Minimizing agglomeration, aeration and maintaining the coating of the pharmaceutical composition comprising ibuprofen

Abstract

Pharmaceutical compositions comprising ibuprofen and methods of making the pharmaceutical compositions using a solventless mixing process are provided. Excess coating material that is not bound to the coated ibuprofen can be removed by a sieving process. The coating and the quantitative ratio can also be optimized to minimize the amount of excess unbound coating material. In addition, the compositions can be formulated to maintain the functional coating of the coated ibuprofen and minimize the exposure of ibuprofen when mixed into a suspension.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application Nos. 62 / 809,307, 62 / 809,287, and 62 / 809,293, each filed on February 22, 2019, the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to methods of coating ibuprofen, and more particularly to methods of minimizing excess coating material to prevent agglomeration of coated ibuprofen in lyophilized orally disintegrating dosage forms during storage, methods of minimizing aeration of drug suspensions containing ibuprofen to improve dose weight accuracy while maintaining the integrity of a functional coating on the ibuprofen, and methods of maintaining a coating of coated ibuprofen prepared by a solvent-free mixing process and formulated to delay the release of ibuprofen after oral administration. Background of the Invention

[0005] Pharmaceutical compositions generally comprise active pharmaceutical ingredients and one or more inactive ingredients. Active pharmaceutical ingredients (API) are biologically active and are designed to directly affect the symptoms, diseases, conditions and / or ailments of patients. An example of an active pharmaceutical ingredient is ibuprofen. On the other hand, the inactive ingredients of pharmaceutical compositions are pharmaceutically inert and can be used for various purposes, including but not limited to improving long-term stabilization, filling or diluting solid formulations, promoting drug absorption, regulating the viscosity of liquid formulations, enhancing solubility and / or contributing to the manufacture of pharmaceutical compositions.

[0006] In addition, some inactive ingredients can be used to mask the taste of APIs (e.g., ibuprofen). Many APIs are known to exhibit unpleasant organoleptic properties, such as bitterness, burning, and numbness, if allowed to dissolve in the mouth. For example, some orally administered pharmaceutical compositions are designed to disperse in the mouth to enable administration in the absence of water and are targeted to pediatric patients, elderly patients, animal patients, and / or other types of patients who may have difficulty swallowing. For these types of orally administered pharmaceutical compositions, inactive ingredients can be used to form a "functional coating" to mask the taste of the API or ibuprofen.

[0007] For example, the taste of an API can be masked using an inactive ingredient by wet or dry coating the API particles to produce a functional coating that surrounds the API particles to prevent release of the API in the mouth. In wet granulation coating, the inactive ingredients (polymers and additives) are dissolved or dispersed in a solvent or water to form a suspension or solution. The suspension or solution can then be sprayed onto the surface of the API particles to form a film coating by evaporation of the solvent or water. Examples of wet granulation coating techniques include microencapsulation, fluidized bed coating, spray drying, pan coating, and the like. In dry granulation coating (also known as solventless coating), the API particles are physically coated with fine particles of the inactive ingredients (polymers and additives) to form a granular composite. Examples of dry granulation coating include hot melt coating, supercritical coating, impingement coating, electrostatic coating. API particles coated with taste-masking inactive ingredients can provide a more pleasant experience for patients who have difficulty swallowing or are sensitive to the taste that would otherwise result in a negative patient experience and poor compliance.

[0008] Additionally, one type of pharmaceutical composition is an orally disintegrating tablet (ODT). ODTs are pharmaceutical compositions that are targeted to pediatric patients, geriatric patients, animal patients, and / or other types of patients that can have difficulty swallowing.

[0009] To accurately dispense the pharmaceutical composition into small, administrable forms, the hydrophobic coated API particles can be placed into a matrix solution / suspension to form a drug suspension. Mixing to form the drug suspension allows for improved incorporation accuracy. Typically, this drug suspension comprising the hydrophobic coated API particles can be incorporated into a mold, dried, and then the molded article can be transferred to, for example, a bottle. However, this handling of the pharmaceutical composition can increase the risk of, for example, damage and contamination.

[0010] Accordingly, in fact, many API suspensions today are incorporated into preformed blister packs. Preformed blister packs eliminate one of the above-mentioned handling steps. Instead of being incorporated into a mold and then the molded article is transferred to a bottle for packaging, preformed blister packs allow the manufacturer to incorporate the drug suspension into a preformed blister pack that can be dried, then sealed and packaged. Thus, the preformed blister pack serves as both a mold and a package in which the pharmaceutical composition can be stored. SUMMARY

[0011] Methods are provided that minimize agglomeration of coating material for coated ibuprofen prepared using various mixing methods. Over time, agglomeration of coating material can decrease the stability of a drug product. For example, if a drug product contains agglomerated coating material, its disintegration time can increase over time. An increased disintegration time and / or decreased dissolution rate means an unstable drug product. An unstable drug product can result in a shorter shelf life than intended. Thus, the provided embodiments can help minimize agglomeration of coating material for coated ibuprofen to improve the stability of the drug product during storage and increase its shelf life.

