WO2019108265A1

WO2019108265A1 - Hydrogels based on methylcellulose

Info

Publication number: WO2019108265A1
Application number: PCT/US2018/041738
Authority: WO
Inventors: Jaime L. CURTIS-FISK; Oliver Petermann
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 a methylcellulose and water by heat treatment and syneresis. The hydrogel also comprises an ion exchange resin and a pharmaceutical or nutritional ingredient. The methylcellulose has a viscosity of at least 1,000 mPa»s, when measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s-1, and anhydroglucose units joined by 1-4 linkages wherein hydroxy groups of anhydroglucose units are substituted with methyl groups such that s23/s26 is 0.36 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 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.

Description

HYDROGELS BASED ON METHYLCELLULOSE

FIELD

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

INTRODUCTION

Methylcellulose is 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,

methylcellulose does not present itself as an alternative to gelatin due to the unusual gelling behavior of methylcellulose. Methylcellulose is known to exhibit reverse thermal gelation in water, in other words, aqueous 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 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.

Most grades of methylcellulose gel at around 50 to 60 °C. Grades of methylcellulose that gel in water at a relatively low temperature, 38 to 44 °C, is generally available under the trade name METHOCEL SG or SGA (The Dow Chemical Company). US Patent No. 6,235,893 teaches methylcellulose that gels as low as 31 °C. Grades of methylcellulose that gel in water and form quite strong gels at body temperature are disclosed in International Patent Applications WO2011/139763 and WO2014/168915. These grades of

methylcellulose are consumed as cold solutions in water, i.e., having room temperature or lower. Upon ingestion the aqueous solutions of methylcellulose warm up to body temperature and form a gel mass in the individual's body, which induces satiety. However, even when aqueous solutions of these grades of methylcellulose form strong gels at a temperature of about 37 °C, 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. However, producing, transporting and storing methylcellulose gels at temperatures of more than 30 °C to avoid their melt back and potentially even maintain the shape of the methylcellulose gels is energy consuming and inconvenient.

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 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 novel gelatin-free hydrogels or gummies or pastilles based on methylcellulose 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 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 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 methylcellulose and water by heat treatment and syneresis and comprising an ion exchange resin and a pharmaceutical or nutritional ingredient, wherein the methylcellulose has a viscosity of at least 1,000 mPa»s, when measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s ¹, and anhydroglucose units joined by 1-4 linkages wherein hydroxy groups of anhydroglucose units are substituted with methyl groups such that s23/s26 is 0.36 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 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 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 1.S wt.-%, based on the total weight of the aqueous composition, of the above-mentioned methylcellulose, 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 IS 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 from reference hydrogels.

DESCRIPTION OF EMBODIMENTS

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

The methylcellulose used for preparing the hydrogel of the present invention has anhydroglucose units joined by 1-4 linkages. Each anhydroglucose unit contains hydroxyl groups at the 2, 3, and 6 positions. Partial or complete reaction of these hydroxyls creates cellulose derivatives. For example, treatment of cellulosic fibers with caustic solution, followed by a methylating agent, yields cellulose ethers substituted with one or more methyl groups. If the hydroxyl groups are not substituted with other groups than methyl groups, this cellulose derivative is known as methylcellulose.

An essential feature of the present invention is the use of a specific methylcellulose wherein hydroxy groups of anhydroglucose units are substituted with methyl groups such that s23/s26 is 0.36 or less, preferably 0.33 or less, more preferably 0.30 or less, most preferably 0.27 or less, or 0.26 or less, and particularly 0.24 or less or 0.22 or less. Typically s23/s26 is 0.08 or more, 0.10 or more, 0.12 or more, 0.14 or more, or 0.16 or more.

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 two hydroxy groups in the 2- and 3 -positions are substituted with methyl groups and the 6-positions are unsubstituted hydroxy 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 two hydroxy groups in the 2- and 6-positions are substituted with methyl groups and the 3-positions are unsubstituted hydroxy groups. The term“OH groups substituted with methyl groups” as used herein means that OH groups have been reacted to OC¾ groups.

Formula I below illustrates the numbering of the hydroxy groups in anhydroglucose units.

