Spray-dried excipient blend

Abstract

Granular compositions containing blended excipients are prepared by spray-drying microcrystalline cellulose with a small amount of polyalkylene oxide. Spray-dried granular compositions may have superior fluidity compared to physically blended compositions. Tablets prepared from spray-dried compositions may have excellent resistance to crushing.

Description

[Technical Field]

[0001] This application relates to the field of excipients useful for oral pharmaceuticals. [Background technology]

[0002] Oral pharmaceutical tablets typically contain a small amount of active ingredient in a larger amount of excipients. Excipients can perform numerous other functions, such as diluting the active ingredient, controlling the rate at which it is released, aiding in the absorption of the active ingredient, mitigating side effects, extending shelf life, providing durable tablets, providing lubrication during tableting, modifying flavor, and giving tablets a distinctive appearance. Excipients must also be safe for use in oral pharmaceuticals and, in general, must be able to meet regulatory and / or approval standards.

[0003] Many materials are approved and used as excipients. Some common examples include cellulose and its derivatives such as microcrystalline cellulose and cellulose ethers; metal oxides such as calcium phosphate, calcium carbonate, calcium sulfate, rock salt, and titanium dioxide; silicates and their derivatives such as fumed silica and colloidal silica; carbohydrates such as sugars or other sweeteners; starch; fatty alcohols; fatty acid salts; waxes; polyethylene glycol polymers; acrylic polymers; and proteins.

[0004] It is desirable to identify approved combinations of excipients that, without impairing other properties of the excipients, can provide one or more of the following: improved processability or properties, such as better flowability, easier mixing to provide a homogeneous blend, or better resistance to crushing of the resulting tablets. [Overview of the project]

[0005] One aspect of the present invention is a process for producing a granular excipient composition, 1. The following dry components: a. 3 to 25 wt percent water-soluble polyalkylene glycol that is solid up to at least 35°C, and b. 75-97 weight percent microcrystalline cellulose, A step of preparing a slurry containing in a solvent that dissolves polyalkylene glycol but not microcrystalline cellulose, wherein the weight percentage is based on the dry components by total weight excluding the solvent. 2. The process includes the step of spray-drying the slurry to form a dried granular composition.

[0006] MCC, polyalkylene glycol, and other excipients and / or active ingredients in granular compositions that are solid at room temperature are generally referred to as “dry” components, even if they are soluble in water. The solvent in the slurry is described as the “solvent,” even if the MCC and optionally other dry components are insoluble in water but suspended.

[0007] A second aspect of the present invention is a dried granular composition, which is produced by the process of the present invention, and a. 3 to 25 wt percent water-soluble polyalkylene glycol that is solid up to at least 35°C, b. A dry granular composition containing 75-97% by weight of microcrystalline cellulose.

[0008] A third aspect of the present invention is a granular composition, a. 3 to 25 wt percent water-soluble polyalkylene glycol that is solid up to at least 35°C, b. 75-97 weight percent microcrystalline cellulose, The granular composition contains, and the granules contain particles of microcrystalline cellulose that are whole or partially encapsulated by polyalkylene glycol.

[0009] A fourth aspect of the present invention is a method for using the granular composition of the present invention, comprising the step of compressing the granular composition into a solid tablet.

[0010] The fifth aspect of the present invention is a solid tablet, which contains (1) a pharmaceutically useful amount of an oral medicine and (2) is dispersed in the compressed granular composition of the present invention.

[0011] The granular composition of the present invention is useful as an excipient for oral medicines and other tableted supplements, vitamins, active substances, etc. In some embodiments, the granular composition of the present invention may have high fluidity, and the tablets made using the granular composition may have high resistance to grinding. The granular composition may also be useful for modifying the dissolution rate of the resulting tablets.

Brief Description of the Drawings

[0012] [Figure 1] The particle size distributions of the granular compositions in Examples 2 and 3 and Comparative Examples 2 and 3 of the present invention are shown.

Modes for Carrying Out the Invention

[0013] The granular composition of the present invention contains microcrystalline cellulose and a polyalkylene glycol. Both components are common excipients that are approved for use in oral medicines and are widely available.

