Spray-dried excipient blends

Abstract

A particulate composition containing blended excipients is prepared by spray drying a sugar alcohol and a polyalkylene oxide in the presence of a small amount of a hydrophobic flow promoter. The spray-dried particulate composition may have excellent flowability compared to a physically blended composition. Tablets prepared from the spray-dried composition may have excellent crush resistance.

Description

Technical Field

[0001] This application relates to the field of excipients for oral pharmaceutical products. Background Technology

[0002] Oral medication tablets typically contain a small amount of active ingredient and a large amount of excipients. Excipients dilute the active ingredient and perform a wide range of other functions, such as controlling the rate of release of the active ingredient, aiding in its absorption, reducing side effects, extending shelf life, providing durable tablets, providing lubrication during tablet compression, altering flavor, and giving the tablet a unique appearance. Excipients must also be safe for use in oral medications and generally must meet regulatory and / or approval standards.

[0003] Many materials are approved and used as excipients. Some common examples include cellulose and its derivatives, calcium phosphate, calcium carbonate, calcium sulfate, rock salt, metal oxides (such as titanium dioxide), silicates and their derivatives (such as pyrolytic 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] The aim is to identify approved combinations of excipients that can provide improved processability or properties of the resulting tablets, such as better flowability or better crush resistance, without impairing other properties of the excipients. Summary of the Invention

[0005] One aspect of the present invention is a method for preparing a particulate excipient composition, the method comprising the following steps:

[0006] 1. Prepare a solution containing the following dry components in a solvent:

[0007] a. 5% to 50% by weight of water-soluble polyalkylene glycol, wherein the water-soluble polyalkylene glycol is solid at at least 35°C;

[0008] b. 50% to 95% by weight of a sugar alcohol, wherein the sugar alcohol is solid at at least 50°C.

[0009] The weight percentages are based on the total weight of the dry components excluding the solvent; and

[0010] 2. The solution is spray-dried in a drying chamber in the presence of a hydrophobic flow aid in an amount sufficient to reduce the adhesion of the spray-dried particles to the surface of the drying chamber to form a dry particle composition.

[0011] All percentages are based on a combined weight of polyalkylene glycols and sugar alcohols.

[0012] A second aspect of the present invention is a dry granule composition prepared by the method of the present invention, the dry granule composition comprising:

[0013] a. 5% to 50% by weight of a water-soluble polyalkylene glycol, wherein the water-soluble polyalkylene glycol is solid at at least 35°C; and

[0014] b. 50% to 95% by weight of a sugar alcohol, wherein the sugar alcohol is solid at at least 50°C; and

[0015] c. Hydrophobic flow aids

[0016] All percentages are based on a combined weight of polyalkylene glycols and sugar alcohols.

[0017] A third aspect of the present invention is a particulate composition comprising:

[0018] a. 5% to 50% by weight of a water-soluble polyalkylene glycol, wherein the water-soluble polyalkylene glycol is solid at at least 35°C; and

[0019] b. 50% to 97% by weight of a sugar alcohol, wherein the sugar alcohol is solid at at least 50°C; and

[0020] c. 0.1% to 5% by weight of hydrophobic flow aids,

[0021] The individual particles of the granular composition contain a mixture of the polyalkylene glycol and the sugar alcohol, and the hydrophobic flow aid is primarily located on the surface of the particles, and all percentages are based on the combined weight of the polyalkylene glycol and the sugar alcohol.

[0022] A fourth aspect of the invention is a method of using the granular composition of the invention, the method comprising the step of compressing the granular composition into a solid tablet.

[0023] The fifth aspect of the invention is a solid tablet comprising: a pharmaceutically effective amount of an oral drug dispersed in (2) the compressed granule composition according to the invention.

[0024] The granular compositions of the present invention can be used as excipients for oral pharmaceuticals and other tablet supplements, vitamins, active substances, etc. In some embodiments, the granular compositions of the present invention can have high flowability, and tablets prepared using the granular compositions can have high crush resistance. The granular compositions can also be used to modify the dissolution rate of the resulting tablets. Detailed Implementation

[0025] The particulate compositions of the present invention contain polyalkylene glycols, sugar alcohols, and hydrophobic flow aids. Sugar alcohols, polyalkylene glycols, and some hydrophobic flow aids (such as pyrolytic silica) are common and widely available excipients approved for use in oral pharmaceutical products.

