WO2019022820A1 - Procédé de production d'un hydrogel à base d'hydroxyalkyl méthylcellulose - Google Patents

Procédé de production d'un hydrogel à base d'hydroxyalkyl méthylcellulose Download PDF

Info

Publication number
WO2019022820A1
WO2019022820A1 PCT/US2018/033812 US2018033812W WO2019022820A1 WO 2019022820 A1 WO2019022820 A1 WO 2019022820A1 US 2018033812 W US2018033812 W US 2018033812W WO 2019022820 A1 WO2019022820 A1 WO 2019022820A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogel
hydroxyalkyl
water
aqueous solution
temperature
Prior art date
Application number
PCT/US2018/033812
Other languages
English (en)
Inventor
Oliver Petermann
Roland Adden
Original Assignee
Dow Global Technologies Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dow Global Technologies Llc filed Critical Dow Global Technologies Llc
Publication of WO2019022820A1 publication Critical patent/WO2019022820A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to novel hydrogels and a process for preparing them.
  • Hydroxyalkyl methylcelluloses such as hydroxypropyl methylcelluloses
  • 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.
  • 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
  • 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.
  • BSE Bovine spongiform encephalopathy
  • hydroxyalkyl methylcelluloses such as hydroxypropyl methylcelluloses
  • Hydroxyalkyl methylcelluloses are known to exhibit reverse thermal gelation in water, in other words, aqueous hydroxypropyl methylcellulose materials are soluble at cooler temperatures and gel at warmer temperatures. The reverse thermal gelation in water is discussed in detail in the Article Thermal Gelation Properties of Methyl and Hydroxypropyl Methylcellulose by N. Sarkar, Journal of Applied Polymer Science, Vol. 24, 1073-1087
  • HPMC HPMC depends on the concentration and grade of HPMC. At a concentration of 1.5 weight percent, most HPMC grades gel at around 65 to 75 °C. Special grades of HPMC that gel at a concentration of 1.5 weight percent in water at a relatively low temperature, typically at 40 to 60 °C, are described in International patent applications WO 2012/051035 Al, WO2012/173838 Al and WO2015/047762 Al. Aqueous solutions of special grades of HPMC that even start to gel at lower temperatures, typically at 30 - 40 °C or even less, are disclosed in International patent application WO2015/009796.
  • one aspect of the present invention is a process for producing a hydrogel from a hydroxyalkyl methylcellulose and water, comprising the steps of
  • aqueous solution comprising at least 2.5 wt.-% of a hydroxyalkyl methylcellulose, based on the total weight of the aqueous solution, the hydroxyalkyl methylcellulose having i) a viscosity of at least 500 mPa»s, when measured as a 2 wt.
  • 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
  • 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
  • step 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 97.0 weight percent, based on the total weight of the hydrogel, and
  • Another aspect of the present invention is a hydrogel formed from a hydroxyalkyl 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 97.0 weight percent, based on the total weight of the hydrogel, and the hydroxyalkyl methylcellulose has i) a viscosity of at least 500 mPa»s, when measured as a 2 wt.
  • Figure 1 is a photographical representation of the hydrogel of Example 1-i after its storage for 1 day at room temperature.
  • Figure 2 is a photographical representation of the hydrogel of Example 1-ii after its storage for 1 day at 4 °C.
  • Figure 3 is a photographical representation of the hydrogel of Comparative Example A-i after its storage for 1 day at room temperature.
  • Figure 4 is a photographical representation of the hydrogel of Comparative Example A-ii after its storage for 1 day at 4 °C. After storage for 1 day at 4 °C it is no longer a hydrogel but has melted back to a liquid of low viscosity.
  • gel refers to a soft, solid, or solidlike material which comprises at least two components, one of which is a liquid present in abundance (Almdal, Dyre, J., Hvidt, S., Kramer, O.; Towards a phenomological definition of the term 'gel'. Polymer and Gel Networks 1993, 1, 5-17).
  • a hydrogel is a gel wherein water is the main liquid component.
  • the hydroxyalkyl methylcellulose used for preparing the hydrogel of the present invention comprises methyl groups and hydroxyalkyl groups, preferably hydroxy-Ci-3-alkyl groups, such as hydroxypropyl or hydroxy ethyl.
  • Preferred hydroxyalkyl methylcelluloses are hydroxyethyl methylcelluloses and, more preferably, hydroxypropyl methylcelluloses.
  • hydroxyalkyl methylcellulose is its unique distribution of methyl groups on the anhydroglucose units such that [ s23/s26 - 0.2*MS(hydroxyalkyl) ] is 0.35 or less, preferably 0.32 or less, more preferably 0.30 or less, most preferably 0.27 or less, particularly 0.25 or less, and especially 0.23 or less.
  • [ s23/s26 - 0.2*MS(hydroxyalkyl) ] is 0.35 or less, preferably 0.32 or less, more preferably 0.30 or less, most preferably 0.27 or less, particularly 0.25 or less, and especially 0.23 or less.