[0014] Microcrystalline cellulose (MCC) is described in Rowe et al, Handbook of Pharmaceutical Excipients, 5 th Ed at 132-135 (2006). MCC is generally produced by partially depolymerizing natural cellulose. In many embodiments, the MCC used in the present invention is of pharmaceutical grade. In some embodiments, MCC meets the standards of the United States Pharmacopeia for excipients. In some embodiments, MCC meets the standards of Commission Regulation (EU) No 231 / 2012 (specification E460). In some embodiments, MCC meets both standards.

[0015] Like ordinary cellulose, MCC contains repeating cyclic glucose units linked by 1 to 4 beta-glycosidic bonds. In some embodiments, the average degree of polymerization of MCC is less than 400, less than 350, 300 or less, or 250 or less. In some embodiments, the average degree of polymerization of MCC is at least 120, at least 150, at least 180, or at least 200.

[0016] In some embodiments, the MCC contains at least 95% by weight cellulose, or at least 97% by weight, or up to 98% by weight. In some embodiments, the MCC contains essentially 100% by weight cellulose, or up to 99.9% by weight, or up to 99.7% by weight, or up to 99.5% by weight.

[0017] In some embodiments, the MCC contains 0.5% by weight or less of a water-soluble material at 20°C, or 0.3% by weight or less, or 0.24% by weight or less. There is no minimum required level of water-soluble material. In some embodiments, the MCC contains such a small amount of water-soluble material that it is not measurable (essentially 0.0% by weight).

[0018] In some embodiments, the MCC contains 0.7% by weight or less of ash, or 0.5% by weight or less, or 0.4% by weight or less. There is no minimum required level of ash. In some embodiments, the MCC contains so little ash that it is not measurable (essentially 0.0% by weight).

[0019] In some embodiments, the MCC has a D10 particle size of at least 5 microns or at least 6 microns. In some embodiments, the MCC has a D50 particle size of at least 10 microns, or at least 15 microns, or at least 20 microns, or at least 40 microns, or at least 60 microns, or at least 80 microns, or at least 90 microns. In some embodiments, the MCC has a D50 particle size of up to 300 microns, or up to 250 microns, or up to 200 microns, or up to 150 microns, or up to 120 microns, or up to 100 microns, or up to 80 microns, or up to 60 microns, or up to 40 microns.

[0020] Suitable MCCs are commercially available from several suppliers, including DuPont de Nemours, Inc., Roquette Freres, JRS Pharma GmbH; FMC Corp., and Sigma-Aldrich. They can also be produced by known processes, such as those described in the background art and modes for carrying out the invention in U.S. Patent Application Publication 2006 / 0020126(A1).

[0021] Polyalkylene glycol contains repeating units that satisfy formula 1, In the formula, R 1 and R 2 Each of them is either hydrogen or an alkyl group. In some embodiments, R 1 and R 2 Each of them is,

[0022] [ka] Independently, it contains six or fewer carbon atoms, or four or fewer carbon atoms, or two or fewer carbon atoms, or one or fewer carbon atoms. In some embodiments, R 1 and R 2Together, on average, contain eight or fewer carbon atoms, or six or fewer carbon atoms, or four or fewer carbon atoms, or two or fewer carbon atoms, or one or fewer carbon atoms, or 0.5 or fewer carbon atoms, or 0.25 or fewer carbon atoms. In some embodiments, R 1 and R 2 are both hydrogen in at least 80 percent, or at least 90 percent, or essentially 100 percent of the repeating units. In some embodiments, the polyoxyalkylene chain, if desired, contains ethylene oxide [-CH2-CH2-O-] units, propylene oxide [-CH2(CH3)-CH2--O-] units, or units of both types, in any desired ratio in the same molecular chain.

[0023] In some embodiments, the polyalkylene glycol is polyethylene glycol. In some embodiments, the polyalkylene glycol is a polyethylene glycol / polypropylene glycol copolymer. In some embodiments, the polyalkylene glycol is a poloxamer, a triblock copolymer composed of two chains of polyethylene glycol adjacent to a central chain of polypropylene glycol. In many poloxamers, the polypropylene glycol chain is hydrophobic and the polyethylene glycol chain is hydrophilic. Examples of polyethylene glycols used as excipients are described in Rowe et al, Handbook of Pharmaceutical Excipients, 5 th Ed at 545-550 (2006).

