Compositions Comprising Highly Substituted Hydroxypropyl Methylcellulose and Sugar Alcohols

Abstract

The composition comprises a mixture of hydroxypropyl methylcellulose having a DS of 1.0 to 2.7 and an MS of 0.40 to 1.30, where the sum of the DS and MS is 1.8 to 3.6, where DS is the degree of substitution of methoxyl groups and MS is the molar substitution of hydroxypropoxyl groups, with a sugar alcohol in a weight ratio of hydroxypropyl methylcellulose to sugar alcohol of 98:2 to 85:15. The composition can be used, for example, to purge extrusion equipment.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a composition comprising highly substituted hydroxypropyl methylcellulose and a sugar alcohol, a process for reducing the adhesive properties of highly substituted hydroxypropyl methylcellulose during hot melt extrusion, and a process for purging extrusion equipment of contaminant material that has adhered to the interior surfaces of the equipment using the composition. [Background technology]

[0002] Background of the Invention Hydroxypropyl methylcellulose is a cellulose ether frequently used to prepare pharmaceutical formulations, such as amorphous solid dispersions of poorly soluble drugs. G. Van den Mooter, “The Use of Amorphous Solid Dispersions: A Formulation Strategy to Overcome Poor Solubility and Dissolution Rate,” Drug Discovery Today: Technology (2011), doi:10.1016 / j.ddtec.2011.10.002, discusses the preparation of amorphous solid dispersions to improve the rate and extent of dissolution of poorly soluble drugs and thereby increase their bioavailability. The two most commonly applied manufacturing methods for preparing amorphous solid dispersions appear to be spray drying and hot melt extrusion. In the most common setup for hot melt extrusion, a powder blend is introduced via a feeder into a heated barrel equipped with a rotating screw, where it is heated and vigorously mixed in a softened or partially or completely molten state, and then moved toward a die that forms the melt into strands, films, pellets, tablets, or capsules. The amount of heat and shear applied, as well as the rate at which the extrudate cools as it exits the die, contribute to the physical structure of the solid dispersion. Amorphous solid dispersions are produced when the drug is present in a substantially amorphous, non-crystalline state.

[0003] European Patent Application EP 0 872 233 discloses a solid dispersion comprising (a) loviride and (b) one or more pharmaceutically acceptable water-soluble polymers. Among the various water-soluble polymers described, hydroxypropyl methylcellulose (HPMC), particularly HPMC 2910, which has about 29 weight percent methoxyl groups and about 10 weight percent hydroxypropoxyl groups, is said to be preferred.

[0004] When polymeric materials undergo extrusion, particularly hot-melt extrusion, they soften into a flowable mass and are conveyed through the extruder barrel by the screw. Some of the extruded material tends to remain in the extrusion equipment as contaminants, which can adhere to the internal surfaces or within the voids (e.g., screw flights) of the extrusion equipment. To avoid the incorporation of contaminants into the new polymer, which can contaminate subsequent batches and result in poor appearance and / or properties, cleaning of the equipment is required before a new batch of polymeric material is processed in the extruder. One way to address this problem is to disassemble the equipment and remove the contaminant materials from its components by physical means, such as brushing, or by applying a liquid cleaning solution, or both. Such procedures are very time-consuming, and recent efforts have been made to develop purge compositions that can be processed through the extruder to remove contaminants without requiring disassembly of the equipment or making disassembly easier by reducing the risk of exposure.

[0005] Prior to this invention, formulators typically used some form of purging method, but relied on the neat polymer that was the base of their formulation, which could be very sticky and / or difficult to process. Other products exist for pharmaceutical manufacturing, but these have limited usable operating ranges or settings. For example, HME Cleaner Plus (GMP) from Biogrund contains HPMC, MC, propylene glycol, and colloidal silica; the product brochure states that it is effective between 160 and 200°C. Below this range, it becomes sticky and above it degrades destructively.

[0006] U.S. Patent Application Publication No. 2014 / 0142018 discloses a purge composition for cleaning extruders and injection molding machines, comprising a cellulose ether and a solvent, which is a polyhydric alcohol such as a glycol, or its ether or ester, or an ethanolamine. The purge composition is prepared by heating and melting the cellulose ether in the solvent and cooling the solution until solidified. The cellulose ether can be, for example, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, or hydroxypropyl methylcellulose acetate succinate. Purging is carried out at a temperature above the melting temperature of the contaminant.

[0007] WO 2011 / 056459 discloses a method for cleaning the interior of polymer processing equipment, where contaminant materials have adhered to the interior of the processing equipment. The purge composition used to clean the processing equipment includes starch, water, and a polyol plasticizer. As the purge composition is conveyed through the processing equipment, it removes residual polymer and contaminants adhered to the interior surfaces.

[0008] WO 2014 / 014752 discloses a solid dispersion containing a highly substituted grade of hydroxypropyl methylcellulose, which has been found to have beneficial properties for preparing solid dispersions by hot-melt extrusion. However, when the highly substituted grade of hydroxypropyl methylcellulose is processed (mixed, kneaded, or extruded) in a "plastic" state above its glass transition temperature (Tg), such as by hot-melt extrusion, the plastic mass exhibits high stickiness and adhesiveness. The increased adhesiveness of the plastic mass has the disadvantage of requiring significant efforts to clean processing equipment such as extruders or mixers. Summary of the Invention [Problem to be solved by the invention]

[0009] Summary of the Invention It is an object of the present invention to provide compositions comprising highly substituted hydroxypropyl methylcellulose that are significantly less sticky and tacky during hot melt extrusion than pure hydroxypropyl methylcellulose and are therefore useful for preparing solid dosage forms with reduced loss of extruded mass due to adhesion of the composition to extrusion equipment and tableting means.

