WO2018039214A1 - Éthers de cellulose estérifiés comprenant des groupes maléyle - Google Patents

Éthers de cellulose estérifiés comprenant des groupes maléyle Download PDF

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WO2018039214A1
WO2018039214A1 PCT/US2017/047989 US2017047989W WO2018039214A1 WO 2018039214 A1 WO2018039214 A1 WO 2018039214A1 US 2017047989 W US2017047989 W US 2017047989W WO 2018039214 A1 WO2018039214 A1 WO 2018039214A1
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cellulose ether
esterified cellulose
groups
esterified
degree
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PCT/US2017/047989
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Oliver Petermann
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Dow Global Technologies Llc
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B13/00—Preparation of cellulose ether-esters
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D101/00—Coating compositions based on cellulose, modified cellulose, or cellulose derivatives
    • C09D101/08—Cellulose derivatives
    • C09D101/32—Cellulose ether-esters

Definitions

  • This invention concerns novel esterified cellulose ethers comprising maleyl groups and their use for producing capsule shells or for coating dosage forms.
  • esterified cellulose ethers are useful in the pharmaceutical field, such as hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate phthalate (HPMCAP), hydroxypropyl methyl cellulose acetate maleate (HPMCAM) or hydroxypropyl methyl cellulose acetate succinate (HPMCAS).
  • HPMCP hydroxypropyl methyl cellulose phthalate
  • HPMCAP hydroxypropyl methyl cellulose acetate phthalate
  • HPMCAM hydroxypropyl methyl cellulose acetate maleate
  • HPMCAS hydroxypropyl methyl cellulose acetate succinate
  • U.S. Patent No. 5,776,501 discloses a coating base for solid enteric pharmaceutical preparations whose dissolution pH ranges from 3 - 4.
  • the coating base is a cellulose acetate maleate which is prepared by substituting a water-soluble cellulose derivative with 0.2 to 0.5 acetyl group and 0.35 to 0.6 maleyl groups per glucose ring of the cellulose derivative. Hydroxypropyl methylcellulose acetate maleate is particularly preferred because of its high solubility in an organic solvent and high strength of the resulting coating film.
  • the US patent discloses that the number of substituted acetyl groups suitably ranges from 0.2 to 0.5. If it is less than 0.2, the resulting coating base in unsufficient in hydrophobicity. Specifically the U.S.
  • Patent discloses the production of HPMCAM having i) a degree of substitution for acetyl groups (DSacetyi) of 0.31 and a degree of substitution for maleyl groups (DSmaieyi) of 0.45; ii) a DSacetyi of 0.48 and a DS ma ie y i of 0.45; iii) a DS aC etyi of 0.31 and a DS ma ie y i of 0.36; iv) a DSacetyi of 0.31 and a DSmaieyi of 0.59; and, as comparative examples, v) a DSacetyi of 0.62 and a DS ma ie y i of 0.40; vi) a DSacetyi of 0.37 and a DS ma ie y i of 0.30.
  • HPMCAM at mass ratios HPMC: acetic anhydride of 1 : (0.4 - 1.0) and HPMC: maleic anhydride of 1 : (0.28 - 0.4), respectively.
  • HPMC Hydroxypropyl methyl cellulose
  • Enteric polymers are those that are resistant to dissolution in the acidic environment of the stomach. Dosage forms coated with such polymers protect the drug from inactivation or degradation in the acidic environment or prevent irritation of the stomach by the drug.
  • enteric coating polymers having carboxyl groups in their undissociated form have very low solubility in water.
  • the degree of neutralization defines the ratio of deprotonated carboxylic groups over the sum of deprotonated and protonated carboxylic groups; i.e., the lower the degree of neutralization, the more carboxyl groups are present in their undissociated form.
  • a HPMCAM sample is insoluble in purified water when its degree of neutralization is less than 0.3. In 0.1 M aqueous NaCl solution it is even insoluble over essentially the entire range of degree of neutralization, i.e., from nearly zero and up to 1.
  • Esterified cellulose ethers which comprise maleyl groups of a low degree of neutralization are dissolved in organic solvents before use due to their low solubility in water.
  • organic solvents for enteric coatings is considered
  • esterified cellulose ethers which comprise maleyl groups and which are soluble in water even when the degree of neutralization of the maleyl groups is less than 0.3.