[0024] The polyalkylene glycol should be water-soluble. In some embodiments, it is soluble in water at 20 °C up to at least 20 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent. Maximum solubility is not required, but solubilities exceeding 100 weight percent or 80 weight percent may be unnecessary for some applications.

[0025] The polyalkylene glycol should be solid up to 35°C. In some embodiments, it has a melting temperature of at least 40°C, or at least 45°C, or at least 50°C, or at least 54°C. In some embodiments, it has a melting temperature of 100°C or less, or 80°C or less, or 70°C or less, or 65°C or less.

[0026] In some embodiments, the polyalkylene glycol has a number average molecular weight of at least 2000 Da, or at least 3000 Da, or at least 4000 Da, or at least 5000 Da, or at least 6000 Da, or at least 7000 Da, or at least 7500 Da, or at least 8000 Da. In some embodiments, the polyalkylene glycol has a number average molecular weight of up to 25,000 Da, or up to 20,000 Da, or up to 15,000 Da, or up to 12,000 Da, or at most 10,000 Da.

[0027] In some embodiments, the polyalkylene glycol has a viscosity of at least 200 cSt, or at least 400 cSt, or at least 450 cSt, or at least 500 cSt, at 100°C. In some embodiments, the polyalkylene glycol has a viscosity of up to 5000 cSt, or up to 3000 cSt, or up to 2000 cSt, or up to 1000 cSt, at 100°C.

[0028] Suitable polyalkylene glycols are commercially available under the CARBOWAX SENTRY® and Kollisolv trademarks. Others may be produced by known processes, such as polymerization of the corresponding alkylene oxide monomer in the presence of an acid or base initiator. See, for example, U.S. Patent Application Publication 2007 / 0179199(A1) and “Introduction of Polyethylene Glycol (PEG)” (available from BOC Sciences at https: / / peg.bocsci.com / resources / technical-information / introduction-of-polyethylene-glycol-peg).

[0029] The granular composition contains 3 to 25 weight percent of polyalkylene glycol. In some embodiments, the granular composition contains at least 4 weight percent of polyalkylene glycol, or at least 5 weight percent, or at least 6 weight percent, or at least 7 weight percent, or at least 8 weight percent, or at least 9 weight percent, or at least 10 weight percent. In some embodiments, the granular composition contains up to 23 weight percent of polyalkylene glycol, or up to 20 weight percent, or up to 18 weight percent, or up to 16 weight percent, or up to 14 weight percent, or up to 12 weight percent, or up to 10 weight percent, or up to 8 weight percent, or up to 6 weight percent.

[0030] The granular composition contains 75 to 97 percent by weight of microcrystalline cellulose. In some embodiments, the granular composition contains at least 77 percent by weight of microcrystalline cellulose, or at least 80 percent by weight, or at least 82 percent by weight, or at least 84 percent by weight, or at least 86 percent by weight, or at least 88 percent by weight, or at least 90 percent by weight. In some embodiments, the granular composition contains up to 95 percent by weight of microcrystalline cellulose, or up to 93 percent by weight, or up to 92 percent by weight, or up to 91 percent by weight, or up to 90 percent by weight.

[0031] The granular composition optionally contains 0 to 22 weight percent of other excipients useful for oral pharmaceuticals and tablets. A wide range of excipients serving many different purposes are available, such as: • Fillers and diluents, • Binder, • Anti-solidification agent, • Suspensions and thickeners, ·coating, Flavoring agents and sweeteners, • Disintegrant, • Coloring agents, Lubricants and flow promoters, • Preservatives, • Surfactants, • Sustained-release agent, • Blending aids and mixing aids, and • Compression aid.

