To stabilize the disintegration time of pharmaceuticals, minimize the aggregation of drug particle coating materials during storage.

Abstract

To provide pharmaceutical compositions and methods for preparing pharmaceutical compositions using solventless mixing methods.SOLUTION: Excess coating material that is not bound to a coated API particle may be removed by a sieving process. Coating and dosing ratios can also be optimized to minimize an amount of excess unbound coating material. Specifically, a coating ratio and / or a dosing ratio can be used to minimize a residual amount of excess unbound coating material to minimize agglomeration of coating material during storage. In some embodiments, a pharmaceutical composition is provided, the pharmaceutical composition comprising: 65 to 85%w / w API particles; 15 to 30%w / w coating material coating the API particles; and 3 to 15%w / w matrix surrounding the coated API particles, wherein the pharmaceutical composition comprises a disintegration time rate of less than 10 seconds for at least six months under storage conditions of at least 25°C and at least 60% relative humidity.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the priority of U.S. Provisional Application No. 62 / 809,307, filed on February 22, 2019, the entire content of which is incorporated herein by reference.

[0002] This relates to a process for coating active pharmaceutical ingredient (API) particles, and more particularly to a process for minimizing excess coating material and preventing aggregation of the coated material in a freeze - dried orally disintegrating dosage form during storage.

Background Art

[0003] Pharmaceutical compositions typically contain both an active pharmaceutical ingredient and one or more inactive ingredients. The active pharmaceutical ingredient (API) is biologically active and is designed to directly affect a patient's symptoms, disease, disorder, and / or illness. On the other hand, the inactive ingredient(s) of a pharmaceutical composition are pharmaceutically inactive and can be used for various purposes including improving long - term stabilization, filling or diluting solid dosage forms, promoting drug absorption, adjusting the viscosity of liquid dosage forms, improving solubility, and / or assisting in the manufacture of the pharmaceutical composition, but are not limited thereto.

[0004] In addition, some inactive ingredients can be used to mask the taste of the API. Many APIs are known to exhibit unpleasant sensory properties such as bitterness, a burning sensation, and numbness when dissolved in the mouth. For example, some orally administered pharmaceutical compositions are designed to disperse in the mouth to enable administration without water and target pediatric patients, elderly patients, animal patients, and / or other types of patients who may have difficulty swallowing. In the case of these types of orally administered pharmaceutical compositions, an "functional coating" can be formed using inactive ingredients to mask the taste of the API.

[0005] For example, the taste of the API may be masked by using an inert component to wet or dry coat the API particles, creating a functional coating that surrounds the API particles and prevents the release of the API in the mouth. In wet particle coating, the inert component (polymer and additive) is dissolved or dispersed in a solvent or water to form a suspension or solution. This suspension or solution can then be sprayed onto the surface of the API particles, and a film coating can be formed by the evaporation of the solvent or water. Examples of techniques for wet particle coating include microencapsulation, fluid floor coating, spray drying, and pan coating. In dry particle coating (also called solvent-free coating), the API particles are physically coated with fine particles of the inert component (polymer and additive) to form a particle composite. Examples of dry particle coating include hot melt coating, supercritical coating, impaction coating, and electrostatic coating. API particles coated with taste-masking inert components can provide a more comfortable experience for patients with dysphagia or taste sensitivity that would otherwise result in a negative patient experience and poor compliance.

[0006] For example, a dry, solvent-free mixing method may use high-energy vibrations or acoustic resonance to mix the API with the inert component(s). Furthermore, coating API particles with a functional coating can temporarily delay the release of the API in the patient's mouth during the dispersion of the pharmaceutical composition, but still ensure that at least 90% of the API released without coating is released from the functionally coated API within a suitable amount of time for absorption. By coating the API with a taste-masking inert component, the dissolution rate of the coated API particles can be controlled, ensuring that the majority of the coated API particles are not released until after the coated API particles have entered the patient's stomach. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] A method is provided for minimizing the aggregation of coating materials for coated API particles produced using various mixing processes. API particles coated using conventional mixing processes often experience excessive aggregation of coating materials, particularly during storage. Aggregation of coating materials can reduce the stability of the drug over time. For example, the disintegration time of a drug may increase over time if it contains aggregated coating material. Increased disintegration time and / or decreased dissolution rate implies an unstable drug. An unstable drug may result in a shorter shelf life than desired. Therefore, the embodiments provided can help minimize the aggregation of coating materials for coated API particles, improve the stability of the drug during storage, and increase its shelf life.

[0008] For example, the described method includes removing excess coating material from coated API particles to minimize the possibility of aggregation of coating material particles. In particular, the provided method includes sieving the coated API particles so that the final pharmaceutical product is adequately surrounded by a dry matrix, thereby minimizing any aggregation of coating material particles during storage. The described pharmaceutical composition provides a disintegration time and dissolution rate that remains relatively stable over time. [Means for solving the problem]

[0009] In some embodiments, a pharmaceutical composition is provided, comprising 65-85% w / w API particles, a coating material for coating the API particles at 15-30% w / w, and a matrix surrounding the coated API particles at 3-15% w / w, wherein the pharmaceutical composition has a decay time of less than 10 seconds for at least 6 months under storage conditions of at least 25°C and at least 60% relative humidity. In some embodiments, the coating material comprises a first coating material and a second coating material, wherein the pharmaceutical composition comprises 10-30% w / w of the first coating material and 0.5-10% w / w of the second coating material. In some embodiments, the first coating material comprises wax. In some embodiments, the second coating material comprises silica. In some embodiments of the pharmaceutical composition, the pharmaceutical composition has a decay time of less than 10 seconds for at least 6 months under storage conditions of at least 30°C and at least 65% relative humidity. In some embodiments of the pharmaceutical composition, the pharmaceutical composition includes a decay time of less than 10 seconds for at least 6 months under storage conditions of at least 40°C and at least 75% relative humidity. In some embodiments of the pharmaceutical composition, the API particles include one or more of the following: anti-inflammatory agents, analgesics, antipsychotics, antiemetics, laxatives, antidiarrheals, antihistamines, or antidepressants. In some embodiments of the pharmaceutical composition, the coating material includes silica as one or more of the following: protective agents or flow aids. In some embodiments of the pharmaceutical composition, the coating material includes wax. In some embodiments of the pharmaceutical composition, the coating material includes one or more of the following: carnauba wax, candelilla wax, or synthetic waxes. In some embodiments of the pharmaceutical composition, the coating ratio used to combine the API particles with the coating material includes 5-85% w / w of coating material and 15-95% w / w of uncoated API particles. In some embodiments of the pharmaceutical composition, the matrix includes matrix-forming agents and structure-forming agents. In some embodiments of the pharmaceutical composition, the matrix-forming agent comprises one or more of the following: water-soluble materials, water-dispersible materials, polypeptides, polysaccharides, polyvinyl alcohol, polyvinylpyrrolidone, and acacia.In some embodiments of the pharmaceutical composition, the matrix-forming agent comprises a polypeptide. In some embodiments of the pharmaceutical composition, the polypeptide comprises gelatin. In some embodiments of the pharmaceutical composition, the structure-forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin. In some embodiments of the pharmaceutical composition, the structure-forming agent comprises mannitol.