Methylcellulose can be characterized by the weight percent of methoxyl groups. By convention, the weight percent is an average weight percentage based on the total weight of the cellulose repeat unit, including all substituents. The content of the methoxyl group is reported based on the mass of the methoxyl group (i.e.,— OCH₃). The determination of the % methoxyl in methylcellulose (MC) polymer is carried out according to the United States Pharmacopeia (USP 37,“Methylcellulose”, pages 3776-3778). The % methoxyl can be converted into degree of substitution (DS) for methyl substituents, DS(methyl). DS(methyl), also designated as DS(methoxyl), of a methylcellulose is the average number of OH groups substituted with methyl groups per anhydroglucose unit. Preferably, the methylcellulose has % methoxyl of 18% or more; more preferably 25% or more. Preferably, the

methylcellulose has % methoxyl of 40% or less; more preferably 35% or less. Even more preferably, methylcellulose has a DS(methyl) of 1.55 or higher; more preferably 1.65 or higher; and most preferably 1.70 or higher. DS(methyl) is preferably 2.25 or lower; more preferably 2.20 or lower; and most preferably 2.10 or lower.

The viscosity of the methylcellulose that is used in the process and the hydrogel of the present invention is important. The viscosities of standard grades of methylcellulose that gel at around 50 to 60 °C is typically measured as a 2 wt.-% solution in water at 20 °C.

However, the methylcellulose that is utilized in the present invention gels at lower temperature. Therefore, the viscosity of the 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 methylcellulose utilized in the present invention has a viscosity of at least 1000 mPa»s, generally at least 2000 mPa»s, preferably at least 3500 mPa»s, more preferably at least 5000 mPa»s, and most preferably at least 10,000 mPa»s. Generally, the methylcellulose has a viscosity of up to 100,000 mPa»s. Preferably, the methylcellulose has a viscosity of up to 80,000 mPa»s, more preferably up to 60,000 mPa»s, and most preferably up to 40,000 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 methylcellulose utilized in the process and in the hydrogel of the present invention are described in International Patent Application WO 2014/168915 Al, pages 13 - 16, the teaching of which is incorporated herein by reference.

In step a) of the process of the present invention an aqueous composition comprising at least 1.5 wt.-% of the above-described methylcellulose is prepared, based on the total weight of the aqueous composition. Preferably an aqueous composition comprising at least 1.8 wt.-%, more preferably at least 2.1 wt.-%, and most preferably at least 2.5 wt.-% methylcellulose is prepared. Typically an aqueous solution 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 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 3 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 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 methylcellulose 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 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 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 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 a methylcellulose is prepared, the above described methylcellulose is typically utilized in ground and dried form. When a methylcellulose is used wherein hydroxy groups of anhydroglucose units are substituted with methyl groups such that s23/s26 is 0.27 or less, the 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. When a methylcellulose is used wherein hydroxy groups of anhydroglucose units are substituted with methyl groups such that s23/s26 is more than 0.27 and up to 0.36, the methylcellulose is generally mixed with water at a temperature of from 5 to 25 °C, preferably from 11 to 23 °C, and more preferably from 13 to 21 °C. A low or high shear rate can be applied to prepare the aqueous solution. In one embodiment of the invention the aqueous solution is prepared at a shear rate of at least 1000 s ¹, as described in International Patent Application WO2014/168915. 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

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 methylcellulose, 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. More preferably, the methylcellulose described above is the only thickener or gelling agent in the aqueous composition. The sum of the 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 solutions of the methylcellulose described in more details above can gel at a temperature as low as about 31 °C. Increasing the concentration of the 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.-%, even more preferably at least 35 wt.-%, and most preferably even at least 40 weight percent of water is liberated from the hydrogel. Generally up to 90 wt.-%, more preferably up to 80 wt.-%, even more preferably up 70 wt-%, and most preferably up to 65 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 80 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 50 wt.-%, and most preferably at least 60 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 methylcellulose in the aqueous composition. The higher the chosen temperature and the concentration of the 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 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 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 ° 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(21 °C) of at least 10 N, more preferably at least 12 N. Typically the produced hydrogels have a gel fracture force F _GF(21 °C) of up to 30 N, more typically up to 20 N. How to determine the gel fracture force F _GF(21 °C) is described in the Examples section.

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

The weight of the methylcellulose is preferably at least 3.0 wt.-%, more preferably at least 3.5 wt.-%, and most preferably at least 4.0 wt.-%, based on the total weight of the hydrogel. The weight of the 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 25 wt.-%, and most preferably up to 20 wt.-%, based on the total weight of the hydrogel.

