WO2017146853A1

WO2017146853A1 - Aqueous composition comprising water-soluble esterified cellulose ethers

Info

Publication number: WO2017146853A1
Application number: PCT/US2017/014849
Authority: WO
Inventors: Oliver Petermann; Matthias Knarr; Racquel JEMISON; Joshua S. Katz; Susan L. Jordan
Original assignee: Dow Global Technologies Llc; Rohm And Haas Company
Priority date: 2016-02-24
Filing date: 2017-01-25
Publication date: 2017-08-31

Abstract

An aqueous composition is provided which comprises a) from 0.6 to 30 weight percent, based on the total weight of the aqueous composition, of an esterified cellulose ether comprising aliphatic monovalent acyl groups and groups of the formula - C(O) - R - COOA, R being a divalent hydrocarbon group and A being hydrogen or a cation, wherein the total degree of ester substitution is from 0.03 to 0.70, b) a tonicity-adjusting agent, and c) an aqueous diluent.

Description

AQUEOUS COMPOSITION COMPRISING WATER-SOLUBLE ESTERIFIED

CELLULOSE ETHERS FIELD

This invention concerns aqueous compositions comprising water-soluble esterified cellulose ethers, their use for application to a mucosa and their use for inducing satiety.

INTRODUCTION

Esters of cellulose ethers, their uses and processes for preparing them are generally known in the art. When the esterified cellulose ethers comprise ester groups which carry carboxylic groups, the solubility of the esterified cellulose ethers in aqueous liquids is typically dependent on the pH. For example, the solubility of hydroxypropyl methyl cellulose acetate succinate (HPMCAS) in aqueous liquids is pH-dependent due to the presence of succinate groups, also called succinyl groups or succinoyl groups. HPMCAS is known as enteric polymer. In the acidic environment of the stomach HPMCAS is protonated and therefore insoluble. The pH-dependent solubility is dependent on the degree of substitution of acidic functional groups. The dissolution time of various types of HPMCAS dependent on pH and on the degree of neutralization of HPMCAS is discussed in detail in McGinity, James W. Aqueous Polymeric Coatings for Pharmaceutical Dosage

Forms, New York: M. Dekker, 1989, pages 105 - 113. This publication illustrates in Fig. 16 on p. 112 the dissolution time of several grades of HPMCAS, which have different degrees of substitution with succinoyl, acetyl and methoxyl groups, in pure water and in 0.1 NaCl depending on the degree of neutralization of the HPMCAS. Depending on the HPMCAS and the presence or absence of NaCl, HPMCAS is soluble when it has a degree of neutralization between about 0.55 and 1. Below a degree of neutralization of about 0.55, all HPMCAS grades are insoluble in pure water and in 0.1 NaCl.

Copending International Patent Application No. PCT/US16/021330, filed on 08 March, 2016 and published as WO 2016/148977, which claims the priority of US

Provisional Application No. 62/133514, filed 16 March 2015, and International Patent

Application No. PCT/US 16/021326, filed on 08 March, 2016 and published as WO

2016/148976, which claims the priority of US Provisional Application No. 62/133518, filed on 16 March 2015, disclose novel esterified cellulose ethers which are soluble in water although the degree of neutralization of the carboxylic groups is not more than 0.4. The aqueous solutions of many of these esterified cellulose ethers gel at slightly elevated temperature, typically at 30 to 55 °C. This makes them very suitable for coating

pharmaceutical dosage forms or for producing capsule shells wherein heated pins are dipped into solutions of these esterified cellulose ethers.

For other important end-uses a gelation temperature of not more than 37 °C is desired. Exemplary of such end-uses are pharmaceutical compositions for transmucosal delivery of physiologically active agents, for example nasal drops and sprays. However, known nasal drops and sprays often rapidly exit the nasal cavity either via dripping from the nostrils or via the back of the nasal cavity into the nasopharynx, which can lead to insufficient efficacy of the physiologically active agent(s). High- viscosity delivery systems, such as ointments or gels, are retained in the nasal cavity for a longer time period, but the exact dosage of ointments and gels is difficult to meter and subsequently deliver to the desired location within the nasal cavity. Similar problems are experienced if pharmaceutical compositions are applied to other mucosae, such as the mucous membrane of the eyes or to mucosae in the oral cavity, such as the buccal mucosa. Another end-use is administering to individuals aqueous compositions which gel in the individual's stomach and which induce satiety.

The gelation temperature of aqueous solutions of the esterified cellulose ethers disclosed in the above-mentioned co-pending International Patent Applications can typically be decreased by increasing the concentration of these esterified cellulose ethers in the aqueous solution, but this is often not desired for cost reasons. Moreover, an excessively high concentration of esterified cellulose ethers in aqueous solutions makes the handling of such aqueous solutions more difficult at room temperature. Additionally the viscosity increases at room temperature with increasing concentrations which limits potential end use application and palatability.

Accordingly, it would be highly desirable to find new aqueous compositions that have a lower gelation temperature than those disclosed in the above-mentioned co-pending International Patent Application No. PCT/US16/021330, filed on 08 March, 2016 and published as WO 2016/148977, which claims the priority of US Provisional Application No. 62/133514, filed 16 March 2015, and International Patent Application No.

PCT/US16/021326, filed on 08 March, 2016 and published as WO 2016/148976, which claims the priority of US Provisional Application No. 62/133518, filed on 16 March 2015. It would be particularly desirable to find new aqueous compositions which have a gelation temperature of not more than 37 °C. SUMMARY

One aspect of the present invention is an aqueous composition which comprises a) from 0.6 to 30 weight percent, based on the total weight of the aqueous composition, of an esterified cellulose ether comprising aliphatic monovalent acyl groups and groups of the formula - C(O) - R - COOA, R being a divalent hydrocarbon group and A being hydrogen or a cation, wherein the total degree of ester substitution is from 0.03 to 0.70,

b) a tonicity-adjusting agent, and

c) an aqueous diluent.

Another aspect of the present invention is a method for inducing satiety or for reversibly reducing stomach void volume or for reducing caloric intake of an individual, which method comprises administering to said individual the above-mentioned aqueous composition.