[0010] In some embodiments, a pharmaceutical composition is provided, which is prepared by a process comprising: coating API particles with a first coating material to form coated API particles, wherein the coating material comprises one or more deformable components; applying mechanical stress to the coated API particles to deform one or more deformable components; coating the coated API particles with silica; applying mechanical stress to embed the silica in the coated API particles; sieving the coated API particles to remove excess coating material, wherein the excess coating material comprises coating material not bonded to the coated API particles; mixing the coated API particles in a matrix solution / suspension to form a pharmaceutical suspension; and administering the pharmaceutical suspension into a mold, wherein the pharmaceutical composition has a decay time of less than 10 seconds for at least 6 months under storage conditions of at least 25°C and at least 60% relative humidity. In some embodiments of the pharmaceutical composition, the dosage ratio used to combine coated API particles with a matrix solution / suspension includes 5-60% w / w coated API particles to 40-95% w / w matrix solution / suspension. In some embodiments of the pharmaceutical composition, the coating ratio used to combine API particles with a coating material includes 5-85% w / w coating material and 15-95% w / w uncoated API particles. In some embodiments of the pharmaceutical composition, the pharmaceutical composition includes freezing the administered suspension under subzero conditions and lyophilizing it to form a lyophilized pharmaceutical composition. In some embodiments of the pharmaceutical composition, the pharmaceutical composition includes a decay time of less than 10 seconds for at least 6 months under storage conditions of at least 30°C and at least 65% relative humidity. In some embodiments of the pharmaceutical composition, the pharmaceutical composition includes a decay time of less than 10 seconds for at least 6 months under storage conditions of at least 40°C and at least 75% relative humidity.In some embodiments of the pharmaceutical composition, the pharmaceutical composition contains 65-85% w / w API particles. In some embodiments of the pharmaceutical composition, the pharmaceutical composition contains 15-30% w / w coating material. In some embodiments of the pharmaceutical composition, the pharmaceutical composition contains 3-15% w / w matrix. In some embodiments of the pharmaceutical composition, the method used to prepare the pharmaceutical composition includes sieving uncoated API particles. In some embodiments of the pharmaceutical composition, sieving coated API particles includes passing the coated API particles through a device having two or more sieves. In some embodiments of the pharmaceutical composition, sieving coated API particles includes sieving the coated API particles to an average particle size of 75 μm or more. In some embodiments of the pharmaceutical composition, sieving coated API particles includes sieving the coated API particles to an average particle size of 200 μm or less. In some embodiments of the pharmaceutical composition, the API particles include one or more of the following: anti-inflammatory agents, analgesics, antipsychotics, antiemetics, laxatives, antidiarrheals, antihistamines, or antidepressants. In some embodiments of the pharmaceutical composition, the coating material includes silica as one or more of the following: a protective coating or a flow aid. In some embodiments of the pharmaceutical composition, one or more deformable components of the coating material include wax. In some embodiments of the pharmaceutical composition, the wax includes one or more of the following: carnauba wax, candelilla wax, or synthetic wax. In some embodiments of the pharmaceutical composition, the matrix includes a matrix-forming agent and a structure-forming agent. In some embodiments of the pharmaceutical composition, the matrix-forming agent includes one or more of the following: water-soluble materials, water-dispersible materials, polypeptides, polysaccharides, polyvinyl alcohol, polyvinylpyrrolidone, and acacia. In some embodiments of the pharmaceutical composition, the matrix-forming agent includes a polypeptide. In some embodiments of the pharmaceutical composition, the polypeptide includes gelatin.In some embodiments of the pharmaceutical composition, the structure-forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin. In some embodiments of the pharmaceutical composition, the structure-forming agent comprises mannitol.

[0011] In some embodiments, a method is provided for treating a patient, the method comprising administering a therapeutic dose of a pharmaceutical composition to the patient. In some embodiments of the method, the patient is a human.

[0012] In some embodiments, a method is provided for preparing a pharmaceutical composition, the method comprising: coating API particles with a first coating material to form coated API particles, wherein the coating material comprises one or more deformable components; applying mechanical stress to the coated API particles to deform one or more deformable components of the coating material to form a continuous film layer on the surface of the API particles; applying mechanical stress to coat the coated API particles with silica to form a second coating by partially embedding or embedding silica in the deformable coating; sieving the coated API particles to remove excess coating material; mixing the coated API particles in a matrix solution / suspension to form a pharmaceutical suspension; and administering the pharmaceutical suspension into a mold. In some embodiments of the method, the dosage ratio used to combine the coated API particles with the matrix solution / suspension comprises 5-60% w / w coated API particles to 40-95% w / w matrix solution / suspension. In some embodiments of the method, the coating ratio used to combine API particles with a coating material comprises 5–85% w / w of coating material and 15–95% w / w of uncoated API particles. In some embodiments of the method, the method includes freezing the administered suspension at a temperature below zero degrees and lyophilizing it to form a lyophilized pharmaceutical composition. In some embodiments of the method, the method includes sieving the uncoated API particles. In some embodiments of the method, sieving the coated API particles includes passing the coated API particles through a device having two or more sieves. In some embodiments of the method, sieving the coated API particles includes sieving the coated API particles to an average particle size of 75 μm or larger.In some embodiments of the method, sieving the coated API particles includes sieving the coated API particles to an average particle size of 200 μm or less. In some embodiments of the method, the API particles include one or more of the following: anti-inflammatory agents, analgesics, antipsychotics, antiemetics, laxatives, antidiarrheals, antihistamines, or antidepressants. In some embodiments of the method, the coating material includes silica as one or more of the following: protective coatings or flow aids. In some embodiments of the method, one or more deformable components of the coating material include wax.

[0013] In some embodiments of the method, the wax comprises one or more of carnauba wax, candelilla wax, or synthetic waxes. In some embodiments of the method, the matrix comprises a matrix-forming agent and a structure-forming agent. In some embodiments of the method, the matrix-forming agent comprises one or more of water-soluble materials, water-dispersible materials, polypeptides, polysaccharides, polyvinyl alcohol, polyvinylpyrrolidone, and acacia. In some embodiments of the method, the matrix-forming agent comprises a polypeptide. In some embodiments of the method, the polypeptide comprises gelatin. In some embodiments of the method, the structure-forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin. In some embodiments of the method, the structure-forming agent comprises mannitol.

[0014] Herein, the present invention will be described with reference to the accompanying drawings, merely as an example. [Brief explanation of the drawing]

[0015] [Figure 1A] The following are API particles coated with deformable coating material particles (i.e., a first coating layer) according to several embodiments. [Figure 1B] The following are some embodiments showing API particles coated with a continuous film layer of deformable coating material (i.e., a first coating layer). [Figure 1C]The following are some embodiments showing API particles coated with a continuous film layer of deformable coating material (i.e., the first coating layer) together with partially embedded and / or embedded silica particles (i.e., the second coating layer) on the surface of the first coating layer. [Figure 2] Scanning electron microscope (SEM) images of uncoated API particles in several embodiments are shown. [Figure 3] SEM images of coated API particles in several embodiments are shown. [Figure 4] This is a flowchart of a mixing process for preparing coated API particles according to several embodiments. [Figure 5] (A~P) These are a series of micrographs taken of the sieved coated APIs of Examples 1~8. [Modes for carrying out the invention]

[0016] Exemplary embodiments of methods for minimizing and / or preventing aggregation of coating material in coated API particles are described herein. In particular, methods according to some embodiments include minimizing and / or preventing aggregation of coating material in a pharmaceutical by removing excess coating material particles. In some embodiments, the method may include sieving raw API particles and / or coated API particles. Specifically, the methods provided may include sieving API particles and / or coated API particles to remove any undesirable particles, such as excess coating material particles. The sieving process according to the disclosed embodiments may help prevent and / or minimize the possibility of aggregation of coating material that could adversely affect the decay time and / or dissolution rate of the final product.

[0017] The methods for minimizing and / or preventing aggregation of coating material particles according to the embodiments described herein can be applied to a dry solvent-free mixing process for coating API particles. Accordingly, the methods provided are described below in the context of one or more dry solvent-free mixing processes for coating API particles. However, other variations of the coating / encapsulation process can also be used. For example, sugar coating, film coating, other variations of microencapsulation, compression coating, other variations of dry coating, melt coating, dip coating, rotary die coating, electrostatic coating, and / or other suitable types of coating can be used.

[0018] Generally, a solvent-free mixing process for coating API particles involves mixing a coating material with the API particles to produce coated API particles. The coated API particles are then mechanically and / or thermally stressed to deform the deformable coating material to create a continuous film surrounding the API particles. The coated API particles are then mixed with a matrix solution / suspension to form a pharmaceutical suspension. The pharmaceutical suspension containing the coated API particles can be administered to a preformed mold such as a blister pack and further processed to produce a dispensable pharmaceutical composition (e.g., lyophilized agent, wafer, tablet, etc.).

[0019] However, when the final product is stored, any excess coating material particles not bound to the coated API particles can aggregate. The amount and / or severity of aggregation can increase over time. Aggregation of the excess coating material can increase the disintegration time of the pharmaceutical and / or decrease the dissolution rate, and can adversely affect any functional properties of the coating material. An increase in disintegration time can also cause unacceptable dispersion and mouthfeel characteristics in vivo.

[0020] Thus, by sieving the coated API particles, excess coating material can be removed, and it has been found that the amount of aggregation of excess coating material during storage can be minimized. Further, some embodiments include optimizing the coating ratio (the amount of coating material relative to the amount of uncoated API) and also optimizing the dosing ratio (the amount of coated API particles relative to the matrix solution / suspension containing all other inert ingredients) can also minimize the aggregation of excess coating material particles.

