WO2019022817A1

WO2019022817A1 - Process for producing a hydrogel based on methylcellulose

Info

Publication number: WO2019022817A1
Application number: PCT/US2018/033799
Authority: WO
Inventors: Oliver Petermann
Original assignee: Dow Global Technologies Llc
Priority date: 2017-07-26
Filing date: 2018-05-22
Publication date: 2019-01-31

Abstract

A stable hydrogel can be formed from a methylcellulose and water by heat treatment and syneresis, wherein the hydrogel, at a temperature of 21 C, has a water content of 15 to 96.15 weight percent and the methylcellulose has a viscosity of at least 1,000 mPas, 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

PROCESS FOR PRODUCING A HYDROGEL 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 gelatin-free, methylcellulose-based hydrogels or gummies or pastilles 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, methylcellulose-based hydrogels or gummies or pastilles that even maintain a substantially stable shape at room temperature or even at refrigerator temperature (4 °C).

Accordingly, one aspect of the present invention is a process for producing a hydrogel from a methylcellulose and water, which comprises the steps of a) preparing an aqueous solution comprising at least 1.9 wt.-% of a methylcellulose, based on the total weight of the aqueous solution, the 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, b) heating the aqueous solution of step a) to form a hydrogel from the aqueous solution, c) maintaining the formed hydrogel at least at a temperature at which the hydrogel has been formed in step b) for a sufficient time period to liberate at least 15 weight percent of water from the hydrogel, based on the water weight in the aqueous solution in step a), provided that the remaining water content in the hydrogel is from 15 to 96.15 weight percent, based on the total weight of the hydrogel, and d) separating liberated water from the hydrogel and cooling the hydrogel to a temperature of 25 °C or less simultaneously or in any sequence.

Another aspect of the present invention is a hydrogel formed from a methylcellulose and water by heat treatment and syneresis, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 15 to 96.15 weight percent, based on the total weight of the hydrogel, and 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.

BRIEF DESCRIPTION OF DRAWINGS

Figures 1 and 2 are photographical representations of the hydrogels of Examples 1 and 2 after heat treatment and repulsion of water from the hydrogels.

Figures 3 and 4 are photographical representations of the hydrogels of Examples 1 and 2 after cooling to room temperature but before storage.

Figure 5 is a photographical representation of the hydrogel of Example 1 after its storage for 4 days at 4 °C.

Figure 6 is a photographical representation of the hydrogel of Example 2 after its storage for 3 hours at 4 °C.

Fig. 7 illustrates from left to right the texture of the gels of Comparative Examples E- i, F-i, G-i, and of Examples 3-i, 4-i, and 5-i after storage for 1 day at room temperature. Figure 8 illustrates the controlled drug release from hydrogels of the present invention.

Figure 9 illustrates the gel fracture force of two replicated measurements for an inventive hydrogel and a comparative 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 present in abundance (Almdal, Dyre, J., Hvidt, S., Kramer, O.; Towards a phenomological definition of the term 'gel'. Polymer and Gel Networks 1993, 1, 5-17). A hydrogel is a gel wherein water is the main liquid component.

The 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 OCH3 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, preferably at least 2000 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 solution comprising at least 1.9 wt.-% of the above-described methylcellulose is prepared, based on the total weight of the aqueous solution. Preferably an aqueous solution comprising at least 2.0 wt.- %, more preferably at least 2.5 wt.-%, even more preferably at least 2.8 wt.-%, and most preferably at least 3.0 wt.-% methylcellulose is prepared. Typically an aqueous solution comprising up to 20 wt.-%, more typically up to 15 wt.-%, even more typically up to 10 or 8 wt.-%, and most typically up to 6 wt.-% of the above-described methylcellulose is prepared, based on the total weight of the aqueous solution.

The preferred concentration of methylcellulose in the aqueous solution that is produced in step a) of the process of the present invention is dependent on the viscosity and the s23/s26 ratio of the methylcellulose. When the methylcellulose has a viscosity of at least 10,000 mPa»s, measured as a 2 wt.-% solution in water, an aqueous solution is prepared that generally comprises from 1.9 to 7 wt.-%, typically from 2.5 to 6.5 wt.-%, more typically from 3.0 to 6 wt.-% methylcellulose. When the methylcellulose has a viscosity of less than 10,000 mPa»s, measured as a 2 wt.-% solution in water, it may be useful to prepare an aqueous solution that comprises from 5 to 20 wt.-%, typically from 6 to 15 wt.-% methylcellulose.