  • esterified cellulose ether wherein the ester groups are (i) maleyl groups or (ii) a combination of maleyl groups and aliphatic monovalent acyl groups, the total degree of substitution of ester groups is from 0.05 to 0.65, the degree of neutralization of the maleyl groups is less than 0.3, and at least 85 wt.% of the esterified cellulose ether is soluble in a mixture of 2.5 weight parts of the esterified cellulose ether and 97.5 weight parts of water at 2 °C.
  • Another aspect of the present invention is a liquid composition which comprises at least one above-described esterified cellulose ether dissolved an aqueous diluent.
  • Yet another aspect of the present invention is a liquid composition which comprises at least one above-described esterified cellulose ether and an organic diluent.
  • Yet another aspect of the present invention is a process for coating a dosage form which comprises the step of contacting an above-mentioned liquid composition with the dosage form.
  • Yet another aspect of the present invention is a process for the manufacture of capsule shells which comprises the step of contacting the above-mentioned liquid composition with dipping pins.
  • Yet another aspect of the present invention is a coated dosage form wherein the coating comprises at least one above-described esterified cellulose ether.
  • Yet another aspect of the present invention is a polymeric capsule shell which comprises at least one above-described esterified cellulose ether.
  • Yet another aspect of the present invention is a capsule which comprises the above- mentioned capsule shell and further comprises a drug or a nutritional or food supplement or a combination thereof.
  • Yet another aspect of the present invention is a solid dispersion of at least one active ingredient in at least one above-described esterified cellulose ether.
  • the esterified cellulose ethers of the present invention have a solubility in water at 2 °C such that at least 85 wt.% of the esterified cellulose ether is soluble in a mixture of 2.5 weight parts of the esterified cellulose ether and 97.5 weight parts of water at 2 °C. Clear solutions are obtained at a temperature of 2 °C or below. When the temperature of the prepared solution is increased to 15 °C or even to 20 °C, no precipitation occurs. Moreover, aqueous solutions of the preferred embodiments of the esterified cellulose ether of the present invention gel at slightly elevated temperature. This renders the esterified cellulose ether of the present invention very useful in a variety of application, e.g. for producing capsules or for coating dosage forms. The advantages of the esterified cellulose ether of the present invention will be described in more detail below.
  • the esterified cellulose ether has a cellulose backbone having ⁇ -1,4 glycosidically bound D-glucopyranose repeating units, designated as anhydroglucose units in the context of this invention.
  • the esterified cellulose ether preferably is an esterified alkyl cellulose, esterified hydroxyalkyl cellulose or hydroxyalkyl alkylcellulose, more preferably an esterified hydroxyalkyl methylcellulose. This means that in the esterified cellulose ether of the present invention, at least a part of the hydroxyl groups of the anhydroglucose units are substituted by alkoxyl groups or hydroxyalkoxyl groups or a combination of alkoxyl and hydroxyalkoxyl groups.
  • the hydroxyalkoxyl groups are typically hydroxy methoxyl, hydroxyethoxyl and/or hydroxypropoxyl groups. Hydroxyethoxyl and/or hydroxypropoxyl groups are preferred. Typically one or two kinds of hydroxyalkoxyl groups are present in the esterified cellulose ether. Preferably a single kind of hydroxyalkoxyl group, more preferably hydroxypropoxyl, is present.
  • the alkoxyl groups are typically methoxyl, ethoxyl and/or propoxyl groups. Methoxyl groups are preferred.
  • Illustrative of the above-defined esterified cellulose ethers are esterified alkylcelluloses, such as esterified methylcelluloses and propylcelluloses; esterified hydroxyalkylcelluloses, such as esterified
  • esterified hydroxyethylcelluloses such as esterified hydroxyethyl methylcelluloses, hydroxymethyl ethylcelluloses, ethyl hydroxyethylcelluloses, hydroxypropyl
  • esterified cellulose ether is an esterified hydroxyalkyl methylcellulose, such as an esterified hydroxypropyl methylcellulose.
  • the degree of the substitution of hydroxyl groups of the anhydroglucose units by hydroxyalkoxyl groups is expressed by the molar substitution of hydroxyalkoxyl groups, the MS(hydroxyalkoxyl).
  • the MS (hydroxyalkoxyl) is the average number of moles of hydroxyalkoxyl groups per anhydroglucose unit in the esterified cellulose ether. It is to be understood that during the hydroxyalkylation reaction the hydroxyl group of a
  • hydroxyalkoxyl group bound to the cellulose backbone can be further etherified by an alkylation agent, e.g. a methylation agent, and/or a hydroxyalkylation agent.
  • an alkylation agent e.g. a methylation agent, and/or a hydroxyalkylation agent.