[0026] Polyalkylene glycols contain repeating units that satisfy Formula 1:

[0027]

[0028] Where R 1 and R 2 Each of them is a hydrogen or alkyl group. In some embodiments, R 1 and R 2 Each of them independently contains no more than 6 carbon atoms, no more than 4 carbon atoms, no more than 2 carbon atoms, or no more than 1 carbon atom. In some embodiments, R 1 and R 2 Each contains, on average, no more than 8 carbon atoms, no more than 6 carbon atoms, no more than 4 carbon atoms, no more than 2 carbon atoms, no more than 1 carbon atom, no more than 0.5 carbon atoms, or no more than 0.25 carbon atoms. In some embodiments, R 1 and R 2 The repeating units are all hydrogen in at least 80% or at least 90% or substantially 100%. In some embodiments, the polyoxyalkylene chain contains, as desired, ethylene oxide [—CH2—CH2—O—] units, propylene oxide [—CH2(CH3)—CH2-O—] units, or both types of units in any desired ratio within the same molecular chain.

[0029] 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 poloxamer, which is a triblock copolymer consisting of a central chain of polypropylene glycol and two polyethylene glycol chains on either side. In many poloxamers, the polypropylene glycol chains are hydrophobic, and the polyethylene glycol chains are hydrophilic. Examples of polyethylene glycols used as excipients are described in Rowe et al. Handbook of Pharmaceutical Excipients, 5th Edition 545-550 (2006)

[0030] Polyalkylene glycols should be water-soluble. In some embodiments, they are soluble in water at 20°C at a concentration of at least 20% by weight, at least 40% by weight, at least 50% by weight, or at least 60% by weight. Maximum solubility is not desired, but for some applications, solubility exceeding 100% by weight or 80% by weight may be unnecessary.

[0031] The polyalkylene glycol should be solid at a maximum of 35°C. In some embodiments, it has a melting temperature of at least 40°C, at least 45°C, at least 50°C, or at least 54°C. In some embodiments, it has a melting temperature not exceeding 100°C, 80°C, 70°C, or 65°C.

[0032] In some embodiments, the polyalkylene glycol has a number average molecular weight of at least 2000 Da, at least 3000 Da, at least 4000 Da, at least 5000 Da, at least 6000 Da, at least 7000 Da, at least 7500 Da, or at least 8000 Da. In some embodiments, the polyalkylene glycol has a number average molecular weight of at most 25,000 Da, at most 20,000 Da, at most 15,000 Da, at most 12,000 Da, or at most 10,000 Da.

[0033] In some embodiments, the polyalkylene glycol has a viscosity at 100°C of at least 200 cSt, at least 400 cSt, at least 450 cSt, or at least 500 cSt. In some embodiments, the polyalkylene glycol has a viscosity at 100°C of at most 5000 cSt, at most 3000 cSt, at most 2000 cSt, or at most 1000 cSt.

[0034] Suitable polyalkylene glycols can be used for carbowax sentry. ™ Trademarks and the Kollisolv trademark are commercially available. Other preparations can be made by known methods, such as polymerization of the corresponding epoxide monomers in the presence of an acid or base initiator. See, for example, U.S. Patent Publication US 2007 / 0179199 A1 and “Introduction of Polyethylene Glycol (PEG)”, provided by BOC Sciences. https: / / peg.bocsci.com / resources / technical- information / introduction-of-polyethylene-glycol-peg .

[0035] Sugar alcohols are alkyl polyols having hydroxyl groups attached to each carbon atom. In some embodiments, sugar alcohols are linear and satisfy formula 2:

[0036]

[0037] Where n is the number of repeating units. In some embodiments, the sugar alcohol is cyclic.

[0038] In some embodiments, the sugar alcohol contains at least 4 carbon atoms (n=2), 5 carbon atoms (n=3), or 6 carbon atoms (n=4). In some embodiments, the sugar alcohol contains up to 18 carbon atoms (n=16), 12 carbon atoms (n=10), 8 carbon atoms (n=6), or 6 carbon atoms (n=4).

[0039] Sugar alcohols should be solid at a maximum of 50°C. In some embodiments, they have a melting temperature of at least 70°C, at least 90°C, or at least 100°C. In some embodiments, they have a melting temperature not exceeding 220°C, 205°C, 180°C, 170°C, or 165°C.