Yet another aspect of the present invention is a method for applying a physiologically active agent to a mucosa, which method comprises administering to the mucosa of an individual the above-mentioned aqueous composition.

Yet another aspect of the present invention is the use of the above-mentioned aqueous composition for application to a mucosa.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 illustrates the viscosity as a function of temperature of aqueous solutions of a first HPMCAS in the absence or presence of sodium chloride or calcium chloride as tonicity-adjusting agent.

Figure 2 illustrates the viscosity as a function of temperature of aqueous solutions of the first HPMCAS in the absence or presence of glucose as tonicity-adjusting agent.

Figure 3 illustrates the viscosity as a function of temperature of aqueous solutions of a second HPMCAS in the absence or presence of sodium chloride.

Fig. 4 illustrates how to determine the gelation temperature of aqueous solutions. DESCRIPTION OF EMBODIMENTS

An essential ingredient, also designated as component, of the composition of the present invention is an above-mentioned esterified cellulose ether a). Esterified cellulose ethers a) are described in copending International Patent Application No.

PCT/US16/021330, filed on 08 March, 2016 and published as WO 2016/148977, which claims the priority of US Provisional Application No. 62/133514, filed 16 March 2015, and

International Patent Application No. PCT/US 16/021326, filed on 08 March, 2016 and published as WO 2016/148976, which claims the priority of US Provisional Application

No. 62/133518, filed on 16 March 2015, all filed by the Applicant(s) of the present patent application.

The esterified cellulose ether a) comprised in the composition of the present invention has a cellulose backbone having β-1,4 glycosidically bound D-glucopyranose repeating units, designated as anhydroglucose units in the context of this invention. The esterified cellulose ether a) preferably is an esterified alkyl cellulose, hydroxyalkyl cellulose or hydroxyalkyl alkylcellulose. This means that in the esterified cellulose ether a) comprised in the composition 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 hydroxymethoxyl, 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 a). 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 ether a) are esterified alkylcelluloses, such as esterified methylcelluloses, ethylcelluloses, and propylcelluloses; esterified hydroxy alkylcelluloses, such as esterified hydroxyethylcelluloses,

hydroxypropylcelluloses, and hydroxybutylcelluloses; and esterified hydroxyalkyl alkylcelluloses, such as esterified hydroxyethyl methylcelluloses, hydroxymethyl ethylcelluloses, ethyl hydroxyethylcelluloses, hydroxypropyl methylcelluloses,

hydroxypropyl ethylcelluloses, hydroxybutyl methylcelluloses, and hydroxybutyl ethylcelluloses; and those having two or more hydroxyalkyl groups, such as esterified hydroxyethylhydroxypropyl methylcelluloses. Most preferably, the esterified cellulose ether a) 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 alkylating agent, e.g. a methylating agent, and/or a hydroxyalkylating 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.

The term "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 hydroxyalkoxyl units are covalently bound to each other by ether bonding. Within this definition it is not important whether the terminal hydroxyl group of a hydroxyalkoxyl substituent is further alkylated or not; both alkylated and non-alkylated hydroxyalkoxyl substituents are included for the determination of

MS(hydroxyalkoxyl). The esterified cellulose ether a) generally has a molar substitution of hydroxyalkoxyl groups of at least 0.05, preferably at least 0.08, more preferably at least 0.12, and most preferably at least 0.15. The degree of molar substitution is generally not more than 1.00, preferably not more than 0.90, more preferably not more than 0.70, and most preferably not more than 0.50.

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). In the above-given definition of DS, the term "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 ether a) preferably has a

DS(alkoxyl) of at least 1.0, more preferably at least 1.1, even more preferably at least 1.2, most preferably at least 1.4, and particularly at least 1.6. The DS(alkoxyl) is preferably not more than 2.5, more preferably not more than 2.4, even more preferably not more than 2.2, and most not more than 2.05.

Most preferably the esterified cellulose ether a) 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 esterified cellulose ether a) has aliphatic monovalent acyl groups and groups of the formula - C(O) - R - COOA, wherein R is a divalent hydrocarbon group and A is hydrogen or a cation. The cation preferably is an ammonium cation, such as NH₄ ⁺ or an alkali metal ion, such as the sodium or potassium ion, more preferably the sodium ion. Most preferably, A is hydrogen.

The aliphatic monovalent acyl groups are preferably selected from the group consisting of acetyl, propionyl, and butyryl, such as n-butyryl or i-butyryl. Preferred groups of the formulas - C(O) - R - COOA are - C(O) - CH₂ - CH₂ -COOA.

In the esterified cellulose ether the degree of neutralization of the groups

- C(O) - R - COOA is generally not more than 0.4, preferably not more than 0.3, more preferably not more than 0.2, most 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 term "degree of neutralization" as used herein defines the ratio of deprotonated carboxylic groups over the sum of deprotonated and protonated carboxylic groups, i.e.,

Degree of neutralization = [-C(0)-R- COO^" ] / [-C(0)-R-COO^" + -C(0)-R-COOH].

Specific examples of esterified cellulose ethers a) are hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxybutyl methyl cellulose propionate succinate (HBMCPrS), hydroxyethyl hydroxypropyl cellulose propionate succinate (HEHPCPrS); or methyl cellulose acetate succinate (MCAS). Hydroxypropyl methylcellulose acetate succinates (HPMCAS) are the most preferred esterified cellulose ethers a). The esterified cellulose ether a) in the composition of the present invention has aliphatic monovalent acyl groups and groups of the formula - C(O) - R - COOA, such that the total degree of ester substitution is from 0.03 to 0.70. The sum of i) the degree of substitution of aliphatic monovalent acyl groups and ii) the degree of substitution of groups of formula -C(O) - R - COOA, of which the degree of neutralization is generally not more than 0.4, is an essential feature of the esterified cellulose ether a). The total degree of ester substitution is at least 0.03, generally at least 0.07, preferably at least 0.10, more preferably at least 0.15, most preferably at least 0.20, and particularly at least 0.25. The total degree of ester substitution in the esterified cellulose ether a) is not more than 0.70, generally not more than 0.67, preferably up to 0.65, more preferably up to 0.60, and most preferably up to 0.55 or up to 0.50. In one aspect of the present invention esterified cellulose ethers a) having a total degree of ester substitution of from 0.10 to 0.65 and particularly from 0.20 to 0.60 are preferred. In another aspect of the present invention esterified cellulose ethers a) having a total degree of ester substitution of from 0.20 to 0.50 and particularly from 0.25 to 0.44 are preferred.