  • Multiple subsequent hydroxyalkylation etherification reactions with respect to the same carbon atom position of an anhydroglucose unit yields a side chain, wherein multiple hydroxyalkoxyl groups are covalently bound to each other by ether bonds, each side chain as a whole forming a hydroxyalkoxyl substituent to the cellulose backbone.
  • hydroxyalkoxyl groups thus has to be interpreted in the context of the MS(hydroxyalkoxyl) as referring to the hydroxyalkoxyl groups as the constituting units of hydroxyalkoxyl substituents, which either comprise a single hydroxyalkoxyl group or a side chain as outlined above, wherein two or more hydroxyalkoxy units are covalently bound to each other by ether bonding.
  • the terminal hydroxyl group of a hydroxyalkoxyl substituent is further alkylated, e.g. methylated, or not; both alkylated and non-alkylated hydroxyalkoxyl substituents are included for the determination of MS (hydroxyalkoxyl).
  • the esterified cellulose ether of the invention generally has a molar substitution of hydroxyalkoxyl groups in the range 0.05 to 1.00, preferably 0.08 to 0.70, more preferably 0.15 to 0.60, most preferably 0.15 to 0.40, and particularly 0.20 to 0.40.
  • the average number of hydroxyl groups substituted by alkoxyl groups, such as methoxyl groups, per anhydroglucose unit, is designated as the degree of substitution of alkoxyl groups, DS(alkoxyl).
  • hydroxyl groups substituted by alkoxyl groups is to be construed within the present invention to include not only alkylated hydroxyl groups directly bound to the carbon atoms of the cellulose backbone, but also alkylated hydroxyl groups of hydroxyalkoxyl substituents bound to the cellulose backbone.
  • the esterified cellulose ethers according to this invention generally have a DS(alkoxyl) in the range of 1.0 to 2.5, preferably from 1.2 to 2.2, more preferably from 1.6 to 2.05, and most preferably from 1.7 to 2.05.
  • esterified cellulose ether is an esterified hydroxypropyl methylcellulose having a DS(methoxyl) within the ranges indicated above for DS(alkoxyl) and an MS(hydroxypropoxyl) within the ranges indicated above for MS (hydroxyalkoxyl).
  • the content of ether groups in the esterified cellulose ether is determined in the same manner as described for "Hypromellose", United States Pharmacopeia and National Formulary, USP 35, pp 3467-3469.
  • ester groups in the esterified cellulose ether of the present invention are (i) maleyl groups or (ii) a combination of maleyl groups and aliphatic monovalent acyl groups, such as acetyl, propionyl, or butyryl, such as n-butyryl or i-butyryl.
  • Specific examples of esterified cellulose ethers of the present invention are hydroxypropyl methyl cellulose acetate maleate (HPMCAM) or hydroxypropyl methyl cellulose maleate (HPMCM).
  • the degree of substitution of maleyl groups is generally at least 0.02, preferably at least 0.03, more preferably at least 0.05, and most preferably at least 0.07.
  • the degree of substitution of maleyl groups is generally not more than 0.45, preferably not more than 0.40, more preferably not more than 0.35, and most preferably not more than 0.30.
  • the presence of aliphatic monovalent acyl groups in the esterified cellulose ether of the present invention is optional but preferred.
  • the esterified cellulose ethers of the present invention generally have a degree of substitution of aliphatic monovalent acyl groups, if present, of at least 0.02, preferably at least 0.04, more preferably at least 0.06, and most preferably at least 0.08.
  • the esterified cellulose ethers generally have a degree of substitution of aliphatic monovalent acyl groups of up to 0.40, preferably up to 0.35, more preferably up to 0.30, and most preferably up to 0.26.
  • the content of the aliphatic monovalent acyl groups in the esterified cellulose ether is determined in the same manner as described for "Hypromellose Acetate Succinate, United States Pharmacopia and National Formulary, NF 29, pp. 1548-1550".
  • the content of the maleyl groups in the esterified cellulose ether is determined as described for the phthalyl groups in "Hypromellose phthalate, United States Pharmacopia and National Formulary, NF 33, pp.6701-6702".
  • An essential feature of the esterified cellulose ethers of the present invention is the total degree of substitution of ester groups, i.e., the total degree of maleyl groups and aliphatic monovalent acyl groups.
  • the total degree of substitution of ester groups is at least 0.05, preferably at least 0.10, more preferably at least 0.15, and most preferably at least 0.20.
  • the total degree of substitution of ester groups is not more than 0.65, preferably not more than 0.60, and in some embodiments not more than 0.55 or not more than 0.50.