[0021] The embodiments provided herein can be applied to coated API particles produced using a dry solventless process. For example, the processes according to some embodiments can be specifically designed to produce pharmaceutical compositions containing APIs with an unpleasant taste that can be administered to pediatric patients, elderly patients, animal patients, and / or other types of patients who may have difficulty swallowing or who may be sensitive to taste. In particular, many APIs have an undesirable taste and / or tingling effect that can be problematic for these patients. Thus, some mixing processes according to the embodiments described herein include coating the API particles with a taste masking coating. Such a coating can control the disintegration time and / or dissolution rate of an orally dispersible pharmaceutical composition such that the release of the API upon oral administration is delayed or significantly reduced during the first few minutes in the mouth, but a satisfactory amount of the API is released within 30 minutes from oral administration after swallowing. (For example, a satisfactory amount of the API may be 90% of the amount of API released without the coating). U.S. Patent No. 9,107,851 (the '851 patent) is directed to an exemplary dry solventless process for coating pharmaceutical ingredients, which is incorporated herein in its entirety.

[0022] However, other variations of the coating / encapsulation process may also be used. For example, sugar coating, film coating, other variations of microencapsulation, compression coating, other variations of dry coating, melt coating, dipping coating, rotary die coating, electrostatic coating, and / or other suitable types of coatings can be used.

[0023] Furthermore, certain data provided herein relate to disintegration time. However, disintegration time is inversely proportional to the dissolution rate. Therefore, the data also, in essence, provide information regarding the dissolution rate. Disintegration time may be measured according to the method specified by the United States Pharmacopeia (Disintegration 701). In some embodiments, disintegration time may be 2 to 30 seconds or 5 to 20 seconds. In some embodiments, disintegration time may be less than 30 seconds, less than 25 seconds, less than 20 seconds, less than 15 seconds, less than 10 seconds, or less than 5 seconds. In some embodiments, disintegration time may be greater than 2 seconds, greater than 5 seconds, greater than 10 seconds, greater than 15 seconds, greater than 20 seconds, or greater than 25 seconds. Similarly, dissolution rate may be tested according to the method specified by the United States Pharmacopeia (Dissolution 711).

[0024] Figures 1A, 1B, 1C, and 1C show different phases of coated API particles according to several embodiments. In some embodiments, API particles can be combined with one or more coating materials to produce coated API particles. This coating may include materials containing water-soluble and / or water-swellable materials as well as water-insoluble materials (described in detail below).

[0025] For example, Figure 1A shows API particles 102 surrounded by particles of coating material 104. To achieve the coated API particles of Figure 1A, the combined API particles (i.e., API particles 102) and one or more coating materials (i.e., coating material particles 104) may be exposed to mechanical and / or thermal energy to produce an ordered mixture of API particles 102 containing discrete layers of coating material particles 104 that layer the surface of the API particles 102. The API particles 102 in Figure 1A are shown as a single layer of discrete particles of the coating material. However, the API particles 102 may have two or more discrete layers of coating particles. Furthermore, Figure 2 shows an SEM image of uncoated API particles.

[0026] Figure 1B shows API particles 102 surrounded by a continuous deformable film layer 104. Specifically, Figure 1B shows that all of the coating material particles 104 may be deformable and can be deformed when subjected to mechanical stress and / or high temperature. Thus, since all coating materials include deformable properties, the coating material 104 in Figure 1B is a relatively smooth and continuous coating layer after exposure to mechanical and / or thermal energy. In some embodiments, the API particles 102 may have two or more relatively smooth and continuous coating layers. As used herein, “continuous film” may be a layer surrounding API particles formed by melting / softening or otherwise decomposing one or more deformable components of individual coating material particles so as to include a single continuous layer surrounding the API particles. Figure 3 also provides SEM images showing coated API particles according to some embodiments.

[0027] In some embodiments, one or more of the coating materials may not be deformable but may be embedded in a deformable coating layer. Thus, the continuous film may contain solid particles of non-deformable material embedded within the deformed coating material. Figure 1C shows that the continuous film 104 may contain one or more solid non-deformable particles 108 of non-deformable material that are partially embedded and / or embedded within the deformed coating material of the continuous film 104. This continuous film 104 in Figure 1B or 1C can ensure coating (e.g., a coating that masks the taste of the API) and delayed API release. In some embodiments, the API particles 102 may have two or more continuous coating layers that are partially embedded and / or embedded together with the non-deformable coating material particles. Figure 3 also provides SEM images showing functionally coated API particles according to some embodiments.

[0028] As used herein, the terms “deformable,” “deformable component,” “deformable component of coating material,” and other related terms refer to one or more components of a water-soluble, water-swellable, and / or water-insoluble material that can decompose when subjected to mechanical stress and / or high temperatures.

[0029] The coated API particle 102 may be any of a number of APIs. Figure 2 shows SEM images of uncoated API particles according to several embodiments. As used herein, “active pharmacokinetic” or “API” refers to a pharmaceutical product that may be used to diagnose, cure, alleviate, treat, or prevent a disease. Any API may be used for the purposes of this disclosure. Preferred APIs include, but are not limited to, analgesics and anti-inflammatory agents, acid-fasts, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarial agents, antimigraine agents, antimuscarinic agents, antitumor agents and immunosuppressants, antiprotasols, antipsychotics, antiemetics, antirheumatic agents, antithyroid agents, antivirals, anxiolytics, laxatives, sedatives, hypnotics and nerve blockers. Examples include beta-blockers, cardiac stimulants, corticosteroids, cough suppressants, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian drugs, gastrointestinal drugs, histamine receptor antagonists, laxatives, lipid regulators, local anesthetics, neuromuscular agents, nitrates and antianginal drugs, nutritional supplements, opioid analgesics, oral vaccines, proteins, peptides and recombinants, laxatives, sex hormones and contraceptives, spermicides and stimulants, and combinations thereof. A list of specific examples of these APIs can be found in U.S. Patent No. 6,709,669, incorporated herein by reference. Where present, the API is present in the pharmaceutical formulation in the amount necessary to exhibit the desired physiological effect as established by clinical research. Those skilled in the art can easily determine an appropriate amount of API to be included in a dosage form prepared in accordance with this disclosure.

[0030] In some embodiments, the coated API particles or pharmaceutical composition may contain 30.0–90.0% w / w of API. In some embodiments, the coated API particles or pharmaceutical composition may contain 40.0–85.0% w / w, 50.0–80.0% w / w, or 70.0–80.0% w / w of API. In some embodiments, the coated API particles or pharmaceutical composition may contain more than 40.0% w / w, more than 50.0% w / w, more than 60.0% w / w, more than 65% w / w, more than 70.0% w / w, more than 75.0% w / w, more than 80.0% w / w, or more than 85.0% w / w of API. In some embodiments, the coated API particles or pharmaceutical composition may contain APIs with concentrations of less than 90.0% w / w, less than 85.0% w / w, less than 80.0% w / w, less than 75.0% w / w, less than 70.0% w / w, less than 60.0% w / w, less than 50.0% w / w, or less than 40.0% w / w.

[0031] In some embodiments, raw API particles can be sieved before the coating process to achieve a narrower particle size range. For example, raw API particles may be sieved to remove particles that are too large and / or too small. In some embodiments, two or more meshes can be used to remove certain particles. For example, a sieving device may have a series of two or more meshes for removing particles of a certain size depending on the size of the mesh(s). The sieve can incorporate a vacuum transfer system to transport particles through the series of meshes of the device. Furthermore, an ultrasonic probe can be incorporated into the sieving device to improve the flow of material during processing and minimize mesh clogging.

[0032] In some embodiments, raw API particles can be sieved using mesh sizes of 30 μm to 500 μm, 50 μm to 450 μm, 100 μm to 400 μm, 150 μm to 350 μm, or 200 μm to 300 μm. In some embodiments, raw API particles can be sieved using mesh sizes of less than 500 μm, less than 450 μm, less than 400 μm, less than 350 μm, less than 300 μm, less than 250 μm, less than 200 μm, less than 150 μm, or less than 100 μm. In some embodiments, raw API particles can be sieved using mesh sizes greater than 30 μm, greater than 50 μm, greater than 100 μm, greater than 150 μm, greater than 200 μm, greater than 250 μm, greater than 300 μm, greater than 350 μm, or greater than 400 μm.