[0010] It is a further object of the present invention to provide a composition that can be used to purge extrusion equipment of contaminants that have adhered to the interior of the equipment, which has the advantages of a significantly wider thermal processing window without significant stickiness or destructive degradation, the ability to purge a wider variety of formulations (due to higher melt viscosity), and GMP for use in manufacturing environments that are free of chemical scrubbing agents (i.e., environmentally friendly). [Means for solving the problem]

[0011] Surprisingly, it has been found that both objectives can be achieved by adding a specific amount of sugar alcohol to the highly substituted hydroxypropyl methylcellulose prior to extrusion.

[0012] Thus, in one aspect, the present invention relates to a composition comprising a mixture of hydroxypropyl methylcellulose having a DS of 1.0 to 2.7 and an MS of 0.40 to 1.30, where the sum of the DS and MS is 1.8 to 3.6, DS is the degree of substitution of methoxyl groups, and MS is the molar substitution of hydroxypropoxyl groups, with a sugar alcohol, in a weight ratio of hydroxypropyl methylcellulose to sugar alcohol of 98:2 to 85:15.

[0013] In another aspect, the present invention relates to a process for producing said composition, comprising blending hydroxypropyl methylcellulose in dry particulate form with an aqueous solution of a sugar alcohol, and drying the resulting wet blend to a moisture content of less than 8% by weight.

[0014] In yet another aspect, the present invention relates to a process for reducing the stickiness of highly substituted hydroxypropyl methylcellulose during hot melt extrusion, the process comprising: a) blending hydroxypropyl methylcellulose having a DS of 1.0 to 2.7 and an MS of 0.40 to 1.30, wherein the sum of the DS and MS is 1.8 to 3.6, where DS is the degree of substitution of methoxyl groups and MS is the molar substitution of hydroxypropoxyl groups, with a sugar alcohol and optionally an active ingredient in a weight ratio of hydroxypropyl methylcellulose to sugar alcohol of 98:2 to 85:15; b) optionally compounding the blend of step a) at a temperature between 95°C and 230°C; c) extruding the blend of step b) at a temperature between 95°C and 230°C; d) recovering the extruded mass from the extruder; Includes:

[0015] In a further aspect, the present invention relates to a process for purging contaminant material adhering to the interior surfaces of an extrusion apparatus from said apparatus, the process comprising: a) filling an extrusion device with a purge composition comprising a mixture of hydroxypropyl methylcellulose having a DS of 1.0 to 2.7 and an MS of 0.40 to 1.30, the sum of the DS and MS being 1.8 to 3.6, DS being the degree of substitution of methoxyl groups, and MS being the molar substitution of hydroxypropoxyl groups, and a sugar alcohol, in a weight ratio of hydroxypropyl methylcellulose to sugar alcohol of 98:2 to 85:15; b) conveying the purge composition through an extrusion device; c) removing the purge composition from the extrusion apparatus, thereby removing substantially all of the contaminant material adhered to the interior surfaces of the extrusion apparatus; Includes:

[0016] In yet a further aspect, the present invention relates to the use of a composition comprising a mixture of hydroxypropyl methylcellulose having a DS of 1.0 to 2.7 and an MS of 0.40 to 1.30, wherein the sum of the DS and MS is 1.8 to 3.2, where DS is the degree of substitution of methoxyl groups and MS is the molar substitution of hydroxypropoxyl groups, and a sugar alcohol in a weight ratio of hydroxypropyl methylcellulose to sugar alcohol of 98:2 to 85:15, for purging contaminant material adhering to the interior surfaces of extrusion equipment from said equipment. [Brief explanation of the drawings]

[0017] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] 1 is a photograph showing the screw of a Leistriz Nano 16 hot melt extruder after extruding HS HPMC without purging. [Figure 2] 1 is a photograph showing the screw of a Leistriz Nano 16 hot melt extruder after purging with a 95:5 ratio of HS HPMC and xylitol. [Figure 3] 1 is a photograph showing the screw of a Leistriz Nano 16 hot melt extruder after purging with a 90:10 ratio of HS HPMC and xylitol. [Figure 4] 1 is a photograph showing the screw of a Leistriz Nano 16 hot melt extruder after extruding copovidone and purging with a 90:10 ratio of HS HPMC and PEG4000. [Figure 5] 1 is a photograph showing the screw of a Leistriz Nano 16 hot melt extruder after extruding copovidone and purging with a 90:10 ratio of HS HPMC and xylitol. [Figure 6] 1 is a photograph showing the screw of a Leistriz Nano 16 hot melt extruder after extruding copovidone and purging with a 90:10 ratio of HS HPMC and sorbitol. [Figure 7]1 is a photograph showing the screw of a Leistriz Nano 16 hot melt extruder after extruding a 90:10 ratio of HPMC2910 and xylitol. [Figure 8] 1 is an image of the melting peak of xylitol obtained by differential scanning calorimetry of a dry blend of HS HPMC and xylitol in a 9:1 ratio. [Figure 9] 1 is an image of the melting peak of xylitol obtained by differential scanning calorimetry of a wet blend of HS HPMC and xylitol in a 9:1 ratio prepared in a ring layer mixer. [Figure 10] 1 is a graph showing the results of thermogravimetric analysis of weight loss for samples of xylitol only, HS HMPC only, and a composition of the present invention prepared in an annular layer mixer with different concentrations of xylitol in an aqueous xylitol solution. DETAILED DESCRIPTION OF THE INVENTION