  • the esterified cellulose ethers of the present invention have been found to gel at elevated temperatures as described in the Examples section, depending on their
  • esterified cellulose ethers of the present invention have enteric properties, as shown in the Examples section.
  • ether and ester groups obtained by the above analyses are converted to DS and MS values of individual substituents according to the formulas below.
  • the formulas may be used in analogue manner to determine the DS and MS of substituents of other cellulose ether esters.
  • M(AGU) 162.14 Da
  • M(H) 1.008 Da
  • the weight percent is an average weight percentage based on the total weight of the cellulose repeat unit, including all substituents.
  • the content of the methoxyl group is reported based on the mass of the methoxyl group (i.e., -OCH3).
  • the content of the hydroxyalkoxyl group is reported based on the mass of the hydroxyalkoxyl group (i.e., -O-alkylene-OH); such as hydroxypropoxyl (i.e., -0-CH2CH(CH3)-OH).
  • the content of the acetyl group is reported based on the mass of the acetyl group (i.e., -C(0)-CH3).
  • the content of the maleyl group is reported based on the mass of the maleyl group
  • the degree of neutralization of the maleyl groups is less than 0.3, preferably not more than 0.2, more preferably not more than 0.1, and particularly not more than 0.05 or even not more than 0.01.
  • the degree of neutralization can even be essentially zero or only slightly above it, e.g. up to 10 ⁇ 3 or even only up to 10 "4 .
  • the degree of neutralization can be evaluated by titration as described by H. Kokubo et al. in "Development of Cellulose Derivatives as Novel Enteric Coating Agents Soluble at pH 3.5-4.5 and Higher" in Chem. Pharm. Bull. 45(8) 1350 - 1353 (1997), Vol. 45, No. 8, at page 1350.
  • the counter-cations preferably are ammonium cations, such as NH 4 + , or alkali metal ions, such as sodium or potassium ions, more preferably sodium ions.
  • esterified cellulose ether of the present invention Another essential property of the esterified cellulose ether of the present invention is its water-solubility. Surprisingly, it has been found that the esterified cellulose ether of the present invention has solubility properties that at least 85 wt.%, typically at least 90 wt.%, more typically at least 95 wt.%, and in many cases at least 98 wt.% of the esterified cellulose ether is soluble in a mixture of 2.5 weight parts of the esterified cellulose ether and 97.5 weight parts of water at 2 °C.
  • this degree of solubility is also observed in a mixture of 5 or 10 weight parts of the esterified cellulose ether and 95 or 90 weight parts of water at 2 °C or even in a mixture of 20 weight parts of the esterified cellulose ether and 80 weight parts of water at 2 °C.
  • This water solubility is observed even when the degree of neutralization of the maleyl groups is less than 0.3, as defined above.
  • the esterified cellulose ether of the present invention can be dissolved as up to 20 weight percent solution or in the most preferred embodiments even as up to 30 weight percent solution in water at a temperature of 2 °C.
  • the term "an x weight percent solution in water at 2 °C" as used herein means that x g of the esterified cellulose ether is soluble in (100 - x) g of water at 2 °C.
  • the esterified cellulose ether of the present invention is soluble in an aqueous liquid at a temperature of 2 °C, even when the esterified cellulose ether has a low degree of neutralization of maleyl groups as described above and even when the esterified cellulose ether is blended with an aqueous liquid that does not increase the degree of neutralization of the esterified cellulose ether to 0.3 or more or to a more preferred range listed above, e.g., when the esterified cellulose ether is blended with only water, such as deionized or distilled water. Clear solutions without sediment are obtained at 2 °C.
  • aqueous solutions of an esterified cellulose ether of the present invention gel at elevated temperature, typically at 25 to 70 °C, more typically at 30 to 60 °C. This renders the esterified cellulose ethers of the present invention very useful in a variety of application, e.g. for producing capsules and for coating dosage forms.
  • Gelation of the esterified cellulose ethers of the present invention typically occurs at concentrations of 2 to 30 weight percent, more typically at 5 to 20 weight percent, based on the total weight of esterified cellulose ether and aqueous liquid.
  • the gelation is reversible, i.e. upon cooling to 20 °C the gel transforms into a liquid aqueous solution.
  • the aqueous liquid in which the esterified cellulose ether of the present invention is soluble may additionally comprise a minor amount of an organic liquid diluent; however, the aqueous liquid should generally comprise at least 80, preferably at least 85, more preferably at least at least 90, and particularly at least 95 weight percent of water, based on the total weight of the aqueous liquid.