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, or 0.26 or less, and particularly 0.24 or less or 0.22 or less, generally an aqueous solution is prepared that comprises from 1.9 to 10 wt.-%, preferably from 2.5 to 6.0 wt.-% methylcellulose. When such methylcellulose also has a viscosity of at least 10,000 mPa»s, measured as a 2 wt.-% solution in water, typically a solution is prepared that comprises from 1.9 to 6.0 wt.-%, preferably 2.5 to 4.5 wt.-% methylcellulose.

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, generally an aqueous solution is prepared that comprises from 2.5 to 20 wt.-%, preferably from 3.0 to 15 wt.-% methylcellulose. When such methylcellulose also has a viscosity of at least 10,000 mPa»s, measured as a 2 wt.-% solution in water, typically a solution is prepared that comprises from 2.5 to 7.0, preferably from 3.0 to 5.0 wt.-% methylcellulose.

In step a) of the process, wherein an aqueous solution of 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.

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

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

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

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

Generally the aqueous solution prepared in step a) of the present invention is gelatin- free. Other than the methylcellulose described above, the aqueous solution prepared in step a) of the present invention preferably does not comprise a significant amount of ingredients, such as thickeners or gelling agents, that are able to increase the gel strength of the produced hydrogel at room temperature (21 °C) or at a lower temperature. More preferably, the methylcellulose described above is the only thickener or gelling agent in the aqueous solution. The sum of the methylcellulose and water is generally at least 70 percent, preferably at least 80 percent, more preferably at least 90 percent, and most preferably at least 95 percent, based on the total weight of the aqueous solution of the above-described methylcellulose.

In step b) of the process of the present invention, the aqueous solution of step a) is heated to form a hydrogel from the aqueous solution. It is known that aqueous solutions of the methylcellulose described in more details above can gel at a temperature as low as 31 °C. Increasing the concentration of the methylcellulose or incorporating active ingredients or optional additives, such as tonicity-adjusting agents in the aqueous solution in step a) of the process of the present invention lowers the gelation temperature of the aqueous solution. For practical reasons the aqueous solution of step a) is generally heated to a temperature of at least 55 °C, preferably at least 65 °C, more preferably at least 70 °C, even more preferably at least 75 °C, and most preferably at least 80 °C to form a hydrogel from the aqueous solution. Generally the aqueous solution is heated to a temperature of up to 95 °C, typically up to 90 °C, and more typically up to 87 °C.

In step c) of the process of the present invention, the formed hydrogel is maintained at least at a temperature at which the hydrogel has been formed in step b) for a sufficient time period to liberate at least 15 weight percent of water from the hydrogel, based on the weight of water in the aqueous solution in step a). Generally at least 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. In the most preferred embodiments of the process at least 45 wt.-% or even at least 50 wt.-% of water is liberated from the hydrogel. Generally up to 90 wt.-%, preferably up to 85 wt.-%, more preferably up to 80 wt.-%, even more preferably up to 75 wt.-%, and most preferably up to 70 wt.-% of water is liberated from the hydrogel, based on the weight of water in the aqueous solution in step a). In the most preferred embodiments of the process up to 65 wt.-% of water is liberated from the hydrogel.

In any event a sufficient amount of water is liberated from the hydrogel provided that the remaining water content in the hydrogel is from 15 to 96.15 weight percent, based on the total weight of the hydrogel. The remaining water content of the hydrogel is preferably up to 96.0 wt.-%, more preferably up to 95.5 wt.-%, and most preferably up to 95.0 weight percent, based on the total weight of the hydrogel. In some embodiments of the invention the remaining water content of the hydrogel is only up to 94.5 wt.-% or even only up to 94.1 wt.-%, based on the total weight of the hydrogel. The remaining water content of the hydrogel is preferably at least 30 wt.-%, more preferably at least 50 wt.-%, and most preferably at least 70 weight percent, based on the total weight of the hydrogel. In some embodiments of the invention the remaining water content of the hydrogel is even at least 80 wt.-% or even at least 85 wt.-%, based on the total weight of the hydrogel.