[0018] Detailed Description of the Invention The compositions of the present invention comprise hydroxypropyl methylcellulose, which has a cellulose backbone with β-1,4 glycosidically linked D-glucopyranose repeating units, referred to in the context of the present invention as anhydroglucose units, and which, in the case of unsubstituted cellulose, has the formula [ka] The anhydroglucose unit is represented by the formula: ##STR1## which describes the numbering of the carbon atoms in the anhydroglucose unit. The numbering of the carbon atoms in the anhydroglucose unit is referenced to indicate the position of the substituents covalently bonded to each carbon atom. At least a portion of the hydroxyl groups of the cellulose backbone at positions 2, 3, and 6 of the anhydroglucose unit are substituted with a combination of methoxyl and hydroxypropoxyl groups. The hydroxyl groups of the cellulose backbone at positions 2, 3, and 6 of the anhydroglucose unit are not substituted with groups other than methoxyl and hydroxypropoxyl groups.

[0019] The average number of methoxyl groups per anhydroglucose unit is expressed as the degree of substitution of methoxyl groups, DS. In the definition of DS, the term "hydroxyl groups substituted by methoxyl groups" should be interpreted in the present invention to include not only methylated hydroxyl groups directly attached to carbon atoms of the cellulose backbone, but also methylated hydroxyl groups of hydroxypropoxyl substituents attached to the cellulose backbone.

[0020] The degree of substitution of the hydroxyl groups at the 2-, 3-, and 6-positions of anhydroglucose units with hydroxypropoxyl groups is expressed by the molar substitution MS of hydroxypropoxyl groups. MS is the average number of moles of hydroxypropoxyl groups per anhydroglucose unit in hydroxypropyl methylcellulose. It should be understood that during the hydroxypropoxylation reaction, the hydroxyl groups of the hydroxypropoxyl groups attached to the cellulose backbone may be further etherified with a methylating agent and / or a hydroxypropylating agent. Therefore, the term "hydroxypropoxyl group," in the context of MS, should be interpreted as referring to the hydroxypropoxyl group as a constituent unit of a hydroxypropoxyl substituent, containing either a single hydroxypropoxyl group or a side chain in which two or more hydroxypropoxyl units are covalently bonded to each other by ether bonds. In this definition, it is immaterial whether the terminal hydroxyl group of the hydroxypropoxyl substituent is further methylated; for the purpose of determining MS, both methylated and unmethylated hydroxypropoxyl substituents are included.

[0021] The hydroxypropyl methylcellulose utilized in the compositions of the present invention has a DS of 1.0 to 2.7 and an MS of 0.40 to 1.30. Preferably, the hydroxypropyl methylcellulose has a DS of 1.0 to 2.5, more preferably 1.1 to 2.3, and most preferably 1.6 to 2.3. Preferably, the hydroxypropyl methylcellulose has an MS of 0.50 to 1.30, more preferably 0.60 to 1.20. Any preferred range of DS can be combined with any preferred range of MS. Most preferably, the hydroxypropyl methylcellulose has a DS of 1.6 to 2.3 and an MS of 0.60 to 1.30. The sum of the DS and MS is preferably at least 1.8, more preferably at least 1.9, and most preferably at least 2.5, and preferably up to 3.6, more preferably up to 3.40, and most preferably up to 3.2.

[0022] Highly substituted hydroxypropyl methylcellulose has been found to be particularly useful for hot melt extrusion and is hereinafter referred to as "HS HPMC." The HS HPMC utilized in this invention is described in U.S. Pat. No. 4,614,545 and WO 2014 / 014752.

[0023] The degree of substitution of methoxyl groups (DS) and the molar substitution of hydroxypropyl groups (MS) can be determined by Zeisel cleavage of HS HPMC with hydrogen iodide followed by quantitative gas chromatographic analysis (G. Bartelmus and R. Ketterer, Z. Anal. Chem., 286 (1977) 161-190). The determination of methoxyl% and hydroxypropoxyl% is carried out according to the United States Pharmacopoeia (USP 35, "Hypromellose", pages 3467-3469). The values ​​obtained are methoxyl% and hydroxypropoxyl%. These are subsequently converted to the degree of substitution of methyoxyl substituents (DS) and the molar substitution of hydroxypropoxyl substituents (MS). The residual amount of salt is taken into account in the conversion.

[0024] The HS HPMC utilized in the compositions of the present invention can have a wide viscosity range. Typically, it is within the range of 5 to 150,000 mPa·s, measured as a 2 wt. % aqueous solution at 20°C according to USP 35, "Hypromellose," pages 3467-3469. It has been found that the compositions of the present invention can be prepared by extrusion, typically melt extrusion, over a wide viscosity range of HS HPMC. The compositions may also be prepared using HS HPMC with a low viscosity of 1.2 to 500 mPa·s, preferably 1.2 to 200 mPa·s, and especially 2.4 to 120 mPa·s, measured as a 2 wt. % aqueous solution at 20°C. HS HPMC of such a viscosity can be obtained by subjecting higher viscosity HS HPMC to a partial depolymerization process. Partial depolymerization processes are well known in the art and are described, for example, in European Patent Applications EP 1,141,029; EP 210,917; EP 1,423,433; and US Pat. No. 4,316,982.

