巴西专利BR112015019807B1 hydroxypropyl methylcellulose succinate, composition, solid dispersion, dosage form and capsule wrap

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HYDROXYPROPYL SUCCINATE ACETATE METHYLCELLULOSE, COMPOSITION, SOLID DISPERSION, DOSAGE FORM AND CAPSULE WRAP. Esterified cellulose ethers comprising (i) monovalent aliphatic acyl groups or (ii) groups of the formula -C (O) -R-COOA, where R is a divalent aliphatic or aromatic hydrocarbon group and A is hydrogen or a cation, or ( iii) a combination of monovalent aliphatic acyl groups or groups of the formula -C (O) -R-COOA, which has a viscosity of up to 2.33 mPa s, measured as a 2.0% w / w solution of the ether of cellulose esterified in 0.43% w / w aqueous NaOH at 20oC, and which has a viscosity of up to 13 mPa s, measured as a 10% w / w solution of the cellulose ether esterified in acetone at 20 ° C are useful for preparing solid dispersions comprising drugs.
公开号:BR112015019807B1
申请号:R112015019807-4
申请日:2014-02-28
公开日:2020-12-08
发明作者:Meinolf Brackhagen；Steven J. Guillaudeu；Nicholas S. Grasman；Oliver Petermann；Robert L. Schmitt；Matthias Sprehe
申请人:Dow Global Technologies Llc；
IPC主号:

专利说明:

[0001] This invention relates to new esterified cellulose ethers, solid dispersions of an active ingredient in such esterified cellulose ether, as well as liquid compositions, coated dosage forms and capsules comprising such esterified cellulose ether.
[0002] Cellulose ethers esters, their uses and the processes for preparing them are generally known in the art. Known methods for producing cellulose ether esters include reacting a cellulose ether with a monocarboxylic acid anhydride or an aliphatic dicarboxylic acid anhydride or a combination thereof, for example, as described in US patents Nos. 4,226,981 and 4,365,060 .
[0003] Several known esterified cellulose ethers are useful as enteric polymers for pharmaceutical dosage forms, such as methyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose succinate, or hydroxypropyl methyl cellulose succinate. 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. U.S. patent 4,365,060 discloses enterosoluble capsules which are said to have excellent enterosolubility behavior.
[0004] U.S. Patent No. 5,776,501 teaches the use of a water-soluble cellulose ether having a viscosity of 3 to 10 cp (mPa's), determined as a 2% by weight aqueous solution. If the viscosity is less than 3 cp, the coating film finally obtained for solid enteric pharmaceutical preparations is insufficient in strength while, if it exceeds 10 cp, the viscosity observed when it is dissolved in a solvent to perform a substitution reaction becomes extremely high.
[0005] U.S. Patent Application Publication No. 2004/0152886 discloses the production of hydroxypropyl methylcellulose phthalate starting from hydroxypropyl methylcellulose having a viscosity of 3 to 20 cp, measured as a 2% w / w aqueous solution.
[0006] International patent applications WO 2005/115330 and WO 2011/159626 disclose the preparation of hydroxypropyl methylcellulose succinate acetate (HPMCAS). An HPMC having an apparent viscosity of 2.4 to 3.6 cp (mPa * s) is recommended as a starting material. Alternatively, an HPMC starting material of 600 to 6000 Dalton, preferably 3000 to 50,000 Dalton, more preferably 6,000 to 30,000 Dalton is recommended. According to Keary [Keary, C.M .; Carbohydrate Polymers 45 (2001) 293-303, tables 7 and 8], an HPMC having an average molecular weight of about 85-100 kDa has a viscosity of about 50 mPa-s, determined as a 2% aqueous solution in weight.
[0007] A large number of currently known drugs have low water solubility, so complex techniques are required to prepare a dosage form. A known method includes dissolving such a drug together with a pharmaceutically acceptable water-soluble polymer, such as an esterified cellulose ether, in an organic solvent that is optionally mixed with water and spray drying the solution. The esterified cellulose ether aims at reducing the crystallinity of the drug, thus minimizing the activation energy necessary for the dissolution of the drug, as well as establishing hydrophilic conditions around the drug molecules, thus improving the solubility of the drug itself in order to increase the its bioavailability, i.e., its absorption in vivo by an individual upon ingestion.
[0008] Unfortunately, the known esterified cellulose ethers often cannot be used efficiently in spray drying operations. When known esterified cellulose ethers are dissolved at a high concentration in an organic solvent, such as a concentration of 7-10 weight percent, and such solution is combined with a drug and spray-dried, the resulting solution having a high viscosity, it is difficult to spray-dry and tends to clog the spray-drying device. When a highly diluted solution is used, an unduly high amount of organic solvent must be evaporated. Similar problems occur when cellulose ethers are dissolved in organic solvents and used for coating purposes, such as coating tablets.
[0009] Consequently, it would be highly desirable to find esterified cellulose ethers that could be used efficiently in spray drying and coating processes. It would be particularly desirable to find new esterified cellulose ethers that are suitable for improving the solubility of drugs.
[00010] One aspect of the present invention is an esterified cellulose ether comprising (i) monovalent aliphatic acyl groups or (ii) groups of the formula -C (O) -R- COOA, where R is a divalent aromatic or aliphatic hydrocarbon group and A is hydrogen or a cation, or (iii) a combination of aliphatic monovalent acyl groups or groups of the formula -C (O) -R-COOA, which has a viscosity of up to 2.33 mPa ^ s, measured as a solution at 2.0% w / w of cellulose ether esterified in aqueous NaOH at 0.43% w / w at 20oC, and which has a viscosity of up to 13 mPa-s, measured as a 10% w / w solution of the ether of cellulose esterified in acetone at 20oC.
[00011] Another aspect of the present invention is a composition comprising a liquid diluent and at least one esterified cellulose ether described above.
[00012] Yet another aspect of the present invention is a solid dispersion of at least one active ingredient and at least one esterified cellulose ether described above.
[00013] Yet another aspect of the present invention is a dosage form that is coated with at least one of the esterified cellulose ether described above.
[00014] Yet another aspect of the present invention is a capsule wrapper comprising at least one of the esterified cellulose ether described above.
[00015] The esterified cellulose ether has a cellulose chain having repetitive units of D-glycopyranose [3-1.4 glycosidically linked, referred to as anhydroglycosis units in the context of this invention. The esterified cellulose ether is preferably alkyl cellulose, hydroxyalkyl cellulose or esterified hydroxyalkyl alkyl cellulose. This means that in the esterified cellulose ether of the present invention, at least part of the hydroxyl groups of the anhydroglycoside units is replaced by alkoxy groups, or hydroxyalkoxy groups or a combination of alkoxy groups or hydroxyalkoxy groups. Hydroxyalkoxy groups are typically hydroxymethoxy groups, hydroxyethoxy and / or hydroxypropoxy groups. Hydroxyethoxy and / or hydroxypropoxy groups are preferred. Typically two or more types of hydroxyalkoxy groups are present in the esterified cellulose ether. Preferably a single type of hydroxyalkoxy group, more preferably hydroxypropoxy, is present. are typically methoxy, ethoxy and / or propoxy groups. Methoxy groups are preferred. Illustrative of the esterified cellulose ethers defined above are esterified alkylcelluloses, such as methylcelluloses, ethylcelluloses and esterified propylcelluloses; esterified hydroxyalkyl celluloses, such as hydroxyethylcellulose, hydroxypropylcelluloses and esterified hydroxybutylcelluloses; and esterified hydroxyalkyl alkylcelluloses, such as hydroxyethyl methylcelluloses, hydroxymethyl ethylcelluloses, ethyl hydroxyethyl celluloses, hydroxypropyl methylcelluloses, hydroxypropyl ethylcelluloses, hydroxybutyl methylcelluloses, and esterified hydroxybutyl ethylcelluloses; and those having two or more hydroxyalkyl groups, such as esterified hydroxyethylhydroxypropyl methylcelluloses. Most preferably, the esterified cellulose ether is a hydroxyalkyl methylcellulose, such as hydroxypropyl methylcellulose.
[00016] The degree of substitution of hydroxyl groups of anhydroglycosis units by hydroxyalkoxy groups is expressed by the molar substitution of hydroxyalkoxy groups, MS (hydroxyalkoxy). MS (hydroxyalkoxy) is the average number of moles of hydroxyalkoxy groups per anhydroglycosis unit in esterified cellulose ether. It should be understood that during the hydroxyalkylation reaction the hydroxyl group of a hydroxyalkoxy group attached to the cellulose backbone may be further etherified by an alkylating agent, e.g., a methylating agent, and / or a hydroxyalkylating agent. Subsequent multiple hydroxyalkylation etherification reactions with respect to the same carbon atom position of an anhydroglycosis unit produce a side chain, where multiple hydroxylacoxyl groups are covalently linked to each other by ether bonds, each side chain as a whole forming a hydroxyalkoxy substituent in the main cellulose chain.
[00017] The term "hydroxyalkoxy groups", therefore, should be interpreted in the context of MS (hydroxyalkoxy) as referring to hydroxyalkoxy groups as the constituent units of the hydroxyalkoxy substituents, which either comprise a single hydroxyalkoxy group or a side chain as presented above , where two or more hydroxyalkoxy groups are linked to each other by ether bond. Within this definition, it is not important whether the terminal hydroxyl group of a hydroxyalkoxy substituent is additionally alkylated or not; both alkylated and non-alkylated hydroxyalkoxy substituents are included for the determination of MS (hydroxyalkoxy). The esterified cellulose ether of the invention generally has a molar substitution of hydroxyalkoxy groups in the range of 0.05 to 1.00, preferably from 0.08 to 0.90, more preferably from 0.12 to 0.70, most preferably from 0.15 to 0.60 and especially from 0.21 to 0.50.
[00018] The average number of hydroxyl groups substituted by alkoxy groups, such as methoxy groups, per unit of anhydroglycosis, is designated as the degree of substitution of alkoxy groups, DS (alkoxy). In the definitions given above for DS, the term "hydroxyl groups substituted by alkoxy groups" is to be understood according to the present invention as including not only alkylated hydroxyl groups linked directly to the carbon atoms of the cellulose main chain, but also alkylated hydroxyl groups hydroxyalkoxy substituents attached to the cellulose main chain. The cellulose ethers esterified according to this invention preferably have a DS (alkoxy) in the range of 1.0 to 2.5, more preferably from 1.1 to 2.4, even more preferably from 1.2 to 2.2 , most preferably from 1.6 to 2.05, and particularly from 1.7 to 2.05.
[00019] Most preferably, the esterified cellulose ether is an esterified hydroxypropyl methylcellulose having a DS (methoxy) within the ranges indicated above for MS (hydroxyalkoxy).
[00020] The esterified cellulose ether of the present invention has (i) aliphatic monovalent acyl groups or (ii) groups of the formula -C (O) -R-COOA, where R is a divalent aromatic or aliphatic hydrocarbon group and A is hydrogen or a cation, or (iii) a combination of monovalent aliphatic acyl groups or groups of the formula -C (O) -R-COOA. The cation is preferably an ammonium cation, such as NH4 + or an alkali metal ion, such as sodium or potassium ion, more preferably sodium ion. Most preferably, A is hydrogen.
[00021] The aliphatic monovalent acyl groups are preferably selected from the group consisting of acetyl, propionyl, and butyryl, such as n-butyryl or i-butyryl.
[00022] Preferred groups of the formula -C (O) -R-COOA are -C (O) -CH2-CH2-COOA, such as - (CO) -CH2-CH2-COOH or C (O) -CH2-CH2 -COONa +, -C (O) -CH = CH-COOA, such as -C (O) -CH = CH-COOH or -C (O) -CH = CH-COONa +, or -C (O) -C6H4- COOA, such as -C (O) -C6H4-COOH, or -C (O) -C6H4-COONa +.
[00023] In the -C (O) -C6H4-COOA groups, the carbonyl group and the carboxylic group are preferably arranged in ortho positions.
[00024] Preferred esterified cellulose ethers are i) HPMCXY, where HPMC is hydroxypropyl methyl cellulose, X is A (acetate), or X is B (butyrate) or Xé Pr (propionate) and Y is S (succinate), or Y éP (phthalate) or Y is M (maleate), such as hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylmethylcellulose maleate acetate (HPMCAM), hydroxypropyl methylcellulose succinate acetate (HPMCAS), or ii) hydroxypropylmethyl cellulose (HPC) methacrylpropylmethylcellulose hydroxypropyl cellulose succinate (HPCAS), hydroxybutyl methyl cellulose succinate (HBMCPrS), hydroxyethyl hydroxypropyl cellulose propionate (HEHPCPrS); and methyl cellulose succinate acetate (MCAS).
[00025] Hydroxypropyl methylcellulose succinate acetate (HPMCAS) is the most preferred esterified cellulose ether.
[00026] The esterified cellulose ethers generally have a degree of substitution of aliphatic monovalent acyl groups, such as acetyl, propionyl, or butyryl groups, from 0 to 1.75, preferably from 0.05 to 1.50, more preferably from 0.10 to 1.25, and most preferably from 0.20 to 1.00.
[00027] The esterified cellulose ethers generally have a degree of substitution of groups of formula -C (O) -R-COOA, such as succinyl, from 0.05 to 1.6, preferably from 0.05 to 1.30 , more preferably from 0.05 to 1.00, and most preferably from 0.10 to 0.70 or even 0.10 to 0.60.
[00028] 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 is generally 0.05 to 2.0, preferably of 0.10 to 1.4, more preferably from 0.20 to 1.15, most preferably from 0.30 to 1.10 and particularly from 0.40 to 1.00.
[00029] The content of acetate and succinate groups is determined according to "Hypromellose Acetate Succinate", United States Pharmacopeia and National Formulary, NF 29, pgs. 1548-1550. The reported values are corrected for volatiles (determined as described in the “loss on drying” section in the HPMCAS monograph above). The method can be used in a similar way to determine the content of propionyl, butyryl, phthalyl, and other ester groups.
[00030] The content of ester groups in the esterified cellulose ether is determined in the same manner as described in "Hypromellose", United States Pharmacopeia and National Formulary, USP 35, pgs. 3467-3469.
[00031] The contents of the ether and ester groups obtained by the above analyzes are converted into individual DS and MS desubstituting values according to the formulas below. The formulas can be used in a similar way to determine the DS and MS of substituents from other ethers of ethers cellulose.