The esterified cellulose ethers a) generally have a degree of substitution of aliphatic monovalent acyl groups, such as acetyl, propionyl, or butyryl groups, of at least 0.03 or 0.05, preferably at least 0.10, more preferably at least 0.15, most preferably at least 0.20, and particularly at least 0.25 or at least 0.30. The esterified cellulose ethers generally have a degree of substitution of aliphatic monovalent acyl groups of up to 0.69, preferably up to 0.60, more preferably up to 0.55, most preferably up to 0.50, and particularly up to 0.45 or even only up to 0.40. The esterified cellulose ethers a) generally have a degree of substitution of groups of formula -C(O) - R - COOA, such as succinoyl, of at least 0.01, preferably at least 0.02, more preferably at least 0.05, and most preferably at least 0.10. The esterified cellulose ethers generally have a degree of substitution of groups of formula -C(O) - R - COOA of up to 0.65, preferably up to 0.60, more preferably up to 0.55, and most preferably up to 0.50 or up to 0.45. As indicated above, the degree of neutralization of the groups - C(O) - R - COOA is generally not more than 0.4.

Moreover, in the esterified cellulose ether a) the sum of i) the degree of substitution of aliphatic monovalent acyl groups and ii) the degree of substitution of groups of formula -C(O) - R - COOA and iii) the degree of substitution of alkoxyl groups, DS(alkoxyl), generally is not more than 2.60, preferably not more than 2.55, more preferably not more than 2.50, and most preferably not more than 2.45. The esterified cellulose ether a) generally has a sum of degrees of substitution of i) aliphatic monovalent acyl groups and ii) groups of formula -C(O) - R - COOA and iii) of alkoxyl groups of at least 1.7, preferably at least 1.9, and most preferably at least 2.1.

The content of the acetate and succinate ester groups is determined according to "Hypromellose Acetate Succinate", United States Pharmacopeia 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 method may be used in analogue manner to determine the content of propionyl, butyryl and other ester groups.

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.

The contents of 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.

% cellulose backbone

%MeO %HP0

M(0CH₃) M(HPO)

DS(Me) = MS(HP) =

%cellulose backbone %cellulose backbone

M(AGU) M(AGU) %Acetyl %Succinoyl

_ M (Acetyl) _ M(Succinoyl)

%cellulose backbone %cellulose backbone

M(AGU) M(AGU)

M(MeO) = M(OCH₃) = 31.03 Da M(HPO) = M(OCH₂ CH(OH)CH₃) = 75.09 Da M (Acetyl) = M(COCH₃) = 43.04 Da M(Succinoyl) = M(C0C₂H₄C00H) = 101.08 Da M(AGU) = 162.14 Da M(OH) = 17.008 Da M(H) = 1.008 Da

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 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 aliphatic monovalent acyl groups is reported based on the mass of -C(O) - Ri wherein Ri is a monovalent aliphatic group, such as acetyl (-C(0)-CH3). The content of the group of formula -C(O) - R - COOH is reported based on the mass of this group, such as the mass of succinoyl groups (i.e., - C(O) - CH₂ - CH₂ - COOH).

Another essential property of the esterified cellulose ether a) is its water-solubility, even when the degree of neutralization of the groups - C(O) - R - COOA is not more than 0.4, as described further above. The esterified cellulose ether generally has a solubility in water of at least 2.0 weight percent at 2 °C, i.e., it can be dissolved as an at least 2.0 weight percent solution, preferably at least 3.0 weight percent solution, more preferably at least 5.0 weight percent solution or even at least 10.0 weight solution in water at 2 °C. Generally the esterified cellulose ether a) 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 b) is soluble in (100 - x) g of water at 2 °C.

In more general terms, the esterified cellulose ether a), even when the degree of neutralization of the groups - C(O) - R - COOA is not more than 0.4, as described further above, is soluble in an aqueous liquid at a temperature of less than 10 °C, more preferably less than 8 °C, even more preferably 5 °C or less, and most preferably up to 3 °C, 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 a) to more than 0.4 or a preferred range listed above, e.g., when the esterified cellulose ether is blended with only water, such as deionized or distilled water. Clear or turbid solutions with only a small portion of sediment or in the preferred embodiments even without sediment are obtained at 2 °C. When the temperature of the prepared solution is increased to 20°C, no precipitation occurs.

The esterified cellulose ether a) comprised in the composition of the present invention generally has a viscosity of at least 1.2 mPa-s, preferably least 1.8 mPa-s, and more preferably least 2.4 mPa-s, and generally no more than 200 mPa-s, preferably no more than 100 mPa-s, more preferably no more than 50 mPa-s, and most preferably no more than 30 mPa-s, measured as a 2.0 weight percent solution of the esterified cellulose ether in 0.43 wt. % aqueous NaOH at 20°C according to "Hypromellose Acetate Succinate, United States Pharmacopia and National Formulary, NF 29, pp. 1548-1550".

The esterified cellulose ether a) generally has a weight average molecular weight M_w of up to 500,000 Dalton, preferably up to 250,000 Dalton, more preferably up to 200,000 Dalton, and most preferably up to 150,000 Dalton. Generally it has a weight average molecular weight M_w of at least 10,000 Dalton, preferably at least 15,000 Dalton, more preferably at least 20,000 Dalton, and most preferably at least 30,000 Dalton. M_w and the number average molecular weight M_n are measured according to Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 743 using a mixture of 40 parts by volume of acetonitrile and 60 parts by volume of aqueous buffer containing 50 mM NaH2P0₄ and 0.1 M NaNCh as mobile phase. The mobile phase is adjusted to a pH of 8.0. The measurement of Mw and M_n is described in more details in the Examples.