[0032] Useful excipients include dibasic phosphates such as calcium phosphate, calcium carbonate, calcium sulfate, rock salt, metal oxides such as titanium dioxide, colloidal silica, carbohydrates such as sugars or other sweeteners, starch, cellulose ethers, fatty alcohols, fatty acid salts, waxes, acrylic polymers, and proteins. More common examples include magnesium stearate, starch, silicone / titanium dioxide, colloidal silicon dioxide, stearic acid, sodium starch glycolate, gelatin, talc, sucrose, calcium stearate, food coloring, croscarmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, povidone, and crospovidone. Several excipients are further described in Kibbe, Handbook of Pharmaceutical Excipients, Third Ed. (2000), paragraphs [9]-

[19] (inclusive) of PCT Publication 2011 / 024028, and paragraphs

[0073] -

[0084] (inclusive) of PCT Publication 2021 / 231946(A1). Furthermore, fumed silica may be added to improve spray-drying performance.

[0033] In some embodiments, the concentration of other excipients is at least 1 weight percent, or at least 2 weight percent, or at least 3 weight percent, or at least 4 weight percent, or at least 5 weight percent. In some embodiments, the concentration of other excipients is up to 20 weight percent, or up to 18 weight percent, or up to 16 weight percent, or up to 14 weight percent, or up to 12 weight percent, or up to 10 weight percent, or up to 8 weight percent, or up to 6 weight percent.

[0034] In some embodiments, excipients, particularly surface modifiers, are included to improve the fluidity of the spray-dried granular composition. We assume, though not intended to restrict, that surface modifiers improve miscibility by roughening the surface of the spray-dried particles. Examples of surface modifiers include inorganic salts such as dibasic calcium phosphate and other dibasic phosphates.

[0035] In some embodiments, the granular composition further contains one or more active ingredients. The active ingredients may include any pharmaceutical, probiotic, or nutrient that is solid at room temperature and suitable for oral administration. Examples of active ingredients are described in numerous sources, including PCT Publication 2021 / 231946(A1), paragraphs

[0065] to

[0072] (inclusive). Examples of potential active ingredients include vitamins such as vitamins A, B, C, D, and / or E; probiotics such as bacteria; analgesics such as aspirin, acetaminophen, or ibuprofen; decongestants; antibiotics; antacids; and other nutritional supplements. In some embodiments, the granular composition contains a single active ingredient. In some embodiments, such as multivitamins, the composition may contain multiple active ingredients.

[0036] The active ingredient may be present in a pharmaceutically effective concentration, which may vary depending on the active ingredient. Some pharmaceutical tablets may contain a low active dose of 5 mg or less. On the other hand, some vitamin tablets may contain 1000 mg or more of active vitamins.

[0037] In the process of the present invention, MCC and polyalkylene glycol, along with optionally other excipients and / or active ingredients (dry components), are mixed in a solvent that dissolves polyalkylene glycol but not MCC to form a well-dispersed slurry. The slurry is then spray-dried to produce the granular composition of the present invention.

[0038] For clarity, MCC and polyalkylene glycol must be mixed in the slurry. However, any other excipients and active ingredients may be added to the granular composition at one or more stages of its production and use. Other excipients and / or active ingredients may be added to the slurry before the granular composition is spray-dried. They may be introduced into the spray-drying chamber when the granular composition is dried. They may be physically mixed with the granular composition after it has been recovered from spray-drying and / or before it is compressed into tablets.

[0039] To form a slurry, MCC and polyalkylene glycol, along with optionally other dry components, are mixed in a solvent that dissolves the polyalkylene glycol but not the MCC, until a homogeneous slurry is formed. The amount of solvent should be sufficient to dissolve the water-soluble components, including the polyalkylene glycol, and to suspend or disperse the water-insoluble components, including the microcrystalline cellulose. In some embodiments, the solvent contains water or at least 50 weight percent water. In some embodiments, the solvent contains a lower alkanol, dichloromethane, chloroform, or acetonitrile. In some embodiments, the solvent consists essentially of water. In some embodiments, excess solvent is kept low to minimize the need for drying in the spray-drying process.