[0040] Examples of suitable sugar alcohols include erythritol, xylitol, mannitol, and sorbitol. In some embodiments, the sugar alcohol is mannitol. In some embodiments, the sugar alcohol is sorbitol. In some embodiments, the sugar alcohol comprises a mixture of two or more sugar alcohols. The mixture may have a lower melting temperature than the pure sugar alcohol, thereby allowing the melting temperature to be controlled by controlling the mixture. For example, mannitol melts at about 165°C, and sorbitol melts at about 200°C, while a eutectic mixture of mannitol and sorbitol may melt at a temperature below 100°C depending on the selected proportions.

[0041] Suitable sugar alcohols are commercially available. Other sugar alcohols can be prepared by hydrogenating the corresponding sugar.

[0042] The granular composition contains 5% to 50% by weight of polyalkylene glycol based on the combined weight of polyalkylene glycol and sugar alcohol. In some embodiments, the granular composition contains at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% by weight of polyalkylene glycol based on the combined weight of polyalkylene glycol and sugar alcohol. In some embodiments, the granular composition contains up to 40%, at most 30%, at most 25%, at most 20%, at most 18%, or at most 16% by weight of polyalkylene glycol based on the combined weight of polyalkylene glycol and sugar alcohol.

[0043] The granular composition contains 50% to 95% by weight of a sugar alcohol based on the combined weight of the polyalkylene glycol and the sugar alcohol. In some embodiments, the granular composition contains at least 60% by weight, or at least 70% by weight, or at least 75% by weight, or at least 80% by weight, or at least 82% by weight, or at least 84% by weight, or at least 88% by weight of a sugar alcohol based on the combined weight of the polyalkylene glycol and the sugar alcohol. In some embodiments, the granular composition contains at most 92% by weight, or at most 91% by weight, or at most 90% by weight of a sugar alcohol based on the combined weight of the polyalkylene glycol and the sugar alcohol.

[0044] The particulate composition further contains a hydrophobic flow aid suitable for pharmaceutical use. In some embodiments, the flow aid includes silica, pyrolytic silica, aluminosilicate, or mixtures thereof. In some embodiments, the flow aid includes hydrophobic pyrolytic silica, and in some embodiments, the flow aid consists essentially of hydrophobic pyrolytic silica. Pyrolytic silica is a powder containing molten amorphous silica with low bulk density and high surface area. Pyrolytic silica is hydrophilic but can be made hydrophobic by treatment with a hydrophobic material such as silicone.

[0045] In some embodiments, the D90 particle size of the hydrophobic flow aid is (90% of the particles are smaller than) at most 200 mesh (74 micrometers), at most 270 mesh (53 micrometers), or at most 325 mesh (44 micrometers). In some embodiments, the D90 particle size of the hydrophobic flow aid is (90% of the particles are smaller than) at least 500 mesh (25 micrometers) or at most 400 mesh (37 micrometers).

[0046] In some embodiments, the hydrophobic flow aid has a flow rate of at least 100 m 2 / g or at least 150m 2 / g or at least 175m 2 / g BET surface area. In some embodiments, the hydrophobic flow aid has a maximum of 500m². 2 / g or up to 300m 2 / g or up to 250m 2 / g or at most 225m 2 / g of BET surface area.

[0047] In some embodiments, the hydrophobic flow aid has a loose bulk density of up to 200 g / L, up to 150 g / L, up to 100 g / L, up to 70 g / L, or up to 60 g / L. In some embodiments, the hydrophobic flow aid has a loose bulk density of at least 10 g / L, at least 20 g / L, at least 40 g / L, or at least 50 g / L.

[0048] The amount of hydrophobic flow aid used in this method is sufficient to reduce the adhesion of the spray-dried particles to the surface of the drying chamber. In some embodiments, the particle composition contains at least 0.1% by weight, or at least 0.3% by weight, or at least 0.5% by weight, or at least 0.7% by weight, or at least 0.9% by weight, or at least 1% by weight of the hydrophobic flow aid based on the combination of polyalkylene glycols and sugar alcohols. In some embodiments, the particle composition contains at most 5% by weight, or at most 4% by weight, or at most 3% by weight, or at most 2% by weight of the hydrophobic flow aid based on the combination of polyalkylene glycols and sugar alcohols.