[0012] For example, the described methods include removing excess coating material from coated ibuprofen to minimize the likelihood of agglomeration of coating material particles. In particular, the provided methods include sieving coated ibuprofen such that the final drug product is fully surrounded by a dry matrix, thereby minimizing any agglomeration of coating material particles upon storage. The described drug compositions provide a relatively stable disintegration time and dissolution rate over time.

[0013] Also provided are compositions and methods of making the compositions that can minimize the aeration of hydrophobic coated ibuprofen in a suspension. For example, hydrophobic coated ibuprofen can be mixed into a matrix solution / suspension to form a drug suspension, precisely incorporated into a mold to form a solid drug composition (e.g., article, tablet, etc.) for administration to a patient. However, the hydrophobicity of the coated ibuprofen causes the coated ibuprofen to resist dispersion into the solution / suspension. Thus, this can result in air being entrained by the drug suspension, also known as aeration. The entrained air or aeration of the drug suspension can cause phase separation of the coated ibuprofen in the drug suspension, thereby resulting in a non-homogenous drug suspension. The aeration and non-homogenous drug suspension can result in poor dose weight accuracy of the drug suspension containing the hydrophobic ibuprofen incorporated into a preformed blister pack, as well as poor content uniformity in the finished product (i.e., drug composition).

[0014] Due to the high viscosity of the drug suspension, conventional mechanical means of anti-aeration and / or minimizing aeration have not been found to be successful. For example, aeration minimization can be achieved by applying a vacuum to the drug suspension, but this method can be unsuitable depending on the composition and further processing requirements. In particular, applying a vacuum to the drug suspension can cause the suspension to rise because the viscous suspension "grips" onto the entrained air. Volatile formulation components can also be lost during vacuum processing. Furthermore, conventional anti-aerators (e.g., ethanol or simethicone emulsion) similarly cannot effectively anti-aerate the suspension.

[0015] Accordingly, the compositions and methods provided herein minimize the aeration of a pharmaceutical suspension comprising hydrophobic coated ibuprofen to improve the homogeneity of the suspension and increase the dose weight accuracy. Specifically, the provided embodiments can include a matrix solution / suspension comprising a chemical compound comprising a terpene and / or terpineol. In some embodiments, the matrix solution / suspension can comprise the terpene limonene. By introducing a chemical compound comprising a terpene, such as limonene, the hydrophobic coated ibuprofen can more readily incorporate into the matrix solution / suspension, thereby minimizing the overall aeration of the pharmaceutical suspension.

[0016] Also provided herein are pharmaceutical compositions and methods of making pharmaceutical compositions that are formulated to maintain the functional coating of the functionally coated ibuprofen during the manufacturing process. The functionally coated ibuprofen is typically mixed to form a pharmaceutical suspension. The pharmaceutical suspension allows for precise incorporation to form an administrable pharmaceutical product. Typically, the shear forces required to incorporate the functionally coated ibuprofen into the pharmaceutical suspension can cause erosion of the functional coating. This erosion of the coating can destroy or compromise the properties of the functional coating. Accordingly, the functionally coated ibuprofen with the eroded coating can experience increased dissolution rates and reduced taste masking properties when orally administered to a patient.

[0017] However, the pharmaceutical compositions and methods of making pharmaceutical compositions provided herein include maintaining the coating of the functionally coated ibuprofen in the pharmaceutical suspension with a hydrophobic fumed silica. Specifically, the hydrophobic fumed silica can provide a protective layer that surrounds and / or is partially or completely embedded within the functionally coated ibuprofen particles. In some embodiments, the solvent-free method of producing the functionally coated ibuprofen can produce ibuprofen comprising a first coating. According to some embodiments, the hydrophobic fumed silica can be added during the solvent-free mixing process to produce a second protective coating that surrounds and / or is partially or completely embedded within the functionally coated ibuprofen.

[0018] Additionally, the second protective coating can limit the interaction between the functionally coated ibuprofen and the matrix solution / suspension such that the functional coated ibuprofen minimizes the impact on the performance characteristics of the matrix.