[00032] By convention, the weight percentage is a weight percentage based on the average total weight based on the total weight of the repetitive cellulose unit, including all substituents. The content of the methoxy group is reported based on the mass of the methoxy group (i.e., -OCH3). The content of the hydroxyalkoxy group is reported based on the mass of the hydroxyalkoxy group (i.e., -O-alkylene-OH); such as hydroxypropoxy (i.e., -O-CH2CH (CH3) -OH). The content of the aliphatic monovalent acyl groups is reported based on the mass of -C (O) -R1 where R1 is a monovalent aliphatic group, such as acetyl (-C (O) CH3). The content of the -C (O) -R-COOH group is reported on the basis of the mass of this group, as well as the mass of succinyl groups (i.e., -C (O) -CH2-CH2-COOH).
[00033] The esterified cellulose ethers of the present invention have a viscosity of up to 2.33 mPa-s, or up to 2.25 mPa-s, preferably up to 2.10 mPa ^ s, more preferably up to 1.95 mPa-s , even more preferably up to 1.80 mPa ^ s, most preferably up to 1.70 mPa-s and particularly up to 1.55 mPa ^ s, measured as a 2% w / w solution of the cellulose ether esterified in aqueous NaOH at 0.43% w / d at 20oC. Generally the viscosity of the esterified cellulose ether is 1.20 mPa-s or more, typically 1.30 mPa-s or more, and more typically 1.40 or more, measured as a 2.0% w / w solution / w of cellulose ether esterified in 0.43% aqueous NaOH w / w at 20oC. The 2.0% by weight solution of the esterified cellulose ether is prepared as described in "Hypromellose Acetate Succinate", United States Pharmacopeia and National Formulary, NF 29, pgs. 1548-1550 ”, followed by an Ubbelohde viscosity measurement according to DIN 515621: 1999-01 (January 1999). It has been found that the viscosity of the cellulose ether esterified in 0.43% w / w aqueous NaOH is very similar to the viscosity of the cellulose ether which is useful as a starting material to produce the esterified cellulose ether.
[00034] Furthermore, the esterified cellulose ethers of the present invention have a viscosity of only up to 13 mPa-s, generally up to 12 mPa-s, preferably up to 11 mPa-s, and more preferably up to 10 mPa-s, measured as a 10% w / w solution of the cellulose ether esterified in acetone at 20oC. In some embodiments of the present invention, esterified cellulose ethers can be produced having a viscosity of only up to 8.0 mPa-s, preferably only up to 6.5 mPa-s, more preferably only only up to 5.0 mPa-s, most preferably only up to 4.0 mPa-s and particularly only up to 3.0 mPa-s, measured as a 10% w / w solution of the cellulose ether esterified in acetone at 20 ° C. The esterified cellulose ethers of the present invention typically have a viscosity of 1.50 mPa-s or more, more typically 1.65 mPa-s or more, and most typically 1.80 mPa-s or more, measured as a 10% w / w solution of the cellulose ether esterified in acetone at 20oC. In some embodiments of the present invention, esterified cellulose ethers have a viscosity of 5.0 mPa-s or more, typically 6.5 mPa-s or more. The viscosity of the esterified cellulose ethers of the present invention, measured as a 10% w / w solution in acetone, is considerably lower than the viscosity of esterified cellulose ethers known in acetone. The low viscosity of the esterified cellulose ethers of the present invention is highly advantageous when a liquid composition comprising the esterified cellulose ether is subjected to spray drying, for example to prepare solid dispersions comprising an active ingredient and an esterified cellulose ether. The 10% w / w solution of the cellulose ether esterified in acetone can be prepared as described in the examples below.
[00035] The average molecular weights of the esterified cellulose ethers of the present invention depend on several factors, such as the viscosity of the cellulose ether, measured as a 2.0% w / w solution in water at 20oC, which is used for preparing the esterified cellulose ethers of the present invention, and the weight ratios between the cellulose ether, the diluent and the catalyst that are used in the esterification reaction, as will be explained in more detail below.
[00036] In one embodiment of the present invention, the esterified cellulose ether generally has an average molecular weight Mw of 10,000 to 90,000 Dalton, or 10,000 to 70,000 Dalton, or 12,000 to 50,000 Dalton. In this embodiment of the invention, esterified cellulose ethers generally have a numerical average molecular weight Mn of 8000 to 20,000 Dalton or 9000 to 18,000 Dalton and / or an average molecular weight z, Mz, of 20,000 to 900,000 Dalton or 25,000 to 500,000 Dalton.
[00037] In another embodiment of the present invention, esterified cellulose ethers generally have an average molecular weight Mw of 90,000 to 350,000 Dalton, or 90,000 to 300,000 Dalton, or 100,000 to 250,000 Dalton, or 110,000 to 200,000 Dalton In this embodiment of the invention, esterified cellulose ethers generally have a numerical average molecular weight Mn of 8,000 Dalton to 40,000 Dalton or 9,000 Dalton to 35,000 Dalton and / or an average molecular weight z, Mz, of 550,000 Dalton to 1,500,000 Dalton or 600,000 Dalton to 1,000,000 Dalton.
[00038] Mw, Mn and Mz are measured according to the 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 NH2PO4 and NaNO3 0 , 1 M as a mobile phase. The mobile phase is adjusted to a pH of 8.0. The measurement of Mw, Mn and Mz is described in more detail in the examples.
[00039] The examples below describe how to prepare the esterified cellulose ethers of the present invention. Some aspects of the process for preparing these esterified cellulose ethers will be described in more general terms below.
[00040] The esterified cellulose ethers of the present invention are produced from a cellulose ether having a viscosity of 1.20 to 2.33 mPa-s, typically from 1.20 to 2.25 mPa-s, preferably from 1.20 to 2.10 mPa ^ s, more preferably from 1.20 to 1.95 mPa ^ s, even more preferably from 1.20 to 1.80 mPa-s, most preferably from 1.20 to 1 , 70 mPa-s, and particularly from 1.20 to 1.55 mPa-s, measured as a 20% w / w solution in water at 20oC (+ 0, 1oC)
[00041] The 2.0% w / w solution of cellulose ether in water is prepared according to the United States Pharmacopeia (USP 35, “Hypromellose”, pages 3467 to 3469), followed by an Ubbelohde viscosity measurement of according to DIN 51562-1: 1999-01 (January 1999). A low viscosity cellulose ether used as a starting material allows good miscibility of the reaction mixture used to produce the esterified cellulose ethers resulting in a homogeneous reaction mixture. Preferably, cellulose ether is used that has a type of ether groups and the degree (s) of substitution of ether groups as described above. The cellulose ethers described above and their production are described in the orders international patent WO2009 / 061821 and WO2009 / 061815.
[00042] The cellulose ether is reacted with (i) an aliphatic monocarboxylic acid anhydride or ii) a dicarboxylic acid anhydride or iii) a combination of an aliphatic monocarboxylic acid anhydride and a dicarboxylic acid anhydride. Preferred aliphatic monocarboxylic acid anhydrides are selected from the group consisting of acetic anhydride, butyric anhydride and propionic anhydride. Preferred dicarboxylic acid anhydrides are selected from the group consisting of succinic anhydride, maleic anhydride and phthalic anhydride. If a dicarboxylic acid anhydride and an aliphatic monocarboxylic acid anhydride are used in combination, the two anhydrides may be introduced into the reaction vessel at the same time or separately one after the other. The amount of each anhydride to be introduced into the reaction vessel is determined depending on the degree of esterification that is desired to be obtained in the final product, usually 1 to 10 times the stoichiometric amounts of the desired degree of replacement of the anhydroglycosis units by esterification. If a dicarboxylic acid anhydride is used, the molar ratio between a dicarboxylic acid anhydride and the cellulose ether anhydroglycosis units is generally 0.1 / 1 or more, and preferably 0.13 / 1 or more . The molar ratio between the dicarboxylic acid and the anhydroglycoside units of the cellulose ether is generally 1.5 / 1 or less, and preferably 1/1 or less. If an aliphatic monocarboxylic acid anhydride is used, the molar ratio between an aliphatic monocarboxylic acid anhydride and the cellulose ether anhydroglycosis units is generally 0.9 / 1 or more, and preferably 1.0 / 1 or more. The molar ratio between the anhydride of an aliphatic monocarboxylic acid and the cellulose ether anhydroglycosis units is generally 8/1 or less, preferably 6/1 or less, and more preferably 4/1 or less. The molar number of anhydroglycosis units of the cellulose ether used in the process can be determined from the weight of the cellulose ether used as a starting material, calculating the average molecular weight of the anhydroglycosis units replaced from the DS (alkoxyl) and MS (hydroxyalkoxy).
[00043] The esterification of the cellulose ether is preferably carried out in an aliphatic carboxylic acid as a reaction diluent, such as acetic acid, propionic acid, or butyric acid. The reaction diluent may comprise minor amounts of other solvents and diluents that are liquid at room temperature and do not react with cellulose ether, such as aromatic or aliphatic solvents such as benzene, toluene, 1,4-dioxane, or tetrahydrofuran; or halogenated C1-C3 derivatives, such as dichloromethane or methyl dichloroether, but the amount of aliphatic carboxylic acid is preferably more than 50 percent, more preferably at least 75 percent, and even more preferably at least 90 percent, based on the total weight of the reaction diluent.
[00044] Most preferably, the reaction diluent consists of an aliphatic carboxylic acid. Hence, the esterification process is described below with reference to the use of an aliphatic carboxylic acid as a reaction diluent, although the process is not limited to this.
[00045] It has been discovered that the viscosity of an esterified cellulose ether, measured as a 10% w / w solution in acetone at 20oC, can be influenced by three main parameters of the esterification reaction: 1. the viscosity of the cellulose ether used as a starting material; 2. the molar ratio [aliphatic carboxylic acid / cellulose ether anhydroglycosis units]; and 3. the molar ratio [esterification catalyst / cellulose ether anhydroglycosis units]. Based on the general teaching here and the more specific teachings in the examples, the person skilled in the art will know how to choose these three main esterification parameters in order to arrive at the esterified cellulose ethers of the present invention.