For practical reasons the formed hydrogel is generally maintained at a temperature of at least 55 °C, preferably at least 65 °C, more preferably at least 70 °C, even more preferably at least 75 °C, and most preferably at least 80 °C. Generally the temperature in step c) is up to 95 °C, typically up to 90 °C, and more typically up to 87 °C. Generally maintaining the formed hydrogel at an above-mentioned temperature for at least 1 hour, preferably at least 1.5 hours, more preferably for at least 2 hours, and most preferably at least 3 hours is sufficient for expelling or liberating an amount of water as described above. During the heating of the hydrogel for an extended time period as described above, syneresis takes place and water is expelled or liberated from the hydrogel. Water is typically liberated from the hydrogel in its liquid state, however a portion of the expelled or liberated water can evaporate. In some embodiments of the invention even most or all of the expelled or liberated water can directly evaporate, e.g., by placing the formed hydrogel on a sieve or in or on another device that facilitates water evaporation. The preferred time periods to liberate an amount of water and to achieve a remaining water content as described above depends on the temperature and on the concentration of the methylcellulose in the aqueous solution. 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 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 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. However, it has surprisingly been found that the produced hydrogel can even be stored in expelled water at room temperature, e.g. at 20 - 25 °C, for an extended time period, such as up to 1 week or even up to 2 weeks without melting back of the hydrogel to an aqueous solution. Even storage in a refrigerator at 4 °C up to 5 days is possible. However, during storage for an extended time period some of the expelled water may diffuse back into the hydrogel, which may weaken the hydrogel. Therefore, 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 G_F(21 °C) of at least 10 N, more preferably at least 12 N even more preferably at least 14 N and in the most preferred embodiments even at least 16 N. Typically the produced hydrogels have a gel fracture force G_F(21 °C) of up to 30 N, more typically up to 22 N. How to determine the gel fracture force G_F(21 °C) is described in the Examples section.

Another aspect of the present invention is a hydrogel formed from a methylcellulose and water by heat treatment and syneresis, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 15 to 96.15 weight percent, based on the total weight of the hydrogel, and the methylcellulose is as described in detail above. The water content of the hydrogel is preferably up to 96.0 wt.-%, more preferably up to 95.5 wt.-%, and most preferably up to 95.0 weight percent, based on the total weight of the hydrogel. In some embodiments of the invention the water content of the hydrogel is only up to 94.5 wt.-% or even only up to 94.1 wt.-%, based on the total weight of the hydrogel. The water content of the hydrogel is preferably at least 30 wt.-%, more preferably at least 50 wt.-%, and most preferably at least 70 weight percent, based on the total weight of the hydrogel. In some embodiments of the invention the water content of the hydrogel is even at least 80 wt.-% or even at least 85 wt.-%, based on the total weight of the hydrogel.

The term "formed by heat treatment and syneresis" as used herein means that heat treatment is sufficient to liberate at least 15 weight percent of water from the hydrogel, based on the weight of water used to form the hydrogel. The term "formed by heat treatment and syneresis" preferably means that heat treatment is sufficient to liberate at least 20 wt.-%, preferably at least 25 wt.-%, more preferably at least 30 wt.-%, even more preferably at least 35 wt.-%, most preferably even at least 40 weight percent of water and in some embodiments even at least 45 wt.-% or even at least 50 wt.-% of water from the hydrogel, based on the weight of water used to form the hydrogel. In the hydrogel formed from a methylcellulose and water by heat treatment and syneresis generally up to 90 wt.-%, preferably up to 85 wt.-%, more preferably up to 80 wt.-%, even more preferably up to 75 wt.-%, most preferably up to 70 wt.-% and in some embodiments up to 65 wt.-% of water has been liberated from the hydrogel, based on the weight of water used to form the hydrogel. Ways to conduct the heat treatment are described further above.

Preferred embodiments of the methylcellulose are described above. The hydrogel of the present invention preferably has a gel fracture force GF(21 °C) of at least 10 N, more preferably at least 12 N, even more preferably at least 14 N and in the most preferred embodiments even at least 16 N. Typically the hydrogel has a gel fracture force G_F(21 °C) of up to 30 N, more typically of up to 22 N. How to determine the gel fracture force 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 one or more active ingredients, such as fertilizers, herbicides or pesticides, or biologically active ingredients, such as vitamins, herbals and mineral supplements or drugs. The amount of the active ingredients generally is not more than 15 percent, preferably not more than 10 percent, more preferably not more than 5 percent, and most preferably not more than 2 percent, based on the total weight of the hydrogel at a temperature of 21 °C.

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

The hydrogel of the present invention is formed from 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 that are able to increase the gel strength of the hydrogel at room temperature (21 °C) or at a lower temperature. The sum of the methylcellulose and water is generally at least 70 percent, preferably at least 80 percent, more preferably at least 90 percent, and most preferably at least 95 percent, based on the total weight of the hydrogel.