[0040] In some embodiments, the slurry contains at least 1 weight percent of dry components, or at least 5 weight percent, or at least 10 weight percent. In some embodiments, the slurry contains up to 60 weight percent of dry components, or up to 50 weight percent. In some embodiments, the slurry contains at least 40 weight percent of solvent, or at least 50 weight percent. In some embodiments, the slurry contains up to 99 weight percent of solvent, or up to 95 weight percent, or up to 90 weight percent. In some embodiments, one or more of the dry components may already be dissolved or suspended in the solvent, which may be taken into consideration when calculating the total solvent in the slurry. The ratio of dry components in the slurry reflects the proportions already described.

[0041] In some embodiments, the dry components of the slurry may affect the acidity of the slurry. In some embodiments, the pH of the slurry is at least 4, or at least 5, or at least 6, or at least 7. In some embodiments, the pH of the slurry is up to 10, or up to 8, or up to 7.5, or up to 7. In some embodiments, the pH may be controlled by a buffer. Suitable buffers are known and commercially available. Examples include citric acid, and citrates, and phosphates.

[0042] The slurry is spray-dried according to known techniques. Spray drying equipment is commercially available with instructions for its use, and spray drying is described in numerous publications, including Santos et al., "Spray Drying - A Overview," available at http: / / dx.doi.org / 10.5772 / intechopen.72247; the "Spray Dry Manual," published by Bete Performance Spray Engineering at www.BETE.com; and More Swati et al., "Review on Spray Drying Technology" 4(2)IJPCBS 219-225(2014).

[0043] In summary, the spray drying process has the following sub-steps: 1. The slurry is atomized (sprayed) in a drying chamber to form atomized droplets. 2. The atomized droplets are brought into contact with a heated gas in a drying chamber under conditions that dry the droplets into dry granules, and 3. Separate the dried granules from the gas and recover them.

[0044] In some embodiments, the drying chamber may have a cylindrical section and a narrow conical section at the bottom from which the dried granules are collected and removed from the drying chamber. Several different types of atomizers are known, including spray nozzles and rotary atomizers. In some embodiments, the heated gas is air, and in some embodiments, the heated gas is an inert gas such as nitrogen or carbon dioxide.

[0045] The spray drying process can be classified as follows: 1. Parallel flow: Both slurry and drying gas are supplied into the drying chamber from the top of the chamber and flow together in the same direction from the bottom of the chamber. 2. Counterflow: Slurry is supplied into the drying chamber at the top of the chamber, flows to the bottom, and flows out from the bottom. Drying gas is supplied into the drying chamber near or below the bottom of the cylindrical section of the chamber and flows out upward from the top of the drying chamber in the opposite direction to the slurry / granules. 3. Mixing mode: The slurry is supplied into the chamber and atomized near the bottom of the cylindrical section of the chamber. The drying gas is supplied into the drying chamber at the top of the chamber. The dried granules fall to the bottom of the chamber and are collected there, while the drying gas can flow out at the bottom or midway through the chamber. The spray drying process in the present invention may use any one of these configurations. In some embodiments, it is a mixed-mode spray drying.

[0046] In some embodiments, other excipients and / or active ingredients may be sprayed into the drying chamber separately from the slurry. For example, in a mixed-mode spray dryer, the slurry containing MCC and polyalkylene oxide may be supplied and atomized at a normal point near the bottom of the cylindrical section of the chamber. One or more other excipients or active ingredients may be sprayed separately into the drying chamber near or above the top of the cylindrical section.

[0047] The spray drying process of the present invention is carried out at a temperature and gas flow rate such that atomized droplets dry rapidly without substantially decomposing the components of the granular composition. Typically, the temperature at the inlet is higher than the temperature at the outlet. In some embodiments, the inlet temperature is at least 100°C, or at least 120°C, or at least 130°C, or at least 140°C. In some embodiments, the inlet temperature is 200°C or less, or 180°C or less, or 160°C or less, or 150°C or less. The gas flow rate varies depending on the apparatus, and generally, the rate should be fast enough to rapidly dry the atomized particles without agglomerating them, but slow enough so that the granules are not carried away with the gas.