[0019] In some embodiments, the pharmaceutical composition comprises: 65-85% w / w ibuprofen; 15-30% w / w coating material coating the ibuprofen; and 3-15% w / w matrix surrounding the ibuprofen. In some embodiments, the pharmaceutical composition comprises 50-400 mg ibuprofen. In some embodiments, the coating material comprises a first coating material and a second coating material and the pharmaceutical composition comprises 10-30% w / w first coating material and 0.5-10% w / w second coating material. In some embodiments, the first coating material comprises a wax. In some embodiments, the second coating material comprises silicon dioxide. In some embodiments, the pharmaceutical composition comprises 1-5% w / w anti-aeration agent. In some embodiments, the first coating material comprises one or more of carnauba wax, synthetic wax, or candelilla wax. In some embodiments, the matrix comprises a matrix former and a structure former. In some embodiments, the matrix former comprises one or more of a water-soluble material, a water-dispersible material, a polypeptide, a polysaccharide, polyvinyl alcohol, polyvinylpyrrolidone, and gum arabic. In some embodiments, the matrix former comprises a polypeptide. In some embodiments, the polypeptide comprises gelatin. In some embodiments, the structure former comprises one or more of mannitol, dextrose, lactose, galactose, and a cyclodextrin. In some embodiments, the structure former comprises mannitol. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 25°C and at least 60% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 3 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 30°C and at least 65% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 30°C and at least 65% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 40°C and at least 75% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 40°C and at least 75% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 25°C and at least 60% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 30°C and at least 65% relative humidity.In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 40 °C and at least 75% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 25 °C and at least 60% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 30 °C and at least 65% relative humidity. In some embodiments, the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 40 °C and at least 75% relative humidity. In some embodiments, the pharmaceutical composition has a dissolution test result of 10%, 5%, 3% or less after 5 minutes. In some embodiments, the matrix comprises a viscosity modifier. In some embodiments, the viscosity modifier comprises xanthan gum. In some embodiments, the anti-aeration agent comprises one or more of a terpene or a terpineol. In some embodiments, the anti-aeration agent comprises a liquid flavoring agent. In some embodiments, wherein the anti-aeration agent comprises a liquid flavoring agent comprising limonene. In some embodiments, the anti-aeration agent comprises one or more of an orange flavoring agent, a lemon flavoring agent, a grapefruit flavoring agent, a lime flavoring agent, a strawberry flavoring agent, or a mint flavoring agent. In some embodiments, the pharmaceutical composition comprises 3-10% w / w matrix former. In some embodiments, the pharmaceutical composition comprises 3-10% w / w structure former.

[0020] In some embodiments, the pharmaceutical composition can be prepared by a method comprising: coating ibuprofen with a first coating material to form coated ibuprofen, wherein the first coating material comprises one or more deformable components; applying mechanical stress to the coated ibuprofen to deform the one or more deformable components; coating the coated ibuprofen with a second coating material comprising silicon dioxide; applying mechanical stress to embed the second coating material onto the first coating material of the coated ibuprofen; sieving the coated ibuprofen to remove excess first coating material, wherein the excess first coating material comprises first coating material that did not bind to the coated ibuprofen; forming a drug suspension comprising the twice-coated ibuprofen and a matrix solution or suspension; incorporating the drug suspension into a mold; and freeze-drying the incorporated drug suspension in the mold to form the pharmaceutical composition. In some embodiments, sieving the coated ibuprofen comprises passing the coated ibuprofen through a device comprising two or more sieves. In some embodiments, sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 75 pm or greater. In some embodiments, sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 200 pm or less. In some embodiments, the weight of the incorporated drug suspension is within 10% of the target dose weight. In some embodiments, the weight of the incorporated drug suspension has a uniformity within 5% of the target dose weight. In some embodiments, the weight of the incorporated drug suspension has a uniformity within 2.5% of the target dose weight. In some embodiments, the weight of the incorporated drug suspension has a uniformity within 1% of the target dose weight. In some embodiments, mixing the coated ibuprofen into the matrix solution or suspension comprises in-line mixing at 15-20 degrees Celsius. In some embodiments, the coated ibuprofen experiences less than 40% particle size loss within the first 2 hours after mixing into the solution matrix. In some embodiments, the coated ibuprofen experiences less than 30% particle size loss within the first 2 hours after mixing into the solution matrix. In some embodiments, the coated ibuprofen experiences less than 20% particle size loss within the first 2 hours after mixing into the solution matrix.

[0021] In some embodiments, the method of treating a patient comprises administering to the patient a pharmaceutical composition of any one disclosed herein. In some embodiments, the patient is a human.

[0022] In some embodiments, the method of making a pharmaceutical composition comprises: coating ibuprofen with a first coating material to form coated ibuprofen, wherein the first coating material comprises one or more deformable components; applying mechanical stress to the coated ibuprofen to deform the one or more deformable components; coating the coated ibuprofen with a second coating material comprising silicon dioxide; applying mechanical stress to embed the second coating material onto the first coating material of the coated ibuprofen; sieving the coated ibuprofen to remove excess first coating material, wherein the excess first coating material comprises first coating material that is not bound to the coated ibuprofen; forming a pharmaceutical suspension comprising the twice-coated ibuprofen and a matrix solution or suspension; incorporating the pharmaceutical suspension into a mold; and freeze-drying the incorporated pharmaceutical suspension in the mold to form the pharmaceutical composition. BRIEF DESCRIPTION OF DRAWINGS

[0023] The present application will now be described, by way of example only, with reference to the accompanying drawings in which:

[0024] Figure 1A shows API particles coated with a deformable coating material of particles (i.e., first coating layer) according to some embodiments;

[0025] Figure 1B shows API particles coated with a deformable coating material of a continuous film layer (i.e., first coating layer) according to some embodiments;

[0026] Figure 1C shows API particles coated with a deformable coating material of a continuous film layer (i.e., first coating layer) according to some embodiments, wherein particles of silicon dioxide (i.e., second coating layer) are partially embedded and / or embedded on the surface of the first coating layer;

[0027] Figure 2 shows a scanning electron microscope (SEM) image of uncoated API particles according to some embodiments;

[0028] Figure 3 shows a SEM image of coated API particles according to some embodiments;

[0029] Figures 4A-4J is a series of micrographs taken of sieved coated ibuprofen of Examples 1-4;