  • 0.2*MS(hydroxyalkyl) ] is 0.07 or more, more typically 0.10 or more, and most typically 0.13 or more. More specifically, in the case of hydroxyethyl methylcelluloses the upper limit for [ s23/s26 - 0.2*MS(hydroxyalkyl) ] is 0.35; preferably 0.32, more preferably 0.30 and most preferably 0.27. In the case of hydroxypropyl methylcelluloses the preferred upper limit for [ s23/s26 - 0.2*MS(hydroxyalkyl) ] generally is 0.30, preferably 0.27; more preferably 0.25 and most preferably 0.23. As used herein, the symbol " * " represents the multiplication operator.
  • 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
  • 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.
  • anhydroglucose units wherein only the two hydroxy groups in the 2- and 3-positions of the anhydroglucose unit are substituted with methyl groups means that the 6-positions are not substituted with methyl; for example, they can be unsubstituted hydroxy groups or they can be substituted with hydroxyalkyl groups or methylated hydroxyalkyl groups.
  • the term "the molar fraction of anhydroglucose units wherein only the two hydroxy groups in the 2- and 6-positions of the anhydroglucose unit are substituted with methyl groups” means that the 3-positions are not substituted with methyl; for example, they can be unsubstituted hydroxy groups or they can be substituted with hydroxyalkyl groups or methylated hydroxyalkyl groups.
  • Formula I illustrates the numbering of the hydroxy groups in anhydroglucose units.
  • Formula I is only used for illustrative purposes and does not represent the cellulose ethers of the invention; the substitution with hydroxyalkyl groups is not shown in Formula
  • the hydroxyalkyl methylcellulose preferably has a DS(methyl) of from 1.2 to 2.2, more preferably from 1.25 to 2.10, and most preferably from 1.40 to 2.05.
  • the degree of the methyl substitution, DS(methyl), of a hydroxyalkyl methylcellulose is the average number of OH groups substituted with methyl groups per anhydroglucose unit.
  • the term "OH groups substituted with methyl groups" does not only include the methylated OH groups at the polymer backbone, i.e., that are directly a part of the anhydroglucose unit, but also methylated OH groups that have been formed after hydroxyalkylation.
  • the hydroxyalkyl methylcellulose has an MS(hydroxyalkyl) of from 05 to 1.00, preferably from 0.07 to 0.80, more preferably from 0.08 to 0.70, most preferably from 0.10 to 0.60, and particularly from 0.10 to 0.50.
  • the degree of the hydroxyalkyl substitution is described by the MS (molar substitution).
  • the MS (hydroxyalkyl) is the average number of hydroxyalkyl groups which are bound by an ether bond per mole of anhydroglucose unit. During the hydroxyalkylation, multiple substitutions can result in side chains.
  • the hydroxyalkyl methylcellulose preferably has a preferred DS(methyl) and a preferred MS (hydroxyalkyl) in combination.
  • the determination of the % methoxyl and % hydroxypropoxyl in hydroxypropyl methylcellulose is carried out according to the United States Pharmacopeia (USP 40).
  • the values obtained are % methoxyl and % hydroxypropoxyl. These are subsequently converted into degree of substitution (DS) for methyl substituents and molar substitution (MS) for hydroxypropyl substituents. Residual amounts of salt are taken into account in the conversion.
  • the DS(methyl) and MS(hydroxyethyl) in hydroxyethyl methylcellulose is effected by Zeisel cleavage with hydrogen iodide followed by gas chromatography. (G. Bartelmus and R. Ketterer, Z. Anal. Chem. 286 (1977) 161-190).
  • the viscosity of the hydroxyalkyl methylcellulose that is used in the process and the hydrogel of the present invention is important.
  • the hydroxyalkyl methylcelluloses that are utilized in the present invention typically gel at lower temperatures than standard grades of hydroxyalkyl methylcelluloses. Therefore, the viscosity of the hydroxyalkyl methylcellulose that is used in the process and the hydrogel of the present invention is measured as a 2 wt.- % solution in water at 5 °C at a shear rate of 10 s 1 to obtain accurate results.
  • the hydroxyalkyl methylcellulose utilized in the present invention has a viscosity of at least 500 mPa»s, preferably at least 1000 mPa»s, more preferably at least 2000 mPa»s, even more preferably at least 3000 mPa»s, and most preferably at least 4000 mPa»s.
  • the hydroxyalkyl methylcellulose has a viscosity of up to 150,000 mPa»s.
  • the hydroxyalkyl methylcellulose has a viscosity of up to 100,000 mPa»s, more preferably up to 50,000 mPa»s, even more preferably up to 20,000 mPa»s, and most preferably up to 8000 mPa»s. All these viscosities are measured as a 2 wt.-% solution in water at 5 °C at a shear rate of 10 s 1 .
  • an aqueous solution comprising at least 2.5 wt.-% of the above-described hydroxyalkyl methylcellulose is prepared, based on the total weight of the aqueous solution.
  • an aqueous solution comprising at least 2.8 wt.-%, more preferably at least 3.0 wt.-%, even more preferably least 3.3 wt.-% and most preferably at least 3.6 wt.-% hydroxyalkyl methylcellulose is prepared.
  • 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 hydroxyalkyl methylcellulose is prepared, based on the total weight of the aqueous solution.
  • step a) of the process wherein an aqueous solution of hydroxyalkyl
  • methylcellulose is prepared, the above described hydroxyalkyl methylcellulose is typically utilized in ground and dried form.