[0049] Hydrophobic flow aids, such as hydrophobic pyrolytic silica, are known and commercially available, such as those that can be applied to DOWSIL. ™ The trademarks Cabosil and Aerosil are commercially available. Pyrolytic silica can also be prepared by flame pyrolysis of silicon tetrachloride or by evaporation of quartz sand in a high-temperature electric arc, and can be converted into hydrophobic pyrolytic silica by treatment with organosilanes. See, for example, European Patent Publication EP0928818A2.

[0050] The granule composition optionally contains 0% to 22% by weight of other excipients for oral pharmaceutical products and tablets. A variety of excipients are available for many different purposes, such as...

[0051] • Fillers and diluents

[0052] • Adhesives,

[0053] • Anti-caking agent

[0054] •Suspensors and viscosity agents

[0055] • Coating,

[0056] • Flavoring agents and sweeteners,

[0057] • Disintegrants,

[0058] • Colorants,

[0059] • Lubricants and flow aids,

[0060] •preservative,

[0061] • Surfactants,

[0062] • Controlled-release agents,

[0063] • Blending and mixing aids; and

[0064] • Compression aids.

[0065] Examples of useful excipients include microcrystalline cellulose, 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, microcrystalline cellulose, fatty alcohols, fatty acid salts, waxes, acrylic polymers, and proteins. More common examples include magnesium stearate, calcium phosphate, starch, silicone / titanium dioxide, colloidal silica, microcrystalline cellulose, stearic acid, sodium glycolate starch, gelatin, talc, sucrose, calcium stearate, edible dyes, cross-linked carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, povidone, and cross-linked povidone. Some excipients are further described in Kibbe, Handbook of Pharmaceutical Excipients, Third Edition (2000); paragraphs [9] to

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

[0073] to

[0084] (inclusive) of PCT Publication WO 2021 / 231946 A1.

[0066] In some embodiments, the particulate composition contains at least 1% by weight, or at least 2% by weight, or at least 3% by weight, or at least 4% by weight, or at least 5% by weight, of other excipients based on the combination of sugar alcohol and polyalkylene glycol. In some embodiments, the particulate composition contains at most 20% by weight, or at most 18% by weight, or at most 16% by weight, or at most 14% by weight, or at most 12% by weight, or at most 10% by weight, or at most 8% by weight, or at most 6% by weight, of other excipients based on the combination of sugar alcohol and polyalkylene glycol.

[0067] In some embodiments, the granule composition further comprises one or more active ingredients. The active ingredient may comprise any medicine, probiotic, or nutrient that is solid at room temperature and suitable for oral administration. Examples of active ingredients are described in numerous sources, such as paragraphs

[0065] through

[0072] (including the start and end paragraphs) of PCT publication WO 2021 / 231946 A1. Examples of potential active ingredients include vitamins, such as vitamin A, vitamin B, vitamin C, vitamin D, and / or vitamin E, and other nutritional supplements; probiotics, such as bacteria; analgesics, such as aspirin, acetaminophen, or ibuprofen; decongestants; antibiotics; antacids; and other medicines. In some embodiments, the granule composition comprises a single active ingredient. In some embodiments (such as multivitamins), the composition may comprise multiple active ingredients.

[0068] The active ingredient can be present at a pharmaceutically effective concentration, which can vary depending on the active ingredient. Some drug tablets may contain as low as 5 mg or less of active ingredient. On the other hand, some vitamin tablets may contain 1000 mg or more of active vitamin.

[0069] In the method of the present invention, sugar alcohols and polyalkylene glycols, along with optionally other excipients and / or active ingredients (collectively, “dry components”), are mixed in a solvent to form a solution. The solution is then spray-dried in the presence of a hydrophobic flow aid to prepare the particulate composition of the present invention.

[0070] For clarity, the sugar alcohol and polyalkylene glycol must be mixed into the solution, and the hydrophobic flow aid must be introduced separately into the spray drying chamber during spray drying of the solution. However, any other excipients and active ingredients may be added to the granule composition at one or more stages of its production and use. Other excipients and / or active ingredients may be dissolved or suspended in the solution prior to spray drying of the granule composition. They may be introduced into the spray drying chamber when the granule composition is dried. They may be physically mixed with the granule composition after recovery from spray drying and / or before compression into tablets.