The production of the esterified cellulose ether a) is described in copending

International Patent Application No. PCT/US16/021330, filed on 08 March, 2016 and published as WO 2016/148977, which claims the priority of US Provisional Application No. 62/133514, filed 16 March 2015, and International Patent Application No.

PCT/US16/021326, filed on 08 March, 2016 and published as WO 2016/148976, which claims the priority of US Provisional Application No. 62/133518, filed on 16 March 2015, all filed by the Applicants of the present patent application, and in the Examples of the present invention. These International Patent Applications describe the reaction of a cellulose ether with an aliphatic monocarboxylic acid anhydride, such as acetic anhydride, butyric anhydride or propionic anhydride, and with a dicarboxylic acid anhydride, such as succinic anhydride, in an aliphatic carboxylic acid, such as acetic acid, as a reaction diluent.

In the International Patent Application No. PCT/US16/021330, filed on 08 March,

2016 and published as WO 2016/148977, which claims the priority of US Provisional Application No. 62/133514, filed 16 March 2015, the esterified cellulose ether a) is produced in the absence of an esterification catalyst, and in particular in the absence of an alkali metal carboxylate. This is in contrast to known processes. According to the general procedure described in the International Patent Application No. PCT/US16/021330, a cellulose ether, preferably one of the type listed further above, is reacted with an aliphatic monocarboxylic acid anhydride, such as acetic anhydride, butyric anhydride and propionic anhydride, and with a dicarboxylic acid anhydride, such as succinic anhydride. The molar ratio between the anhydride of an aliphatic monocarboxylic acid and the anhydroglucose units of the cellulose ether generally is from 0.1 / 1 to 7 / 1, preferably from 0.3 / 1 to 3.5 / 1, and more preferably from 0.5 / 1 to 2.5 / 1. The molar ratio between the anhydride of a dicarboxylic acid and the anhydroglucose units of cellulose ether generally is from 0.1 / 1 to 2.2 / 1, preferably from 0.2 / 1 to 1.2 / 1, and more preferably from 0.3 / 1 to 0.8. The molar number of anhydroglucose units of the cellulose ether 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(hydroxyalkoxyl). 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, most preferably acetic acid. The molar ratio [aliphatic carboxylic acid / anhydroglucose units of cellulose ether] generally is at least 0.7 / 1, preferably at least 1.2 / 1, and more preferably at least 1.5 / 1. The molar ratio [aliphatic carboxylic acid / anhydroglucose units of cellulose ether] is generally up to 10 / 1, and preferably up to 9 / 1. Lower ratios, such as up to 7 / 1 or even only up to 4 / 1 and under optimized conditions even only up to 2 / 1 can also be used, which makes optimal use of the amount of reaction diluent needed. In contrast to the known processes, the esterified cellulose ethers of the present invention are produced in the absence of an esterification catalyst, and in particular in the absence of a alkali metal carboxylate. The reaction temperature for the esterification is generally from 60° C to 110 ⁰ C, preferably from 70 ⁰ C to 100 ⁰ C. The esterification reaction is typically completed within 2 to 8 hours, more typically within 3 to 6 hours. After completion of the esterification reaction, 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 subsequently washed with water, preferably at a temperature of from 70 to 100 °C.

Another essential ingredient, also designated as component, of the composition of the present invention is a tonicity-adjusting agent. One or more tonicity-adjusting agents may be included in the composition of the present invention to partially or fully achieve tonicity with body fluids, e.g. fluids of the nasal cavity or fluids of the eye, resulting in reduced levels of irritation. In one aspect of the present invention the tonicity-adjusting agent is an alkali or alkaline earth metal halide, preferably an alkali or alkaline earth metal chloride. Examples of pharmaceutically acceptable tonicity-adjusting agents include, but are not limited to, sodium chloride, potassium chloride, xylitol, calcium chloride, glucose, glycerin, mannitol, sorbitol or a combination of two or more of these tonicity-adjusting agents. In a preferred embodiment, the tonicity-adjusting agent is sodium chloride. In another preferred embodiment, the tonicity-adjusting agent is glucose.

Surprisingly, it has been found that by including an above-described esterified cellulose ether a) and a tonicity-adjusting agent b) in combination in an aqueous composition, aqueous compositions can be provided which exhibit a gelation temperature of up to 37 °C, typically up to 35 °C, and more typically up to 33 °C. The gelation temperature of the composition of the present invention is generally at least 21 °C, more typically at least 24 °C, and most typically at least 27 °C. It has been found that a composition of the present invention which comprises the esterified cellulose ether a) described further above in combination with a tonicity-adjusting agent exhibits thermal gelation at a lower temperature than a comparable composition comprising the same type and amount of esterified cellulose ether a) without the tonicity-adjusting agent. Alternatively, a lower concentration of the afore-mentioned esterified cellulose ether a) can be utilized in the presence of a tonicity- adjusting agent while still achieving thermal gelation of the composition at the desired temperature. The effects of the tonicity-adjusting agent in combination with the esterified cellulose ether a) described further above are illustrated in more detail in the Examples section. The Examples and Comparative Examples illustrate that the gelation temperature can be adjusted by adjusting the concentration and type of the tonicity-adjusting agent and/or of the esterified cellulose ether a). For example, if storage of a composition is desired at room temperature, the concentration or type of the tonicity-adjusting agent and/or of the esterified cellulose ether a) can be adjusted to provide the desired low viscosity at room temperature based on the teaching in the Examples. By decreasing the concentration of the tonicity-adjusting agent and/or of the esterified cellulose ether a), the gelation temperature of the aqueous composition can be increased and vice versa.