  • the hydroxyalkyl methylcellulose is generally mixed with water while cooling the aqueous mixture to a temperature of not higher than 10 °C, preferably not higher than 8 °C, more preferably not higher than 6.5 °C, even more preferably not higher than 5 °C, and particularly from 0.5 to 2 °C.
  • Water or the aqueous solution of hydroxyalkyl 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.
  • active ingredients such as fertilizers, herbicides or pesticides, or biologically active ingredients, such as vitamins, herbals and mineral supplements or drugs.
  • 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 hydroxyalkyl methylcellulose.
  • 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.
  • 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 optional ingredients like active ingredients or additives may be added to the hydroxyalkyl methylcellulose, to water or to the aqueous solution before or during the process for producing the aqueous solution of hydroxyalkyl methylcellulose as described above. Alternatively, optional ingredients may be added after the preparation of the aqueous solution.
  • 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 aqueous solution of hydroxyalkyl methylcellulose.
  • the aqueous solution prepared in step a) of the present invention is gelatin- free.
  • 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 hydroxyalkyl methylcellulose described above is the only thickener or gelling agent in the aqueous solution.
  • the sum of the hydroxyalkyl 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 hydroxyalkyl methylcellulose.
  • 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.
  • aqueous solutions of the hydroxyalkyl methylcellulose described in more details above can gel at a temperature as low as 30 °C.
  • Increasing the concentration of the hydroxyalkyl methylcellulose or incorporating 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • at least 45 wt.-% or even at least 50 wt.-% of water is liberated from the hydrogel.
  • 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).
  • up to 60 wt.-% of water is liberated from the hydrogel.
  • the remaining water content in the hydrogel is from 15 to 97.0 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 95.0 wt.-%, and most preferably up to 94.0 weight percent, based on the total weight of the hydrogel.
  • the remaining water content of the hydrogel is only up to 93.5 wt.-% or even only up to 93.0 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.
  • 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.
  • the temperature in step c) is up to 95 °C, typically up to 90 °C, and more typically up to 87 °C.
  • 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.
  • the formed hydrogel is maintained at an above-mentioned temperature for a time period of up to 12 hours, typically up to 10 hours, more typically up to 8 hours and in preferred embodiments up to 6 hours.
  • Syneresis of hydrogels formed from hydroxyalkyl methylcellulose and water is known. However, it is important in the present invention to cause sufficient syneresis by heating to liberate an amount of as described above.
  • 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.
  • the hydrogel is cooled to a temperature of 0 °C or more, more typically of 4 °C or more.
  • 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).
  • 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.
  • 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.
  • the produced hydrogels have a gel fracture force G F (21 °C) of up to 30 N, more typically up to 25 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 hydroxyalkyl 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 97.0 weight percent, based on the total weight of the hydrogel, and the hydroxyalkyl methylcellulose is as described in detail above.
  • the water content of the hydrogel is preferably up to 96.0 wt.-%, more preferably up to 95.0 wt.-%, and most preferably up to 94.0 weight percent, based on the total weight of the hydrogel.
  • the water content of the hydrogel is only up to 93.5 wt.-% or even only up to 93.0 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.
  • 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.
  • formed by heat treatment and syneresis 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.
  • hydrogel formed from a hydroxyalkyl 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 60 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.
  • the hydrogel of the present invention preferably has 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.
  • the hydrogel has a gel fracture force G F (21 °C) of up to 30 N, more typically of up to 25 N. How to determine the gel fracture force G F (21 °C) is described in the Examples section.
  • the hydrogel of the present invention may comprise a minor amount of one or more organic liquids which are preferably physiologically acceptable, such as ethanol or one or more animal or vegetable oils, but the total amount of organic liquids is preferably not more than 10 percent, more preferably not more than 5 percent, even more preferably not more than 2 percent, based on the total weight of water and organic liquid in the hydrogel at a temperature of 21 °C. Most preferably, the hydrogel does not comprise an organic liquid.