[0071] To form this solution, the sugar alcohol and polyalkylene glycol, along with optionally other dry components, are mixed in a solvent until a homogeneous solution is formed. In some embodiments, the solvent comprises water or comprises at least 50% by weight of water (referred to as an aqueous solvent). In some embodiments, the solvent comprises lower alkanols, 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 step.

[0072] In some embodiments, the solution contains at least 1% by weight of dry components, or at least 5% by weight, or at least 10% by weight of dry components. In some embodiments, the solution contains up to 60% by weight of dry components, or up to 50% by weight of dry components. In some embodiments, the solution contains at least 40% by weight of solvent, or at least 50% by weight of solvent. In some embodiments, the solution contains up to 99% by weight of solvent, or up to 95% by weight, or up to 90% by weight of solvent. In some embodiments, one or more of these dry components may have been dissolved or suspended in a solvent, and this solvent may be taken into account when calculating the total solvent in the solution. The percentage of dry components in the solution reflects the proportions already discussed.

[0073] In some embodiments, the dry components of the solution may affect the acidity of the solution. In some embodiments, the pH of the solution is at least 4, at least 5, at least 6, or at least 7. In some embodiments, the pH of the solution is at most 10, at most 8, at most 7.5, or at most 7. In some embodiments, the pH can be controlled by a buffer solution. Suitable buffer solutions are known and commercially available. Examples may include citrate esters and citrate salts, as well as phosphates.

[0074] The solution was spray-dried according to known techniques. Spray drying equipment is commercially available with its instruction manual, and spray drying is described in many publications, such as Santos et al., “Spray Drying - A Overview,” available from: http: / / dx.doi.org / 10.5772 / intechopen.72247 ; "Spray Dry Manual" published by Bete PerformanceSpray Engineering on www.BETE.com; and More Swati et al., "Review on Spray Drying Technology" 4(2) IJPCBS 219-225 (2014).

[0075] In summary, the spray drying step has the following sub-steps:

[0076] 1. The solution is atomized (sprayed) in a drying chamber to form atomized droplets, while a hydrophobic flow aid is introduced into the drying chamber in an amount sufficient to reduce the adhesion of the spray-dried particles to the surface of the drying chamber;

[0077] 2. The atomized droplets are contacted with heated gas in a drying chamber under conditions that dry the droplets into dry particles, in the presence of a hydrophobic flow aid; and

[0078] 3. Separate and recover the dried particles from the gas.

[0079] In some embodiments, the drying chamber may have a cylindrical portion and a narrowed conical portion at the bottom, where the dried particles 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 other embodiments, the heated gas is an inert gas, such as nitrogen or carbon dioxide.

[0080] Spray drying methods are sometimes classified as:

[0081] 1. Co-flow: The solution and the drying gas are both fed into the drying chamber at the top and flow out of the bottom of the chamber together in the same direction.

[0082] 2. Countercurrent: The solution is fed from the top of the drying chamber to the middle of the chamber, flows to the bottom, and exits from the bottom. The drying gas is fed into the chamber near or below the bottom of the cylindrical portion of the drying chamber, and flows upward in the opposite direction to the solution / particles, exiting from the top of the drying chamber.

[0083] 3. Mixing Mode: The solution is fed into the chamber and atomized near the bottom of the cylindrical section of the chamber. Drying gas is fed into the chamber at the top. The dried particles fall to the bottom of the chamber and are recovered there, while the drying gas may exit at the bottom or midpoint of the chamber.

[0084] The spray drying step in this invention can use any of these configurations. In some embodiments, it is a hybrid spray drying mode.

[0085] The hydrophobic flow aid is sprayed separately from the solution into the drying chamber. For example, in one embodiment of a mixed-mode spray dryer, a solution containing sugar alcohol and polyoxyethylene can be fed and atomized at a common point near the bottom of the cylindrical portion of the chamber, and the hydrophobic flow aid can be sprayed separately into the drying chamber near or above the top of the cylindrical portion.

[0086] In some embodiments, other excipients and / or active ingredients may also be sprayed separately from the solution into the drying chamber, as described for hydrophobic flow aids.