[0025] The composition of the present invention comprises, as a second component, a sugar alcohol in a weight ratio of HS HPMC to sugar alcohol of 98:2 to 85:15. Preferably, the weight ratio of HS HPMC to sugar alcohol is 95:5 to 90:10. The sugar alcohol may be selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, erythritol, glycerol, arabitol, ribitol, galactitol, fucitol, inositol, and lactitol, and mixtures thereof, but is preferably xylitol or sorbitol, and most preferably xylitol.

[0026] The compositions of the present invention can be used to prepare solid dispersions of one or more active ingredients, most preferably one or more drugs. The term "drug" is conventional and refers to a compound that has beneficial prophylactic and / or therapeutic properties when administered to animals, particularly humans. Preferably, the drug is a poorly soluble drug, meaning that the drug has an aqueous solubility of about 0.5 mg / mL or less at a physiologically relevant pH (e.g., pH 1-8). The present invention finds greater utility as the aqueous solubility of the drug decreases. Thus, the compositions of the present invention are preferred for low-solubility drugs having an aqueous 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 that observed in any physiologically relevant aqueous solution (e.g., having a pH value between 1 and 8), including USP simulated gastrointestinal buffers. Examples of low-solubility drugs are, for example, those disclosed on pages 17-22 of WO 2005 / 115330.

[0027] According to one aspect of the present invention, the compositions of the present invention are prepared by mixing HS HPMC, as defined above, one or more sugar alcohols, and optionally one or more active ingredients, and extruding the mixture. The term "extrusion" as used herein includes processes known as ram extrusion, hot melt extrusion, injection molding, fusion processing, or filament manufacturing. Techniques for extruding compositions containing active ingredients, such as drugs, are known and are described in Joerg Breitenbach, "Melt extrusion: from process to drug delivery technology," European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107-117, or European Patent Application EP 0 872 233. In one embodiment, the HS HPMC, sugar alcohol, and optionally the active ingredient may be mixed in particulate form, preferably in powder form. The HS HPMC, sugar alcohol, and optionally the active ingredient may be premixed before feeding the mixture into a device utilized for extrusion, preferably hot melt extrusion. Devices useful for extrusion, particularly useful extruders, are known in the art. Alternatively, the HS HPMC, sugar alcohol, and optionally the active ingredient may be fed separately into the extruder and blended in the device before or during the heating step.

[0028] Preferably, the HS HPMC, sugar alcohol, and optionally the active ingredient are preblended in a mixer from which they are fed into the extruder. In the context of the present invention, the term "preblended in a mixer" is intended to encompass methods such as melt granulation, co-grinding assisted dry blending, acoustic mixing assisted dry blending, high shear granulation wet blending, wet blending in an annular layer mixer, kneading, and any other method that provides a mixture of the HS HPMC, sugar alcohol, and optionally the active ingredient prior to its extrusion.

[0029] In a currently preferred embodiment, HS HPMC in dry particulate form is blended with an aqueous solution of a sugar alcohol and the resulting wet blend is dried to a moisture content of less than 8% by weight. The aqueous solution of the sugar alcohol is preferably blended with the HS HPMC by spraying the solution onto the HS HPMC in a mixer such as an annular bed mixer or granulator. The wet blend may preferably be dried, for example in a fluidized bed dryer, to a moisture content of less than 5% by weight, or even less than 1% by weight.

[0030] A useful annular layer mixing process for pre-blending HS HPMC, sugar alcohol, and optionally an active ingredient, comprises the following steps: a step in which a sugar alcohol is dissolved in an aqueous liquid; The dried particles of HS HPMC and optionally an active ingredient are conveyed by a screw conveyor at a defined speed into an annular bed mixer; a rapidly rotating agitator moving the HS HPMC particles to the interior surface of a tube within the annular layer mixer to form an annular layer moving from the inlet to the outlet of the annular layer mixer; pumping an aqueous solution of sugar alcohol into an annular bed mixer so that the solution is sprayed evenly onto the HS HPMC particles; A wet blend of HS HPMC, sugar alcohol, and optionally an active ingredient is collected at the outlet of the annular layer mixer; and The wet blend is dried, for example in a fluid bed dryer. may include:

[0031] The pre-blend of HS HPMC, sugar alcohol, and optionally active ingredient(s) in a granulator is carried out by the following steps: a step in which a sugar alcohol is dissolved in an aqueous liquid; The HS HPMC is placed in a mixing bowl of a granulator, such as a high shear wet granulator; the granulator is started so that the internal mixing elements, e.g., horizontal agitators and vertical impellers, begin to agitate and move the powdered HS HPMC; an aqueous solution of sugar alcohol being sprayed at a controlled rate onto the stirred HS HPMC until the amount of sugar alcohol applied reaches the determined w / w% ratio for the desired finished composition; the resulting wet mass is removed from the granulator and, optionally, subjected to wet milling; drying the wet mass by static or fluid drying methods, including but not limited to tray drying, vacuum drying, oven drying, or fluidized bed drying; The dried mass is then optionally subjected to dry milling to the desired final particle size. may include:

[0032] The aqueous liquid in which the sugar alcohol is dissolved can be either water alone or water mixed with a small amount of organic solvent. The aqueous liquid preferably comprises 50 to 100 wt %, more preferably 75 to 100 wt %, of water, based on the total weight of water and organic solvent, and preferably 0 to 50 wt %, more preferably 0 to 25 wt % of organic solvent. Preferred organic solvents are 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. The aqueous liquid preferably contains only water as a solvent.