[00046] Surprisingly, it has been found that an esterified cellulose ether with significantly lower viscosity, measured as a 10% w / w solution in acetone, is obtained, when a cellulose ether is used as a starting material that has a viscosity from 1.20 to 2.33 mPa ^ s, measured as a 2.0% w / w solution in water at 20oC, than when a cellulose ether with a viscosity of 3 mPa-s or more is used as disclosed in the art above, while keeping the other reaction parameters constant. As illustrated in the examples and comparative examples, the viscosity in acetone is much lower than would be expected in view of the slightly lower viscosity of the cellulose ether used as the starting material.
[00047] The appropriate molar ratio of [aliphatic carboxylic acid / cellulose ether anhydroglycosis units] depends on the viscosity of the cellulose ether used as the starting material. When the viscosity of the cellulose ether used as a starting material is 1.9 - 2.33 mPa ^ s, measured as a 2.0% w / w solution in water at 20oC, the molar ratio of [aliphatic carboxylic acid / cellulose ether anhydroglycosis units] of 2.8 / 1.0 or more, preferably 3.0 / 1.0 or more, more preferably 4.0 / 1.0 or more and most preferably 5 , 0 / 1.0 or more. As illustrated by the examples, when the viscosity of the cellulose ether used as the starting material is, for example, 2.25 mPa-s, measured as a 2.0% w / w solution in water, a ratio in a weight of 4.0 / 1.0 or more is appropriate to obtain the esterified cellulose ethers of the present invention. On the other hand, when the viscosity of the cellulose ether used as a starting material is, for example, 2.0 mPa-s, measured as a 2.0% w / w solution in water, typically a ratio in weight of 3.0 / 1.0 or more is sufficient to obtain the esterified cellulose ethers of the present invention. When the viscosity of the cellulose ether used as the starting material is only 1.2 - 1.8 mPa ^ s, measured as a 2.0% w / w solution in water at 20oC, the molar ratio of [carboxylic acid aliphatic / cellulose ether anhydroglycosis units] may be even lower, such as 1.5 / 1 or more, typically 1.7 / 1 or more, more typically 1.9 / 1 or more, while still preparing esterified cellulose ethers having a viscosity of up to 13 mPa ^ s, measured as a 10% w / w solution of the cellulose ether esterified in acetone at 20oC.
[00048] If an esterified cellulose ether is obtained that has too high a viscosity, measured as a 10% w / w solution in acetone, the molar ratio of [aliphatic carboxylic acid / cellulose ether anhydroglycosis units] should be increased and / or the viscosity of the cellulose used as a starting material, measured as a 2.0% w / w solution in water, should be reduced in line with the present teaching.
[00049] The upper limit of [aliphatic carboxylic acid / cellulose ether anhydroglycosis units] is not critical to obtain the esterified cellulose ethers of the present invention. However, to achieve a reasonably high molecular weight, which is often desired, the molar ratio of [aliphatic carboxylic acid / cellulose ether anhydroglycosis units] is preferably up to 11.5 / 1.0, or up to 10.0 / 1.0 or up to 8.0 / 1.0. The higher the molar ratio of [aliphatic carboxylic acid / cellulose ether anhydroglycosis units], the lower the average weight molecular weight of esterified cellulose ethers will generally be, if the other reaction parameters are kept constant. When the weight average molecular weight of an esterified cellulose ether increases, this typically means that its viscosity in acetone also increases. However, it has been very surprisingly found that when cellulose ethers are used as a starting material that have a viscosity of only 1.20 to 2.0 mPa ^ s, more preferably 1.20 to 1.80 mPa-s, and the more preferably from 1.20 to 1.60 mPa ^ s, measured as a 2.0% w / w solution in water at 20oC, esterified cellulose ethers can be produced that have a high average molecular weight but still a low viscosity in acetone.
[00050] The esterification reaction is generally conducted in the presence of an esterification catalyst, preferably in the presence of an alkali metal carboxylate, such as sodium acetate or potassium acetate. The molar ratio of [alkali metal carboxylate / cellulose ether anhydroglycosis units] is generally from [0.4 / 1.0] to [3.8 / 1.0], and preferably from [0.6 / 1.0] a [2.7 / 1.0]. The higher the ratio of [alkaline metal carboxylate / cellulose ether anhydroglycosis units], the higher the average weight molecular weight of esterified cellulose ethers will generally be, if the other reaction parameters are kept constant in the defined ranges. If an esterified cellulose ether is obtained that has too high a viscosity, measured as a 10% w / w solution in acetone, the molar ratio of [alkaline metal carboxylate / cellulose ether anhydroglycosis units] should be reduced and / or the molar ratio of [aliphatic carboxylic acid / cellulose ether anhydroglycosis units] should be increased and / or the viscosity of the cellulose ether used as the starting material, measured as a 2.0% w / w solution in water at 20oC, it should be reduced in line with the present teaching.
[00051] The reaction mixture is generally heated to 60 ° C to 110 ° C, preferably from 70 to 100 ° C, for a period of time sufficient to complete the reaction, i.e., typically 2 to 25 hours, more typically 2 to 8 hours. The reaction mixture should be meticulously mixed in order to provide a homogeneous reaction mixture. Upon completion of the esterification reaction, the reaction product may be precipitated from the reaction mixture in a known manner, as described in US patent No. 4,226,981, in international patent application WO 2005/115330 or in European patent application EP 0 219 426. In a preferred embodiment of the invention, the reaction product is precipitated from the reaction mixture as described in provisional US patent application 61/616207, filed on March 27, 2012 or its corresponding international PCT patent application / US13 / 030394, published as WO2013 / 148154.
[00052] Another aspect of the present invention is a composition comprising a liquid diluent and one or more of the esterified cellulose ethers described above. The term “liquid diluent”, as used here, means a diluent that is liquid at 25oC and at atmospheric pressure. The liquid diluent may be water and an organic solvent or a mixture of water and an organic diluent. Preferably, the amount of the liquid diluent is sufficient to provide sufficient fluidity and processability to the composition for the desired use, such as for spray drying or coating purposes.
[00053] The term "organic liquid diluent", as used here, means an organic solvent or a mixture of two or more organic solvents. Preferred liquid organic diluents are polar organic solvents having one or more heteroatoms, such as oxygen, nitrogen or halogen such as chlorine. Most preferred organic 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, ketones, such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; acetates, such as ethyl acetate; halogenated hydrocarbons, such as methylene chloride; or nitriles, such as acetonitrile.
[00054] In one embodiment, the composition of the present invention comprises, as a liquid diluent, an organic diluent alone or mixed with a minor amount of water. In this embodiment, the composition of the present invention preferably comprises more than 50, more preferably at least 65, and most preferably at least 75 weight percent of an organic liquid diluent and preferably less than 50, more preferably up to 35, and most preferably up to 25 weight percent water, based on the total weight of the organic liquid diluent and water. This embodiment of the invention is particularly useful if the present invention comprises an active ingredient of poor water solubility.
[00055] In another embodiment, the composition of the present invention comprises as a liquid diluent water alone or with a minor amount of an organic liquid diluent as described above. In this embodiment, the composition of the invention preferably comprises at least 50, more preferably up to 65, and more preferably at least 75 percent by weight of water and preferably up to 50, more preferably up to 35, and most preferably up to 25 percent by weight of an organic liquid thinner, based on the total weight of the organic liquid thinner and water. This embodiment of the invention is particularly useful for providing coatings or capsules from aqueous compositions comprising the esterified cellulose ether of the present invention. When preparing an aqueous solution, it is preferred that at least a portion of the groups of formula -C (O) -R-COOA are in their salt form.
[00056] The composition of the present invention comprising an organic diluent and one or more of the esterified cellulose ethers described above is useful as an excipient system for active ingredients, and particularly useful as an intermediate to prepare an excipient system for active ingredients, such as fertilizers, herbicides or pesticides, or biologically active ingredients, such as vitamins, herbs and mineral supplements and drugs. Accordingly, the composition of the present invention preferably comprises one or more active ingredients, more preferably one or more drugs. The term "drug" is conventional, denoting a compound having beneficial prophylactic and / or therapeutic properties when administered to an animal, especially humans. Preferably, the drug is a "low solubility drug", meaning that the drug has an aqueous solubility at a physiologically relevant pH (e.g., pH 1-8) of about 0.5 mg / ml or less. This invention finds greater utility as the aqueous solubility of the drug decreases. Therefore, the compositions of the present invention are preferred for low solubility drugs having a water solubility of less than 0.1 mg / ml or less than 0.05 mg / ml or less than 0.02 mg / ml, or even less than 0.01 mg / mL where the aqueous solubility (mg / mL) is the minimum observed in any physiologically relevant aqueous solution (eg, those with pH values between 1 and 8) including simulated gastric and intestinal buffers according to USP. The active ingredient does not need to be a low solubility ingredient in order to benefit from this invention, although low solubility active ingredients represent a preferred class for use with this invention. An active ingredient that exhibits appreciable water solubility in the desired environment of use may have a water solubility of up to 1 to 2 mg / mL, or even as high as 20 to 40 mg / mL. Useful low-solubility drugs are listed in international patent application WO 2005/115330, pages 17 - 22.