The total weight of the 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 methylcellulose and the ion exchange resin is preferably up to 50 wt.-%, more preferably up to 40 wt.-%, even more preferably up to 35 wt.-%, and most preferably up to 25 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 80 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 50 wt-%, and most preferably at least 60 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.-%, even more preferably at least 35 wt.-%, and most preferably even at least 40 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.-%, and in some embodiments up to 70 wt.-% or 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 FQ_Y(2 \ °C) of at least 10 N, more preferably at least 12 N. Typically the hydrogel has a gel fracture force F _GF(21 °C) of up to 30 N, more typically of up to 20 N. How to determine the gel fracture force F _GF(21 °C) is described in the Examples section.

The hydrogel of the present invention may comprise a minor amount of one or more organic liquids which are preferably physiologically acceptable, such as ethanol or one or more animal or vegetable oils, but the total amount of organic liquids is preferably not more than 10 percent, more preferably not more than 5 percent, even more preferably not more than 2 percent, based on the total weight of water and organic liquid in the hydrogel at a temperature of 21 °C. Most preferably, the hydrogel does not comprise an organic liquid. The hydrogel of the present invention may comprise 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 methylcellulose and water. This means that no other gelling agents than the above described 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 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 % methoxyl in Methylcellulose (MC)

The determination of the % methoxyl in methylcellulose (MC) polymer is carried out according to the United States Pharmacopeia (USP 37,“Methylcellulose”, pages 3776- 3778).

Determination of the viscosity of Methylcellulose

The steady-shear-flow viscosity h(5 °C, 10 s^-1, 2 wt.% MC) of an aqueous 2-wt.% methylcellulose 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).

Determination of the Gel Fracture Forces 21 °C) of the Hydrogel

The gel fracture forces F_GF(2l °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 (90mmxl00mmx9mm 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. It is identified as F _GF(21 °C).

Drug dissolution test

The release of a drug (propranolol HC1) is conducted in 900 mL of a USP phosphate buffer having a pH 5.8 for 24 h at 37.5°C with a USP dissolution apparatus (Erweka Dissolution Tester 626, Erweka GmbH) equipped with standard USP II hanging baskets and paddles rotating at a speed of 50 rpm. The gels are added to the dissolution media using baskets. The absorbance of drug at each sample time is measured using a Shimadzu UV-Vis spectrophotometer (Shimadzu Deutschland GmbH, Duisburg, Germany). The concentration of propranolol HC1 is calculated using a standard calibration curve at a wavelength of 289 nm.

Determination of s23/s26 of Methylcellulose

The approach to measure the ether substituents in methylcellulose is generally known. See for example the approach described in principle for Ethyl Hydroxyethyl Cellulose 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, the determination of s23/s26 is conducted as described in International Patent Application No. WO 2014/168915 Al, pages 18 - 21, the teaching of which is incorporated herein by reference.

Examples 1 - 3 and Reference Examples A and B

A methylcellulose (MC) is used that has a methoxyl content of 30.4 %, a viscosity of 8610 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 0.23.

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.

30 g of a 3.0 wt.-% solution of MC containing 2 or 5 wt.-% of the API Propranolol

HC1, each based on the total weight of the solution, in deionized water is prepared. Finally the ion exchange resin (IER) is mixed with the aqueous MC solution comprising the API.

The amounts of water, MC and API are as 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. During the heat treatment the hydrogel undergoes 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. After 30 minutes of heating a solid gel has been formed that is separated from the water, mechanically dried with a tissue an weighed to determine Weight I. The solid gel is then dried at 85 °C for 90 minutes on a metal pan to allow any additional expelled water to evaporate. The dried gel is then weighed to determine Weight II, i.e., the weight after drying. The total heating period at 85 °C is 2 hours. In Reference Examples A and B the liberated water contains Propranolol HC1 at about the same concentration (mass per volume) as in the liquid aqueous composition before gelation. In Examples 1 - 3 the liberated water contains Propranolol HC1 at a smaller concentration (mass per volume) than in the liquid aqueous composition before gelling because some of the Propranolol HC1 is associated with the ion exchange resin and remains in the hydrogel.

Table 1 below lists the hydrogel Weight I, the hydrogel Weight II and the liquid loss. The liquid loss corresponds to the weight of the liquid aqueous composition before gelling minus the hydrogel Weight II. The MC content and the IER content are calculated based on the amounts of the MC and the IER in the liquid aqueous composition before gelling and the hydrogel Weight II. The texture of the hydrogel is visually inspected.