  • the hydrogel of the present invention may comprise one or more active ingredients, such as fertilizers, herbicides or pesticides, or biologically active ingredients, such as vitamins, herbals and mineral supplements or drugs.
  • 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.
  • optional ingredients are additives, such as coloring agents, pigments, opacifiers, flavoring agents, antioxidants, preservatives, salts, such as sodium chloride, or combinations thereof.
  • 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 the optional ingredients is generally not more than 15 percent, preferably not more than 10 percent, more preferably not more than 5 percent, and most preferably not more than 2 percent, based on the total weight of the hydrogel at a temperature of 21 °C.
  • the hydrogel of the present invention is formed from a hydroxyalkyl methylcellulose and water. This means that no other gelling agents than the above described hydroxyalkyl methylcellulose are needed for gel formation at room temperature (21 °C) or at a lower temperature. Generally the hydrogel of the present invention is gelatin-free. Other than the hydroxyalkyl methylcellulose described above, the hydrogel preferably does not comprise a significant amount of ingredients, such as thickeners or gelling agents, that are able to increase the gel strength of the hydrogel.
  • the sum of the hydroxyalkyl 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.
  • HPMC hydroxypropyl methylcellulose
  • the steady-shear-flow viscosity ⁇ (5 °C, 10 s 1 , 2 wt.% HPMC) of an aqueous 2-wt.% HPMC solution is measured at 5 °C at a shear rate of 10 s 1 with an Anton Paar Physica
  • the determination of the % methoxyl and % hydroxypropoxyl in HPMC is carried out according to the United States Pharmacopeia (USP 40).
  • the values obtained are % methoxyl and % hydroxypropoxyl. These are subsequently converted into degree of substitution (DS) for methyl substituents and molar substitution (MS) for hydroxypropyl substituents. Residual amounts of salt have been taken into account in the conversion.
  • Powdered sodium hydroxide freshly pestled, analytical grade, Merck, Darmstadt, Germany
  • ethyl iodide for synthesis, stabilized with silver, Merck-Schuchardt, Hohenbrunn, Germany
  • a thirty fold molar excess of the reagents sodium hydroxide and ethyl iodide per hydroxyl group of the anhydroglucose unit are added and the solution is vigorously stirred under nitrogen in the dark for three days at ambient temperature.
  • the perethylation is repeated with addition of the threefold amount of the reagents sodium hydroxide and ethyl iodide compared to the first reagent addition and further stirring at room temperature for additional two days.
  • reaction mixture can be diluted with up to 1.5 mL DMSO to ensure good mixing during the course of the reaction.
  • 5 mL of 5 % aqueous sodium thiosulfate solution is poured into the reaction mixture and the obtained solution is then extracted three times with 4 mL of
  • Hydrolysis of about 5 mg of the perethylated samples is performed under nitrogen in a 2 mL screw cap vial with 1 mL of 90 % aqueous formic acid under stirring at 100 °C for 1 hour.
  • the acid is removed in a stream of nitrogen at 35-40 °C and the hydrolysis is repeated with 1 mL of 2M aqueous trifluoroacetic acid for 3 hours at 120 °C in an inert nitrogen atmosphere under stirring.
  • the acid is removed to dryness in a stream of nitrogen at ambient temperature using ca. 1 mL of toluene for co-distillation.
  • the residue of the reduction is acetylated with 600 of acetic anhydride and 150 ⁇ ⁇ of pyridine for 3 hrs at 90 °C.
  • the sample vial is filled with toluene and evaporated to dryness in a stream of nitrogen at room temperature.
  • the residue is dissolved in 4 mL of dichloromethane and poured into 2 mL of water and extracted with 2 mL of dichloromethane. The extraction is repeated three times.
  • the combined extracts are washed three times with 4 mL of water and dried with anhydrous sodium sulfate.
  • the dried dichloromethane extract is subsequently submitted to GC analysis. Depending on the sensitivity of the GC system, a further dilution of the extract can be necessary.
  • Gas-liquid (GLC) chromatographic analyses are performed with Hewlett Packard 5890A and 5890A Series II type of gas chromatographs equipped with J&W capillary columns DB5, 30 m, 0.25 mm ID, 0.25 ⁇ phase layer thickness operated with 1.5 bar helium carrier gas.
  • the gas chromatograph is programmed with a temperature profile that holds constant at 60 °C for 1 min, heats up at a rate of 20 °C / min to 200 °C, heats further up with a rate of 4 °C / min to 250 °C, heats further up with a rate of 20 °C / min to 310 °C where it is held constant for another 10 min.
  • the injector temperature is set to 280 °C and the temperature of the flame ionization detector (FID) is set to 300 °C.
  • l lL of the samples is injected in the splitless mode at 0.5 min valve time. Data are acquired and processed with a LabSystems Atlas work station.
  • Quantitative monomer composition data are obtained from the peak areas measured by GLC with FID detection. Molar responses of the monomers are calculated in line with the effective carbon number (ECN) concept but modified as described in the table below.
  • ECN effective carbon number
  • the peak areas are multiplied by molar response factors MRFmonomer which are defined as the response relative to the 2,3,6-Me monomer.