[0033] The coating 104 surrounding the API particles 102 may include materials containing water-soluble and / or water-swellable and water-insoluble materials. In some embodiments, the coating may directly coat the API particles or coat API particles that already have one or more coatings. In some embodiments, the ratio of coating material to API particles may be optimized to minimize excess coating material. For example, the coating material may include a mixture of API and coating material or a final pharmaceutical composition in amounts of 5-85% w / w, 10-50%, or 15-30%. In some embodiments, the coating material may include a mixture of API and coating material or a final pharmaceutical composition in amounts of less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, or less than 10%. In some embodiments, the coating material may include a mixture of API and coating material or the final pharmaceutical composition in amounts of more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, or more than 75%. In some embodiments, the percentage of coating material may include two or more coating material layers.

[0034] The water-swellable material of the coating material may contain particles with a median particle size of about 0.5 μm to about 20 μm or about 1 μm to about 10 μm. In some embodiments, the water-swellable material may be about 10 times smaller than the API to allow for regular mixing and coating. The water-swellable material can expand upon water absorption such that the diameter of the water-swellable particles increases by at least about 120 to 600%. The coating material or pharmaceutical composition may contain 0 to 8% w / w or 0.1 to 0.9% w / w of water-swellable material. In some embodiments, the coating material or pharmaceutical composition may contain 0.5 to 6.0% w / w, 1.0 to 4.0% w / w, 1.5 to 3.5% w / w, or 2.0 to 3.0% w / w of water-swellable material. In some embodiments, the coating material or pharmaceutical composition may contain water-swellable material in amounts less than 8.0% w / w, less than 6.0% w / w, less than 4.0% w / w, less than 2.0% w / w, less than 1.0% w / w, or less than 0.5% w / w. In some embodiments, the coating material or pharmaceutical composition may contain water-swellable material in amounts greater than 0.1% w / w, greater than 0.5% w / w, greater than 1.0% w / w, greater than 2.0% w / w, greater than 3.0% w / w, greater than 5.0% w / w, or greater than 6.0% w / w. The water-swellable material of the coating material may be deformable under mechanical stress and / or high temperatures (as described in detail below). The water-swellable material may be one or more of crospovidone, croscarmellose, sodium starch glycolate, or any other suitable disintegrants used in the pharmaceutical industry as additives or blends prepared for tableting.

[0035] The water-soluble material of the coating material may contain particles with a median particle size of about 0.5 μm to about 20 μm or about 1 μm to about 10 μm. In some embodiments, the water-soluble material may be about 10 times smaller than the API to allow for regular mixing and coating. The water-soluble material may have water solubility of at least about 50 mg / mL in water at a neutral pH and 20°C. Furthermore, the water-soluble material may have a water content of about 3 to 60 μg / m³. 2It may have an intrinsic dissolution rate of s. The water-soluble material of the coating material may be deformable under mechanical and / or thermal energy. The coating material or pharmaceutical composition may contain 0 to 35% w / w of water-soluble material. In some embodiments, the coating material or pharmaceutical composition may contain 0.5 to 25% w / w, 1.0 to 15% w / w, 1.5 to 10% w / w, or 2.0 to 3.0% w / w of water-soluble material. In some embodiments, the coating material or pharmaceutical composition may contain water-soluble materials in amounts less than 35% w / w, less than 30% w / w, less than 25% w / w, less than 20% w / w, less than 15% w / w, less than 10% w / w, less than 5.0% w / w, less than 4.5% w / w, less than 4.0% w / w, less than 3.5% w / w, less than 3.0% w / w, less than 2.5% w / w, less than 2.0% w / w, less than 1.5% w / w, less than 1.0% w / w, or less than 0.5% w / w. In some embodiments, the coating material or pharmaceutical composition may contain a water-soluble material in an amount greater than 0.1% w / w, greater than 0.5% w / w, greater than 1.0% w / w, greater than 1.5% w / w, greater than 2.0% w / w, greater than 2.5% w / w, greater than 3.0% w / w, greater than 4.0% w / w, greater than 5.0% w / w, greater than 8.0% w / w, greater than 10% w / w, greater than 15% w / w, greater than 20% w / w, greater than 25 wt / % w / w, or greater than 30% w / w. The water-soluble material may be one or more of sucrose, mannitol, sorbitol, polyvinylpyrrolidone, hydroxypropyl cellulose, lactose, poly-(ethylene oxide), and any other suitable micronizable material or polyol.

[0036] The above 3-60 μg / m² 2 In addition to the intrinsic dissolution rate of s, the provided process also provides a dissolution rate of approximately 60-300 μg / m³. 2This allows for the use of water-soluble and / or water-swellable materials having a higher intrinsic dissolution rate. However, API particles having a coating material with a higher intrinsic dissolution rate should be dry-coated with hydrophobic silica. Dry-coated API particles in which the coating contains a water-soluble and / or water-swellable material having a higher intrinsic dissolution rate can increase the disintegration time of the API, thereby failing to effectively mask the taste of the API. Therefore, the in vivo taste-masking performance of the coating can be improved by dry-coating the API particles with silica as a second coating material to slow down the dissolution rate. The coated API may contain 0.5–35% w / w of silica. In some embodiments, the coated ibuprofen or the final pharmaceutical composition may contain 0.5–20% w / w, 0.5–10% w / w, or 0.5–5% w / w of hydrophobic fumed silica. In some embodiments, the coated ibuprofen or the final pharmaceutical composition may contain hydrophobic fumed silica in amounts greater than 0.5% w / w, greater than 1.0% w / w, greater than 1.5% w / w, greater than 2.0% w / w, greater than 2.5% w / w, greater than 3.0% w / w, greater than 4.0% w / w, greater than 5.0% w / w, greater than 10% w / w, greater than 15% w / w, greater than 20% w / w, greater than 25% w / w, or greater than 30% w / w. In some embodiments, the coated ibuprofen or the final pharmaceutical composition may contain hydrophobic fumed silica in amounts less than 35% w / w, less than 25% w / w, less than 15% w / w, less than 10% w / w, less than 5.0% w / w, less than 4.0% w / w, less than 3.5% w / w, less than 3.0% w / w, less than 2.5% w / w, less than 2.0% w / w, less than 1.5% w / w, or less than 1.0% w / w.Examples of silica that may be used include, but are not limited to, Aerosil R972 silica (Degussa), CAB-O-SIL EH-5 silica (Cabot), OX-50 silica (Degussa), COSM055 (Catalyst & Chemical Ind. Co. Ltd (Japan)), P-500 hydrophilic silica (Catalyst & Chemical Ind. Co. Ltd (Japan)), and TS5 silica (Cabot). Furthermore, suitable devices that may be used for dry coating with silica include, but are not limited to, Comil (U3 Quadro Comil of Quadro Pennsylvania, US), LabRAM (Resodyne Minnesota, US), Magnetically Assisted Impact Coater (MAIC, Aveka Minnesota, US), and Fluid Energy Mill (FEM, Qualification Micronizer of Sturtevant Massachusetts, US).

[0037] The water-insoluble material of the coating material may also contain particles with an average particle size smaller than that of the API. For example, the water-insoluble material may have an average particle size of about 1–20 μm, about 1–12 μm, about 2–10 μm, about 5–12 μm, or about 5–6 μm. In some embodiments, the water-insoluble material may be about 10 times smaller than that of the API to allow for regular mixing and coating. The water-insoluble material of the coating material may be deformable under mechanical stress and / or high temperatures. The coating material or pharmaceutical composition may contain 5–70% w / w, 10–60% w / w, 10–50% w / w, 10–40% w / w, 10–35% w / w, or 15–30% w / w of water-insoluble material. In some embodiments, the coating material or pharmaceutical composition may contain water-insoluble material in amounts greater than 5% w / w, 10% w / w, 15% w / w, 20% w / w, 25% w / w, 30% w / w, 35% w / w, or 40% w / w. In some embodiments, the coating material or pharmaceutical composition may contain water-insoluble material in amounts less than 70% w / w, 60% w / w, 50% w / w, 45% w / w, 40% w / w, 35% w / w, or less than 30% w / w. Suitable examples of water-insoluble material include, but are not limited to, ethylcellulose, polyethylene, polypropylene, polytetrafluoroethylene, carnauba wax, candela wax, castor wax, polyamide wax, and / or synthetic waxes.

[0038] In some embodiments, mechanical and / or thermal energy can be used to deform one or more water-insoluble materials, water-expandable materials, and / or water-insoluble materials. For example, mechanical stress can be applied to functionally coated API particles using PharmaRAM II acoustic mixers, RAM5 Pharma mixers, or RAM55 Pharma mixers (Resodyn Mixers). The coated API particles may be exposed to up to 100 times gravity (100G acceleration) during this acoustic mixing process. These high forces cause particle-particle collisions that generate energy in the form of heat, which can be used to deform one or more water-insoluble materials, water-expandable materials, and / or water-insoluble materials on the API.