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 Examples A and B are used for reference purposes but do not represent prior art.

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 in the hydrogel released during the experiment, is determined and plotted in Fig. 1. Figure 1 illustrates the controlled release of Propranolol HC1 over time from the hydrogels of Examples 1 - 3 and Reference Examples A and B. The extended release of Propranolol HC1 from the hydrogels of Examples 1 - 3 and Reference Examples A and B is compared with a Control, where the drug 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. 1 illustrates that the release of the API from the hydrogels of Examples 1 to 3 is extended over a longer time period than from the hydrogels of Reference Examples A and B. Reference Examples A and B are used for reference purposes to illustrate the API release from hydrogels without IER. However, Reference Examples A and B do not represent the prior art.

Examples 4 - 5

In all experiments the same methylcellulose (MC), ion exchange resin (IER) and active pharmaceutical ingredient (API) are used as in Examples 1 - 3. Aqueous solutions of the MC 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 2 below. Then the liquid aqueous compositions are centrifuged (Sorvall Lynx 4000 centrifuge at 4000 rpm at l0°C) until the compositions are free of air bubbles.

The 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 treatments the hydrogels undergo syneresis to a very large degree wherein the entire amount of MC, of IER and of API associated with the IER, remains in the hydrogel and the major portion of the water originally present in the aqueous solution is expelled from the hydrogel. The hydrogels are removed from the liberated water, mechanically dried with a tissue and weighed to determine the weight of the hydrogel. 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.

Table 2 below lists the weight 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 MC content and the IER content are calculated based on the amounts of the MC and the IER in the liquid aqueous composition before gelling and the weight of the hydrogel. The texture of the hydrogel is visually inspected.

In Examples 4 and 5 hydrogels of stable shape are obtained that maintain their shape when the hydrogels are cooled to room temperature and stored at room temperature.

The produced hydrogels are placed on a glass container without delay and allowed to cool to room temperature. The gel fracture force F_GF(21 °C) of the produced hydrogel of Example 4 is determined after having stored the gel over night at a temperature of 21 °C. The gel fracture force F_GF(21 °C) is listed in Table 2 below.

Examples 6 and 7

Hydrogels are prepared according to the same procedure as in Examples 4 and 5, except that the liquid aqueous compositions are not centrifuged. Table 2 below lists the weight of the hydrogel and the liquid loss. The liquid loss, the MC content and the IER content are calculated as in Examples 4 and 5.

In Examples 6 and 7 hydrogels of stable shape are obtained that maintain their shape when the hydrogels are cooled to room temperature and stored at room temperature. The storage stability of the hydrogel of Example 6 in a refrigerator was also tested; it even maintains its shape when it is stored in a refrigerator.

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Claims

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

the methylcellulose has

a viscosity of at least 1,000 mPa»s, when measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s^-1, and

anhydroglucose units joined by 1-4 linkages wherein hydroxy groups of anhydroglucose units are substituted with methyl groups such that s23/s26 is 0.36 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 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 viscosity of the methylcellulose is from 2,000 to 100,000 mPa»s, when measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s ¹.

3. The hydrogel of claim 1 or 2, wherein the methylcellulose has a degree of methyl substitution of from 1.55 to 2.25.

4. The hydrogel of any one of claims 1 to 3, 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.

5. The hydrogel of any one of claims 1 to 4, wherein the weight of the methylcellulose is from 3.0 to 20 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 ion exchange resin is from 0.4 to 30 weight percent, based on the total weight of the hydrogel.

7. The hydrogel of any one of claims 1 to 6, wherein the total weight of the methylcellulose and the ion exchange resin is from 3.5 to 50 weight percent, based on the total weight of the hydrogel.

8. The hydrogel of any one of claims 1 to 7, 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.

9. The hydrogel of any one of claims 1 to 8, having a gel fracture force F _GF(21 °C) of at least 10 N.

10. A process for producing a hydrogel from a 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 1.5 wt.-%, based on the total weight of the aqueous composition, of a methylcellulose having a viscosity of at least 1,000 mPa»s, when measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s ¹, and having anhydroglucose units joined by 1-4 linkages wherein hydroxy groups of anhydroglucose units are substituted with methyl groups such that s23/s26 is 0.36 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 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 1.8 wt.-% of a 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).