  • MRFmonomer which are defined as the response relative to the 2,3,6-Me monomer.
  • the 2,3,6-Me monomer is chosen as reference since it is present in all samples analyzed in the determination of s23 / s26.
  • the mole fractions of the monomers are calculated by dividing the corrected peak areas by the total corrected peak area according to the following formulas:
  • s23 [ (23-Me + 23-Me-6-HAMe + 23-Me-6-HA + 23 -Me-6-HAHAMe + 23-Me- 6-HAHA ];
  • s26 [ (26-Me + 26-Me-3-HAMe + 26-Me-3-HA + 26-Me-3-HAHAMe + 26-Me- 3 -HAH A], wherein
  • s23 is the sum of the molar fractions of anhydroglucose units which meet the following conditions:
  • s26 is the sum of the molar fractions of anhydroglucose units which meet the following conditions:
  • 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).
  • HPMC is produced according to the following procedure. Finely ground wood cellulose pulp is loaded into a jacketed, agitated reactor. The reactor is evacuated and purged with nitrogen to remove oxygen and then evacuated again. The reaction is carried out in two stages. In the first stage a 50 weight percent aqueous solution of sodium hydroxide is sprayed onto the cellulose in an amount of 1.2 moles of sodium hydroxide per mole of anhydroglucose units in the cellulose and the temperature is adjusted to 40°C.
  • the reactor is vented and cooled down to about 50°C.
  • the contents of the reactor are removed and transferred to a tank containing hot water.
  • the crude HPMC is then neutralized with formic acid and washed chloride free with hot water (assessed by AgNCb flocculation test), cooled to room temperature and dried at 55 °C in an air-swept drier. The material is then ground.
  • the produced HPMC is used that has a DS(methyl) of 1.50 and an
  • MS(hydroxyalkyl) of 0.14 which corresponds to a methoxyl content of 24.3 % and a hydroxypropoxyl content of 5.5 %.
  • the HPMC has a viscosity of 4890 MPa»s, measured as a 2 wt. % solution in water at 5 °C at a shear rate of 10 s 1 , and a ratio s23/s26 of 0.18.
  • HPMC is used that has been produced as described above and that has the properties as described above.
  • the HPMC concentration based on the total weight of the aqueous solution, is 4.0 wt-%.
  • the aqueous solutions are then heated to 85 °C and kept at 85 °C for a time period as listed in Tables 1 and 2 below.
  • the temperature of 85 °C is held by placing the glass container in a water bath of 90 °C.
  • 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 at room temperature or in a refrigerator as listed in Tables 1 and 2 below.
  • 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 1 and 2.
  • the consistency of the hydrogels is assessed after the time periods listed in Tables 1 and 2 below.
  • Example 1-i and 1-ii All hydrogels are produced twice but stored under different conditions. Repeated experiments are designated as Example 1-i and 1-ii or as Comparative Example A-i and A- ii. The repetitions show good reproducibility of hydrogel formation and syneresis.
  • Figure 1 is a photographical representation of the hydrogel of Example 1-i after its storage for 1 day at room temperature. Its dimensional stability is clearly visible.
  • Figure 2 is a photographical representation of the hydrogel of Example 1-ii after its storage for 1 day at 4 °C. It still has a reasonable thermal stability.
  • Figure 3 is a photographical representation of the hydrogel of Comparative Example A-i after its storage for 1 day at room temperature. It is nearly dimensionally stable.
  • Figure 4 is a photographical representation of the hydrogel of Comparative Example A-ii after its storage for 1 day at 4 °C. After storage for 1 day at 4 °C it is no longer a hydrogel but has melted back to a liquid of low viscosity.
  • Example 1 is repeated, except that the aqueous HPMC solution is heated to 90 °C and kept at 90 °C for 6 hours.
  • the gel fracture force G F (21 °C) of the produced hydrogel is determined after having stored the gel over night at 21 °C listed in Table 3 below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Inorganic Chemistry (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Un hydrogel stable peut être formé à partir d'une hydroxyalkyl méthylcellulose et d'eau par traitement thermique et synérèse, l'hydrogel ayant une teneur en eau de 15 à 97,0 % en poids, et l'hydroxyalkyl méthylcellulose ayant une viscosité ≥ 500 mPa»s sous la forme d'une solution à 2% en poids dans de l'eau à 5 °C à un taux de cisaillement de 10 s-1, une substitution molaire d'hydroxyalkyl de 0,05 à 1,00, et des groupes hydroxy d'unités anhydroglucose substitués par des groupes méthyle de sorte que [ s23/s26 - 0.2*MS(hydroxyalkyl) ] est ≤ 0.35, où s23 correspond à la fraction molaire des unités anhydroglucose, les deux groupes hydroxy en positions 2 et 3 de l'unité anhydroglucose étant les seuls à être substitués par des groupes méthyle, et s26 correspond à la fraction molaire des unités anhydroglucose, les deux groupes hydroxy en positions 2 et 6 de l'unité anhydroglucose étant les seuls à être substitués par des groupes méthyle.
PCT/US2018/033812 2017-07-26 2018-05-22 Procédé de production d'un hydrogel à base d'hydroxyalkyl méthylcellulose WO2019022820A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762537012P 2017-07-26 2017-07-26
US62/537,012 2017-07-26