[0087] The spray drying method of the present invention is carried out at a temperature and gas flow rate at which the atomized droplets are rapidly dried without substantially degrading the components of the particulate composition. Typically, the inlet temperature is higher than the outlet temperature. In some embodiments, the inlet temperature is at least 100°C, at least 120°C, at least 130°C, or at least 140°C. In some embodiments, the inlet temperature does not exceed 200°C, 180°C, 160°C, or 150°C. The gas flow rate will vary depending on the equipment; generally, the rate should be fast enough to quickly dry the atomized particles without causing them to agglomerate, but slow enough to prevent the particles from being carried away by the gas.

[0088] In some embodiments, the atomized droplets become sufficiently dry to prevent significant further agglomeration within 60 seconds, 30 seconds, or 15 seconds. There is no minimum drying time, but in some embodiments, a drying time of less than 1 second or 5 seconds is unnecessary. In some embodiments, the resulting particles contain no more than 15% by weight, no more than 10% by weight, no more than 8% by weight, or no more than 7% by weight of water. In some embodiments, the resulting particles contain at least 1% by weight, at least 2% by weight, at least 3% by weight, or at least 5% by weight of water.

[0089] Spray-dried particles are separated from and recovered from the drying gas by known methods, such as through cyclone separators, bag filters, or electrostatic precipitators.

[0090] We hypothesize that spray drying results in a different morphology of the particulate composition compared to when the components are physically blended. Physical blending produces a mixture of discrete particles containing sugar alcohols and polyepoxides, as well as other excipients and / or active ingredients, with virtually no mixing within these particles. On the other hand, we hypothesize that spray drying of the solution prepares particles, each containing a mixture of sugar alcohols and polyepoxides (and any other components dissolved or suspended in the solution). In some embodiments, the mixture of sugar alcohols and polyepoxides in these particles can be substantially homogeneous. When spray drying is performed in the presence of a separately added hydrophobic flow aid, we hypothesize that the flow aid is primarily embedded at or near the surface of these particles.

[0091] The ratio of dry components in the particles reflects the ratios already discussed.

[0092] In some embodiments, the particles of the particulate composition have an average particle size (D) of at least 5 micrometers, at least 8 micrometers, at least 10 micrometers, at least 20 micrometers, at least 50 micrometers, at least 75 micrometers, or at least 100 micrometers. 平均 In some embodiments, the particles of the particulate composition have an average particle size of up to 300 micrometers, up to 250 micrometers, up to 200 micrometers, up to 150 micrometers, up to 100 micrometers, up to 75 micrometers, up to 50 micrometers, up to 40 micrometers, or up to 30 micrometers. For example, some large-particle particulate compositions may have an average particle size of 75 micrometers to 200 micrometers or 100 micrometers to 150 micrometers, while some small-particle particulate compositions may have an average particle size of 5 micrometers to 50 micrometers or 10 micrometers to 30 micrometers.

[0093] In some embodiments, the angle of repose of the large-particle granular composition of the present invention is no more than 40°, 38°, 36°, 34°, 32°, or 30°. In some embodiments, the angle of repose of the large-particle granular composition of the present invention is at least 20°, 25°, 26°, 27°, or 28°. In some embodiments, the angle of repose of the large-particle granular composition of the present invention is no more than 50°, 40°, or 38°. In some embodiments, the angle of repose of the small-particle granular composition of the present invention is at least 25°, 30°, or 33°. In some embodiments, the angle of repose of the granular composition of the present invention is at least 1°, 2°, 3°, 5°, or 7° lower than that of the physical blend of the starting components (having a similar particle size profile). In some embodiments, the angle of repose of the granular composition of the present invention is no more than 15° or 10° lower than that of the physical blend of the starting components (having a similar particle size profile). In some embodiments, a low angle of repose can indicate that the particulate composition flows well and is easy to process.

[0094] The granular compositions of the present invention can be compressed into tablets by known methods. Prior to compression, as previously described, the granular compositions may optionally be blended with an active ingredient or other excipients. Blending can be performed using known equipment, such as impellers or rollers. In some embodiments, the composition to be compressed contains at least 50% by weight, or at least 60% by weight, or at least 70% by weight, or at least 80% by weight, or at least 90% by weight, or at least 95% by weight, or at least 98% by weight of the granular composition of the present invention (e.g., recovered from a dry spray). In some embodiments, the composition to be compressed contains at most 100% by weight, or no more than 99.99% by weight, or no more than 99.9% by weight, or no more than 99.5% by weight, or no more than 99% by weight of the granular composition of the present invention (e.g., recovered from a dry spray).