[0030] Figure 5 is a graph providing an assessment of the d10 particle size of functional coated ibuprofen comprising a second protective coating of different concentrations of silicon dioxide according to some embodiments;

[0031] Figure 6 is a graph providing an assessment of the d50 particle size of functional coated ibuprofen comprising a second protective coating of different concentrations of silicon dioxide according to some embodiments;

[0032] Figure 7 A graph showing evaluation of d90 particle size of functionally coated ibuprofen with a second protective coating comprising different concentrations of silicon dioxide according to some embodiments;

[0033] Figure 8 A graph showing low volume dissolution of ibuprofen coated with palm wax with different levels of hydrophobic fumed silica according to some embodiments;

[0034] Figure 9 A graph showing low volume dissolution of ibuprofen coated with Sasol (synthetic) wax comprising different levels of hydrophobic fumed silica according to some embodiments;

[0035] Figure 10 A graph showing evaluation of d10 particle size of hydrophobic coated ibuprofen with different concentrations of liquid flavoring agent;

[0036] Figure 11 A graph showing evaluation of d50 particle size of hydrophobic coated ibuprofen with different concentrations of liquid flavoring agent;

[0037] Figure 12 A graph showing evaluation of d90 particle size of hydrophobic coated ibuprofen with different concentrations of liquid flavoring agent;

[0038] Figure 13 A graph showing evaluation of d10 particle size of hydrophobic coated ibuprofen with different concentrations of pure limonene;

[0039] Figure 14 A graph showing evaluation of d50 particle size of hydrophobic coated ibuprofen with different concentrations of pure limonene;

[0040] Figure 15 A graph showing evaluation of d90 particle size of hydrophobic coated ibuprofen with different concentrations of pure limonene; and

[0041] Figure 16 A graph showing comparison of various particle size analysis of hydrophobic coated ibuprofen with strawberry and orange liquid flavoring agents. DETAILED DESCRIPTION

[0042] Described herein are exemplary embodiments of methods for minimizing and / or preventing agglomeration of coating materials for coated ibuprofen, methods for maintaining a coating of coated ibuprofen, and methods for minimizing aeration of ibuprofen in a pharmaceutical suspension. Also described are pharmaceutical compositions containing ibuprofen prepared by any one or more of the disclosed methods. Each of these methods and pharmaceutical compositions is described in detail below. Pharmaceutical compositions containing ibuprofen can be prepared using any combination of features of the following preparation methods.

[0043] Figure 1A 、 Figure 1B and Figure 1C Illustration of the different phases of coated API particles (e.g., ibuprofen) according to some embodiments. In some embodiments, API particles can be combined with one or more coating materials to produce a coated API. Such coatings can include materials including water-soluble and / or water-swellable materials and water-insoluble materials (described in detail below).

[0044] For example, Figure 1A API particles 102 are shown surrounded by coating material particles 104. Figure 1A In order to coat API particles, the combined API (i.e., API particles 102) and one or more coating materials (i.e., coating material particles 104) can be exposed to mechanical and / or thermal energy to produce an ordered mixture of API particles 102 comprising discrete layers of coating material particles 104 stratifying the surface of the API particles 102. Figure 1A The API particles 102 have a single layer of discrete particles of coating material. However, the API particles 102 may have two or more discrete layers of coated particles. In addition, Figure 2 SEM images of uncoated API particles are shown.

[0045] Figure 1B An API particle 102 is shown surrounded by a continuously deforming membrane layer 104. Specifically, Figure 1B As shown, all coating material particles 104 are deformable and can deform when subjected to mechanical stress and / or elevated temperature. Therefore, since all coating materials contain deformable features, Figure 1B The coating material 104 is a relatively smooth and continuous coating layer after exposure to mechanical and / or thermal energy. In some embodiments, the API particle 102 may have two or more relatively smooth and continuous coating layers. As used herein, a "continuous film" may be a layer surrounding the API particle that is formed by melting / softening or otherwise decomposing one or more deformable components of individual coating material particles so that they comprise a single continuous layer surrounding the API particle. Figure 3 Also provided are SEM images of coated API particles according to some embodiments.

[0046] In some embodiments, one or more coating materials can not be deformable, but can be embedded in a deformable coating layer. Thus, the continuous film can comprise solid particles of non-deformable material embedded in a deformable coating material. Figure 1C The continuous film 104 can comprise solid non-deformable particles 108 of one or more non-deformable materials partially embedded and / or embedded within a deformable coating material of the continuous film 104. Figure 1B or Figure 1C Such a continuous film 104 can ensure a coating (e.g., a coating that masks the taste of the API) and delayed release of the API. In some embodiments, the API particles 102 can have two or more continuous coating layers partially embedded and / or embedded with non-deformable coating material particles. Figure 3 SEM images showing functional coated API particles according to some embodiments are also provided.

[0047] As used herein, the terms “deformable,” “deformable component,” “deformable component of a 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 disintegrate upon being subjected to mechanical stress and / or elevated temperatures.

[0048] In some embodiments, the coated API particles can comprise ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition can comprise 30.0 to 90.0% w / w ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition can comprise 40.0 to 85.0% w / w, 50.0 to 80.0% w / w, or 70.0 to 80.0% w / w ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition can comprise 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 ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition can comprise 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 ibuprofen.