[0033] The composition or its individual components fed into the extruder are passed through a heated zone of the extruder at a temperature sufficient to melt or soften the composition or at least one or more of its components, forming a homogeneously dispersed mixture. The mixture is then extruded and exits the extruder. Typical extrusion temperatures, as determined by the extruder's heating zone configuration, are 95-230°C, preferably 100-200°C, and more preferably 110-190°C. The operating temperature range should be selected to minimize degradation or alteration of the active ingredient and other components of the composition during processing. Single- or multi-screw extruders, preferably twin-screw extruders, can be used in the extrusion process of the present invention. The molten or softened mixture obtained in the extruder is forced through one or more exit holes, such as one or more nozzles or dies. The molten or softened mixture then exits the die or other such element having one or more holes, at which point the extruded blend (hereafter referred to as the extrudate) begins to harden. Upon exiting the die, the extrudate is still in a softened state and can be easily shaped, molded, chopped, spheronized into beads, cut into strands, tableted, or otherwise processed into a desired physical form. The extrudate can then be cooled and hardened and crushed into a powder form.

[0034] It has surprisingly been found that when sugar alcohol is added to HS HPMC in a weight ratio of 98:2 to 85:15 HS HPMC to sugar alcohol, the adhesiveness of the molten or softened mixture is dramatically reduced, allowing the composition to move from the mixer through the extruder with little or no residue sticking to the walls or tooling of the extrusion equipment, and also reducing the resources required to clean the extrusion equipment. Furthermore, the molten or softened mixture exiting the die can be subjected to processing, such as tableting, without significant sticking to processing tools, such as a tablet press.

[0035] In the process for purging the extrusion apparatus, the purge composition is passed through the extrusion apparatus, removing it along with substantially all contaminant material adhering to the interior surfaces of the apparatus.

[0036] In the context of the present invention, the term "extrusion equipment" should be broadly understood to mean any equipment or part thereof used in some stage of the extrusion process, including, but not limited to, ram extrusion, hot melt extrusion, injection molding, heat fusing, and filament production, and including any part exposed to the polymer or other material being extruded, such as, for example, kneaders, blenders, mixers, screws, and the interior surfaces of the extruder barrel or tube.

[0037] As evidenced in Examples 2-4 below, the purge compositions of the present invention, when subjected to hot melt extrusion, were found to adhere much less to the metal surfaces of the extrusion equipment than the highly substituted HPMC polymer alone.

[0038] The temperature at which the purging is carried out is suitably from 95°C to 230°C, preferably from 100°C to 200°C, for example from 110°C to 190°C.

[0039] The contaminant material removed by purging with the composition of the present invention can be any material remaining in the extrusion equipment after use, such as residual extruded polymeric material, degradation products produced during extrusion, or additives such as pigments, colorants, fillers, etc.

[0040] Unlike some of the purge compositions disclosed in the literature, it has been found that the compositions of the present invention can be prepared without the addition of water or organic solvents, and that the extrusion and / or purge process can be carried out without the addition of water or organic solvents.

[0041] However, it has surprisingly been found that when a purge composition is prepared by blending HS HPMC in dry particulate form with an aqueous solution of a sugar alcohol and then drying the blend, the composition exhibits improved thermal stability, as determined by reduced weight loss at temperatures between 165°C and 200°C, compared to a purge composition prepared from a dry blend of HS HPMC and a sugar alcohol. See Figure 10 and Example 5 below. The increased thermal stability of this composition can be advantageous because it increases the operating range of the composition in an extruder and increases run time. Increased thermal stability may also reduce risks associated with decomposition, such as the formation of unknown impurities and outgassing.

[0042] The present invention is further illustrated in the following examples.

[0043] Materials and Methods Preparation of highly substituted HPMC (HS HPMC) In a reaction vessel equipped with an agitator, temperature control and a vacuum line, 2 kg of ground cellulose is alkalized with 6.3 kg of 50% by weight aqueous sodium hydroxide at about 30°C.

[0044] The vessel is then evacuated, and after evacuating, 4.6 kg of methyl chloride and 1.2 kg of propylene oxide are added. The temperature within the vessel is then increased from 30° C. to 90° C. After 8 hours, the HPMC is washed with water at about 90° C., recovered, and measured to have a median particle size of DIFI as determined by a QIPIC image analysis system as described below. 50 / LEFI 50 / EQPC 50 The mixture was dried to a powder with a molecular weight of 65 / 182 / 113, respectively.

[0045] The resulting HPMC has 28% methoxyl substitution and 21% hydroxypropoxyl substitution. The viscosity of a 2 wt % aqueous solution of HPMC is 75,000 mPa.s, measured using an Ubbelohde viscometer.

[0046] Particle size and shape using the QICPIC image analysis system The Sympatec QICPIC image analyzer consists of a particle dispersion system, a laser, and a high-speed camera (1024x1024) with a maximum frame rate of 500 frames / s. Dispersed by a pressurized air system and a nozzle, the particles are illuminated by a laser beam. A shadow image of the particles is captured by the camera. Particle images, up to 40,000 frames per measurement, are converted into average particle properties by WINDOX software. The properties used in this report are the median values ​​for which 50% of the particles are smaller than a specified size (μm): EQPC(x 50 = 50%): diameter of a circle with the same area as the projected area of ​​the particle DIFI(x 50 = 50%): The diameter of the fiber is calculated by dividing the projected area by the sum of the lengths of all branches of the projected fiber. LEFI(x 50 = 50%): The length of a fiber is defined by the longest direct connection between its opposite ends.