  • organic liquid diluent as used herein means an organic solvent or a mixture of two or more organic solvents. Preferred organic liquid diluents are polar organic solvents having one or more heteroatoms, such as oxygen, nitrogen or halogen like chlorine.
  • More preferred organic liquid diluents are alcohols, for example multifunctional alcohols, such as glycerol, or preferably monofunctional alcohols, such as methanol, ethanol, isopropanol or n-propanol; ethers, such as tetrahydrofuran;
  • multifunctional alcohols such as glycerol
  • monofunctional alcohols such as methanol, ethanol, isopropanol or n-propanol
  • ethers such as tetrahydrofuran
  • the organic liquid diluents have 1 to 6, most preferably 1 to 4 carbon atoms.
  • the aqueous liquid may comprise a basic compound, but the degree of neutralization of the maleyl groups of the esterified cellulose ether in the resulting blend of esterified cellulose ether and aqueous liquid should be less than 0.3 or a preferred upper limit as described further above.
  • the aqueous liquid does not comprise a substantial amount of a basic compound. More preferably, the aqueous diluent does not contain a basic compound.
  • the aqueous liquid comprises from 80 to 100 percent, preferably 85 to 100 percent, more preferably 90 to 100 percent and most preferably 95 to 100 percent of water, and from 0 to 20 percent, preferably 0 to 15 percent, more preferably 0 to 10 percent, and most preferably 0 to 5 percent of an organic liquid diluent, based on the total weight of the aqueous liquid.
  • the aqueous liquid consists of water, e.g., deionized or distilled water.
  • the esterified cellulose ethers of the present invention generally have a viscosity of up to 200 mPa-s, preferably up to 100 mPa-s, more preferably up to 50 mPa-s, and most preferably up to 5.0 mPa s, measured as a 2.0 wt.-% solution of the esterified cellulose ether in 0.43 wt.-% aqueous NaOH at 20 °C.
  • the viscosity is at least 1.2 mPa s, more typically at least 1.8 mPa s, even more typically at least 2.4 mPa s, and most typically at least 2.8 mPa s, measured as a 2.0 wt.-% solution of the esterified cellulose ether in 0.43 wt.-% aqueous NaOH at 20 °C.
  • the esterified cellulose ether of the present invention can be produced by esterifying a cellulose ether, such as an alkyl cellulose, hydroxyalkyl cellulose or hydroxyalkyl alkylcellulose described further above.
  • the cellulose ethers preferably have a DS(alkoxyl) and/or an MS(hydroxyalkoxyl) as described further above.
  • the cellulose ether used as a starting material for esterification generally has a viscosity of from 1.2 to 200 mPa-s, preferably from 1.8 to 100 mPa-s, more preferably from 2.4 to 50 mPa-s and in particular from 2.8 to 5.0 mPa-s, measured as a 2 weight-% aqueous solution at 20 °C according to ASTM D2363 - 79 (Reapproved 2006). Cellulose ethers of such viscosity can be obtained by subjecting a cellulose ether of higher viscosity to a partial depolymerization process. Partial
  • depolymerization processes are well known in the art and described, for example, in European Patent Applications EP 1,141,029; EP 210,917; EP 1,423,433; and US Patent No. 4,316,982.
  • partial depolymerization can be achieved during the production of the cellulose ethers, for example by the presence of oxygen or an oxidizing agent.
  • the cellulose ether is reacted with maleic anhydride and optionally with an aliphatic monocarboxylic acid anhydride, such as acetic anhydride, butyric anhydride and propionic anhydride.
  • the molar ratio between the maleic anhydride and the anhydroglucose units of cellulose ether generally is at least 0.05 : 1, preferably at least 0.10 : 1, more preferably at least 0.15: 1, and most preferably at least 0.20 : 1.
  • the molar ratio between the maleic anhydride and the anhydroglucose units of cellulose ether generally is not more than 0.70 : 1.
  • the molar ratio between the aliphatic monocarboxylic acid anhydride and anhydroglucose units of cellulose ether is in the upper half of the range disclosed below, the molar ratio between the maleic anhydride and the anhydroglucose units of cellulose ether generally is not more than 0.50 : 1 or even not more than 0.30 : 1.
  • the weight ratio between the maleic anhydride and the cellulose ether generally is at least 0.03 : 1, preferably at least 0.05 : 1, more preferably at least 0.07 : 1, and most preferably at least 0.10 : 1.
  • the weight ratio between the maleic anhydride and the cellulose ether generally is not more than 0.34 : 1.