[0095] Equipment for compressing tablets is commercially available and comes with instructions for use. The optimal compression pressure for tablet preparation varies considerably depending on the components chosen for the granule composition. In some embodiments, compression is performed at a pressure of at least 10 MPa, at least 20 MPa, at least 40 MPa, or at least 50 MPa. In some embodiments, compression is performed at a pressure not exceeding 500 MPa, at least 400 MPa, at least 300 MPa, or at least 250 MPa. 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 not exceeding 70°C or at least 40°C.

[0096] The resulting tablets can be of any size suitable for oral administration. In some embodiments, the sum of the length, width, and depth of the tablet is at least 9 mm, at least 11 mm, or at least 13 mm. In some embodiments, the sum of the length, width, and depth of the tablet is at most 35 mm, at most 30 mm, or at most 25 mm. Optionally, the tablets may be coated after compression (e.g., with gelatin or delayed-release coating).

[0097] In some embodiments, the tablets of the present invention may have crush resistance (hardness) of at least 3500 g / mm, at least 4000 g / mm, at least 5000 g / mm, at least 6000 g / mm, at least 7000 g / mm, or at least 8000 g / mm. There is no maximum desired crush resistance, but in some embodiments, crush resistance exceeding 15,000 g / mm or 10,000 g / mm is unnecessary. In some embodiments, the tablets of the present invention may have crush resistance (hardness) at least 1000 g / mm or at least 2000 g / mm higher than tablets prepared from a physical blend of the same components. There is no maximum desired improvement in crush resistance, but in some embodiments, improvements exceeding 8000 g / mm or 6000 g / mm are unnecessary.

[0098] In some embodiments, the tablets of the present invention may dissolve more slowly than tablets prepared from a physical blend of the same ingredients.

[0099] Test methods

[0100] Unless it is clearly apparent from the context that they are different methods, the properties described in this paper are measured using the following test methods.

[0101]

[0102] Example

[0103] The following examples illustrate some embodiments of the present invention.

[0104] The examples use the materials listed in Table 1.

[0105]

[0106] For Examples 1 to 5 (IE1-IE5) of the present invention, the sugar alcohol, polyalkylene glycol, and inorganic excipients of Table 1 were blended with water in the proportions shown in Table 2 to form a homogeneous solution containing about 20% by weight of solids. (The inorganic excipients were not dissolved in the solution but formed a suspension.) The slurry was spray-dried according to the following procedure to prepare a particulate composition. The spray dryer was a Mobile Minor spray dryer (GEA Process Engineering Inc.) equipped with a two-fluid nozzle atomizer. Spray drying was performed under an inert nitrogen atmosphere. Nitrogen was supplied to the atomizer at 1 bar and 50% flow rate (equivalent to a flow rate of 6.0 kg / h) at ambient temperature. The solution was fed into the atomizer using a peristaltic pump (Masterflex L / S) at about 30 mL / min. Heated nitrogen was fed as the drying gas into the top of the drying chamber at a flow rate of about 20 SCFM. The inlet temperature was set to 140°C, and the outlet temperature was balanced between 40°C and 50°C by fine-tuning the solution feed rate. Flow aids were added at the top of the drying chamber via a Coperion K-TRON screw feeder at a feed rate of 0.1 g / min. The resulting spray-dried particulate composition was recovered in a cyclone separator and subsequently vacuum-dried at room temperature to remove residual moisture.

[0107] For Comparative Example CE1, the same procedure as in the embodiments of the present invention was followed, but without the use of flow aids; the product adhered to the spray dryer wall, and the product was not recovered. For Comparative Example CE3, the same procedure as in the embodiments of the present invention was followed, but without the use of alkylene glycols. For Comparative Examples CE2 and Comparative Examples CE4-CE6, the materials were physically blended until a homogeneous particulate composition was obtained. The comparative examples are shown in Table 2.

[0108] Particle size and flowability (angle of repose) of each particulate composition were measured as described in the test methods. Particle size is shown in Table 2. Flowability and miscibility results are shown in Table 3.