[0049] The coating 104 surrounding the API particles 102 can comprise materials including water-soluble and / or water-swellable materials and water-insoluble materials. In some embodiments, the coating can directly coat API particles (e.g., ibuprofen), or it can coat API particles that already contain one or more coatings. In some embodiments, the ratio of coating material to API can be optimized to minimize excess coating material. For example, the coating material can comprise 5-85% w / w, 10-50%, 15-30% of the API and coating material mixture or pharmaceutical composition. In some embodiments, the coating material can comprise 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% of the API and coating material mixture or pharmaceutical composition. In some embodiments, the coating material can comprise 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% of the API and coating material mixture or pharmaceutical composition. In some embodiments, the percentage of coating material can comprise two or more layers of coating material.

[0050] The water-swellable material of the coating material can be particles comprising a median particle size of about 0.5 pm to about 20 pm or about 1 pm to about 10 pm. In some embodiments, the water-swellable material can be about ten times smaller than ibuprofen to enable orderly mixing and coating. Upon absorption of water, the water-swellable material can swell such that the diameter of the water-swellable particles increases by at least about 120-600%. The coating material or pharmaceutical composition can comprise 0 to 8% w / w or 0.1 to 0.9% w / w water-swellable material. In some embodiments, the coating material or pharmaceutical composition can comprise 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 water-swellable material. In some embodiments, the coating material or pharmaceutical composition can comprise 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 water-swellable material. In some embodiments, the coating material or pharmaceutical composition can comprise 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 water-swellable material. The water-swellable material of the coating material can deform under mechanical stress and / or elevated temperature (elaborated below). The water-swellable material can be any one or more of crospovidone, crosscarmellose, sodium starch glycolate, or any other suitable disintegrant used in the pharmaceutical industry as an additive or admixture for tableting.

[0051] The water-soluble material of the coating material can also be particles comprising a median particle size of about 0.5 pm to about 20 pm or about 1 pm to about 10 pm. In some embodiments, the water-soluble material can be about ten times smaller than ibuprofen to enable orderly mixing and coating. The water-soluble material can have a water solubility of at least about 50 mg / ml in water at neutral pH and at 20 °C. Further, the water-soluble material can have a water solubility of about 3-60 pg / mg at 37 °C. The coating material or pharmaceutical composition can comprise 0 to 8% w / w or 0.1 to 0.9% w / w water-soluble material. In some embodiments, the coating material or pharmaceutical composition can comprise 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 water-soluble material. In some embodiments, the coating material or pharmaceutical composition can comprise 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 water-soluble material. In some embodiments, the coating material or pharmaceutical composition can comprise 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 water-soluble material. 2the inherent dissolution rate of the drug. The water-soluble material of the coating material can be deformed under mechanical and / or thermal energy. The coating material or pharmaceutical composition can comprise 0 to 35% w / w water-soluble material. In some embodiments, the coating material or pharmaceutical composition can comprise 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 water-soluble material. In some embodiments, the coating material or pharmaceutical composition can comprise 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 water-soluble material. In some embodiments, the coating material or pharmaceutical composition can comprise more than 0.1% w / w, more than 0.5% w / w, more than 1.0% w / w, more than 1.5% w / w, more than 2.0% w / w, more than 2.5% w / w, more than 3.0% w / w, more than 4.0% w / w, more than 5.0% w / w, more than 8.0% w / w, more than 10% w / w, more than 15% w / w, more than 20% w / w, more than 25% w / w, or more than 30% w / w water-soluble material. The water-soluble material can be one or more of sucrose, mannitol, sorbitol, polyvinylpyrrolidone, hydroxypropyl cellulose, lactose, poly-(ethylene oxide), and any other suitable micropinchable material or polyol.