Publications (1)

Publication Number Publication Date
WO2019022820A1 true WO2019022820A1 (fr) 2019-01-31

Family

ID=62621000

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/033812 WO2019022820A1 (fr) 2017-07-26 2018-05-22 Procédé de production d'un hydrogel à base d'hydroxyalkyl méthylcellulose

Country Status (1)

Country Link
WO (1) WO2019022820A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023025653A1 (fr) * 2021-08-26 2023-03-02 Nutrition & Biosciences Usa 1, Llc Nouvelle hydroxyalkyl méthylcellulose et son utilisation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012051035A1 (fr) 2010-10-12 2012-04-19 Dow Global Technologies Llc Nouveaux éthers de cellulose et utilisation de ceux-ci
WO2012173838A1 (fr) 2011-06-14 2012-12-20 Dow Global Technologies Llc Composition alimentaire comprenant un éther de cellulose
WO2015009796A1 (fr) 2013-07-17 2015-01-22 Dow Global Technologies Llc Composition pour application sur une muqueuse comprenant une méthylcellulose
WO2015047762A1 (fr) 2013-09-25 2015-04-02 Dow Global Technologies Llc Composition pour application à une muqueuse comprenant un éther de cellulose

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012051035A1 (fr) 2010-10-12 2012-04-19 Dow Global Technologies Llc Nouveaux éthers de cellulose et utilisation de ceux-ci
WO2012173838A1 (fr) 2011-06-14 2012-12-20 Dow Global Technologies Llc Composition alimentaire comprenant un éther de cellulose
WO2015009796A1 (fr) 2013-07-17 2015-01-22 Dow Global Technologies Llc Composition pour application sur une muqueuse comprenant une méthylcellulose
WO2015047762A1 (fr) 2013-09-25 2015-04-02 Dow Global Technologies Llc Composition pour application à une muqueuse comprenant un éther de cellulose