[0048] In some embodiments, the atomized droplets dry sufficiently to prevent substantial further aggregation in 60 seconds, 30 seconds, or 15 seconds or less. There is no minimum drying time, but in some embodiments, drying times of less than 1 second or 5 seconds are unnecessary. In some embodiments, the resulting granules contain 15% by weight or less water, or 10% by weight or less, or 8% by weight or less, or 7% by weight or less. In some embodiments, the resulting granules contain at least 1% by weight water, or at least 2% by weight, or at least 3% by weight, or at least 5% by weight.

[0049] The spray-dried granules are separated from the dry gas and recovered by known means, for example, a cyclone separator, a bag filter, or an electrostatic precipitator.

[0050] Spray drying causes the granular composition to take on a different form than it would have if its components were physically blended. Physical blending would produce a mixture containing discrete particles of MCC and polyalkylene oxide, as well as other excipients and / or active ingredients. On the other hand, by spray drying the slurry, the alkylene oxide dries as a coating that partially or completely encapsulates the outside of the MCC particles. In some embodiments, the encapsulated granules have a core containing MCC and a shell containing polyalkylene glycol. In some embodiments, the MCC is mainly found in the core of the particles, and the polyalkylene oxide is mainly found in the shell of the particles.

[0051] In some embodiments, other excipients in the slurry are also located within the shell. If the other excipients are water-soluble, they can be blended with the polyalkylene oxide in the shell. If the other excipients are water-insoluble, the discrete particles can be embedded in the polyalkylene oxide shell on the MCC particles, or they can also be coated with the polyalkylene oxide shell.

[0052] The ratio of dry components in the granules reflects the proportions already mentioned.

[0053] In some embodiments, the particles of the granular composition have an average particle size of at least 50 microns, or at least 75 microns, or at least 100 microns. In some embodiments, the particles of the granular composition have an average particle size of up to 300 microns, or up to 250 microns, or up to 200 microns, or up to 150 microns.

[0054] In some embodiments, the angle of repose of the granular composition of the present invention is 35° or less, or 33° or less, or 32° or less, or 31° or less, or 30° or less. In some embodiments, the angle of repose of the granular composition of the present invention is at least 20°, or at least 25°, or at least 26°, or at least 27°, or at least 28°. In some embodiments, the angle of repose of the granular composition of the present invention is at least 1° lower, or at least 2° lower, or at least 3° lower, or at least 5° lower, or at least 7° lower than the angle of repose of the physical blend of the starting components (the form they had before being added to the slurry). In some embodiments, the angle of repose of the granular composition of the present invention is 15° or less lower, or 10° or less lower than the angle of repose of the physical blend of the starting components. In some embodiments, a low angle of repose may indicate that the granular composition flows well and is easy to process.

[0055] In some embodiments, for example, when a surface-modifying excipient is added to the slurry, the granular composition of the present invention may have an improved ability to form a homogeneous mixture with other dry granules or powders (miscibility). Miscibility is difficult to quantify, but can be visually demonstrated by blending the granular composition with powdered pigments such as iron oxide.

[0056] The granular composition of the present invention may be compressed into tablets by known means. Before compression, the granular composition may optionally be blended with the active ingredient or other excipients as described above. Blending may be performed using known devices such as an impeller or a rotating drum. In some embodiments, the composition to be compressed contains at least 50 weight percent of the granular composition of the present invention (when recovered from spray drying), or at least 60 weight percent, or at least 70 weight percent, or at least 80 weight percent, or at least 90 weight percent, or at least 95 weight percent, or at least 98 weight percent. In some embodiments, the composition to be compressed contains up to 100 weight percent of the granular composition of the present invention (when recovered from spray drying), or 99.99 weight percent or less, or 99.9 weight percent or less, or 99.5 weight percent or less, or 99 weight percent or less.

[0057] Apparatus for compressing tablets is commercially available along with instructions for its use. The optimal compression pressure for producing tablets varies widely depending on the components selected for the granular composition. In some embodiments, compression is performed at a pressure of at least 10 MPa, or at least 20 MPa, or at least 40 MPa, or at least 50 MPa. In some embodiments, compression is performed at a pressure of 500 MPa or less, or 400 MPa or less, or 300 MPa or less, or 250 MPa or less. In some embodiments, compression is performed at a temperature of at least 0°C or at least 20°C. In some embodiments, compression is performed at a temperature of 70°C or less, or 40°C or less.