[0052] In addition to the 3-60 pg / mg inherent dissolution rate of the drug discussed above, the methods provided can also allow for the use of a drug having an inherent dissolution rate of about 60-300 pg / mg 2 In addition to the 3-60 pg / mg inherent dissolution rate of the drug discussed above, the methods provided can also allow for the use of a drug having an inherent dissolution rate of about 60-300 pg / mg 2water-soluble and / or water-swellable material having a higher intrinsic dissolution rate. However, ibuprofen with a coating material having a higher intrinsic dissolution rate is dry coated with hydrophobic silicon dioxide. Dry coated ibuprofen in which the coating comprises a water-soluble and / or water-swellable material having a higher intrinsic dissolution rate can increase the disintegration time of ibuprofen such that it cannot effectively mask the taste of ibuprofen. Thus, dry coating ibuprofen with silicon dioxide as a second coating material to slow the dissolution rate can improve the in vivo taste masking performance of the coating. The coated ibuprofen can comprise 0.5 to 35% w / w silicon dioxide. In some embodiments, the coated ibuprofen or pharmaceutical composition can comprise 0.5 to 20% w / w, 0.5 to 10% w / w, or 0.5 to 5% w / w hydrophobic fumed silicon dioxide. In some embodiments, the coated ibuprofen or pharmaceutical composition can comprise more than 0.5% w / w, more than 1.0% w / w, more than 1.5% w / w, more than 2.0% w / w, more than 2.5% w / w, more than 3.0% w / w, more than 4.0% w / w, more than 5.0% w / w, more than 10% w / w, more than 15% w / w, more than 20% w / w, more than 25% w / w, or more than 30% w / w hydrophobic fumed silicon dioxide. In some embodiments, the coated ibuprofen or pharmaceutical composition can comprise 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 hydrophobic fumed silicon dioxide. Examples of silicon dioxide that can be used include, but are not limited to, Aerosil R972 silicon dioxide (Degussa), CAB-O-SIL EH-5 silicon dioxide (Cabot), OX-50 silicon dioxide (Degussa), COSM055 (Catalyst & Chemical Ind. Co. Ltd (Japan)), P-500 hydrophilic silicon dioxide (Catalyst & Chemical Ind. Co. Ltd (Japan)), and TS5 silicon dioxide (Cabot).In addition, suitable devices that can be used for dry coating with silica include, but are not limited to, Comil (U3 Quadro Comil of Quadro Pennsylvania, U.S.), LabRAM (Resodyne Minnesota, U.S.), Magnetically Assisted Impact Coater (MAIC, Aveka Minnesota, U.S.), and Fluid Energy Mill (FEM, Qualification Micronizer of Sturtevant Massachusetts U.S.).

[0053] The pharmaceutical composition can be prepared by incorporating the drug suspension into preformed blister packs. In some embodiments, the freeze-dried orally disintegrating tablets can be prepared by incorporating the suspension into blister packs. In some embodiments, the drug pump is volumetric, but the process is controlled by weight. Thus, to ensure content uniformity from one dosage form to the next, the incorporation process can be controlled such that the volume-to-weight percentage of the incorporated suspension is consistent. For example, the volume-to-weight percentage can be consistent within 10%, within 8%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1.5%, within 1%, within 0.5%, or within 0.25%. In some embodiments, the weight of the incorporated drug suspension is within 10%, within 8%, within 6%, within 5%, within 4%, within 2.5%, within 2%, within 1.5%, within 1%, within 0.5%, or within 0.25% of the target weight. Additionally, the viscosity of the drug suspension should remain low enough to facilitate incorporation. As noted above, high viscosity of the drug suspension can result in pump jamming during incorporation.

[0054] The water-insoluble material of the coating material can also comprise particles having an average particle size that is less than the average particle size of ibuprofen. For example, the water-insoluble material can comprise an average particle size of about 1-20 pm, about 1-12 pm, about 2-10 pm, about 5-12 pm, or about 5-6 pm. In some embodiments, the water-insoluble material can be about ten times smaller than ibuprofen to achieve orderly mixing and coating. The water-insoluble material of the coating material can deform under mechanical stress and / or elevated temperature. The coating material or pharmaceutical composition can comprise 5 to 70% w / w, 10 to 60% w / w, 10 to 50% w / w, 10 to 40% w / w, 10 to 35% w / w, or 15 to 30% w / w water-insoluble material. In some embodiments, the coating material or pharmaceutical composition can comprise more than 5% w / w, more than 10% w / w, more than 15% w / w, more than 20% w / w, more than 25% w / w, more than 30% w / w, more than 35% w / w, or more than 40% w / w water-insoluble material. In some embodiments, the coating material or pharmaceutical composition can comprise less than 70% w / w, less than 60% w / w, less than 50% w / w, less than 45% w / w, less than 40% w / w, less than 35% w / w, or less than 30% w / w water-insoluble material. Examples of suitable water-insoluble materials include, but are not limited to, ethyl cellulose, polyethylene, polypropylene, polytetrafluoroethylene, carnauba wax, candelilla wax, castor wax, polyamide wax, and / or synthetic wax.

[0055] In some embodiments, mechanical and / or thermal energy can be used to deform one or more water-insoluble materials, water-swellable materials, and / or water-insoluble materials. For example, a functional coated ibuprofen can be subjected to mechanical stress using a PharmaRAM II acoustic mixer, a RAM5 Pharma mixer, or a RAM55 Pharma mixer (Resodyn mixers). During this acoustic mixing process, the coated ibuprofen can be exposed to up to 100 times the force of gravity (100 G acceleration). These high forces cause particle-particle collisions, which generate energy in the form of heat that can be used to deform one or more water-insoluble materials, water-swellable materials, and / or water-insoluble materials on the API.

[0056] However, the above coating process can also produce “loose” or “free” coating material particles. Figure 2 is a SEM image of uncoated API particles. Figure 3 is a SEM image of coated API particles 312. “Loose” or “free” coating material particles 314 are not bound to the coated API particles 312.

[0057] Once sieved, the coated ibuprofen can be mixed into the base solution / suspension to form a drug suspension (e.g., coated ibuprofen plus base solution / suspension) and incorporated by weight into the pouches of preformed blister packs to form aliquots of the drug suspension. Once incorporated, the blister packs with aliquots of the drug suspension are frozen under subzero conditions. The frozen aliquots of the incorporated drug suspension are kept frozen until they are ready for freeze drying, during which the solvent of the drug suspension is removed to form a pharmaceutical composition.