[00057] The liquid composition of the present invention preferably comprises from 1 to 40 percent, more preferably from 5 to 35 percent, even more preferably from 7 to 30 percent, most preferably from 10 to 25 percent of at least one esterified cellulose ether as described above, from 40 to 99 percent, more preferably from 50 to 94.9 percent, even more preferably from 65 to 92.5 percent and most preferably from 70 to 89 percent of a diluent further described above, and from 0 to 40 percent, more preferably from 0.1 to 40 percent, even more preferably from 0.5 to 25 percent, and most preferably from 1 to 15 percent of an active ingredient , based on the total weight of the composition. The low viscosity of the esterified cellulose ether, measured as a 10% solution in acetone at 20oC, allows the incorporation of a high concentration of the esterified cellulose ether, i.e., a high ratio of esterified cellulose ether to the liquid diluent, while still providing a fairly low viscosity liquid composition. This can be used in two ways to produce solid dispersions of an active ingredient in an esterified cellulose ether: 1. Or the ratio of esterified cellulose ether / active ingredient is maintained as in more diluted, known compositions. In this case, a higher concentration of the esterified cellulose ether will also lead to a higher concentration of the active ingredient in the liquid composition, and, consequently, a higher transfer of the active ingredient in the production of solid dispersions while maintaining the same stability of the ingredient. active. 2. Alternatively, only the concentration of the esterified cellulose ether in the liquid composition is increased, but not the concentration of the active ingredient. This leads to a higher ratio of esterified cellulose ether / active ingredient, which leads to improved stabilization of the active ingredient in the esterified cellulose ether matrix by removing the liquid diluent without reducing the transfer of the active ingredient. This means that formulators will be able to operate with a higher content of esterified cellulose ether in the liquid formulation - without the need to reduce the content of the active ingredient in the solid dosage form. The esterified cellulose ethers of the present invention allow for a high loading of the active ingredient in the liquid composition while maintaining a reasonably high transfer in the preparation of a solid composition. The production of semi-ordered instead of amorphous dispersions to achieve a higher transfer of active ingredient as proposed in WO2004 / 014342, page 13, last paragraph, is not necessary.
[00058] In one aspect of the invention, the composition comprising at least one esterified cellulose ether as described above, one or more active ingredients and optionally one or more adjuvants may be used in liquid form, for example, in the form of a suspension, a paste, a sprinkling composition, or a syrup. The liquid composition is useful, for example, for oral, ocular, topical, rectal or nasal applications. The liquid diluent should generally be pharmaceutically acceptable, such as ethanol or glycerol, optionally mixed with water as described above. The low viscosity of cellulose ether esterified in acetone or other organic solvent improves the handling of the liquid composition, as does its ability to be dumped or pumped.
[00059] In another aspect of the invention, the liquid composition of the present invention is used to produce a solid dispersion comprising at least one active ingredient, such as a drug described above, at least one esterified cellulose ether as described above and optionally one or more adjuvants. The solid dispersion is produced by removing the liquid diluent from the composition.
[00060] The esterified cellulose ether of low viscosity in acetone or other organic solvent allows the incorporation of a high concentration of the esterified cellulose ether, and consequently a high concentration of a drug, to the composition while still maintaining a reasonably low viscosity of the liquid composition. This is highly advantageous for achieving high transfer when the liquid composition is used for coating purposes or when the composition comprising the esterified cellulose ether is spray dried, for example, to prepare solid dispersions comprising an active ingredient and an ether of esterified cellulose. In addition, liquid formulations using a high ratio of esterified cellulose ether to active ingredient, as described above, can be formulated with spray drying. A high ratio of esterified cellulose ether to active ingredient is desired to maintain supersaturation of poorly soluble ingredients and to increase their bioavailability.
[00061] A method for removing the liquid diluent from the liquid composition is by fusing the liquid composition to a film or capsule or applying the liquid composition to a solid carrier which in turn may comprise an active ingredient. The use of the liquid composition of the present invention for coating purposes is a preferred aspect of the present invention.
[00062] A preferred method for producing a solid dispersion is by spray drying. The term "spray drying" refers to processes involving breaking such liquid mixtures into small droplets (atomization) and quickly removing the solvent from the mixture in the spray drying apparatus where there is a great drag force for solvent evaporation of the droplets. Spray drying processes and spray drying equipment are generally described in Perry's Chemical Engineers'Handbook, pages 20-54 to 20-57 (Sixth Edition 1984). More details regarding spray drying are reviewed by Marshall, “Atomization and Spray-Drying Handbook ”, 50 Chem. Eng. Prog.Monogr.Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition 1985). A useful spray drying process is described in the international patent application WO 2005/115330, page 34, line 7 - page 35, line 25. Alternatively, the solid dispersion of the present invention may be prepared i) by mixing 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 mixture is extruded. The term "extrusion", as used here, includes processes known as injection molding, melt casting and compression molding. Techniques for extruding, preferably extruded melt compositions comprising an active ingredient are known and described by Joerg Breitenbach, Melt extrusion: from process to drug delivery technology, European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107-117 or in the European patent application EP 0 872 233. The solid dispersion of the present invention preferably comprises 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 a) as described above, and 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 solid dispersion. The remaining amount, if any, consists of one or more adjuvants c) as described below. The solid dispersion may comprise one or more of the esterified cellulose ethers a), one or more of the active ingredients b), and optionally one or more of the adjuvants c), however their total amount is generally in the ranges mentioned above.
[00063] Once the solid dispersion comprising at least one active ingredient and at least one esterified cellulose ether having been formed, several processing operations can be used to facilitate incorporation of the dispersion into a dosage form. These processing operations include drying, granulating, and grinding. The inclusion of optional adjuvants in the solid dispersion may be useful for formulating the composition as dosage forms. The solid dispersion of the present invention can be in various forms, such as in the form of filaments, pellets, granules, pills, tablets, capsules, microparticles, capsule fillers or injection molded capsules, or in the form of a powder, film, cream , suspension or paste.
[00064] The amount of the active ingredient in the dosage form is generally at least 0.1 percent, preferably at least 1 percent, more preferably at least 3 percent, most preferably at least 5 percent and generally up to 70 percent, preferably up to 50 percent, more preferably up to 30 percent, most preferably up to 25 percent, based on the total weight of the dosage form.
[00065] In another aspect of the invention, the composition of the present invention comprising a liquid diluent and one or more of the esterified cellulose ethers described above can be used to coat dosage forms, such as tablets, granules, pellets, capsules, lozenges , suppositories, pessaries or implantable dosage forms, to form a coated composition. If the composition of the present invention comprises an active ingredient, such as a drug, a drug layer formation may be obtained, i.e., the dosage form and the coating may comprise different active ingredients for different end uses and / or have different release kinetics.
[00066] In yet another aspect of the invention, the composition of the present invention comprising a liquid diluent and one or more of the esterified cellulose ethers described above may be used for the manufacture of capsules in a process comprising the step of contacting the liquid composition with immersion pins.
[00067] The liquid composition and solid dispersion of the present invention may additionally comprise optional additives, such as coloring agents, pigments, opacifiers, taste and flavor enhancers, antioxidants, and any combination thereof. Optional additives are preferably pharmaceutically acceptable. Useful amounts and types of one or more optional adjuvants are generally known in the art and depend on the intended end use for the liquid composition or solid dispersion of the present invention.
[00068] Some embodiments of the invention will now be described in detail in the following examples. Examples
[00069] Unless otherwise mentioned, all parts and percentages are by weight. In the examples, the following test procedures are used. Viscosity of Hydroxypropyl Methyl Cellulose (HPMC) Samples
[00070] The viscosity of the HPMC samples was measured as a 2.0 wt% solution in water at 20oC + 0.1oC. The 2.0% by weight HPMC solution in water was prepared according to A United States Pharmacopeia (SP 35, “Hypromellose”, pages 3467-3469), followed by an Ubbelohde viscosity measurement according to DIN 51562-1 : 1999-01 (January 1999). Viscosity of Hydroxypropyl Methyl Cellulose Acetate Succinate (HPMCAS)
[00071] The 2.0% by weight solution of HPMCAS in 0.43% w / w aqueous NaOH was prepared as described in "Hypromellose Acetate Succinate", United States Pharmacopeia and National Formulary, NF 29, pgs. 1548-1550 ”, followed by an Ubbelohde viscosity measurement according to DIN 51562-1: 1999-01 (January 1999). The 10% w / w solution of the cellulose ether esterified in acetone was prepared first by determining the loss on drying of the HPMCAS according to "Hypromellose Acetate Succinate", United States Pharmacopeia and National Formulary, NF 29, pgs. 1548-1550 ”. Subsequently, 10.00 g of HPMCAS, based on dry weight, were mixed with 100 g of acetone under vigorous stirring at room temperature. The mixture was rolled in a roller mixer for about 24 hours. The solution was centrifuged at 2000 rpm for 3 minutes using a Megafuge 1.0 centrifuge, commercially available from Heraeus Holding GmbH, Germany, followed by an Ubbelohde viscosity measurement at 20oC according to DIN 51562-1: 1999-01 (January 1999) . HPMCAS Ether and Ester Groups Content