[0058] The resulting tablets may be of any size suitable for oral administration. In some embodiments, the sum of the length + width + depth of the tablet is at least 9 mm, or at least 11 mm, or at least 13 mm. In some embodiments, the sum of the length + width + depth of the tablet is up to 35 mm, or up to 30 mm, or up to 25 mm. Optionally, the tablets may be coated with gelatin or a delayed-release coating after they have been compressed.

[0059] In some embodiments, the tablets of the present invention may have a crushing resistance (hardness) of at least 6000 gf / mm, or at least 7000 gf / mm, or at least 7500 gf / mm, or at least 8000 gf / mm, or at least 8500 gf / mm, or at least 9000 gf / mm. There is no maximum required crushing resistance, but in some embodiments, crushing resistance exceeding 15,000 gf / mm or 10,000 gf / mm is unnecessary. In some embodiments, the tablets of the present invention may have a crushing resistance (hardness) that is at least 100 gf / mm higher, or at least 200 gf / mm higher, or at least 300 gf / mm higher, or at least 500 gf / mm higher, or at least 1000 gf / mm higher than tablets made from a physically blended mixture of the same components. While there is no maximum required improvement in grinding resistance, in some embodiments, improvements exceeding 2000 gf / mm or 1500 gf / mm are unnecessary.

[0060] In some embodiments, the tablets of the present invention may dissolve faster than tablets made from a physically blended mixture of the same components, for example, in 50% or less of the dissolution time, or 30% or less of the dissolution time, or 10% or less of the dissolution time.

[0061] Test method The properties described herein are measured using the following test methods unless the context makes it clear that a different method is intended.

[0062] [Table 1]

[0063] Mixability: Weigh 0.5 g of the powder to be tested into two drum vials and seal them using caps with flat inserts. Invert the sealed vials to allow the powder to flow to the top of the vials, then flip them over again with the right side up. Use as a coloring agent. Add 0.02 g of iron oxide (0.5 microns) to the vials. Reseal the vials and invert them once more to allow all the material to flow to the top of the vials. Rotate the glass vials using a Yuhappy VH-2 powder mixer, in which the V-shaped mixing container was removed and replaced with a block capable of holding two drum glass vials (17 × 60 mm, Qorpak item no. GLC-00986). Set the mixer to 20 rpm and mix for 2, 15, 30, and 90 minutes. At each point, stop the mixer and photograph the vials in an imaging chamber with side illumination before returning them to the mixer. Since all images are taken under the same lighting conditions, image analysis can be used to quantify how effectively the iron oxide was mixed into the co-excipient. Using ImageJ, a region of the image is selected for analysis, and the average L * a * b * Report the value. Overall color difference ΔE between the sample and the pure white material. * ΔE * =[(L * 試料 -L * 白 ) 2 +(a * 試料 -a * 白 ) 2 +(b * 試料 -b * 白 ) 2 Calculated by ], in the formula, L * 白 =100, a * 白 =0, and b * 白= 0. Higher ΔE after mixing. * The value indicates better mixing ability. [Examples]

[0064] The following examples illustrate several embodiments of the present invention.

[0065] In the example, the materials listed in Table 1 are used.

[0066] [Table 2]

[0067] For Examples 1-3 of the present invention (Inventive Examples IE1, IE2, and IE3), the materials from Table 1 are blended with water in the proportions shown in Table 2 to form a homogeneous slurry containing approximately 20 weight percent solid. The slurry is spray-dried according to the following procedure to produce a granular composition. The spray dryer is a Mobile Minor spray dryer (GEA Process Engineering Inc.) equipped with a two-fluid nozzle atomizer. Spray drying is performed under an inert atmosphere of nitrogen. Nitrogen is supplied to the atomizer at 1 bar and 50% flow rate at ambient temperature, which corresponds to a flow rate of 6.0 kg / hour. The slurry is supplied to the atomizer at approximately 30 mL / min using a peristaltic pump (Masterflex L / S). Heated nitrogen is supplied as a drying gas to the top of the drying chamber at a flow rate of approximately 20 SCFM. The inlet temperature is set to 140°C, and the outlet temperature is equalized to 40-50°C by fine-tuning the slurry supply rate. A flow aid is added at the top of the drying chamber through a Coperion K-TRON screw feeder at a supply rate of 0.1 g / min. The resulting spray-dried granular composition is collected in a cyclone and subsequently vacuum-dried at room temperature to remove residual moisture.