[0058] The matrix solution / suspension may include a matrix former, a structure former, and a solvent. For example, the matrix former may include any water-soluble or water-dispersible material that is pharmacologically acceptable or inert for the functional coated ibuprofen. In some embodiments, the matrix former may be a polypeptide, such as gelatin. Gelatin may be at least partially hydrolyzed (by heating in water). Other suitable matrix former materials include, but are not limited to, polysaccharides, such as hydrolyzed polydextrose, dextrin, and alginates, polyvinyl alcohol, polyvinyl pyrrolidone, and / or gum arabic. In some embodiments, the amount of the matrix in the pharmaceutical composition (e.g., orally disintegrating tablet) may be 1-30% w / w. In some embodiments, the amount of the 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 may 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.

[0059] In some embodiments, the amount of matrix forming agent in the matrix solution / suspension or drug suspension can be about 0.1 to 10% w / w. In some embodiments, the amount of matrix forming agent in the matrix solution / suspension or drug suspension can include 1.0 to 8.0% w / w or 2.0 to 5.0% w / w. In some embodiments, the amount of matrix forming agent in the matrix solution / suspension or drug suspension can 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 matrix forming agent in the matrix solution / suspension or drug suspension can 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 can be about 3-15% w / w, about 4-10% w / w, or about 4-7% w / w. In some embodiments, the amount of matrix forming agent in the pharmaceutical composition can 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 can 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.

[0060] The structural forming agent or bulking agent of the matrix can include a sugar. For example, suitable structural forming agents include, but are not limited to, mannitol, dextrose, lactose, galactose, glycine, cyclodextrin, or combinations thereof. The structural forming agent can be used as a bulking agent in lyophilization because it crystallizes to provide structural firmness to the lyophilized dosage form. In some embodiments, the amount of structural forming agent in the matrix solution / suspension can be about 0.1 to 10% w / w. In some embodiments, the amount of structural forming agent in the matrix solution / suspension or drug suspension can include 1.0 to 8.0% w / w or 1.5 to 5.0% w / w. In some embodiments, the amount of structural forming agent in the matrix solution / suspension or drug suspension can 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 4.0% w / w, more than 5.0% w / w, or more than 8.0% w / w. In some embodiments, the amount of structural forming agent in the matrix solution / suspension or drug suspension can 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 structural forming agent in the pharmaceutical composition can be about 3-15% w / w, about 4-10% w / w, or about 4-7% w / w. In some embodiments, the amount of structural forming agent in the pharmaceutical composition can 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 structural forming agent in the pharmaceutical composition can 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.

[0061] In some embodiments, the matrix solution / suspension and the drug suspension can include a viscosity modifier. For example, the viscosity modifier according to the embodiments provided herein can include a vegetable gum, such as xanthan gum, algin, guar gum, or locust bean gum; a protein, such as collagen or gelatin; a sugar, such as agar, carboxymethylcellulose, pectin, or carrageenan; a starch, such as arrowroot, cornstarch, Katakuri starch, potato starch, sago, or tapioca starch; and / or other suitable viscosity modifiers. In some embodiments, the amount of viscosity modifier in the matrix solution / suspension, the drug suspension, or the pharmaceutical composition can be from 0 to 0.2% w / w or from 0.01 to 0.1% w / w. In some embodiments, the amount of viscosity modifier in the matrix solution / suspension, the drug suspension, or the pharmaceutical composition can be greater than 0.01% w / w, greater than 0.03% w / w, greater than 0.05% w / w, greater than 0.07% w / w, greater than 0.1% w / w, greater than 0.12% w / w, greater than 0.15% w / w, or greater than 0.17% w / w. In some embodiments, the amount of viscosity modifier in the matrix solution / suspension, the drug suspension, or the pharmaceutical composition can be less than 0.2% w / w, less than 0.18% w / w, less than 0.15% w / w, less than 0.12% w / w, less than 0.1% w / w, less than 0.08% w / w, less than 0.06% w / w, or less than 0.03% w / w.

[0062] The solvent of the matrix solution / suspension and the drug suspension can be water, but the suspension solution can also include a co-solvent. In some embodiments, the solvent can be ethanol, an alcohol, isopropyl alcohol, other lower alkyl alcohol, water (e.g., purified water), or a combination thereof. For example, a suitable solvent and / or co-solvent can be an alcohol, such as t-butyl alcohol. In some embodiments, the remainder of the drug suspension is solvent (i.e., Q.S. 100%).

[0063] The matrix solution / suspension and the drug suspension can also contain additional pharmaceutically acceptable agents or excipients. Such additional pharmaceutically acceptable agents or excipients include, but are not limited to, sugars, inorganic salts (e.g., sodium chloride and aluminosilicates), modified starches, preservatives, antioxidants, viscosity enhancers, colorants, flavorants, pH adjusters, sweeteners, taste-masking agents, and combinations thereof. Suitable colorants can include red, black, and yellow iron oxide and FD&C dyes (e.g., FD&C Blue No. 2 and FD&C Red No. 40) and combinations thereof. Suitable flavorants can include peppermint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, and grape flavorants and combinations of these. Suitable pH adjusters can include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, sodium hydroxide (e.g., a 3% w / w solution of sodium hydroxide), and combinations thereof. Suitable sweeteners can include aspartame, acesulfame K, and thaumatin and combinations thereof. Suitable taste-masking agents can include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion complexes, adsorbates, or microencapsulated actives and combinations thereof. Suitable amounts of these various additional excipients can be readily determined by one skilled in the art, if desired.