[0047] Moisture content measurement Moisture content is measured by loss on drying using a Satorius MA150 moisture analyzer. The heat source is a ceramic IR heating element that provides stable, consistent, and rapid heating of 2-3g samples. For the compositions and wet blends of the present invention, a temperature of 130°C is used to evaporate the moisture from the product. LOD is calculated by the following formula:

number

[0048] Modulated Differential Scanning Calorimetry (mDSC) Using a TA Discovery DSC, the sample was heated under nitrogen starting from 20°C to 200°C using a modulation of 2°C / min and 0.63°C / min, then cooled to 20°C at a rate of 20°C / min. The material was reheated from 20°C to 200°C using a modulation of 2°C / min and 0.63°C / min.

[0049] Thermogravimetric analysis (TGA) The material was heated under air from 30°C to 130°C at a rate of 20°C / min. Using a TA Discovery TGA, the temperature was held at 130°C for 10 minutes (isothermal step), followed by subsequent isothermal steps of 150°C (10 minutes), 165°C (10 minutes), 200°C (10 minutes), and finally to 300°C at a rate of 20°C / min. [Example]

[0050] Example 1 Thermoplastic compounding step: A 30 ml kneading cell W30 of a Brabender Plasti-Corder PL 2000 torque kneader with a metal cover head was heated to the appropriate temperature (see the table below). After automatic calibration of the empty cell, HS HPMC (composition 1 in the table; C1) or a homogenous mixture of HS HPMC and sorbitol was filled into the cell. Homogenization was carried out using the closure head at 30 rpm until a constant torque was reached.

[0051] Extrusion test: A capillary rheometer (Malvern RH10, Malvern Instruments) equipped with a die of appropriate diameter was heated (see table below for temperatures) and filled with the paste obtained from the torque kneader test. Vertical extrusion through the die was carried out with the piston driven in the range of 10 mm / min.

[0052] [Table 1]

[0053] From the above table it is clear that composition 1, which contained HS HPMC but no sorbitol, was sticky and could not be removed from the extrusion tool without leaving a residue, whereas compositions 2-5, which contained sorbitol in addition to HS HPMC, could be removed in one piece and were not sticky.

[0054] Example 2 Sample preparation HS HPMC prepared as above and xylitol (Xivia CM 90) were accurately weighed into glass bottles in the desired ratios (95:5, 9:1, 85:15), processed to remove xylitol agglomerates, and blended in a Turbula blender for 5 minutes.

[0055] Extrusion Extrusion tests were performed in a Leistritz Nano 16 hot melt extruder. The feed and four heating zone temperatures were set as follows: water-cooled feed, 150°C, 160°C, 165°C, and 165°C die. The screw speed was set at 175 RPM. 60 grams of purge composition was added in each case. After each test, the screw and barrel were cleaned as necessary to ensure a clean system for the next run.

[0056] Initial tests were performed using only HS HPMC, which resulted in significant material remaining on the screw, making it very difficult to remove from the extruder (Figure 1).

[0057] The second test involved 95:5 HS HPMC:xylitol, which resulted in significantly less material remaining on the screw (Figure 2). Minimal force was required to remove the screw.

[0058] The third test involved a 90:10 HS HPMC:xylitol blend that left very little material on the screw or barrel walls and required no force to remove the screw from the extruder (Figure 3).

[0059] This also resulted in a clean die assembly; the remaining material on the die block easily peeled off and could be removed by hand (image not shown).

[0060] Also, increasing the xylitol content to 15% resulted in a clean screw (image not shown).

[0061] Example 3: Comparison with alternative additives Sample preparation In a Turbula blender, HS HPMC prepared as above was blended for 5 minutes in a 90:10 ratio with either xylitol, sorbitol, or polyethylene glycol 4000. If necessary, the additive was first sieved to remove lumps.

[0062] Hot Melt Extrusion All tests were carried out in a Leistritz Nano 16 hot melt extruder. Before introducing the purge composition, 30 grams of copovidone was manually fed into the extruder to simulate the compound to be processed. Then, 60 grams of the purge composition was introduced, and after the composition had finished exiting, the screw was removed for imaging.

[0063] result The composition containing PEG 4000 resulted in significant material remaining on the screw (Figure 4), making screw removal moderately difficult. No apparent copovidone remained. The composition containing xylitol resulted in a clean screw, no apparent copovidone remaining (Figure 5), and screw removal was easy. The composition containing sorbitol resulted in some residual material on the screw, especially on the leading flight, but screw removal was easy (Figure 6).

[0064] Example 4: Comparison with alternative HPMC substitutions Sample preparation HPMC type 2910 (available from DuPont) with a 2% aqueous solution viscosity of either 5 mPa.s or 50 mPa.s was blended with xylitol in a 90:10 ratio by first sieving out any xylitol clumps, manually blending into the HPMC, and then blending in a Turbula blender for 5 minutes.

[0065] Hot Melt Extrusion All tests were performed in a Leistritz Nano 16 hot melt extruder. Heat zone temperatures were set at 150°C, 160°C, 165°C, and 165°C. The screw speed was set at 175 RPM. 100 grams of the blend was introduced into the feed throat, and once there was no material remaining in the feed throat, the screw speed was increased to 250 RPM. After the composition had finished exiting, the screw was removed for imaging.