The composition of the present invention is in the form of an aqueous composition, preferably in the form of an aqueous solution. It comprises c) an aqueous diluent. The aqueous diluent may incorporate a minor amount of an organic diluent; however, the composition of the present invention generally comprises at least 55, preferably at least 65, more preferably at least 75, most preferably at least 90, and particularly at least 95 weight percent of water and up to 45, preferably up to 35, more preferably up to 25, most preferably only up to 10, and particularly only up to 5 weight percent of an organic diluent, based on the total weight of the aqueous diluent, i.e. based on the total weight of the organic diluent and water. In one embodiment of the invention the aqueous diluent c) consists of water. Preferred organic diluents are polar organic solvents having one or more

heteroatoms, such as oxygen, nitrogen or halogen like chlorine. More preferred organic diluents are alcohols, for example multifunctional alcohols, such as propylene glycol, polyethylene glycol, polypropylene glycol and glycerol; or preferably monofunctional alcohols, such as ethanol, isopropanol or n-propanol; or acetates, such as ethyl acetate. More preferably the organic diluent has 1 to 6, most preferably 1 to 4 carbon atoms. The organic diluent is preferably pharmaceutically acceptable, such as ethanol or glycerol. The total weight of the aqueous diluent is generally at least 50 percent, typically at least 60 percent, and more typically at least 70 percent, based on the total weight of the aqueous composition. The total weight of the aqueous diluent is generally up to 99 percent, typically up to 95 percent, and more typically up to 90 percent, based on the total weight of the aqueous composition. The composition of the present invention may comprise a basic compound. However, in one embodiment of the invention the amount and type of basic compound, if present, is chosen that the degree of neutralization of the groups - C(O) - R - COOA of the esterified cellulose ether a) in the composition is not more than 0.4, preferably not more than 0.3 or 0.2 or 0.1, more preferably not more than 0.05 or 0.01, and most preferably not more than 10^"3 or even not more than 10^"4. In one embodiment of the invention, the aqueous composition does not contain a basic compound.

The aqueous composition of the present invention comprises from 0.6 to 30 weight percent of the esterified cellulose ether a) and generally from 0.1 to 40 weight percent of the tonicity-adjusting agent b), each being based on the total weight of the composition. The amount of the esterified cellulose ether a) is preferably at least 0.8 weight percent, more preferably at least 1.0 weight percent, and even more preferably at least 1.5 weight percent, based on the total weight of the aqueous composition. In some aspects of the invention the amount of the esterified cellulose ether a) is preferably at least 2 weight percent, more preferably at least 5 weight percent, and most preferably at least 10 weight percent, based on the total weight of the aqueous composition. The amount of the esterified cellulose ether a) is generally up to 25 weight percent, preferably up to 20 weight percent, more preferably up to 15 weight percent, and most preferably up to 10 weight percent, based on the total weight of the aqueous composition. In some aspects of the invention the amount of the esterified cellulose ether a) is preferably up to 6.5 weight percent, more preferably up to 5 weight percent, and most preferably up to 3 weight percent, based on the total weight of the aqueous composition. The amount of the tonicity-adjusting agent b) is generally at least 0.1 weight percent, preferably at least 0.2 weight percent, more preferably at least 0.3 weight percent, and most preferably at least 0.5 weight percent, based on the total weight of the aqueous composition. In some aspects of the invention the amount of the tonicity-adjusting agent b) is preferably at least 2 weight percent, more preferably at least 5 weight percent, and most preferably at least 7.5 weight percent, based on the total weight of the aqueous composition. The amount of the tonicity-adjusting agent b) is generally up to 40 weight percent, preferably up to 30 weight percent, more preferably up to 25 weight percent, and most preferably up to 20 weight percent, based on the total weight of the aqueous composition. In some aspects of the invention the amount of the tonicity-adjusting agent b) is generally up to 10 weight percent, preferably up to 8.0 weight percent, more preferably up to 6.0 weight percent, and most preferably up to 4.0 weight percent or even only up to 2.0 weight percent, based on the total weight of the aqueous composition. The preferred amounts of the esterified cellulose ether a) and the tonicity-adjusting agent b) depend on the desired end-use of the aqueous composition.

In one aspect, the aqueous composition of the present invention is useful for application to mucosae, e.g., for intranasal, buccal, sublingual, vaginal, ocular or rectal application. A low viscosity at 5°C to 15 °C or at 20 to 23 °C, i.e., at a temperature at which the composition is usually stored and/or applied, facilitates the release of the aqueous composition of the present invention from a container comprising such composition, e.g. as drops or by spraying, and the administration of the composition to a mucosa. The temperature of the composition increases after its application to a mucosa. Thermal gelation at the gelation temperature of the composition of the present invention facilitates retention of the composition of the present invention on the mucosa. In this aspect of the present invention the amount of the esterified cellulose ether a) is preferably at least 0.8 weight percent, more preferably at least 1.0 weight percent, and most preferably at least 1.5 weight percent, based on the total weight of the aqueous composition. The upper limit of the esterified cellulose ether a) mainly depends on the desired end-use. If the composition of the present invention is used for vaginal or ocular application or for the application to the inner ear, the amount of the esterified cellulose ether a) is up to 30 weight percent, generally up to 25 weight percent, preferably up to 20 weight percent, and more preferably up to 15 weight percent or up to 10 weight percent, based on the total weight of the aqueous composition. If the composition of the present invention is used for nasal spray delivery, the amount of the esterified cellulose ether a) is generally up to 10 weight percent, preferably up to 6.5 weight percent, more preferably up to 5 weight percent, and most preferably up to 3 weight percent, based on the total weight of the aqueous composition. When the aqueous composition of the present invention is used for application to mucosae, the amount of the tonicity- adjusting agent b) is generally at least 0.1 weight percent, preferably at least 0.2 weight percent, more preferably at least 0.3 weight percent, and most preferably at least 0.5 weight percent, based on the total weight of the aqueous composition. The amount of the tonicity- adjusting agent b) is generally up to 10 weight percent, preferably up to 8.0 weight percent, more preferably up to 6.0 weight percent, and most preferably up to 4.0 weight percent or even only up to 2.0 weight percent, based on the total weight of the aqueous composition. Preferred embodiments of the composition of the present invention are particularly useful for application to the nasal mucosa.