[0039] In this step, when the deformable coating material is mixed with the API particles, API particles surrounded or coated with coating material particles are produced, as shown in Figure 1A. Figure 1A shows API particles 102 coated with individual coating material particles 104 to create coated API particles. In some embodiments, the coated APIs may be further coated with a second uncoated material, as shown in Figure 1C. Figure 1C shows embedded API particles 102 coated with layer deformable coating material 104 and partially embedded with particles of the second coating material 108.

[0040] However, the above coating process can also produce "loose" or "free" coating material particles. Figure 2 is an SEM image of uncoated API particles. Figure 3 is an SEM image of coated API particles 312. However, the "loose" or "free" coating material particles 314 do not bind to the coated API particles 312.

[0041] When API particles are coated with a coating material to produce coated API particles, the coated API particles can be sieved to remove any uncoated, partially coated, or coated excess coating material and residual fine API particles. The excess coating material may include any coating material particles that are not bound to the coated API particles. Any excess coating material may aggregate during storage of the final pharmaceutical composition (i.e., the product). For example, fusion may occur between excess coating particles and coating particles already bound to the API particles, otherwise preventing the disintegration of the unit or tablet, or the entry of a medium that aids in the dissolution of the coated API particles. Thus, aggregation of excess coating material may cause an increase in disintegration time and / or a decrease in the dissolution rate upon administration.

[0042] However, methods for sieving excess coating material from coated API particles have been found to minimize aggregation of the coating material and maintain the initial disintegration time and / or dissolution rate of the final product. The sieving process can be either batch or continuous. Furthermore, this sieving process can be performed in addition to, or instead of, the sieving process performed on the raw API particles described above. In some embodiments, the parameters of the sieving process may differ between uncoated raw API particles and coated API particles.

[0043] In some embodiments, coated API particles can be sieved to remove coating material particles having an average particle size smaller than the desired average particle size of coated API particles. In some embodiments, two or more meshes can be used to remove certain particles. For example, a sieving device may comprise a series of two or more meshes for removing particles of a certain size, depending on the size of the mesh(s). The sieve can incorporate a vacuum transfer system to deliver particles to the series of meshes of the device. Furthermore, an ultrasonic probe can be incorporated into the sieving device to improve the flow of the material during processing and minimize mesh clogging. Flow aids (e.g., silica) may be included to facilitate movement through the sieve. For example, the coating material used to coat API particles may contain a flow aid. Conversely, raw API material may not be cohesive and may not require the assistance of a flow aid during sieving. The sieving process may be a batch process or a continuous process.

[0044] In some embodiments, raw API particles can be sieved using mesh sizes of 30 μm to 500 μm, 50 μm to 450 μm, 100 μm to 400 μm, 150 μm to 350 μm, or 200 μm to 300 μm. In some embodiments, raw API particles can be sieved using mesh sizes of less than 500 μm, less than 450 μm, less than 400 μm, less than 350 μm, less than 300 μm, less than 250 μm, less than 200 μm, less than 150 μm, or less than 100 μm. In some embodiments, raw API particles can be sieved using mesh sizes greater than 30 μm, greater than 50 μm, greater than 100 μm, greater than 150 μm, greater than 200 μm, greater than 250 μm, greater than 300 μm, greater than 350 μm, or greater than 400 μm.

[0045] Once sieved, the coated API particles can be mixed into a matrix solution / suspension to form a pharmaceutical suspension, which can then be dispensed by weight into pre-formed blister pack pockets to form aliquots of the pharmaceutical suspension. Once dispensed, the blister packs containing the aliquot pharmaceutical suspensions are frozen under sub-zero temperatures. The frozen aliquots of the pharmaceutical suspensions are kept frozen until ready for lyophilization, during which time the solvent in the pharmaceutical suspensions is removed to form the pharmaceutical composition.

[0046] The matrix solution / suspension may contain a matrix-forming agent, a structure-forming agent, and a solvent. For example, the matrix-forming agent may contain any water-soluble or water-dispersible material that is pharmacologically acceptable or inert to functionally coated API particles. In some embodiments, the matrix-forming agent may be a polypeptide such as gelatin. Gelatin can be at least partially hydrolyzed (by heating in water). Other suitable matrix-forming agent materials include, but are not limited to, hydrolyzed dextran, dextrin, and alginates, polyvinyl alcohol, polyvinylpyrrolidone, and / or polysaccharides such as acacia. In some embodiments, the amount of matrix in the final pharmaceutical composition (e.g., an orally disintegrating tablet) may be 1 to 30% w / w. In some embodiments, the amount of matrix may be less than 30% w / w, less than 25% w / w, less than 20% w / w, less than 15% w / w, less than 10% w / w, less than 5% w / w, or less than 3% w / w. In some embodiments, the amount of matrix can be greater than 1% w / w, greater than 3% w / w, greater than 5% w / w, greater than 10% w / w, greater than 15% w / w, greater than 20% w / w, or greater than 25% w / w.

[0047] In some embodiments, the amount of matrix-forming agent in the matrix solution / suspension or pharmaceutical suspension may be about 0.1–10% w / w. In some embodiments, the amount of matrix-forming agent in the matrix solution / suspension or pharmaceutical suspension may include 1.0–8.0% w / w or 2.0–5.0% w / w. In some embodiments, the amount of matrix-forming agent in the matrix solution / suspension or pharmaceutical suspension may include greater than 0.1% w / w, greater than 0.5% w / w, greater than 1.0% w / w, greater than 2.0% w / w, greater than 3.0% w / w, greater than 4.0% w / w, greater than 4.5% w / w, greater than 5.0% w / w, or greater than 8.0% w / w. In some embodiments, the amount of matrix-forming agent in the matrix solution / suspension or pharmaceutical suspension may include less than 10% w / w, less than 8.0% w / w, less than 6.0% w / w, less than 5.0% w / w, less than 4.0% w / w, less than 3.0% w / w, less than 2.5% w / w, less than 2.0% w / w, less than 1.5% w / w, or less than 1.0% w / w. In some embodiments, the amount of matrix-forming agent in the pharmaceutical composition may be about 3 to 15% w / w, about 4 to 10% w / w, or about 4 to 7% w / w. In some embodiments, the amount of matrix-forming agent in the pharmaceutical composition may include more than 0.1% w / w, more than 0.5% w / w, more than 1.0% w / w, more than 2.0% w / w, more than 3.0% w / w, more than 4.0% w / w, more than 5.0% w / w, more than 6.0% w / w, more than 7.0% w / w, more than 8.0% w / w, more than 9.0% w / w, more than 10.0% w / w, more than 11.0% w / w, more than 12.0% w / w, more than 13.0% w / w, or more than 14.0% w / w. In some embodiments, the amount of matrix-forming agent in the pharmaceutical composition may include less than 15% w / w, less than 14.0% w / w, less than 13.0% w / w, less than 12.0% w / w, less than 10.0% w / w, less than 9.0% w / w, less than 8% w / w, less than 7% w / w, less than 6% w / w, less than 5% w / w, or less than 4.0% w / w.