[0109] A Carver compression molding machine was used to compress each granular composition to prepare tablets. A 2-gram sample of each granular composition was weighed into a template and a weight of 5000 lbs was applied to prepare a disc-shaped tablet with a diameter of 13 / 16 inches. Tablet hardness and dissolution were tested as described in the test methods. The results are presented in Table 3 below. For dissolution rate:

[0110] • Very fast = less than 10 seconds

[0111] • Fast = 10 to 60 seconds

[0112] • Slow = 60 to 600 seconds, and

[0113] • Very slow = greater than 600 seconds

[0114]

Claims

1. A particulate composition, said particulate composition comprising: a) 5% to 50% by weight of a water-soluble polyalkylene glycol, wherein the water-soluble polyalkylene glycol is solid at at least 35°C; and b) 50% to 97% by weight of a sugar alcohol, wherein the sugar alcohol is solid at at least 50°C; and c) 0.5% to 5% by weight of a hydrophobic flow aid. The individual particles of the granular composition contain a mixture of the polyalkylene glycol and the sugar alcohol, and the hydrophobic flow aid is primarily located on the surface of the particles, and all percentages are based on the combined weight of the polyalkylene glycol and the sugar alcohol.

2. The particulate composition according to claim 1, wherein the sugar alcohol comprises erythritol, xylitol, mannitol or sorbitol.

3. The particulate composition according to claim 2, wherein the particulate composition contains 80% to 95% by weight of sugar alcohol based on the combination of polyalkylene glycol and sugar alcohol.

4. The particulate composition according to claim 3, wherein the sugar alcohol comprises mannitol.

5. The particulate composition according to claim 1, wherein the polyalkylene glycol is polyethylene glycol or a polyethylene glycol-polypropylene glycol copolymer.

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

7. The particulate composition of claim 6, wherein the particulate composition contains 5% to 15% by weight of polyalkylene glycol based on the combination of polyalkylene glycol and sugar alcohol.

8. The particulate composition according to claim 1, wherein the hydrophobic flow aid comprises hydrophobic pyrolytic silica.

9. The particulate composition of claim 8, wherein the particulate composition contains 0.5% to 3% by weight of hydrophobic pyrolytic silica based on the combination of polyalkylene glycols and sugar alcohols.

10. The particulate composition according to claim 1, wherein the particulate composition comprises: a) 80% to 95% by weight of erythritol, xylitol, mannitol or sorbitol b) 5% to 15% by weight of polyethylene glycol or a polyethylene glycol-polypropylene glycol copolymer, wherein the polyethylene glycol or polyethylene glycol-polypropylene glycol copolymer has a molecular weight of at least 4000 Da and at most 12,000 Da, and c) 0.5% to 3% by weight of a hydrophobic flow aid, wherein the hydrophobic flow aid comprises hydrophobic pyrolytic silica. All percentages are based on the combined weight of the polyalkylene glycols and sugar alcohols.

11. The particulate composition of claim 10, further comprising 1% to 20% by weight of other excipients based on the combination of polyalkylene glycols and sugar alcohols, wherein said other excipients are selected from the group consisting of: dibasic phosphates, calcium carbonate, calcium sulfate, rock salt, metal oxides, colloidal silica, carbohydrates, starch, cellulose ethers, microcrystalline cellulose, fatty alcohols, fatty acid salts, waxes, acrylic polymers, and proteins.

12. The particulate composition according to claim 10, wherein the particulate composition has an average particle size of 5 micrometers to 50 micrometers and an angle of repose of not more than 40˚.

13. The particulate composition of claim 10, wherein the particulate composition has an average particle size of 75 micrometers to 200 micrometers and an angle of repose of no more than 30˚.

14. A solid tablet, said solid tablet comprising: An oral medication dispersed in (2) a pharmaceutically effective amount of (1) of the compressed granule composition according to any one of claims 1 to 12.

15. A method for preparing a particulate excipient composition, the method comprising the following steps: a) Prepare a solution containing the following dry components in a solvent: i) 5% to 50% by weight of water-soluble polyalkylene glycol, wherein the water-soluble polyalkylene glycol is solid at at least 35°C; ii) 50% to 95% by weight of sugar alcohols, wherein the sugar alcohols are solid at at least 50°C. The weight percentages are based on the total weight of the dry components excluding the solvent; and b) The solution is spray-dried in a drying chamber in the presence of a hydrophobic flow aid in an amount sufficient to reduce the adhesion of the spray-dried particles to the surface of the drying chamber to form a dry particle composition. All percentages are based on a combined weight of polyalkylene glycols and sugar alcohols.

Images