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

EXAMPLES

Unless otherwise mentioned, all parts and percentages are by weight. In the Examples the following test procedures are used.

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

With the exception of Comparative Examples M - O, the steady-shear-flow viscosity η(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 force G_F(21 °C) of the hydrogel

The gel fracture force GF(21 °C) is measured with a Texture Analyzer (model TA.XTPlus; Stable Micro Systems, 5-Kg load cell) at 21°C. The gels are compressed between a steel plate (90mmxl00mmx9mm with a filter paper0110mm "2294" from Whatman and then a filter vlies 0110mm "0980/1" from Whatman on the top of the plate) and a Teflon cylinder (diameter: 50mm, height: 20mm) with the following parameters: speed until first sample contact: 1.5mm/sec, speed of compression: 1.00 mm sec, trigger force: 0.005N, maximum distance: 20 mm). The plate displacement [mm] and compression force [N] is measured at selected time intervals (400 points/s) until the gel collapses. The maximum compressional force is the maximum height of the peak during gel collapse. It is identified as GF(21 °C). The results of two replicates are averaged and the average results reported in units of Newton. For illustration purposes the measured forces in Newton as a function of the plate displacement for the two replicated measurements for Comparative Example R and Example 30 are shown in Figure 9.

Drug dissolution test

The release of a drug (acetaminophen) is conducted in 900 mL of 0.1 N HC1 for 22 hours at 37°C with a USP dissolution apparatus (Erweka Dissolution Tester 626, Erweka GmbH) equipped with standard USP II paddles rotating at a speed of 50 rpm. The gels are directly added to the dissolution media using no sinkers or baskets. The absorbance of paracetamol at each sample time is measured using a Shimadzu UV-Vis spectrophotometer (Shimadzu Deutschland GmbH, Duisburg, Germany). The concentration of acetaminophen is calculated using a standard calibration curve at a wavelength of 243 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 and 2 and Comparative Examples A - D

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.

In each of the Examples 1 and 2 and Comparative Examples A - D, 35.0 g of an aqueous solution of the MC is prepared in a glass container. The MC concentration, based on the total weight of the aqueous solution, is as listed in Table 1 below. The aqueous solutions are prepared by stirring at 1000 rpm in an ice bath for 6 hours and storage overnight in a refrigerator. Then the solutions are centrifuged (Sorvall Lynx 4000 centrifuge at 4000 rpm at 10°C) until the solutions are free of air bubbles.

The aqueous solutions are then heated to a temperature as listed in Table 1 below and kept at this temperature for a time period as listed in Table 1.

All aqueous solutions gel at the temperature to which they are heated (50 °C or 85

°C, respectively). During the heat treatments for the time periods listed in Table 1 below the hydrogels undergo syneresis to different degrees wherein the entire amount of methyl cellulose remains in the hydrogel and a portion of the water is expelled from the hydrogel. Water that is expelled during the heat treatment is separated from the hydrogels. The hydrogels are mechanically dried with a tissue and weighed while the gel is still hot. The % liberated water after the heat treatment is calculated according to the formula:

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

The produced hydrogels are placed on a glass plate without delay and allowed to cool to room temperature. The texture of each hydrogel is assessed immediately after heat treatment, removal of expelled water and cooling to room temperature, but before storage in a refrigerator.

Figures 1 and 2 illustrate the aqueous solutions of Examples 1 and 2 after heat treatment for 2 hours at 85 °C. Expelled water due to syneresis is clearly visible. The aqueous solutions of Comparative Examples A - D that have undergone heat treatment at lower temperature or for a shorter time period also form gels but expelled water is not clearly visible (no photos shown).

Figures 3 and 4 are photographic al representations of the hydrogels of Examples 1 and 2, respectively, immediately after heat treatment, removal of expelled water and cooling to room temperature but before storage.

The produced hydrogels are then stored at 4 °C in a refrigerator for a time period as listed in Table 1 below. Fig. 5 is a photographical representation of the hydrogel of Example 1 after its storage for 4 days at 4 °C. Surprisingly, the hydrogel of Example 1 remains a firm gel even after storage for an extended period of time in the refrigerator. No melt back occurs. Fig. 6 is a photographical representation of the hydrogel of Example 2 after its storage for 3 hours at 4 °C. It is still a gel, although very soft, and loses its shape after storage for 3 hours at 4 °C. The gels of Comparative Examples A, B, D and E have all melted after storage for 3 hours at 4 °C (no photos shown).