[0048] The structure-forming agent or bulking agent in the matrix solution / suspension may contain sugars. For example, suitable structure-forming agents include, but are not limited to, mannitol, dextrose, lactose, galactose, glycine, cyclodextrin, or combinations thereof. The structure-forming agent can be used as a bulking agent in lyophilization because it crystallizes and provides structural robustness to the lyophilized form. In some embodiments, the amount of structure-forming agent in the matrix solution / suspension may be about 0.1–10% w / w. In some embodiments, the amount of structure-forming agent in the matrix solution / suspension or pharmaceutical suspension may be 1.0–8.0% w / w or 2.0–5.0% w / w. In some embodiments, the amount of the structure-forming agent in the matrix solution / suspension or pharmaceutical suspension may include more than 0.1% w / w, more than 0.5% w / w, more than 1.0% w / w, more than 2.0% w / w, more than 3.0% w / w, more than 4.0% w / w, more than 4.5% w / w, more than 5.0% w / w, or more than 8.0% w / w. In some embodiments, the amount of the structure-forming agent in the matrix solution / suspension or pharmaceutical suspension may include less than 10% w / w, less than 8.0% w / w, less than 6.0% w / w, less than 5.0% w / w, less than 4.0% w / w, less than 3.0% w / w, less than 2.5% w / w, less than 2.0% w / w, less than 1.5% w / w, or less than 1.0% w / w. In some embodiments, the amount of structure-forming agent in the pharmaceutical composition may be about 3–15% w / w, about 4–10% w / w, or about 4–7% w / w. In some embodiments, the amount of structure-forming agent in the pharmaceutical composition may include more than 0.1% w / w, more than 0.5% w / w, more than 1.0% w / w, more than 2.0% w / w, more than 3.0% w / w, more than 4.0% w / w, more than 5.0% w / w, more than 6.0% w / w, more than 7.0% w / w, more than 8.0% w / w, more than 9.0% w / w, more than 10.0% w / w, more than 11.0% w / w, more than 12.0% w / w, more than 13.0% w / w, or more than 14.0% w / w. In some embodiments, the amount of the structural agent in the pharmaceutical composition may include less than 15% w / w, less than 14.0% w / w, less than 13.0% w / w, less than 12.0% w / w, less than 10.0% w / w, less than 9.0% w / w, less than 8% w / w, less than 7% w / w, less than 6% w / w, less than 5% w / w, or less than 4.0% w / w.

[0049] The solvent for the matrix solution / suspension and the pharmaceutical suspension may be water, but the suspension may contain a co-solvent. In some embodiments, the solvent may be ethanol, alcohol, isopropanol, other lower alkanols, water (e.g., purified water), or a combination thereof. For example, a suitable solvent and / or co-solvent may be an alcohol such as tert-butyl alcohol. In some embodiments, the remaining balance of the pharmaceutical suspension is the solvent (i.e., QS 100%).

[0050] Matrix solutions / suspensions and pharmaceutically acceptable suspensions may also contain additional pharmaceutically acceptable agents or excipients. Such additional pharmaceutically acceptable agents or excipients include, but are not limited to, sugars, inorganic salts such as sodium chloride and aluminum silicate, modified starches, preservatives, antioxidants, viscosity improvers, colorants, flavorings, pH adjusters, sweeteners, taste masking agents, and combinations thereof. Suitable colorants include red, black, and yellow iron oxides, as well as FD&C dyes such as FD&C Blue 2 and FD&C Red 40, and combinations thereof. Suitable flavorants include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, and grape flavors, and combinations thereof. Suitable pH adjusters include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, sodium hydroxide (e.g., a 3% w / w sodium hydroxide solution), and combinations thereof. Suitable sweeteners include aspartame, acesulfame K, and thaumatin, as well as combinations thereof. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin-containing compounds, adsorbents or microencapsulation activators, and combinations thereof. Those skilled in the art can easily determine suitable amounts of these various additional excipients as needed.

[0051] Figure 4 provides flowcharts of several embodiments of the mixing process for preparing the pharmaceutical compositions described herein. In step 402, API particles are combined with one or more coating materials, and the combination is exposed to mechanical and / or thermal energy to produce an ordered mixture of API particles containing discrete layers of one or more coating materials (i.e., API particles containing a first coating layer). For example, Figure 1A shows API particles containing discrete layers of coating material particles.

[0052] In step 404, mechanical and / or thermal energy can be applied to the coated API particles to deform one or more deformable components of the coating material onto the surface of the API particles. This process step can form API particles that include a continuous film surrounding them, as shown in Figures 1B, 1C, and / or 3.

[0053] In step 406, coated API particles are combined with silica to form coated API particles comprising at least a first coating of the functional coating material and a second coating of silica. In some embodiments, mechanical and / or thermal energy can be applied to adhere the silica particles to and / or embed them in the first coating of the coated API particles.

[0054] In step 408, the coated API particles are sieved to remove any excess coating material, as discussed in detail above. For example, Figure 3 shows SEM images of the coated API particles 312 and the excess coating material 314.

[0055] In step 410, the sieved coated API particles are mixed into a matrix solution / suspension to form a pharmaceutical suspension for administration to a pre-formed mold. In some embodiments, the pharmaceutical suspension may be administered to a blister pack, lyophilized to remove the solvent and form the pharmaceutical composition, and sealed within the blister pack for protection. This suspension and administration process is covered in detail in GB1548022, US4371516, US4305502, GB211423, and US4758598, each of which is incorporated herein in whole.

[0056] The coating ratio (i.e., the amount of coating material relative to the amount of uncoated API) can be optimized to minimize and / or prevent the aggregation of excess coating material. For example, in some embodiments, the coating ratio may range from 5 to 85% or 10 to 150% w / w of coating material to 15 to 95% or 50 to 90% w / w of uncoated API. In some embodiments, the amount of coating material may be less than 80% w / w, less than 70% w / w, less than 60% w / w, less than 50% w / w, less than 40% w / w, less than 30% w / w, less than 20% w / w, or less than 10% w / w. In some embodiments, the amount of coating material may be greater than 5% w / w, greater than 10% w / w, greater than 20% w / w, greater than 30% w / w, greater than 40% w / w, greater than 50% w / w, greater than 60% w / w, or greater than 70% w / w. In some embodiments, the amount of uncoated API may be less than 95% w / w, less than 85% w / w, less than 75% w / w, less than 65% w / w, less than 55% w / w, less than 45% w / w, less than 35% w / w, or less than 25% w / w. In some embodiments, the amount of uncoated API may be greater than 20% w / w, greater than 30% w / w, greater than 40% w / w, greater than 50% w / w, greater than 60% w / w, greater than 70% w / w, greater than 80% w / w, or greater than 90% w / w.

[0057] The dosage ratio (i.e., the amount of coated API relative to the amount of matrix solution / suspension containing all inactive components) can be optimized to minimize and / or prevent aggregation of excess coating material. For example, in some embodiments, the dosage ratio may range from 5–60% w / w of coated API to 40–95% w / w of matrix solution / suspension. In some embodiments, the dosage ratio may include less than 60% w / w, less than 50% w / w, less than 40% w / w, less than 30% w / w, less than 20% w / w, or less than 10% w / w of coated API. In some embodiments, the dosage ratio may include more than 5% w / w, more than 10% w / w, more than 20% w / w, more than 30% w / w, more than 40% w / w, or more than 50% w / w of coated API. In some embodiments, the dosage ratio may include matrix solutions / suspensions with a dosage of less than 95% w / w, less than 90% w / w, less than 80% w / w, less than 70% w / w, less than 60% w / w, or less than 50% w / w. In some embodiments, the dosage ratio may include matrix solutions / suspensions with a dosage of more than 40% w / w, more than 50% w / w, more than 60% w / w, more than 70% w / w, more than 80% w / w, or more than 90% w / w. [Examples]

[0058] Several tests were conducted to evaluate the effectiveness of removing excess coating material from coated API particles by sieving and to optimize the coating ratio and dosage ratio. The effect of sieving excess coating material was studied by measuring the disintegration times of pharmaceutical compositions containing various coated API particles under various conditions. It can be reasonably assumed that removing excess coating material can minimize the aggregation of the coating material. Optimizing the coating and dosage ratio may also help minimize the aggregation of the coating material. Next, minimizing the amount of aggregation may help maintain the desired disintegration time and / or dissolution rate of the pharmaceutical composition and coated API particles. Therefore, disintegration time is used as a metric for evaluating the amount of aggregation in the following examples. In some embodiments, accelerated disintegration data at 50°C can indicate the presence of excess coating material that has not been sieved.

[0059] Furthermore, coating ratio and dosage ratio information is provided for the following examples. The coating ratio refers to the amount of coating material relative to the amount of uncoated API. The dosage ratio refers to the amount of coated API relative to the matrix solution / suspension containing all inert components.

[0060] Example 1: Ibuprofen was coated with carnauba wax at a coating ratio of 26:74. Lyophilized tablets were produced using a dosage ratio of 40:60. Four separate batches of tablets were tested (batches 1-3 over 2 months and batch 4 over 6 months). These tablet batches were tested under ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) stability conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH, respectively, and samples were taken for batches 1, 2, and 3 at 1 month and 2 months. In addition, each batch was exposed to stress conditions at 50°C to provide accelerated data for both 2 weeks and 4 weeks for each study. Table 1 below provides disintegration time data for batches 1-3 of the coated ibuprofen for 2 months. [Table 1]

[0061] The coated APIs for Batch 2 were inadequately sieved after API coating. Microscopic examination of the sieved coated APIs (Figure 5B) showed the presence of an excess amount of unbound coating material. It also showed that the API particles were inadequately coated. As shown in the last column of Table 1, this batch exhibited a significantly longer decay time under 40°C / 75% RH stability test conditions after 2 months (initial decay time was less than 2 seconds, and decay time at 2 months was approximately 15 seconds). Therefore, this result supports the hypothesis that the presence of an excess amount of unbound coating material in the drug causes an extension of decay time over time (as the drug ages) due to aggregation of the unbound coating material during storage.