In a preferred aspect of the invention, the above described aqueous composition, which is useful for application to mucosae, is used for administering a physiologically active agent to an individual, preferably for transmucosal delivery of a physiologically active agent. In one embodiment of the invention the aqueous composition comprises one or more physiologically active agents, preferably one or more drugs, one or more diagnostic agents, or one or more essential oils, or one or more physiologically active agents which are useful for cosmetic or nutritional purposes. The term "drug" denotes a compound having beneficial prophylactic and/or therapeutic properties when administered to an individual, typically a mammal, especially a human individual. Physiologically active agents that are useful for transmucosal delivery, such as intranasal, buccal, sublingual, vaginal, ocular or rectal delivery, or delivery through a mucosal membrane located on the gums or lips are known in the art, such as drugs utilized in therapies for allergic rhinitis, nasal congestion and infections, in treatments of diabetes, migraine, nausea, smoking cessation, acute pain relief, nocturnal enuresis, osteoporosis, and for administering intranasal vaccine, however the physiologically active agents are not limited to these examples. The composition of the present invention is particularly useful for intranasal delivery of one or more of the above- mentioned agents. Examples of essential oils are menthol, methyl salicylate, thymol, eucalyptus oil, camphor, anise, sweet orange, or combinations thereof. The composition of the present invention typically comprises from 0 to 20 percent or from 0.01 to 10 percent or from 0.1 to 5 percent of a physiologically active agent, based on the total weight of the composition.

In yet another embodiment of the invention the above described aqueous composition, which is useful for application to mucosae, does not comprise a physiologically active agent that is selected from drugs, diagnostic agents, essential oils, or physiologically active agents which are useful for cosmetic or nutritional purposes. Compositions comprising an above- described esterified cellulose ether in combination with a tonicity-adjusting agent, but not a physiologically active agent, are useful, e.g., for rinsing and/or moisturizing the nasal cavity or as artificial tears.

Upon application of the aqueous composition of the present invention to a mucosa of an individual, the temperature of the composition increases and the esterified cellulose ether suspended or, preferably, dissolved in the aqueous composition precipitates or gels when the temperature of the composition of the present invention adjusts to the temperature of the mucosa, i.e., to a temperature of 30 - 37 °C, typically 30 - 35°C. The exact temperature of the mucosa somewhat depends on the type of mucosa, on the individual, on the time of day, and on the conditions of the surrounding environment. In the case of human beings the mucosa in the nasal cavity typically has a temperature of 30 - 35°C, the oral mucosa under the tongue typically has a temperature of about 36.8 + 0.4°C, and the rectal mucosa typically has a temperature of about 37°C.

In another aspect of the invention the aqueous composition is useful in a method for inducing satiety or for reversibly reducing stomach void volume or for reducing caloric intake of an individual. In nutritional terms, satiety is a complex response, involving both an individual's emotional and physical perception of whether or not they have ingested enough. Satiety can be observed as a reduction of appetite immediately following consumption, or as a reduction of food intake at the next meal. For purposes of this specification, "satiety" refers to a net reduction of caloric intake, or a robust reduction in hunger responses, by an individual. It has been suggested by skilled artisans that addition of specific types of compounds to food can enhance suppression of hunger when the compounds form strong gastric gels after consumption of the drinks. In vitro gel fracture force of the aqueous gelled material having a temperature of 37 °C is a proxy for in vivo gelling. As indicated above, it has been found by the inventors of the present patent application that by including an above- described esterified cellulose ether a) and a tonicity-adjusting agent b) in combination in an aqueous composition, aqueous compositions can be provided which gel at a temperature of up to 37 °C, typically up to 35 °C, and more typically up to 33 °C.

It is contemplated that in one embodiment the aqueous composition of the present invention is useful for indications that require gastric volume to be occupied for at least 60 minutes, preferably at least 120 minutes, more preferably at least 180 minutes, and most preferably at least 240 minutes. In a preferred embodiment, the aqueous composition is useful for treating obesity by inducing satiety or reversibly reducing stomach void volume or reducing caloric intake of an individual. Alternatively, in another embodiment, the aqueous composition is useful as a slimming aid, weight loss aid, or weight control aid in a non-obese individual, for example for aesthetic reasons by inducing satiety or reversibly reducing stomach void volume or reducing caloric intake of an individual. When the aqueous composition of the present invention is used for inducing satiety or for reversibly reducing stomach void volume or for reducing caloric intake of an individual, the amount of the esterified cellulose ether a) is generally at least 1.0 weight percent, preferably at least 2 weight percent, more preferably at least 5 weight percent, and most preferably at least 10 weight percent, based on the total weight of the aqueous composition. The amount of the esterified cellulose ether a) is generally up to 25 weight percent, preferably up to 20 weight percent, more preferably up to 15 weight percent, and most preferably up to 10 weight percent, based on the total weight of the aqueous composition. In this aspect of the present invention the amount of the tonicity-adjusting agent b) is generally at least 2 weight percent, preferably at least 5 weight percent, and most preferably at least 7.5 weight percent, based on the total weight of the aqueous composition. The amount of the tonicity-adjusting agent b) is generally up to 40 weight percent, preferably up to 30 weight percent, more preferably up to 25 weight percent, and most preferably up to 20 weight percent, based on the total weight of the aqueous composition. In this embodiment of the invention the tonicity- adjusting agent is preferably glucose. Non-limiting examples of an aqueous composition of the present invention include yogurts, smoothies, drinks, shakes, fruit beverages, beverage shots, sports drinks, and other aqueous solutions, as well as emulsions, including ice creams, creams, mousses, cream cheese, ketchup, spreads, dips, picante, salad dressing, homogenized milk, gravies, puddings, soups or sauces. The composition of the present invention may comprise one or more additional ingredients, such as added vitamins, added minerals, herbs, flavoring agents, colorants, antioxidants, preservatives or mixtures thereof.

The aqueous composition of the present invention is preferably stored at a temperature of from 1 to 23 °C, more preferably from 2 to 17 °C, or more preferably from 3 to 12 °C. EXAMPLES

Unless otherwise mentioned, all parts and percentages are by weight. In the Examples the following test procedures are used. The terms "mPa-s", "mPa*s" and "mPa-s" are used herein as synonyms. They all mean "millipascal-second".

Hydroxypropyl methyl cellulose (HPMC)

The content of ether groups in HPMC is determined as described for "Hypromellose", United States Pharmacopeia and National Formulary, USP 35, pp 3467-3469.

The viscosity of the HPMC is measured as a 2.0 % by weight solution in water at 20°C ± 0.1 °C. The 2.0 % by weight HPMC solution in water is prepared according to

United States Pharmacopeia (USP 35, "Hypromellose", pages 3467-3469), followed by an Ubbelohde viscosity measurement according to DIN 51562-1:1999-01 (January 1999).

Hydroxypropyl methyl cellulose acetate succinate (HPMCAS)

The content of ether groups in the HPMCAS is determined in the same manner as described for "Hypromellose", United States Pharmacopeia and National Formulary, USP 35, pp 3467-3469.

The ester substitution with acetyl groups (-CO-CH3) and the ester substitution with succinoyl groups (-CO-CH2-CH2-COOH) are determined according to Hypromellose Acetate Succinate, United States Pharmacopia and National Formulary, NF 29, pp. 1548- 1550". Reported values for ester substitution are corrected for volatiles (determined as described in section "loss on drying" in the above HPMCAS monograph).

Mw and M_n of HPMCAS are measured according to Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 743 unless stated otherwise. The mobile phase is a mixture of 40 parts by volume of acetonitrile and 60 parts by volume of aqueous buffer containing 50 mM NaH₂P04 and 0.1 M NaNCh. The mobile phase is adjusted to a pH of 8.0. Solutions of the cellulose ether esters (HPMCAS) are filtered into a HPLC vial through a syringe filter of 0.45 μιη pore size. The exact details of measuring M_w and M_n are disclosed in the International Patent Application No. WO 2014/137777 in the section "Examples" under the title "Determination of M_w, M_n and M_z". Water-Solubility of HPMCAS

A 2 wt. percent mixture of HPMCAS and water is prepared by mixing 2.0 g HPMCAS, based on its dry weight, with 98.0 g water under vigorous stirring at 0.5°C for 16 hours. The temperature of the mixture of HPMCAS and water is then increased to 5 °C. The water solubility of the esterified cellulose ether is determined by visual inspection. The determination whether the HPMCAS is water-soluble at 2% at 5 °C or not is done as follows. "Water soluble at 2% - yes" means that a solution without sediment is obtained according to the procedure above. Gelation Temperature of Aqueous Compositions

Aqueous solutions of HPMC or HPMCAS, optionally in combination with a tonicity- adjusting agent are produced by adding milled, ground, and dried HPMC or HPMCAS (under consideration of the water content of the HPMC or HPMCAS) and optionally a tonicity-adjusting agent in the amounts and types listed in Table 3 below to water

(temperature 20 - 25 °C) at room temperature while stirring with an overhead lab stirrer at 750 rpm with a 3-wing (wing = 2 cm) blade stirrer. The solution is then cooled to about 1.5 °C. After the temperature of 1.5 °C is reached the solution is stirred for 6 hours at 500 rpms. Each solution is stored in the refrigerator prior to the characterization.

Rheology measurements of the resulting aqueous solutions are conducted with a Haake RS600 (Thermo Fisher Scientific) rheometer with cup and bob fixtures (CC-25). The sample is heated at a rate of 1°C per minute over a temperature range from 10 to 50 °C with a constant strain (deformation) of 2% and a constant angular frequency of 2 Hz. The measurement collection rate is chosen to be 4 data points / min. Besides the typically used storage modulus G' and loss modulus G", which are obtained from the rheology measurements, the complex viscosity Ιη*Ι can be used to describe the gelation performance as a function of temperature.

In order to analyze the gelation temperature of aqueous solutions, these obtained data of the complex viscosity Ιη*Ι, which are obtained from the oscillation measurements, are first logarithmized and normalized to Ιη*Ι (min) to zero and Ιη*Ι (max) to 100. Linear regression curves are fitted to subsets of these complex viscosity data (increments of 5 data points). A tangent is fitted to the steepest slope of the regression curve. The intersection of this tangent with the x-axis is reported as gelation temperature. Fig. 4 illustrates how the tangent is fitted to the steepest slope of the regression curve to determine the gelation temperature. The comparisons of the complex viscosity Ιη*Ι at 37 °C of the aqueous solutions in comparison to these viscosity values at 10 °C are also relevant.

Production of the HPMCAS Samples I - III

The water-soluble HPMCAS polymer is produced as described in co-pending International Patent Application PCT/US16/021330, filed on 08 March, 2016 and published as WO 2016/148977, which claims the priority of US Provisional Application No.

62/133514, filed 16 March 2015.

Succinic anhydride and acetic anhydride are dissolved at 70°C in glacial acetic acid. Then hydroxypropyl methyl cellulose (HPMC, water free) is added under stirring. The amounts are listed in Table 1 below. The amount of HPMC is calculated on a dried basis. No amount of sodium acetate is added.

The HPMC has a methoxyl substitution (DS_M) of 1.92, a hydroxypropoxyl substitution (MSHP) of 0.24 and a viscosity of 3.0 mPa-s, measured as a 2 % solution in water at 20 °C. The weight average molecular weight of the HPMC is about 20,000 Dalton. The HPMC is commercially available from The Dow Chemical Company as Methocel E3 LV Premium cellulose ether.

Then the reaction mixture is heated up to 85 - 110 °C for 2 - 3 hours until the desired substitution with acetyl groups and succinoyl groups is achieved. Then the crude product is precipitated by adding 1 - 2 L of water having a temperature of 21 °C. Subsequently the precipitated product is separated from the mixture by filtration and washed several times with water having the temperature listed in Table 1 below. Then the product is isolated by filtration and dried at 55°C overnight.