  • the weight ratio between the aliphatic monocarboxylic acid anhydride and the cellulose ether is in the upper half of the range disclosed below, the weight ratio between the maleic anhydride and the cellulose ether generally is not more than 0.25 : 1 or even not more than 0.15 : 1. If the cellulose ether is additionally reacted with an aliphatic
  • the molar ratio between the anhydride of an aliphatic monocarboxylic acid and the anhydroglucose units of the cellulose ether generally is at least 0.05 : 1, preferably at least 0.10 : 1, more preferably at least 0.15 : 1, and most preferably at least 0.20 : 1.
  • the molar ratio between the anhydride of an aliphatic monocarboxylic acid and the anhydroglucose units of the cellulose ether generally is up to 0.70 : 1, preferably up to 0.60 : 1, and more preferably up to 0.50 : 1 or up to 0.45 : 1.
  • the weight ratio between the anhydride of an aliphatic monocarboxylic acid and the cellulose ether generally is at least 0.03 : 1, preferably at least 0.05 : 1, more preferably at least 0.07 : 1, and most preferably at least 0.10 : 1.
  • the weight ratio between the anhydride of an aliphatic monocarboxylic acid and the cellulose ether generally is not more than 0.34 : 1, preferably not more than 0.30 : 1, and more preferably not more than 0.25 : 1 or not more than 0.23 : 1.
  • the molar number of anhydroglucose units of the cellulose ether utilized in the process can be determined from the weight of the cellulose ether used as a starting material, by calculating the average molecular weight of the substituted anhydroglucose units from the DS(alkoxyl) and MS (hydroxy alkoxyl).
  • the esterification of the cellulose ether is conducted in an aliphatic carboxylic acid as a reaction diluent, such as acetic acid, propionic acid, or butyric acid.
  • the reaction diluent can comprise minor amounts of other solvents or diluents which are liquid at room temperature and do not react with the cellulose ether, such as aromatic or aliphatic solvents like benzene, toluene, 1,4-dioxane, or tetrahydrofurane; or halogenated C1-C3 derivatives, like dichloro methane or dichloro methyl ether, but the amount of the aliphatic carboxylic acid should generally be more than 50 percent, preferably at least 75 percent, and more preferably at least 90 percent, based on the total weight of the reaction diluent.
  • reaction diluent consists of an aliphatic carboxylic acid, more preferably acetic acid.
  • the molar ratio [aliphatic carboxylic acid / anhydroglucose units of cellulose ether] generally is from 5 : 1 to 11 : 1.
  • the esterification reaction is conducted in the presence of an esterification catalyst, preferably in the presence of an alkali metal carboxylate, such as sodium acetate or potassium acetate.
  • an alkali metal carboxylate such as sodium acetate or potassium acetate.
  • the molar ratio [alkali metal carboxylate / anhydroglucose units of cellulose ether] is generally from [2.0 / 1.0] to [3.0 / 1.0], and preferably from [2.3 / 1.0] to [2.6 / 1.0].
  • the reaction temperature for the esterification is generally from 85° C to 100 0 C, preferably from 90 0 C to 98° C.
  • the esterification reaction is typically completed within 3 to 5 hours.
  • the esterified cellulose ether can be precipitated from the reaction mixture in a known manner, for example as described in U.S. Patent No. 4,226,981, International Patent Application WO 2005/115330, European Patent Application EP 0 219 426 or International Patent Application WO2013/148154.
  • the precipitated esterified cellulose ether is typically washed with an aqueous liquid at a temperature of from 70 to 100 °C. Suitable aqueous liquids are described further above.
  • Another aspect of the present invention is an aqueous composition
  • aqueous composition comprising one or more of the above described esterified cellulose ethers of the present invention dissolved in an aqueous liquid.
  • the aqueous liquid is a described further above.
  • the esterified cellulose ether of the present invention can be brought into aqueous solution by cooling the aqueous composition to a temperature of - 2 °C to less than 10 °C, preferably of 0 °C to less than 8 °C, more preferably of 0.5 °C to less than 5 °C, and most preferably of 0.5 °C to 3 °C.
  • the aqueous composition preferably comprises at least 5 wt.-%, more preferably at least 10 wt.- %, and preferably up to 30 wt.-%, more preferably up to 20 wt.-% of the esterified cellulose ether of the present invention, based on the total weight of the aqueous composition.
  • aqueous composition comprising one or more of the above described esterified cellulose ethers of the present invention dissolved in an aqueous liquid is useful in the manufacture of capsules which comprises the step of contacting the liquid composition with dipping pins.