[0062] Conversely, the coated APIs for batch 3 were thoroughly sieved after API coating. Microscopic examination of the sieved coated APIs (Figure 5C) showed that the API particles were well coated, due to the absence of unbound coating material. The decay time of the samples from this batch remained largely unchanged over two months for any of the ICH stability conditions. (The decay time throughout the two-month study varied between approximately 1 second and approximately 3 seconds). This supports the hypothesis that minimizing the presence of excess unbound coating material, for example, by sieving, helps prevent aggregation of the coating material in pharmaceuticals, especially when stored at high temperatures over time.

[0063] The coated API for batch 1 was sieved after API coating. Batch 1 showed a similar decay time of less than 2 seconds for the initial time data point compared to batches 2 and 3. However, under the 40C / 75%RH stability test conditions after 2 months, the decay time increased to approximately 7 seconds or less. When stored at 50°C for 4 weeks, the decay time increased to approximately 10 seconds or less. This suggests that the sieving process for this batch did not adequately remove excess coating material, and therefore suggests the presence of residual unbound coating material. Batch 2 experienced even more unbound coating material and a greater degree of aggregation during storage than batch 1. Microscopic examination of the sieved coated API (Figure 5A) showed that the API particles were moderately and sufficiently coated in the presence of residual amounts of unbound coating material.

[0064] Table 2 below shows the decay time data for a 6-month study of coated ibuprofen API (i.e., batch 4). [Table 2]

[0065] The coated APIs for Batch 4 were sieved after API coating. Batch 4 in Table 2 showed little change in decay time throughout the 6-month study period. The initial decay time for Batch 4 was approximately 5 seconds, the final decay time for the 25°C / 60% RH sample was approximately 2 seconds, for the 30°C / 65% RH sample approximately 2 seconds, and for the 40°C / 75% RH sample approximately 2 seconds. However, an increase was observed when stored at 50°C. Since no increase was observed in tablets stored at temperatures below 40°C, this suggests that sieving removed most of the excess unbound coating material, but still left a sufficient amount to cause aggregation when the tablets were placed at 50°C. Microscopic examination (Figure 5D) showed that the sieved coated APIs indicated that the API particles were adequately coated in the presence of residual unbound coating material.

[0066] Example 2: Ibuprofen was coated with sazole (synthetic) wax with a theoretical coating ratio of 26:74. The coated API was sieved after coating. Lyophilized tablets were produced using a 40:60 dosage ratio and tested over two months. The ibuprofen API strength was 200 mg. Each batch was tested under ICH stability conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. In addition, samples were exposed to stress conditions at 50°C to provide accelerated data at weeks 2 and 4 of the study. Table 3 below provides disintegration time data for the 2-month study of coated ibuprofen with a 40:60 dosage ratio. Microscopic examination of the sieved coated API (Figure 5E) showed that the API particles were adequately coated in the presence of small amounts of unbound coating material. [Table 3]

[0067] Batch 5 in Table 3 shows no substantial change in decay time during the 2-month study or under accelerated conditions at 50°C. Specifically, the initial decay time of batch 5 was approximately 3 seconds, and the decay time at 2 months was approximately 4 seconds for all three ICH stability conditions (25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH). The decay time under accelerated conditions at 50°C at 2 weeks was approximately 3 seconds, and the decay time at 4 weeks was approximately 4 seconds. Based on the 50°C data, a small amount of excess unbonded coating material may be present. If so, this small amount of excess unbonded coating material does not cause a significant amount of aggregation during storage, as the decay time does not increase significantly, even if it does. This is in good comparison with batch 3 in Example 1, which used a different wax. These two examples demonstrate that if excess unbonded coating material is efficiently removed by sieving, aggregation of coating material in pharmaceuticals during storage can be minimized or prevented, especially at higher temperatures and during long-term storage.

[0068] Example 3: Ibuprofen was coated with sazole (synthetic) wax with a theoretical coating ratio of 26:74. The coated API was then sieved. Lyophilized tablets were produced using a 50:50 dosage ratio and tested for 3 months. The ibuprofen strength was 200 mg. As in Examples 1 and 2 above, each batch was tested under ICH stability conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. Samples were also exposed to stress conditions at 50°C to provide accelerated data at 2 and 4 weeks during each study. Table 4 below provides data for the 3-month study of ibuprofen coated with 50:50 sazole wax. Microscopic examination of the sieved coated API from batch 6 (Figure 5F) showed that the API particles were well coated, with some unbound coating material present. [Table 4]

[0069] Neither batch 6 nor batch 7 showed a significant change in decay time during the 3-month study. Specifically, the initial decay time of the batch 6 sample was approximately 1 second, and the decay time for each of the three ICH stability conditions (25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH) over the final 3 months was approximately 2 seconds. The decay time for batch 6 under both the 2-week and 4-week accelerated 50°C conditions was approximately 2 seconds.

[0070] The initial decay time of the Batch 7 samples was approximately 2 seconds, and the decay time at the end of the last 3 months under ICH stability conditions of 25°C / 60% and 30°C / 65% was also approximately 2 seconds. The decay time at the end of the last 3 months under ICH stability conditions of 40°C / 75% was approximately 3 seconds. The decay time at both the 2-week and 4-week accelerated 50°C conditions was approximately 5 seconds. A high coating ratio of 50:50 may increase the amount of excess unbonded coating material if left unsieved. Both batches used a higher dosing ratio of 50:50, which means a high load of coated API and any excess unbonded coating material, but these data suggest that the sieving process of coated API is effective in removing excess unbonded coating material to minimize aggregation. Example 4: Paracetamol (APAP) was coated with carnauba wax at a theoretical coating ratio of 26:74. These batches were manually sieved. Lyophilized tablets were produced using dosing ratios of 50:50 and 40:60. The APAP strength was 325 mg. Each batch was tested under ICH stability conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. Samples were also exposed to stress conditions at 50°C to provide accelerated data over two weeks during each study. Table 5 below provides data for a one-month study of APAP coated with carnauba wax. As shown below, all batches showed a significant increase in disintegration time under 40°C / 75% RH stability conditions over one month. Microscopic examination of manually sieved coated APIs showed that batch 8 (Figure 5G) had poor to moderate API particle coating, while batches 9 and 10 (Figures 5H and 5I) had very poor coating. The poor coating was attributed to the presence of excess uncoated coating material as a result of poor sieving performed manually instead of using a vibrating sieve. [Table 5]

[0071] The initial decay time of each batch of samples was approximately 2–4 seconds. When tested after one month, there was little change in decay time under the stability conditions of 25°C / 60% RH and 30°C / 65% RH for any of the batches. Under the 50°C condition, accelerated for two weeks, the decay time of all three batches was over 2 minutes. As mentioned above, all three batches also showed a significant increase in decay time (over 2 minutes) after one month under the stability condition of 40°C / 75% RH. This can be explained by the presence of excess unbound wax coating material that aggregated during pharmaceutical storage.

[0072] Example 5: APAP was coated with sazole (synthetic) wax with a theoretical coating ratio of 26:74 and sieved. A 50:50 dosage ratio was used to produce lyophilized tablets. The APAP strength was 325 mg. The test conditions were the same as those described in Example 4 above. That is, batches were tested under ICH stability conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. Samples were exposed to stress conditions at 50°C to provide accelerated data over two weeks. Table 6 below provides data for a one-month study of APAP coated with sazole (synthetic) wax. As shown below, batch 11 did not show a significant change in decay time for any of the test conditions. Microscopic examination of the sieved coated API (Figure 5J) shows that the API particles are adequately coated in the presence of the unbound coating material. [Table 6]

[0073] The initial disintegration time for batch 11 was less than 2 seconds. When tested for one month under all three stability conditions (25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH), there was little change in disintegration time. Under accelerated 50°C conditions for two weeks, the disintegration time was over 2 minutes. Since no increase was observed in tablets stored at temperatures below 40°C, this suggests that while sieving removed most of the unbound excess coating material, a sufficient amount remained to cause aggregation when the tablets were placed at 50°C. Sazole wax also has a higher melting / softening point, which may occur at higher storage temperatures (e.g., 50°C).