[0066] result The blend containing 50 mPa.s HPMC2910 could not be processed; upon introduction, the torque exceeded the maximum that could be delivered by the motor, resulting in seizure. The blend containing 5 mPa.s HPMC2910 processed successfully, but at much higher pressures (approximately 1500 PSI compared to approximately 300 PSI when processing HS HPMC) and torque. The screw was removed after the run was completed, and a moderate amount of residual material was found (Figure 7). The remaining material became physically hard upon slight cooling; all material remaining on the screw could be removed with a wire wheel without much difficulty. However, the blend could not be pulled cleanly from the die block, and the material remaining in the die was extremely hard and extremely difficult to clean.

[0067] Example 5 Sample preparation The highly substituted HPMC and xylitol prepared as described above were blended in an annular layer mixer (RLM; Corimix CM 20, available from Loedige, Germany) under different process conditions. In the first step, different concentrations of xylitol aqueous solutions were prepared (35 wt%, 45 wt%, and 60 wt%). HS HPMC was added at different dosing rates (25 kg / h and 50 kg / h) via a screw conveyor into the RLM, where an annular layer formed due to its high rotation speed of over 2000 rpm. The xylitol solution was sprayed onto the moving annular layer through several nozzles positioned along the rotating shaft of the RLM. The residence time within the RLM was between 10 and 20 seconds. The solutions were added at different dosing rates to obtain blends with target xylitol concentrations after removing water between 9 wt% and 11 wt%. 20 kg of blends were produced for each of the 10 different settings. The process conditions are summarized in Table 2 below.

[0068] [Table 2]

[0069] The wet blend, having a moisture content between 10-20 wt. %, was then dried to a moisture content of less than 1 wt. % in a standard fluidized bed dryer with an inlet temperature of 50°C or less and an actual product temperature of about 40°C.

[0070] Significant differences were observed between the RLM blend and a dry blend of HS HPMC and xylitol (9:1), which served as a reference. The dry blend showed a strong, sharp xylitol melting peak at 91 °C in the first heating curve (Figure 8), indicating that xylitol did not form a molecular blend with HS HPMC. No melting peak was observed in the second heating curve, indicating a molecular blend formed when xylitol melted during the first heating cycle. The RLM blend showed two broad, weak xylitol melting peaks at 74 and 82 °C in the first heating curve (Figure 9), indicating partial molecular blend formation in the annular layer mixer. The double peak and the decrease in melting point temperature indicate that xylitol may have partially crystallized into different crystalline forms during drying of the blend. The second heating curve no longer showed a xylitol peak, indicating the formation of a complete molecular blend.

[0071] Thermogravimetric analysis showed improved thermal stability for the RLM blends. Improved thermal stability was observed from 165°C onward and was most pronounced upon completion of the final 200°C isothermal step. At the end of the 200°C isothermal step, the weight loss of the dried blend was approximately 9%, slightly more than that of the HS HPMC raw material, while the best RLM blend (#1) lost only about 1.75% weight (Figure 10). In contrast to the weight loss at 200°C, the weight losses at 150 and 165°C were not significantly different for the RLM blends.

[0072] Hot melt extrusion of RLM samples All tests were carried out in a Leistritz Nano 16 hot melt extruder. The heating zone temperatures were set at 150°C, 160°C, 165°C, and 165°C. The screw speed was set at 175 RPM. Before introducing the purge composition, 30 grams of copovidone was manually fed into the extruder to simulate the compound being processed. Subsequently, 60 grams of the purge composition was then introduced and processed to completion. After the composition had finished exiting, the screw was removed for imaging.

[0073] result All tests utilizing the RLM composition for purging resulted in clean screws with no apparent copovidone residue and easy screw removal.

[0074] Example 6 Sample preparation 111 g of xylitol was dissolved in 200 g of water. 999 g of HS HPMC in dry powder form was placed in the mixing bowl of a Powrex Vertical Granulator Model FM-VG-0 and stirred at the following settings: main blade: 300 rpm and cross screw: 1500 rpm. An aqueous solution of xylitol (311.14 g) was sprayed onto the stirred HS HPMC at a spray rate of approximately 11.5 g / min to 12 g / min for 26.16 minutes. The resulting wet mass was dried in an oven at 85°C to approximately 1% moisture.

[0075] Thermogravimetric analysis showed improved thermal stability of Example 6. Improved thermal stability was observed at 165°C. At the end of the isothermal stage at 165°C, the dry blend had a weight loss of 2.9%, while the HS HPMC raw material had a weight loss of about 5%. The weight loss at 150°C was 1.9%, and the weight loss at 130°C was 1.3%.

Claims

1. A composition comprising a mixture of hydroxypropyl methylcellulose having a DS of 1.0 to 2.7 and an MS of 0.40 to 1.30, wherein the sum of the DS and MS is 1.8 to 3.6, DS being the degree of substitution of methoxyl groups, and MS being the molar substitution of hydroxypropoxyl groups, with a sugar alcohol, in a weight ratio of hydroxypropyl methylcellulose to sugar alcohol of 98:2 to 85:

15.

2. 2. The composition of claim 1, wherein the hydroxypropyl methylcellulose has a DS of 1.0 to 2.5, or a DS of 1.0 to 2.

3.

3. 3. The composition of claim 1, wherein the at least one hydroxypropyl methylcellulose has an MS of 0.50 to 1.

30.

4. 4. The composition of claim 1, wherein the hydroxypropyl methylcellulose has a DS of 1.6 to 2.3 and an MS of 0.60 to 1.