[0064] Minimizing and / or preventing agglomeration of coating material of coated ibuprofen

[0065] Methods of preparing pharmaceutical compositions comprising ibuprofen that minimize the amount of excess coating material and / or the amount of agglomeration of excess coating material upon storage are set forth below.

[0066] Methods according to some embodiments include removing excess coating material particles to minimize and / or prevent agglomeration of coating material in the drug product. In some embodiments, the methods can include sieving the raw ibuprofen and / or the coated ibuprofen. In particular, the methods provided can include sieving the ibuprofen and / or the coated ibuprofen to remove any undesired particles, such as excess coating material particles. The sieving process according to the disclosed embodiments can help prevent and / or minimize the potential for agglomeration of coating material that can adversely affect the disintegration time and / or dissolution rate of the final product. The methods can also include optimizing the coating and / or dosing ratio of the process.

[0067] Methods for minimizing and / or preventing agglomeration of coating material particles according to the embodiments described herein can be applied to dry, solvent-free mixing methods for coating ibuprofen. Thus, the methods provided are set forth below in the context of one or more dry, solvent-free mixing methods for coating ibuprofen. However, other variations of the coating / encapsulation process can also be used. For example, other variations of sugar coating, film coating, microencapsulation, compression coating, dry coating, melt coating, dip coating, rotary die coating, electrostatic coating, and / or other suitable types of coating can be used.

[0068] Generally, solventless mixing processes for coating ibuprofen include mixing a coating material with ibuprofen to produce coated ibuprofen. Mechanical and / or thermal stress is then applied to the coated ibuprofen to deform the deformable coating material, resulting in a continuous film surrounding the ibuprofen. The coated ibuprofen is then mixed with a base solution / suspension to form a drug suspension. The drug suspension comprising the coated ibuprofen can be incorporated into preformed molds (e.g., blister packs) and further processed to produce a dispensable pharmaceutical composition (e.g., a lyophilizate, wafer, tablet, etc.).

[0069] However, upon storage of the final product (i.e., the pharmaceutical composition), any excess coating material particles that are not bound to the coated ibuprofen can agglomerate. The amount and / or severity of agglomeration can increase over time. Agglomeration of excess coating material can increase the disintegration time of the pharmaceutical product and / or decrease the dissolution rate of the pharmaceutical product, and adversely affect any functional properties of the coating material. Increased disintegration time can also result in unacceptable in vivo dispersion and mouthfeel characteristics.

[0070] Accordingly, it has been discovered that by sieving the coated ibuprofen, excess coating material can be removed, thereby minimizing the amount of agglomeration of excess coating material upon storage. Further, some embodiments include optimizing the coating ratio (the ratio of the amount of coating material to the amount of uncoated ibuprofen) and optimizing the charge ratio (the ratio of the amount of coated ibuprofen to the amount of aqueous base solution comprising all other non-active ingredients) can also minimize the agglomeration of excess coating material particles.

[0071] The embodiments provided herein can be applied to coated ibuprofen produced using dry solventless processes. Some mixing processes according to the embodiments described herein include coating ibuprofen with a taste-masking coating. Such coatings can control the disintegration time and / or dissolution rate of the orally dispersible pharmaceutical composition such that upon oral administration, release of ibuprofen is delayed or substantially reduced during the first few minutes while the ibuprofen is in the mouth, but a satisfactory amount of ibuprofen is released within 30 minutes of oral administration after swallowing. (For example, a satisfactory amount of ibuprofen can be 90% of the amount of ibuprofen that would be released without coating.) U.S. Patent No. 9,107,851 (the ‘851 Patent) relates to an example dry solventless process for coating a pharmaceutical ingredient, which is incorporated by reference herein in its entirety.

[0072] However, other variations of coating / encapsulation methods 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, spin coating, electrostatic coating, and / or other suitable types of coating can be used.

[0073] Additionally, the specific data provided herein relate to disintegration time. However, disintegration time is inversely related to dissolution rate. Thus, the data also inherently provide information about dissolution rate. Disintegration time can be measured according to the method described by the United States Pharmacopeia (Disintegration 701). In some embodiments, the disintegration time can be 2-30 seconds or 5-20 seconds. In some embodiments, the disintegration time can 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, the disintegration time can 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 can also be tested according to the method described by the United States Pharmacopeia (Dissolution 711).

[0074] In some embodiments, the raw ibuprofen can be sieved prior to the coating process to obtain a narrower particle size range. For example, the raw ibuprofen can be sieved to remove oversized particles and / or to remove undersized particles. In some embodiments, more than one screen can be used to remove certain particles. For example, the sieving apparatus can include a series of two or more screens to remove particles of a particular size depending on the size of the screen. The screens can be incorporated into a vacuum transfer system to transport the particles through the series of screens of the apparatus. