.F. Addison, R.G. Ackman, J. Gas

Chromatogr., 6 (1968) 135-138) and applied to the quantitative analysis of partially alkylated alditol acetates by Sweet et. al (D.P. Sweet, R.H. Shapiro, P. Albersheim, Carbohyd. Res., 40 (1975) 217-225).

ECN increments used for ECN calculations:

In order to correct for the different molar responses of the monomers, the peak areas are multiplied by molar response factors MRFmonomer which are defined as the response relative to the 2,3,6-Me monomer. The 2,3,6-Me monomer is chosen as reference since it is present in all samples analyzed in the determination of s23 / s26. MRFmonomer = ECN2,3,6-Me / ECNmonomer

The mole fractions of the monomers are calculated by dividing the corrected peak areas by the total corrected peak area according to the following formulas:

s23 = [ (23-Me + 23-Me-6-HAMe + 23-Me-6-HA + 23 -Me-6-HAHAMe + 23-Me- 6-HAHA ]; and

s26 = [ (26-Me + 26-Me-3-HAMe + 26-Me-3-HA + 26-Me-3-HAHAMe + 26-Me- 3 -HAH A], wherein

s23 is the sum of the molar fractions of anhydroglucose units which meet the following conditions:

a) the two hydroxy groups in the 2- and 3 -positions of the anhydroglucose unit are substituted with methyl groups and the 6-position is not substituted (= 23-Me);

b) the two hydroxy groups in the 2- and 3-positions of the anhydroglucose unit are substituted with methyl groups and the 6-position is substituted with methylated hydroxyalkyl (= 23-Me-6-HAMe) or with a methylated side chain comprising 2 hydroxyalkyl groups (= 23-Me-6-HAHAMe); and

c) the two hydroxy groups in the 2- and 3 -positions of the anhydroglucose unit are substituted with methyl groups and the 6-position is substituted with hydroxyalkyl (= 23- Me-6-HA) or with a side chain comprising 2 hydroxyalkyl groups (= 23-Me-6-HAHA). s26 is the sum of the molar fractions of anhydroglucose units which meet the following conditions:

a) the two hydroxy groups in the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups and the 3-position is not substituted (= 26-Me);

b) the two hydroxy groups in the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups and the 3-position is substituted with methylated hydroxyalkyl (= 26-Me-3-HAMe) or with a methylated side chain comprising 2 hydroxyalkyl groups (= 26-Me-3-HAHAMe); and

c) the two hydroxy groups in the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups and the 3-position is substituted with hydroxyalkyl (= 26- Me-3-HA) or with a side chain comprising 2 hydroxyalkyl groups (= 26-Me-3-HAHA).

The results of the determination of the substituents in the HAMC are listed in Table 4 below. In the case of HPMC’s hydroxyalkyl (HA) is hydroxypropyl (HP) and methylated hydroxyalkyl (HAMe) is methylated hydroxypropyl (HPMe). Determination of the Gel Fracture Force FGF(2 ! °C) of the Hydrogel

The gel fracture force F GF (2l °C) is measured with a Texture Analyzer (model TA.XTPlus; Stable Micro Systems, 5-Kg load cell) at 2l°C. The gels are compressed between a steel plate (90mm 100mmx9mm 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: 0.005N, 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 being observed visually. It is identified as F GF (2l °C).

Drug dissolution test

The rate of drug release over 24 hours is assessed. The hydrogel samples are dissolved in 0.5M phosphate 6.8 +/- 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 the HPMC used in Example 1

HPMC is produced according to the following procedure. Finely ground wood cellulose pulp is loaded into a jacketed, agitated reactor. The reactor is evacuated and purged with nitrogen to remove oxygen and then evacuated again. The reaction is carried out in two stages. In the first stage a 50 weight percent aqueous solution of sodium hydroxide is sprayed onto the cellulose in an amount of 1.2 moles of sodium hydroxide per mole of anhydroglucose units in the cellulose and the temperature is adjusted to 40°C. After stirring the mixture of aqueous sodium hydroxide solution and cellulose for about 30 minutes at 40°C, 1.5 moles of dimethyl ether, 3.5 moles of methyl chloride and 0.33 moles of propylene oxide per mole of anhydroglucose units are added to the reactor. The contents of the reactor are then heated in 60 min to 80°C. After having reached 80°C, the first stage reaction is allowed to proceed for 20 min.

Then a 50 weight percent aqueous solution of sodium hydroxide at an amount of 1.0 moles of sodium hydroxide per mole of anhydroglucose units is added over a time period of 90 min. The rate of addition is 0.011 moles of sodium hydroxide per mole of

anhydroglucose units per minute. After the second stage addition is completed the contents of the reactor are then kept at a temperature of 80 °C for 120 min.

After the reaction, the reactor is vented and cooled down to about 50°C. The contents of the reactor are removed and transferred to a tank containing hot water. The crude HPMC is then neutralized with formic acid and washed chloride free with hot water (assessed by AgNO 3 flocculation test), cooled to room temperature and dried at 55 °C in an air-swept drier. The material is then ground.

The produced HPMC is used that has a DS(methyl) of 1.50 and an

MS(hydroxyalkyl) of 0.14, which corresponds to a methoxyl content of 24.3 % and a hydroxypropoxyl content of 5.5 %. The HPMC has a viscosity of 4890 MPa»s, measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s -1 , and a ratio s23/s26 of 0.18.

Examples 1 - 2 and Reference Example A-i

A HPMC as described above is used. The HPMC has a DS(methyl) of 1.50, an MS(hydroxyalkyl) of 0.14, a viscosity of 4890 MPa»s, measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s 1 , and a ratio s23/s26 of 0.18.

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 active pharmaceutical ingredient (API) is Propranolol HC1.

Aqueous solutions of the HPMC in deionized water are 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 propranolol HC1 (API) and Amberlite IRP 64 ion exchange resin (IER). The amounts of MC, IER, API and water are listed in Table 1 below. Then the liquid aqueous compositions are centrifuged at 4°C for 30 minutes using a Sorvall Lynx 4000 centrifuge at 6000 rpm. The liquid aqueous compositions 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 containers in an oven maintained at 85 °C.

All aqueous compositions gel at 85 °C. During the heat treatment the hydrogels undergo syneresis wherein the entire amount of MC, of the IER, 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. The hydrogels are removed from the liberated water, mechanically dried with a tissue and weighed immediately after the gel has cooled to room temperature but before storage at room temperature.

In Examples 1 and 2 the liberated water contains the API at a smaller concentration (mass per volume) than in the liquid aqueous composition before gelling because some of the API is associated with the ion exchange resin and remains in the hydrogel.

The produced hydrogels are then placed in separate bags and stored at room temperature for a day. The consistency of the hydrogels is assessed immediately after cooling to room temperature and after storage at room temperature for a day.

Table 1 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 HPMC content and the IER content are calculated based on the amounts of the HPMC and the IER in the liquid aqueous composition before gelling and the weight of the hydrogel.

The produced hydrogels are stored at room temperature for at least 24 hours prior to further analysis. Each of the hydrogels is cut into 8 pieces to simulate chewing. The release of the API (Propranolol HC1) is tested in an USP phosphate buffer having a pH 6.8 in an USP dissolution tester as described above. The % Propranolol HC1 that is dissolved over time, based on the total amount of Propranolol HC1 in the hydrogel released during the experiment, is determined and plotted in Fig. 1. Figure 1 illustrates that the release of Propranolol HC1 from the hydrogels of Examples 1 and 2 is extended over a longer time period than from the hydrogel of Reference Example A-i. Reference Example A-i is used for reference purposes to illustrate the API release from a hydrogel without IER. However, Reference Examples A and B do not represent the prior art. Example 3 and Reference Example A-ii

For measuring the gel fracture forces F GF (21 °C) of some produced hydrogels, hydrogels are prepared according to the same procedure as in Examples 1 - 2 and Reference Example A-i. The hydrogel production in reference Example A-ii is a repetition of the hydrogel production in reference Example A-i. The amounts of MC, IER, API and water utilized in Example 3 are listed in Table 1 below. The gel fracture forces F GF (21 °C) of the produced hydrogels are determined after having stored the gels over night at a temperature of 21 °C. The results are listed in Table 1 below. Examples 4 and 5 and Reference Example B

Hydrogels are prepared according to the same procedure as in Examples 1 - 2 and Reference Example A-i, except that the liquid aqueous compositions are not centrifuged. The concentration of the API (Propranolol HC1) in the water expelled from the hydrogel during the heat treatment is analyzed in Examples 4 and 5. In Example 4 the API concentration in the expelled water is 3.4 mg/ml; in Example 5 the API concentration in the expelled water is 3.0 mg/ml. This is lower than the API concentration based on the water volume in the liquid aqueous compositions before gelling, which is 4.2 mg APT/ml water (in Example 4) and 4.3 mg APT/ml water (in Example 5), respectively. In Examples 4 and 5 the liberated water contains the API at a smaller concentration (mass per volume) than in the liquid aqueous composition before gelling because some of the API is associated with the ion exchange resin and remains in the hydrogel.

Reference Examples A-I, A-ii and B are used for reference purposes but do not represent prior art.