[00072] The content of ether groups in the esterified cellulose ether was determined in the same manner as described for "Hypromellose", United States Pharmacopeia and National Formulary, USP 35, pp. 3467-3469.
[00073] Ester substitution with acetyl groups (-CO-CH3) and ester substitution with succinyl groups (-CO-CH2-CH2-COOH) was determined according to Hypromellose Acetate Succinate, United States Pharmacopeia and National Formulary, NF 29, pgs. 1548-1550. The reported values for ester substitution have been corrected for volatiles (determined as described in the section “loss on drying” in the HPMCAS monograph above). Determination of Mw, Mn and Mz of HPMCAS
[00074] Mw, Mn and Mz were measured according to the Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 743 unless otherwise noted. The mobile phase was a mixture of 40 parts by volume of acetonitrile and 60 parts by volume of aqueous buffer containing 50 mM NaH2PO4 and 0.1 M NaNO3. The mobile phase was adjusted to a pH of 8.0. Solutions of the cellulose ether esters were filtered into an HPLC flask through a 0.45 µm pore size syringe filter.
[00075] More specifically, the chemicals and solvents used were:
[00076] Standard polyethylene oxide materials (abbreviated PEOX 20 K and PEOX 30 K) were purchased from Agilent Technologies, Inc., Palo Alto, CA, catalog numbers PL2083-1005 and PL2083-2005.
[00077] Acetonitrile (HPLC grade, CHROMASOLV Plus) catalog number 34998, sodium hydroxide (semiconductor grade, 99.99%, trace metal base), catalog number 306576, water (HPLC grade, CHROMASOL V Plus), number catalog number 34877 and sodium nitrate (99.995%, trace metal base) catalog number 229938 was purchased from Sigma-Aldrich, Switzerland.
[00078] Sodium dihydrogen phosphate (> 99.999% TraceSelect) catalog number 71492 was purchased from FLUKA, Switzerland.
[00079] The PEOX20 K standard solution at 5 mg / mL, the standard PEOX30 K solution at 2 mg / mL, and the HPMCAS sample solution at 2 mg / mL were prepared by adding a heavy amount of polymer to a flask and dissolving it with a measured volume of mobile phase. All solutions were allowed to dissolve at room temperature in the capped flask for 24 h with stirring using a PTFE coated magnetic bar.
[00080] The standardization solution (PEOX 20K, single preparation, N) and the standard solution (PEOX30 K, double preparation, S1 and S2) were filtered into an HPLC vial through a pore size syringe filter. 0.02 | Jm and 25 mm in diameter (Whatman Anatop 25, catalog number 6809-2002), Whatman.
[00081] The test sample solution (HPMCAS, prepared in duplicate, T1 and T2) and the laboratory standard (HPMCAS, single preparation, LS) were filtered into an HPLC vial through a syringe-sized filter 0.45 µm pore (Nylon, eg Acrodisc 13 mm VWR catalog number 514-4010).
[00082] The chromatographic condition and the starting sequence were conducted as described by Chen, R. et al .; Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 743-748. The SEC-MALLS instrumental arrangement included an HP1100 HPLC system from Agilent Technologies, Inc. Palo Alto, CA; a DAWN Heleos II 18-angled laser light scattering detector and an OPTILAB rex refractive index detector, both from Wyatt Technologies, Inc. Santa Barbara, CA. The analytical size exclusion column (TSK-GEL® GMPWXL, 300 x 7.8 mm) was purchased from Tosoh Bioscience. Both OPTILAB and DAWN were operated at 35oC. The analytical SEC column was operated at room temperature (24 + 5oC). The mobile phase was a mixture of 40 parts by volume of acetonitrile and 60 parts by volume of aqueous buffer containing 50 mM NaH2PO4 and 0.1 M NaNO3 prepared as follows:
[00083] Aqueous buffer: 7.20 g of sodium dihydrogen phosphate and 10.2 g of sodium nitrate were added to 1.2 L of purified water in a clean 2 L glass bottle under stirring until dissolved.
[00084] Mobile phase: 800 ml of acetonitrile were added to 1.2 L of the aqueous buffer prepared above, and stirred until a good mixture was obtained and the temperature balanced with room temperature.
[00085] The pH of the mobile phase was adjusted to 8.0 with 10 M NaOH and this was filtered through a 0.2 m nylon membrane filter. The flow rate was 0.5 ml / min with in-line degassing. The injection volume was 100 µL and the analysis time was 35 min.
[00086] MALLS data was collected and processed by ASTRA software (version 5.3.4.20) using a dn / dc (incremental refractive index) value of 0.120 mL / g for HPMCAS. The light scattering signals from the detectors 1-4, 17, and 18 were not used in the molecular weight calculation. A sequence of representative chromatographic matches is given below: B, N, LS, S1 (5x), S2, T1 (2x), T2 (2x), T3 (2x), T4 (2x), T5 (2x), etc. , S2, LS, W, where B represents the white injection of the mobile phase, N1 represents the normalization solution; LS represents an HPMCAS laboratory standard; S1 and S2 represent standard solutions one and two, respectively; T1, T2, T3, T4, and T5 represent the test sample solutions and W represents the water injection. (2x) and (5x) denotes the number of injections of the same solution.
[00087] Both OPTILAB and DAWN were periodically calibrated according to the procedures and frequencies recommended by the manufacturers. An injection of 100 L L of a 5 mg / mL polyethylene oxide standard (PEOX20 K) was used to normalize all angular light detectors relative to the 90 ° detector for each sequence of starts.
[00088] The use of this mono-dispersed polymer pattern also enabled the volumetric delay between OPTILAB and DAWN to be determined, allowing for an adequate alignment of the light scattering signals with the refractive index signal. This is necessary for calculating the average molecular weight (Mw) of each data slice. Production of Hydroxypropyl Methyl Cellulose Succinate (HPMCAS) of Examples 1-16 and Comparative Examples A to C
[00089] Glacial acetic acid, acetic anhydride, a hydroxypropyl methylcellulose (HPMC), succinic anhydride and sodium acetate (free from water) were introduced in the quantities listed in table 1 below in a reaction vessel under meticulous stirring in order to produce a homogeneous reaction mixture. HPMC had a substitution of methoxy and hydroxypropoxy and a viscosity, measured as a 2% solution in water at 20oC, as listed in table 2 below.
[00090] The mixture was heated to 85oC with stirring for 3 or 3.5 hours, as listed in table 1 below, to perform the esterification. x L of water was added to the reactor under agitation in order to precipitate the HPMCAS. The precipitated product was removed from the reactor and washed with y L of water applying a high shear mixture using an Ultra-Turrax S50-G45 agitator operating at 5200 rpm. The washing was carried out in several portions with intermediate filtration steps in order to obtain a very high purity HPMCAS. HPMCAS products should be washed and filtered until their viscosity is substantially constant (10% w / w in acetone). The numbers of water L x and y are listed in table 1 below. After the last filtration step, the product was dried at 50oC overnight. HPMCAS Production of Comparative Example D
[00091] The production of HPMCAS according to comparative example D was carried out as in examples 1-16, except that a higher viscosity HPMC was used, as listed in table 2 below. HPMC is commercially available from The Dow Chemical Company as Methocel E3 LV Premium cellulose ether. HPMCAS Production of Comparative Example E
[00092] The production of HPMCAS according to comparative example E was carried out as in examples 1-16, except that the type of HPMC and the weight ratios of glacial acetic acid, acetic anhydride, HPMC, succinic anhydride and sodium acetate (water free) were used as disclosed in example 2 of European patent application EP 0 219 426 A2. The quantities used are listed in table 1 below.
[00093] The HPMC used in comparative example E had a viscosity of 3.1 mPa-s, measured as a 2% solution in water at 20oC. HPMC contained 9.3% by weight of hydroxypropyl groups and 28.2% by weight of methoxy groups. This HPMC is commercially available from The Dow Chemical Company as Methocel E3 LV Premium cellulose ether.
[00094] The mixture was heated to 85oC with stirring for 3.5 hours to effect esterification. x L of water was added to the reactor under agitation in order to precipitate the HPMCAS. The precipitated product was removed from the reactor and washed with y L of water applying a high shear mixture using an Ultra-Turrax S50-G45 agitator operating at 5200 rpm. The water numbers x and y are listed in table 1 below. The product was isolated by filtration and dried at 55 ° C for 12 h.
[00095] The ester substitutions obtained from% acetyl and% succinyl in comparative example E were substantially different from those disclosed in example 2 of European patent application EP 0 219 426 A2. Hence, the comparative example E was repeated. The ester substitutions obtained from% acetyl and% succinyl in the comparative example E repeated were substantially the same as in the first comparative example E. The results in table 2 show the average of the two matches in comparative example E. HPMCAS production of Comparative Examples F and G
[00096] The production of HPMCAS according to comparative examples F and G was carried out as in examples 1 to 16, except that the weight ratios of glacial acetic acid, acetic anhydride, HPMC, succinic anhydride and sodium acetate (pivre de water) were used as disclosed in international patent application WO 2005/115330, pages 51 and 52, polymers 1 and 3. The product was obtained, separated and washed as described in international patent application WO 2005/115330. The reaction mixture was quenched in 2.4 L of water, precipitating the polymer. An additional 1 L of water was used to complete the precipitation of comparative example F only. The polymer was isolated and washed with 3 x 300 ml of water. The polymer was dissolved in 600 ml of acetone and again precipitated in 2.4 L of water. To complete the precipitation, another 1 L of water was added. Comparative Examples H to J
[00097] As disclosed in international patent application WO 2011/159626 on pages 1 and 2, HPMCAS is commercially available from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan), known by the trade name "AQOAT". Shin-Etsu manufactures three grades of AQOAT polymers that have different combinations of substitution levels to provide enteric protection at various pH levels, AS-L, ASM, and AS-H, typically followed by the designation “F” for fine or “ G ”, such as AS-LF or AS-LG. Their sales specifications are listed below. Samples of commercially available materials were analyzed as described below.