[0074] Example 6: APAP was coated with sazole (synthetic) wax with a theoretical coating ratio of 24:76 and sieved. Lyophilized tablets were produced using a 50:50 dosage ratio and studied over 3 and 6 months. (Batch 11 from Example 5 was extended from 1 month to 3 months for this example). The APAP strength of all samples was 325 mg. Each batch was tested under ICH stability conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. In addition, samples from each batch were exposed to stress conditions at 50°C to provide accelerated data at week 2 of each study. Table 7 below provides decay time data for coated APAP for the 3-month study (batch 11) and the 6-month study (batch 12) using a 50:50 dosage ratio. Similar to batch 11, microscopic examination of the sieved coated APIs from batch 12 (Figure 5K) showed that the API particles were adequately coated with the unbound coating material. [Table 7]

[0075] Batch 12 showed no substantial change during the 3-month study under ICH stability conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. Specifically, the initial disintegration time was approximately 2 seconds, the final 3-month disintegration time for the 25°C / 60% RH sample was approximately 4 seconds, and the final disintegration times for the 30°C / 65% RH and 40°C / 75% RH samples were approximately 3 seconds. However, 2 weeks of 50°C accelerated data showed a significant change in disintegration time (over 2 minutes). As described in Example 5, sazole wax has a higher melting / softening temperature. This relatively high melting / softening point supports microscopic observations that excess unbound coating material aggregated when stored at 50°C, but not to the same extent when the tablets were stored at 40°C / 75% RH, as no increase was observed in tablets stored at temperatures below 40°C.

[0076] Batch 13 behaved similarly to batch 12, showing no substantial change in decay time over the course of the 6-month study. The initial decay time of the batch 13 samples was approximately 1 second. The final decay time at 6 months for the 25°C / 60% RH and 30°C / 65% RH samples was approximately 2 seconds, while the final decay time at 6 months for the 40°C / 75% RH sample was approximately 3 seconds. Furthermore, data from the 2-week 50°C accelerated decay period resulted in decay times exceeding 2 minutes.

[0077] Observations of batches 12 and 13 compared to batches 5-7 of Examples 3 and 4 showed that both examples exhibited similar disintegration times for samples stored at 25°C / 60%, 30°C / 65%, and 40°C / 75%. However, a difference in disintegration time was observed for samples stored at 50°C. After storing tablets at 50°C for two weeks, the disintegration time for batches 12 and 13 was over 2 minutes. In contrast, the disintegration time was 2-4 seconds. This difference suggests that batches 5-7 had less excess unbonded coating material compared to batches 11-12. This difference did not cause aggregation of the coating material at lower storage temperatures of 25°C, 30°C, and 40°C, but the higher melting / softening temperature of sazole wax was sufficient to produce a difference at 50°C.

[0078] Example 7: APAP was coated with sazole (synthetic) wax with a theoretical coating ratio of 26:74 and sieved. A dose ratio of 40:60 was used to produce lyophilized tablets for study over two months. The APAP strength of all samples was 325 mg. Samples were tested under ICH stability conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. In addition, samples from each batch were exposed to stress conditions at 50°C to provide accelerated data at weeks 2 and 4 of the study. Table 8 below provides the decay times for this study. Microscopic examination of the sieved coated API (Figure 5L) from batch 14, as with batches 12 and 13, showed that the API particles were adequately coated with residual unbound coating material. [Table 8]

[0079] Batch 14 showed no change in decay time or accelerated data during the 2-month study. The initial decay time of the batch 14 sample was approximately 3 seconds. The final 2-month decay time under all three ICH stability conditions was approximately 2 seconds. Furthermore, the 2-week 50°C accelerated data decay time was approximately 3 seconds, and the 4-week 50°C accelerated data decay time was approximately 2 seconds. Comparing this to batch 11 of Example 5 and batch 12 of Example 6, which used a 50:50 dosing ratio, this example demonstrates that reducing the dosing ratio to 40:60 can reduce the amount of excess unbonded coating material residue in the sieved coated API, and minimize excess wax aggregation, especially during storage at higher temperatures over time.

[0080] Example 8: Ibuprofen was coated with carnauba wax at theoretical coating ratios of 22.5:77.5 and 30:70. Lyophilized tablets were produced using the 30:70 dosage ratio and studied over two months. The ibuprofen strength was 200 mg. The batches were stored in an oven at 40°C. Tablets were tested for disintegration time at initial, 25-day, and 2-month intervals. Table 9 below provides the disintegration times for the study. Microscopic examination of unsieved coated API (Figures 5M and 5O) and sieved coated API (Figures 5N and 5P). The API particles were well coated. The sieved samples contained no unbound coating material. [Table 9]

[0081] Batches 15–18 show that, for coated APIs, either unsieved (batches 15 and 17) or sieved (batches 16 and 18), the disintegration time of tablets stored at 40°C using a 30:70 dosage ratio did not increase over time. This supports the hypothesis that by reducing the dosage ratio, such as 30:70, the amount of excess unbound wax is sufficiently reduced to a level that minimizes aggregation of excess unbound material when stored at higher temperatures over time.

[0082] Table 10 provides an overall summary of the results from the above examples. [Table 10-1] [Table 10-2]

[0083] The above description has been given in relation to specific embodiments for illustrative purposes. However, the above exemplary considerations are not intended to be exhaustive or to limit the invention to the exact form disclosed. Many modifications and variations are possible in light of the above teachings. The embodiments have been selected and described to best illustrate the principles of the technique and their practical applications. Thereafter, those skilled in the art will be able to make optimal use of the technique and its various embodiments with various modifications suitable for the specific use intended.

[0084] While this disclosure and examples are fully described with reference to the accompanying drawings, it should be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be understood to be within the scope of this disclosure and examples as defined by the claims.

Claims

1. A method for preparing a pharmaceutical composition, A coating material containing one or more deformable components is mixed with active pharmaceutical ingredient (API) particles. A mixture of API particles and a coating material is exposed to mechanical and thermal energy to deform one or more deformable components and to form coated API particles. The coated API particles are mixed with silica, Exposing a mixture of coated API particles and silica to mechanical and thermal energy to partially embed the silica onto the coated API particles, or to perform at least one of these actions. Here, the coated API particles contain silica at a concentration of 0.5-5% w / w, and the silica slows down the dissolution rate. The coated API particles containing silica are sieved to remove excess coating material that is not bonded to the coated API particles containing silica, The coated API particles containing silica are mixed in a matrix solution / suspension to form a pharmaceutical suspension, The aforementioned pharmaceutical suspension is administered to a mold, Freezing the pharmaceutical suspension in the mold, and A method comprising freeze-drying the frozen pharmaceutical suspension to form a pharmaceutical composition.

2. The method according to claim 1, wherein the ratio used to combine the silica-containing coated API particles with the matrix solution / suspension comprises 5-60% w / w silica-containing coated API particles and 40-96% w / w matrix solution / suspension.

3. The method according to claim 1, further comprising sieving the uncoated API particles.

4. The method according to claim 1, wherein sieving the silica-containing coated API particles comprises passing the silica-containing coated API particles through a device comprising two or more sieves.

5. The method according to claim 1, wherein sieving the silica-containing coated API particles comprises sieving the silica-containing coated API particles to an average particle size of 75 μm to 200 μm.

6. The method according to claim 1, wherein the API particles include one or more of the following: an anti-inflammatory agent, an analgesic, an antipsychotic, an antiemetic, a laxative, an antidiarrheal agent, an antihistamine, or an antidepressant.

7. The method according to claim 6, wherein the API particles contain ibuprofen.

8. The method according to claim 1, wherein the one or more deformable components of the coating material include wax.

9. The method according to claim 8, wherein the wax comprises one or more of carnauba wax, candelilla wax, or synthetic wax.

10. The method according to claim 1, wherein the matrix solution / suspension comprises a matrix-forming agent and a structure-forming agent.

11. The method according to claim 10, wherein the matrix-forming agent comprises one or more of the following: a water-soluble material, a water-dispersible material, a polypeptide, a polysaccharide, a polyvinyl alcohol, a polyvinylpyrrolidone, and acacia.

12. The method according to claim 11, wherein the matrix-forming agent comprises a polypeptide.

13. The method according to claim 12, wherein the polypeptide comprises gelatin.

14. The method according to claim 10, wherein the structure-forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin.

15. The method according to claim 14, wherein the structure-forming agent comprises mannitol.

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