  • an aqueous composition having a temperature of less than 20 °C, more typically less than 15 °C or in some embodiments less than 10 °C is contacted with dipping pins having a higher temperature than the aqueous composition and that have a temperature of at least 21 °C, more typically at least 25 °C, and up to 95 °C, preferably up to 80 °C.
  • aqueous composition comprising one or more of the above described esterified cellulose ethers dissolved in an aqueous liquid is also useful for coating dosage forms, such as tablets, granules, pellets, caplets, lozenges, suppositories, pessaries or implantable dosage forms.
  • Another aspect of the present invention is a liquid composition
  • a liquid composition comprising an organic diluent and one or more of the above described esterified cellulose ethers of the present invention.
  • the organic diluent may be present in the liquid composition alone or mixed with water. Preferred organic diluents are described further above.
  • the liquid composition preferably comprises at least 5 wt.-%, more preferably at least 10 wt.-%, and preferably up to 30 wt.-%, more preferably up to 20 wt.-% of the esterified cellulose ether of the present invention, based on the total weight of the liquid composition.
  • composition of the present invention comprising an aqueous liquid or an organic diluent as described above and one or more of the above described esterified cellulose ethers is also useful as an excipient system for active ingredients and particularly useful as an intermediate for preparing an excipient system for 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 composition of the present invention preferably comprises one or more active ingredients, most preferably one or more drugs.
  • drug is conventional, denoting a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially humans.
  • composition of the present invention is used for producing a solid dispersion comprising at least one active ingredient, such as a drug, at least one esterified cellulose ether as described above and optionally one or more adjuvants.
  • a preferred method of producing a solid dispersion is by spray-drying. Spray-drying processes and spray-drying equipment are described generally in Perry's Chemical Engineers'
  • the solid dispersion of the present invention may be prepared by i) blending a) at least one esterified cellulose ether defined above, b) one or more active ingredients and c) one or more optional additives, and ii) subjecting the blend to extrusion.
  • extrusion includes processes known as injection molding, melt casting and compression molding.
  • the solid dispersion of the present invention preferably comprises a) from 20 to 99.9 percent, more preferably from 30 to 98 percent, and most preferably from 60 to 95 percent of an esterified cellulose ether as described above, and b) preferably from 0.1 to 80 percent, more preferably from 2 to 70 percent, and most preferably from 5 to 40 percent of an active ingredient b), based on the total weight of the esterified cellulose ether a) and the active ingredient b).
  • the combined amount of the esterified cellulose ether a) and the active ingredient b) is preferably at least 70 percent, more preferably at least 80 percent, and most preferably at least 90 percent, based on the total weight of the solid dispersion.
  • the remaining amount, if any, consists of one or more of the adjuvants c) as described below.
  • several processing operations can be used, such as drying, granulation, and milling, to facilitate incorporation of the dispersion into a dosage form, such as strands, pellets, granules, pills, tablets, caplets, microparticles, fillings of capsules or injection molded capsules or in the form of a powder, film, paste, cream, suspension or slurry.
  • the aqueous composition, the liquid composition comprising an organic diluent and the solid dispersion of the present invention may further comprise optional adjuvants, such as coloring agents, pigments, opacifiers, flavor and taste improvers, antioxidants, and any combination thereof.
  • HPMCAM content of ether groups in the HPMCAM is determined in the same manner as described for "Hypromellose", United States Pharmacopeia and National Formulary, USP 35, pp 3467-3469.
  • the content of the acetyl groups in the HPMCAM is determined in the same manner as described for "Hypromellose Acetate Succinate, United States Pharmacopia and National Formulary, NF 29, pp. 1548-1550". Reported values are corrected for volatiles (determined as described in section “loss on drying” in the above HPMCAS monograph).
  • the content of the maleyl groups in the HPMCAM is determined as described for the phthalyl groups in "Hypromellose phthalate, United States Pharmacopia and National Formulary, NF 33, pp.6701-6702".
  • HPMCAM 2.5 weight parts of HPMCAM, based on its dry weight, were added to 97.5 weight parts of deionized water having a temperature of 2 °C followed by stirring for 6 hours at 2°C and storing for 16 h at 2°C. A weighed amount of this mixture was transferred to a weighed centrifuge vial; the transferred weight of the mixture was noted as Ml in g. The transferred weight of HPMCAM [M2] was calculated as (transferred weight of mixture in g/100 g x 2.5g). The mixture was centrifuged for 60 min at 5000 rpm (2823 xg, Biofuge Stratos centrifuge from Thermo Scientific) at 2 °C.