[00098] Samples of commercially available materials were analyzed as described further below. Comparative Examples K, L-1, L-2, M-1 and M-2
[00099] HPMCAS samples were produced as described on pages 34 and 35 of WO 2011/159626. In comparative example K, the recipe for HPMCAS-K (1) in WO 2011/159626 was exactly repeated. In comparative examples L-1 and L-2, the recipe for HPMCAS-K (2) and in comparative examples M-1 and M2 the recipe for HPMCAS-K (3) in WO 2011/159626 were exactly repeated. Comparative examples L and M were each repeated twice as reported as L-1, L-2, M-1 and M-2, respectively, since the results in examples L-1 and M-1 for DOSAc and DOSS deviated from the results in WO 2011/159626 to HPMCAS-K (2) and HPMCAS-K (3).
[000100] The properties of HPMCAS produced according to examples 1-16 and comparative examples AF, K, L-1, L-2, M1 and M-2 and the properties of comparative examples H to J commercially available are listed in table 2 below. In table 2 below, the abbreviations have the following meanings: DSM = DS (methoxy); degree of substitution with methoxy groups; MSHP = MS (hydroxypropyl); degree of substitution with hydroxypropyl groups; DOSAc: degree of substitution of acetyl groups; DOSS: degree of substitution of succinyl groups. Table1
Table2

[000101] The comparison between example 5 and comparative example A, the comparison between example 6 and comparative example B, and the comparison between example 7 and comparative example C illustrate that the use of cellulose ether that has a viscosity of less than 2.33 mPa-s, measured as a 2.0% w / w solution in 20 ° C water, does not automatically lead to the cellulose ethers of the present invention. When an aliphatic carboxylic acid is used as a reaction diluent, the viscosity of the esterified cellulose ether, measured as a 10% w / w solution in 20 ° C acetone, can be varied by varying the molar ratio of [aliphatic carboxylic acid / ether anhydroglycosis units cellulose] in the esterification process. In examples 5, 6 and 7 a higher molar ratio of [aliphatic carboxylic acid / cellulose ether anhydroglycosis units] is used than in comparative examples A, B and C, while other parameters are kept constant. Comparative examples A, B and C are not examples of the prior art although they are not within the scope of the present invention.
[000102] The comparison between example 1 and comparative example D illustrates that cellulose ethers having a viscosity of 3 mPa-s, measured as a 2.0% w / w solution in water at 20oC, are not useful for preparing the esterified cellulose ethers of the present invention. The reaction conditions and ratios between the reagents in comparative example D are essentially the same as in example 1, but the esterified cellulose ether produced from comparative example D has a much higher viscosity, measured as a 10% p solution / w in acetone at 20oC, than example 1.
[000103] Examples 8-13 illustrate esterified cellulose ethers that have too low a viscosity, measured as a 10% w / w solution in acetone at 20oC. These esterified cellulose ethers enable very fast transfer in spray drying operations.
[000104] Examples 13, 15 and 16 illustrate how esterified cellulose ethers can be obtained that have an amazing combination of high molecular weights and low viscosities, both measured as a 10% w / w solution in acetone at 20oC and measured as a 2.0% w / w solution of the cellulose ether esterified in 0.43% aqueous NaOH at 20oC.
[000105] The HPMCAS of comparative examples K, L-1, L-2, M-1 and M-2 were not or were only partially soluble in acetone at a concentration of 10% w / w. In the comparative examples L-1 and L-2 the recovery rate in the HPLC method used was too low to make a reasonably reliable determination of Mw, Mn and Mz. The recovery rate = [HPMCAS weight recovered from the HPLC column / HPMCAS weight introduced into the HPLC column] x 100. Impact of cellulose ethers on the aqueous solubility of a poorly soluble drug
[000106] The ability of the esterified cellulose ethers of examples 4 to 7 and 10 and of comparative examples A-C and H-I to maintain concentrations of drugs in an aqueous solution at supersaturation levels were tested with the poorly soluble drugs Griseofulvin and Phenytoin.
[000107] Griseofulvin has a water solubility of 8.54 mg / L, a logP of 2.2, a Tm of 220oC, a Tg of 85oC, and, consequently, a Tm / Tg = 493oK / 358oK = 1, 39. [Feng, Tao, et al .: J. Pharm. Sci .; Vol. 97, no 8, 2008, pgs. 3207-3221 and W. Curatolo, Pharmaceutical Research, Vol. 26, no 6, June 2009, page 1422]. Griseofulvin belongs to group 2 in the Tm / Tg to log P ratio map (fig. 14 on page 1018 in MOLECULAR PHARMACEUTICS, Vol. 5, no. 6).
[000108] Phenytoin has a solubility in water of 32 mg / L, a logP of 2.47, a Tm of 295oC, a Tg of 71oC, and, consequently, a Tm / Tg = 568oK / 344oK = 1.65. (Friesen et al., MOLECULAR PHARMACEUTICS, Vol. 5, no 6,1003-1019 and W. Curatolo, Pharmaceutical Research, Vol. 26, no 6, June 2009, page 1422]. Phenytoin belongs to group 3 on the map ratio of Tm / Tg against log P (fig. 14 on page 1018 in MOLECULAR PHARMACEUTICS, Vol. 5, no. 6, 2008).
[000109] Solutions of an esterified cellulose ether listed in Table 3 below (950 Ll L, 3.16 mg / mL) in phosphate buffered saline (82 mM sodium chloride, 20 mM dibasic sodium phosphate, potassium phosphate 47 mM monobasic, 0.5% w / w simulated intestinal fluid powder, pH 6.5) at 37oC were robotically released into designated 1 mL flasks arranged in an aluminum well block (8 x 12) heated to 37oC using a Tecan 150 liquid handler. Organic drug solutions at 37oC were released over the phosphate buffered saline aqueous solution comprising an esterified cellulose ether listed in table 3 below. The organic drug solution was a) 20 g / L of griseofulvin in dimethylformamide, 50 µL, maximum final drug concentration of 1000 mg / L, or b) 20 g / L of phenytoin in dimethylformamide, 50 µL, concentration of maximum final drug of 1000 mg / L. The robot aspirated and released liquid in an adjusted sequence for each flask for about 30 s to mix. After 180 minutes, the vials were centrifuged 1 min at about 3200 xg (g = gravitational force from the earth), an aliquot (30 LIL) was transferred to methanol (150 Ll L) in a 96 well, sealed, slightly agitated plate gently to mix, and then the drug concentration was analyzed by HPLC.
[000110] In the control match, an experiment was separately conducted as described above with an aqueous phosphate buffered saline solution that did not contain any amount of cellulose ether.
[000111] Table 3 below lists the concentrations (averages of four experimental replicates) of griseofulvin and phenytoin that did not precipitate in the centrifugation after 180 minutes, but remained dissolved in the phosphate buffered saline. Concentration error margins are around 10%.
[000112] The results in Table 3 below illustrate that the cellulose ethers of the present invention are capable of maintaining the concentration of poorly water-soluble drugs in an aqueous solution at supersaturation levels. When comparing groups of esterified cellulose ethers from the examples and comparative examples having comparable levels of acetyl and succinyl substitution, the data in Table 3 illustrates that the esterified cellulose ethers of the present invention have essentially the same ability to maintain drugs at supersaturation levels that comparable esterified cellulose ethers, even when the esterified cellulose ethers of the present invention have a significantly lower viscosity, measured as a 10% w / w solution in acetone, and a significantly lower average molecular weight. This discovery is highly surprising and illustrates the great advantages of the esterified cellulose ethers of the present invention as excipients for active ingredients of low water solubility. The esterified cellulose ethers of the present invention combine easy processability in solutions, particularly in organic solutions, and high ability to maintain the concentration of poorly water-soluble drugs in an aqueous solution at supersaturation levels.
[000113] The HPMCAS of example 5 has essentially the same ability to maintain drugs in supersaturation and similar substitutions of acetyl and succinyl that the HPMCAS of comparative examples A and J, although the HPMCAS of example 5 has a very average weight molecular weight lower and much lower viscosity, measured as a 10% w / w acetone solution. The same observation can be made when comparing example 6 with comparative examples B and I. The HPMCAS in example 6 has the same or even greater ability to maintain drugs in supersaturation. A similar observation can be made when comparing examples 4 and 10 with comparative example C. The HPMCAS in examples 4 and 10 have slightly less ability to maintain griseofulvin at levels of supersaturation, but the HPMCAS in comparative example C does not dissolve the 10% w / w acetone. The HPMCAS in example 7 has essentially the same ability to maintain drugs in supersaturation as the HPMCAS in comparative example H, although the HPMCAS in example 7 has a much lower average molecular weight and a much lower viscosity, measured as a 10% solution in acetone, than the HPMCAS of the comparative example H.Tabela3