Table 1

Examples 3 - 14 and Comparative Examples E - J

A methylcellulose (MC) is used having 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.

In all experiments 30.0 g of an aqueous solution of the MC is prepared in a glass container by stirring at 1000 rpm in an ice bath for 6 hours and storage overnight in a refrigerator. The MC concentration, based on the total weight of the aqueous solution, is as listed in Tables 2 - 7 below. Then the solutions are centrifuged (Sorvall Lynx 4000 centrifuge at 4000 rpm at 10°C) until the solutions are free of air bubbles.

The aqueous solutions are then heated to 85 °C and kept at 85 °C for a time period as listed in Tables 2 - 7 below.

All aqueous solutions gel at 85 °C. During the heat treatments most hydrogels undergo syneresis. The hydrogels are removed from the liberated water and dried with a tissue. The texture of each hydrogel is assessed immediately after heat treatment, removal of expelled water and cooling to room temperature, but before storage. The mass of each hydrogel after heat treatment as listed in Tables 2 - 7 below is determined by weighing as described above for Example 1. The % liberated water after the heat treatment and the remaining water content are calculated as described above for Example 1.

The produced hydrogels are then placed in separate bags and stored at room temperature or at 4 °C in a refrigerator for a time period as listed in Tables 2 - 7 below. The consistency of the hydrogels is assessed after the time periods listed in Tables 2 - 7 below.

All hydrogels are produced twice but stored under different conditions. Repeated experiments are designated as Examples 3-i and 3-ii, etc. or as Comparative Examples E-i and E-ii, etc. The repetition of the Examples shows good reproducibility of hydrogel formation and syneresis.

Fig. 7 illustrates from left to right the texture of the gels of Comparative Examples E- i, F-i, G-i, and of Examples 3-i, 4-i, and 5-i after storage for 1 day at room temperature.

Examples 15 - 18

Examples 7, 8, 12 and 13 are repeated, except that after removal of the hydrogels from the liberated water, drying them with a tissue and assessing their texture after cooling to room temperature but before storage, the hydrogels are not placed in bags but placed back in the expelled water. After 1 day of storage at room temperature they are removed again from the water and dried with a tissue. Surprisingly, the hydrogels do not melt back, even after storage in the expelled water for a day. The results are listed in Table 8.

Examples 19 - 22 and Comparative Examples K and L

The experiments are carried out as described for Examples 3 - 14 except that a methylcellulose (MC) is used having a methoxyl content of 31 %, a viscosity of about 20,400 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 0.26.

All hydrogels are produced twice but stored under different conditions. Repeated experiments are designated as Examples 19-i and 19-ii, etc. or as Comparative Examples K- i and K-ii, etc.. The results of the assessments are listed in Tables 9 and 10 below.

Comparative Examples M - O

The experiments are carried out as described for Examples 3 - 14 except that a methylcellulose (MC) is used having a methoxyl content of 29 %, a viscosity of 3290

MPa»s, measured as a 2 wt. % solution in water at 20 °C, and a ratio s23/s26 of 0.39. Such methylcelluloses are commercially available as Methocel A4M methylcellulose.

The results of the assessments are listed in Table 13 below. The results show that all aqueous solutions gel at 85 °C. However, even during extended heat treatments the hydrogels do not undergo sufficient syneresis. Moreover, the hydrogels melt back upon storage at room temperature.

Table 2

Table 4

Table 5

Table 6

Table 8

Table 9

Table 10

Table 11

Examples 23 and 24

The same methyl cellulose (MC) as in Examples 1 and 2 and Comparative Examples A - D is used. In all experiments 35.0 g of an aqueous solution of the MC is prepared in a glass container. In Examples 23 and 24 the MC concentrations, based on the total weight of the aqueous solution, are 3 wt.-% and 4 wt.-%, respectively. The aqueous solutions are prepared by stirring at 1000 rpm in an ice bath for 6 hours and storage overnight in a refrigerator. Then the solutions are centrifuged (Sorvall Lynx 4000 centrifuge at 4000 rpm at 10°C) until the solutions are free of air bubbles.

In all experiments 0.35 g of acetaminophen powder is added to a beaker and 34.65 g of the aqueous MC solution is added under stirring to prepare solutions comprising 1 wt.-% of acetaminophen. The mixture is left in the refrigerator overnight and minor lumps of non- dissolved acetaminophen powder are comminuted and homogenized.