The properties of the water-soluble HPMCAS samples are listed in Table 2 below. In Table 2 the abbreviations have the following meanings:

DS_M = DS(methoxyl): degree of substitution with methoxyl groups;

MS_HP = MS (hydroxypropoxyl): molar subst. with hydroxypropoxyl groups;

DSA_c: degree of substitution of acetyl groups;

DS_S: degree of substitution of succinoyl groups. Table 1

Table 2

) Insufficient recovery

Aqueous solutions of HPMC or HPMCAS, optionally in combination with a tonicity- adjusting agent

Table 3

X⁾ weight percent, based on total weight of aqueous solution Solutions of a HPMCAS or a HPMC in water, optionally in combination with a tonicity-adjusting agent, are prepared. The type and concentration of the HPMCAS, HPMC and tonicity-adjusting agent are listed in Table 3 above.

The Examples in Table 3 above illustrate that the aqueous compositions of the present invention have a low viscosity at 10 °C but a high or very high viscosity at 37 °C. This allows storing the aqueous composition in the refrigerator and tolerating some temperature increase before its use; the low viscosity enables convenient handling of the composition. At 37 °C the aqueous compositions have the desired high or very high viscosity.

Examples 3 - 5, Examples 6 and 7 and Comparative Examples D and E illustrate that the gelation temperature can be adjusted by adjusting the concentration of the tonicity- adjusting agent and/or of the HPMCAS. The comparisons between Examples 1 and 2 and between Examples 2 and 3, respectively, illustrate that the gelation temperature can be adjusted by adjusting the type of the tonicity-adjusting agent. For example, if storage of a composition is desired at room temperature, the concentration or type of the tonicity - adjusting agent and/or of the HPMCAS can be adjusted to provide the desired low viscosity at room temperature based on the present teaching.

The comparison between Comparative Example A and Examples 1 and 2 illustrates that the gelation temperature of an aqueous solution of HPMCAS is substantially decreased when the solution also comprises a tonicity-adjusting agent. Figure 1 illustrates the viscosity as a function of temperature of the aqueous solutions of Examples 1 and 2 which comprise dissolved HPMCAS-I in the presence of sodium chloride or calcium chloride as tonicity- adjusting agent. Figure 1 also illustrates the viscosity as a function of temperature of an aqueous solution of HPMCAS-I of Comparative Example A in the absence of a tonicity- adjusting agent.

The comparison between Comparative Example A and Examples 3 - 5 illustrates that the gelation temperature of an aqueous solution of HPMCAS is also substantially decreased when the solution comprises a different type of tonicity-adjusting agent than in Examples 1 and 2. Figure 2 illustrates the viscosity as a function of temperature of the aqueous solutions of Comparative Example A and Examples 3 - 5 which comprise dissolved HPMCAS-I in the absence or presence of various amounts of glucose.

Figure 3 illustrates the viscosity as a function of temperature of aqueous solutions of

HPMCAS -II in the absence or presence of sodium chloride. The gelation temperature of

Examples 6 and 7, which comprise a tonicity-adjusting agent such as sodium chloride, is lower than the gelation temperature of Comparative Example B although the concentration of HPMCAS-II in Examples 6 and 7 and Comparative Example B are identical.

Comparative Example C shows that a significant increase in HPMCAS-II concentration is needed to reduce the gelation temperature of the aqueous solution at a similar degree as quite a small concentration of tonicity-adjusting agent.

The comparison between Comparative Examples D and E on the one hand and Comparative Examples F and G on the other hand illustrate the surprisingly fact that an aqueous solution of an esterified cellulose ether, such as HPMCAS, which is utilized in the present invention, has a considerably lower gelation temperature than an aqueous solution of a cellulose ether, such as HPMC, that has been used as a starting material for esterification.

Claims

1. An aqueous composition comprising

a) from 0.6 to 30 weight percent, based on the total weight of the aqueous

composition, of an esterified cellulose ether comprising aliphatic monovalent acyl groups and groups of the formula - C(O) - R - COOA, R being a divalent hydrocarbon group and A being hydrogen or a cation, wherein the total degree of ester substitution is from 0.03 to 0.70,

b) a tonicity-adjusting agent, and

c) an aqueous diluent.

2. The aqueous composition of claim 1 wherein in component a) the degree of neutralization of the groups - C(O) - R - COOA is not more than 0.4.

3. The aqueous composition of claim 1 or 2 wherein in component a) the aliphatic monovalent acyl groups are acetyl, propionyl or butyryl groups, and the groups of the formula - C(O) - R - COOH are - C(O) - CH₂ - CH₂ - COOH groups.

4. The aqueous composition of any one of claims 1 to 3 wherein component a) is an esterified hydroxyalkyl alkylcellulose.

5. The aqueous composition of any one of claims 1 to 4 wherein component a) is hydroxypropyl methylcellulose acetate succinate.

6. The aqueous composition of any one of claims 1 to 5 wherein the esterified cellulose ether a) has a solubility in water of at least 2.0 weight percent at 2 °C.

7. The aqueous composition of any one of claims 1 to 6 wherein the tonicity- adjusting agent is an alkali or alkaline earth metal halide, xylitol, glucose, mannitol, sorbitol or a combination of two or more of these compounds.

8. The aqueous composition of any one of claims 1 to 7 comprising from 0.8 to 6.5 weight percent of the esterified cellulose ether a), based on the total weight of the composition.

9. The aqueous composition of claim 8 comprising from 0.1 to 10 weight percent of the tonicity-adjusting agent, based on the total weight of the composition.

10. The aqueous composition of any one of claims 1 to 7 comprising from 1.0 to 25 weight percent of the esterified cellulose ether a), based on the total weight of the composition.

11. The aqueous composition of claim 10 comprising from 2 to 40 weight percent of a tonicity-adjusting agent, based on the total weight of the composition.

12. The aqueous composition of any one of claims 1 to 11 additionally comprising a physiologically active agent.

13. A method for inducing satiety or for reversibly reducing stomach void volume or for reducing caloric intake of an individual, comprising administering to said individual the aqueous composition of any one of claims 1 to 11.

14. A method for applying a physiologically active agent to a mucosa comprising administering to the mucosa of an individual the aqueous composition of claim 12.

15. Use of the aqueous composition of any one of claims 1 to 11 for application to a mucosa.