权利要求:
Claims (13)
[0001]
1. Hydroxypropyl methylcellulose succinate acetate (HPMCAS), characterized by the fact that it has a viscosity of up to 2.33 mPa-s, measured as a 2.0% w / w solution of the cellulose ether esterified in 0% aqueous NaOH , 43% w / w at 20oC, and have a viscosity of up to 10 mPa ^ s, measured as a 10% w / w solution of HPMCAS in acetone at 20oC.
[0002]
2. Hydroxypropyl methylcellulose succinate acetate according to claim 1, characterized by the fact that it has a viscosity of 1.20 to 1.80 mPa ^ s, measured as a 2.0% w / w solution of HPMCAS in NaOH 0.43% aqueous at 20oC.
[0003]
Hydroxypropyl methylcellulose succinate acetate, according to either of claims 1 or 2, characterized in that it has a viscosity of up to 8 mPa ^ s, measured as a 10% w / w solution of HPMCAS in acetone at 20oC.
[0004]
4. Hydroxypropyl methylcellulose succinate, according to claim 3, characterized by the fact that it has a viscosity of up to 3 mPa-s, measured as a 10% w / w solution of HPMCAS in acetone at 20oC.
[0005]
5. Hydroxypropyl methylcellulose succinate acetate according to any one of claims 1 to 4, characterized by the fact that it has an average molecular weight Mw of 90,000 to 350,000 Dalton.
[0006]
6. Hydroxypropyl methylcellulose succinate acetate according to any one of claims 1 to 4, characterized by the fact that it has an average molecular weight Mw of 10,000 to 90,000 Dalton.
[0007]
7. Composition, characterized by the fact that it comprises a liquid diluent and at least one HPMCAS, as defined in any one of claims 1 to 6.
[0008]
Composition according to claim 7, characterized in that it additionally comprises at least one active ingredient and optionally one or more adjuvants.
[0009]
Composition according to either of claims 7 or 8, characterized in that it comprises from 10 to 25 percent of at least one HPMCAS, from 70 to 89 percent of a liquid diluent, and from 1 to 15 percent of an active ingredient, based on the total weight of the composition.
[0010]
10. Solid dispersion, characterized by the fact that it comprises at least one active ingredient and at least one HPMCAS, as defined in any of claims 1 to 6.
[0011]
11. Solid dispersion according to claim 10, characterized in that it has been formulated as tablets, pills, granules, pellets, capsules, microparticles, capsule fillers, or as an ointment, cream, suspension or paste.
[0012]
12. Dosage form, characterized by the fact that it is coated with at least one HPMCAS, as defined in any one of claims 1 to 6.
[0013]
13. Capsule wrap, characterized by the fact that it comprises at least one HPMCAS, as defined in any one of claims 1 to 6.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

2019-05-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

2020-04-28| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

2020-09-08| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

2020-12-08| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 28/02/2014, OBSERVADAS AS CONDICOES LEGAIS. |

2021-12-21| B21F| Lapse acc. art. 78, item iv - on non-payment of the annual fees in time|Free format text: REFERENTE A 8A ANUIDADE. |

优先权:

申请号 | 申请日 | 专利标题

US201361774158P| true| 2013-03-07|2013-03-07|

US61/774,158|2013-03-07|

PCT/US2014/019257|WO2014137777A1|2013-03-07|2014-02-28|Novel esterified cellulose ethers of low viscosity|

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