  • HPMCAM that is actually dissolved in the mixture of 2.5 weight parts of HPMCAM and 97.5 weight parts of deionized water. It is calculated as (M4 / M2) x (Ml / M3) x 100, which corresponds to (g HPMCAM in liquid aliquot / g HPMCAM transferred to centrifuge vial) x (g mixture transferred to centrifuge vial / g liquid aliquot after centrifugation) x 100.
  • x stands for the multiplication operator. Water-Solubility at 21 °C
  • the water- solubility at 21 °C was measured in the same manner as at 2 °C, except that 2.5 weight parts of HPMCAM, based on its dry weight, were added to 97.5 weight parts of deionized water having a temperature of 21 °C followed by stirring for 6 hours at 21 °C and storing for 16 h at 21 °C.
  • HPMC methoxyl substitution
  • MSHP hydroxypropoxyl substitution
  • Viscosity 3.0 mPa-s, measured as a 2 % solution in water at 20 °C according to ASTM D2363 - 79 (Reapproved 2006).
  • the weight average molecular weight of the HPMC was about 20,000 Dalton.
  • the HPMC is commercially available from The Dow Chemical Company as Methocel E3 LV Premium cellulose ether. Inertisation with nitrogen was carried out.
  • MS HP MS(hydroxypropoxyl): molar substitution of hydroxypropoxyl groups
  • DSac degree of substitution of acetyl groups
  • DSmai degree of substitution of maleyl groups.
  • Aqueous solutions of 2 wt.% HPMCAM were prepared by mixing 2.0 g HPMCAM, based on its dry weight, with 98.0 g water under vigorous stirring at 0.5°C for 16 hours. The mixture of HPMCAM and water was then stored in a refrigerator at about 2 °C.
  • Aqueous solutions of the HPMCAM of the present invention gel at elevated temperature, typically at 25 to 70 °C, more typically at 30 to 60 °C.
  • Preferred embodiments of aqueous solutions of the HPMCAM of the present invention even gel at a concentration as low as 2 wt.-%. It is very surprising that the cellulose ether acetate maleates gel in spite of their low degree of ester substitution.
  • the HPMC that is used as starting material for preparing the HPMCAM does not gel at a concentration of 2 wt.-%.
  • a 2 wt-% solution of Methocel E3 LV Premium cellulose ether in water after heating to 65 °C does not form a gel but only flocculates.
  • HPMCAM in powder form at a concentration of 2wt. % was stirred in 0.1 N HCl for 2 hours at a temperature of 37 °C to simulate the stomach fluid.
  • HPMCAM in powder form at a concentration of 2 wt.% was stirred in Mcllvaine' s buffer solutions (containing disodium monophosphate and citric acid) that had a temperature of 37 °C and a pH of 3.0; 4.0; 4.5; 5.0; 5.5; 6.0 or 6.8, respectively.
  • Mcllvaine' s buffer solutions containing disodium monophosphate and citric acid

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Abstract

L'invention concerne un éther de cellulose estérifié dans lequel – les groupes ester sont (i) des groupes maléyle ou (ii) une combinaison de groupes maléyle et de groupes acyle monovalents aliphatiques, - le degré total de substitution des groupes ester est de 0,05 à 0,65, - le degré de neutralisation des groupes maléyle est inférieur à 0,3, et – au moins 85 % en poids de l'éther de cellulose estérifié sont solubles dans un mélange de 2,5 parties en poids de l'éther de cellulose estérifié et de 97,5 parties en poids d'eau à 2 C. L'éther de cellulose estérifié est destiné à enrober une forme posologique et à la fabrication de gélules.
PCT/US2017/047989 2016-08-23 2017-08-22 Éthers de cellulose estérifiés comprenant des groupes maléyle WO2018039214A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
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WO2019022819A1 (fr) * 2017-07-26 2019-01-31 Dow Global Technologies Llc Procédé pour la production d'hydrogels à base d'éthers de cellulose estérifiés de faible masse moléculaire
CN113388162A (zh) * 2020-03-13 2021-09-14 信越化学工业株式会社 成膜组合物和膜

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019022819A1 (fr) * 2017-07-26 2019-01-31 Dow Global Technologies Llc Procédé pour la production d'hydrogels à base d'éthers de cellulose estérifiés de faible masse moléculaire
CN113388162A (zh) * 2020-03-13 2021-09-14 信越化学工业株式会社 成膜组合物和膜
CN113388162B (zh) * 2020-03-13 2024-03-15 信越化学工业株式会社 成膜组合物和膜

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