[0068] For Comparative Examples 1-3 (CE1, CE2, and CE3), the materials from Table 1 were physically blended in proportions shown in Table 2 by mixing them in a plastic cup for 24 hours while rotating and inverting until a homogeneous granular composition was obtained.

[0069] For Comparative Examples 4-6 (CE4-CE6), commercially available powder excipient formulations from Table 1 were used in their sold form.

[0070] [Table 3]

[0071] The particle size, fluidity, and miscibility of each granular composition were measured as described in the test method. The particle size distribution is shown in Table 2 and Figure 1. The fluidity and miscibility results are shown in Table 3.

[0072] Each granular composition is compressed using a Carver compression mold to produce tablets. A 2-gram sample of each granular composition is weighed into a mold, and a weight of 5000 pounds is applied to produce a circular disc-shaped tablet with a diameter of 13 / 16 inches. The hardness and dissolution of the tablets are tested as described in the test method. The results are shown in Table 3. Regarding the dissolution rate: • Very fast = less than 10 seconds Fast = 10-60 seconds, • Slow = 60-600 seconds, • Very slow = over 600 seconds

[0073] [Table 4]

Claims

1. A granular composition, a) 3 to 25 wt percent of a water-soluble polyalkylene glycol that is solid up to at least 35°C, b) 75-97 weight percent of microcrystalline cellulose, A granular composition comprising granules containing particles of microcrystalline cellulose that are whole or partially encapsulated by polyalkylene glycol.

2. The granular composition according to claim 1, wherein the granules comprise a core containing microcrystalline cellulose and a shell containing polyalkylene glycol.

3. The granular composition according to claim 2, wherein the polyalkylene glycol is polyethylene glycol or polyethylene glycol-polypropylene glycol copolymer.

4. The granular composition according to claim 3, wherein the polyalkylene glycol has a number average molecular weight of at least 2,000 Da and 25,000 Da or less.

5. The granular composition according to claim 4, wherein the polyalkylene glycol has a molecular weight of at least 4,000 Da and at most 12,000 Da.

6. The granular composition according to claim 2, comprising at least 5% by weight of polyalkylene glycol and at least 80% by weight of microcrystalline cellulose.

7. The granular composition according to claim 2, comprising 5 to 15 weight percent of polyalkylene glycol, 80 to 95 weight percent of microcrystalline cellulose, and 2 to 10 weight percent of one or more other excipients.

8. The granular composition according to claim 7, wherein the other excipient contains colloidal silica.

9. The granular composition according to claim 7, wherein the other excipient contains a dibasic phosphate.

10. The granular composition according to any one of claims 1 to 9, wherein the average particle size of the granules is 50 microns to 200 microns.

11. The granular composition according to claim 10, having an angle of repose of 32° or less.

12. (1) A solid tablet comprising (2) a pharmaceutically useful amount of an oral drug dispersed in the compressed granular composition described in claim 1.

13. The tablet according to claim 12, having a crushing resistance of at least 8000 gf / mm.

14. A process for producing a granular excipient composition, a) The following dry components: i) 3 to 25 wt percent of a water-soluble polyalkylene glycol that is solid up to at least 35°C, and ii) 75-97 weight percent of microcrystalline cellulose, A step of preparing a slurry containing the polyalkylene glycol in a solvent that dissolves the polyalkylene glycol but does not dissolve the microcrystalline cellulose, wherein the weight percentage is based on the total weight dry components excluding the solvent. b) A process comprising the step of spray-drying the slurry to form a dried granular composition.

15. Produced by the process described in claim 14, a) 3 to 25 wt percent of a water-soluble polyalkylene glycol that is solid up to at least 35°C, b) A granular composition containing 75 to 97 weight percent of microcrystalline cellulose.

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