The aqueous solutions are then heated to 85 °C and kept at 85 °C for 2 hours, as listed in Table 12. All aqueous solutions gel at 85 °C. During the heat treatments the hydrogels undergo syneresis. Water that is expelled during the heat treatment is separated from the hydrogels. The hydrogels are mechanically dried with a tissue and weighed while the gel is still hot. The texture of each hydrogel is assessed immediately after heat treatment, removal of expelled water and cooling to room temperature, but before storage in a refrigerator. The % liberated water after the heat treatment and the remaining water content are calculated as described above for Example 1. In each of the experiments about 15 g water is liberated that contains 1 wt.-% acetaminophen, i.e., about 150 mg.

The produced hydrogels are then stored at room temperature for a time period of 12 hours. The release of the drug acetaminophen is tested in 0.1N HC1 in an USP dissolution tester as described above. Figure 8 illustrates the controlled acetaminophen release over time from the hydrogels of Examples 23b and 24a. The % acetaminophen that is dissolved in 0.1 M HC1 over time, based on the total weight of acetaminophen in the hydrogel is determined and plotted in Fig. 8. The hydrogel of Example 24a releases the acetaminophen slightly faster than the hydrogel of Example 23b, but the difference is insignificant. Table 12

based on total weight solution, including acetaminophen

Examples 25 - 31 and Comparative Examples P - R

The experiments are carried out as described for Examples 3 - 14 applying the conditions listed in Table 13 below. The same methylcellulose as in Examples 3 - 14 is utilized. The gel fracture forces _GF(21 °C) of the produced hydrogels are determined after having stored the gels over night at the temperature listed in Table 13 below. For illustration purposes the measured forces in Newton as a function of the plate displacement for the two replicated measurements for Comparative Example R and Example 30 are shown in Figure 9.

Table 13

is _GF(4 °C), measured at 4 °C

Claims

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

a) preparing an aqueous solution comprising at least 1.9 wt.-% of a methylcellulose, based on the total weight of the aqueous solution, the 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,

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

c) maintaining the formed hydrogel at least at a temperature at which the hydrogel has been formed in step b) for a sufficient time period to liberate at least 15 weight percent of water from the hydrogel, based on the water weight in the aqueous solution in step a), provided that the remaining water content in the formed hydrogel is from 15 to 96.15 weight percent, based on the total weight of the hydrogel, and

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

2. The process of claim 1, wherein in step a) an aqueous solution comprising at least 2.5 wt.-% of a methylcellulose is prepared, based on the total weight of the aqueous solution.

3. The process of claim 1 or claim 2, wherein in step b) the aqueous solution is heated to a temperature of at least 55 °C.

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

5. The process of any one of claims 1 to 4, 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.

6. The process of any one of claims 1 to 5, wherein the remaining water content in the hydrogel formed in step c) is from 30 to 96.0 weight percent, based on the total weight of the hydrogel.

7. The process of any one of claims 1 to 6, wherein in step a) an aqueous solution comprising from 1.9 to 10 wt.-% of methylcellulose, based on the total weight of the aqueous solution, is prepared when the methylcellulose has an s23/s26 of 0.27 or less.

8. The process of any one of claims 1 to 6, wherein in step a) an aqueous solution comprising from 2.5 to 20 wt.-% of methylcellulose, based on the total weight of the aqueous solution, is prepared when the methylcellulose has an s23/s26 of more than 0.27 and up to 0.36.

9. The process of any one of claims 1 to 8, wherein in step a) additionally one or more active ingredients and/or one or more additives selected from coloring agents, pigments, opacifiers, flavoring agents, antioxidants, preservatives and salts are incorporated in the aqueous solution.

10. A hydrogel formed from a methylcellulose and water by heat treatment and syneresis, wherein the hydrogel, at a temperature of 21 °C, has a water content of from 15 to 96.15 weight percent, based on the total weight of the hydrogel, and

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.

11. The hydrogel of claim 10, 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.

12. The hydrogel of claim 10 or 11, wherein the methylcellulose has a degree of methyl substitution of from 1.55 to 2.25.

13. The hydrogel of any one of claims 10 to 12, wherein additionally one or more active ingredients and/or one or more additives selected from coloring agents, pigments, opacifiers, flavoring agents, antioxidants, preservatives and salts are incorporated.

14. The hydrogel of any one of claims 10 to 13 having at a temperature of 21°C a water content of from 30 to 96.0 weight percent, based on the total weight of the hydrogel.

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