30.

5. The composition according to any one of claims 1 to 4, wherein the weight ratio of the hydroxypropyl methylcellulose to the sugar alcohol is from 95:5 to 90:

10.

6. 6. The composition according to any one of claims 1 to 5, wherein the sugar alcohol is selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, erythritol, glycerol, arabitol, ribitol, galactitol, fucitol, inositol and lactitol, and mixtures thereof.

7. The composition of claim 6, wherein the sugar alcohol is xylitol or sorbitol.

8. The composition according to any one of claims 1 to 7, wherein the hydroxypropyl methylcellulose has a viscosity of 5 to 150,000 mPa.s as a 2% aqueous solution at 20°C.

9. The composition according to any one of claims 1 to 7, wherein the hydroxypropyl methylcellulose has a viscosity of 1.2 to 500 mPa s as a 2% aqueous solution at 20°C.

10. 10. The composition according to any one of claims 1 to 9, which is a solid dispersion of the active ingredient in the mixture of hydroxypropyl methylcellulose and sugar alcohol.

11. 10. A process for producing the composition of any one of claims 1 to 9, comprising blending the hydroxypropyl methylcellulose in dry particulate form with an aqueous solution of the sugar alcohol, and drying the resulting wet blend to a moisture content of less than 8% by weight.

12. 12. The process of claim 11, wherein the aqueous solution of the sugar alcohol is sprayed onto the hydroxypropyl methylcellulose in an annular layer mixer or granulator.

13. 1. A process for reducing the stickiness of highly substituted hydroxypropyl methylcellulose during hot melt extrusion, comprising: a) blending hydroxypropyl methylcellulose having a DS of 1.0 to 2.7 and an MS of 0.40 to 1.30, wherein the sum of the DS and MS is 1.8 to 3.6, wherein DS is the degree of substitution of methoxyl groups and MS is the molar substitution of hydroxypropoxyl groups, with a sugar alcohol and optionally an active ingredient in a weight ratio of hydroxypropyl methylcellulose to sugar alcohol of 98:2 to 85:15; b) optionally compounding the blend of step a) at a temperature of from 95°C to 230°C; c) extruding the blend of step b) at a temperature of 95°C to 230°C; d) recovering the extruded mass from the extruder; A process involving:

14. 14. The process of claim 13, wherein the weight ratio of hydroxypropyl methylcellulose to sugar alcohol is from 95:5 to 90:

10.

15. 15. The process of claim 13 or 14, wherein the sugar alcohol is selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, erythritol, glycerol, arabitol, ribitol, galactitol, fucitol, inositol and lactitol, and mixtures thereof.

16. 16. The process of claim 15, wherein the sugar alcohol is xylitol or sorbitol.

17. 17. The process of any one of claims 13 to 16, wherein step (a) comprises blending the hydroxypropyl methylcellulose in dry particulate form with an aqueous solution of the sugar alcohol and drying the resulting wet blend to a moisture content of less than 8% by weight.

18. 18. The process of claim 17, wherein the aqueous solution of the sugar alcohol is sprayed onto the hydroxypropyl methylcellulose in an annular layer mixer or granulator.

19. 1. A process for purging an extrusion apparatus of contaminant material adhering to the interior surfaces of said apparatus, comprising: a) filling the extrusion device with a purge composition comprising a mixture of hydroxypropyl methylcellulose having a DS of 1.0 to 2.7 and an MS of 0.40 to 1.30, the sum of the DS and MS being 1.8 to 3.6, DS being the degree of substitution of methoxyl groups, and MS being the molar substitution of hydroxypropoxyl groups, and a sugar alcohol, wherein the weight ratio of hydroxypropyl methylcellulose to sugar alcohol is 98:2 to 85:15; b) conveying the purge composition through the extrusion device; c) removing the purge composition from the extrusion apparatus, thereby removing substantially all of the contaminant material adhered to the interior surfaces of the extrusion apparatus; A process involving:

20. 20. The process of claim 19, wherein step b) is carried out at a temperature of from 95°C to 230°C.

21. 21. The process of claim 19 or 20, wherein the purge composition comprises the hydroxypropyl methylcellulose and sugar alcohol in a weight ratio of 95:5 to 90:

10.

22. 22. The process of any one of claims 19 to 21, wherein the sugar alcohol is selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, erythritol, glycerol, arabitol, ribitol, galactitol, fucitol, inositol and lactitol, and mixtures thereof.

23. 23. The process of claim 22, wherein the sugar alcohol is xylitol or sorbitol.

24. 24. The process of any one of claims 19 to 23, wherein step (a) comprises blending the hydroxypropyl methylcellulose in dry particulate form with an aqueous solution of the sugar alcohol and drying the resulting wet blend to a moisture content of less than 8% by weight.

25. 25. The process of claim 24, wherein the aqueous solution of the sugar alcohol is sprayed onto the hydroxypropyl methylcellulose in an annular layer mixer or granulator.

26. 1. Use of a composition comprising a mixture of hydroxypropyl methylcellulose having a DS of 1.0 to 2.7 and an MS of 0.40 to 1.30, the sum of the DS and MS being 1.8 to 3.6, DS being the degree of substitution of methoxyl groups and MS being the molar substitution of hydroxypropoxyl groups, and a sugar alcohol, in a weight ratio of hydroxypropyl methylcellulose to sugar alcohol of 98:2 to 85:15, for purging contaminant material adhering to the interior surfaces of an extrusion equipment.

Images