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
ALM AL, DYRE, J.; HVIDT, S.; KRAMER, 0.: "Towards a phenomological definition of the term 'gel", POLYMER AND GEL NETWORKS, vol. 1, 1993, pages 5 - 17
BENGT LINDBERG; ULF LINDQUIST; OLLE STENBERG: "Carbohydrate Research", vol. 176, 1988, ELSEVIER SCIENCE PUBLISHERS B.V., article "DISTRIBUTION OF SUBSTITUENTS IN O-ETHYL-O-(2-HYDROXYETHYL)CELLULOSE", pages: 137 - 144
D.P. SWEET; R.H. SHAPIRO; P. ALBERSHEIM, CARBOHYD. RES., vol. 40, 1975, pages 217 - 225
G. BARTELMUS; R. KETTERER, Z. ANAL. CHEM., vol. 286, 1977, pages 161 - 190
HAQUE, A; MORRIS, E.R., CARBOHYDRATE POLYMERS, vol. 22, 1993, pages 161
HAQUE, A; RICHARDSON, R.K.; MORRIS, E.R.; GIDLEY, M.J; CASWELL, D.C, CARBOHYDRATE POLYMERS, vol. 22, 1993, pages 175
N. SARKAR: "Thermal Gelation Properties of Methyl and Hydroxypropyl Methylcellulose", JOURNAL OF APPLIED POLYMER SCIENCE, vol. 24, 1979, pages 1073 - 1087, XP009103302, DOI: doi:10.1002/app.1979.070240420
R.F. ADDISON; R.G. ACKMAN, J. GAS CHROMATOGR, vol. 6, 1968, pages 135 - 138
R.G. ACKMAN, J. GAS CHROMATOGR., vol. 2, 1964, pages 173 - 179

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023025653A1 (fr) * 2021-08-26 2023-03-02 Nutrition & Biosciences Usa 1, Llc Nouvelle hydroxyalkyl méthylcellulose et son utilisation

Similar Documents

Publication Publication Date Title
US9394376B2 (en) Cellulose ethers and their use
EP2836559B1 (fr) Composition comprenant un diluant organique et un éther de cellulose
US9616036B2 (en) Sustained release dosage forms
CZ298196B6 (cs) Matricová tableta pro prodlouzené uvolnování gliclazidu po orálním podání
US20150057356A1 (en) Melt-extruded composition comprising a cellulose ether
CN110496122A (zh) 包含非马沙坦和氢氯噻嗪的药物组合物
WO2015047762A1 (fr) Composition pour application à une muqueuse comprenant un éther de cellulose
WO2019022820A1 (fr) Procédé de production d'un hydrogel à base d'hydroxyalkyl méthylcellulose
US20130289055A1 (en) Compressible, highly viscous polysaccharide and polyol powder
EP3897729B1 (fr) Composition à libération prolongée comprenant une méthylcellulose
JP6353061B2 (ja) 有機液体希釈剤及び特定のヒドロキシアルキルメチルセルロースを含む組成物
US20170028069A1 (en) Composition comprising an organic liquid diluent and a cellulose ether of very low viscosity
WO2019022819A1 (fr) Procédé pour la production d'hydrogels à base d'éthers de cellulose estérifiés de faible masse moléculaire
JP7535520B2 (ja) メチルセルロースを含む徐放性組成物
WO2019108266A1 (fr) Hydrogels à base d'hydroxyalkylméthylcellulose
JP7526727B2 (ja) ヒドロキシアルキルメチルセルロースを含む徐放性組成物
WO2019022817A1 (fr) Procédé de production d'un hydrogel à base de méthylcellulose
EP3463314B1 (fr) Solution aqueuse d'acetate d'ether de cellulose
CN105434385B (zh) 美索舒利缓释片及其制备方法
WO2019022818A1 (fr) Procédé de production d'hydrogels à base d'éthers de cellulose estérifiés
WO2019022821A1 (fr) Polysaccharides solubles dans l'eau à sapidité améliorée
JP2002522376A (ja) 清澄キサンタンガムを含有する圧縮組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18731627

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18731627

Country of ref document: EP

Kind code of ref document: A1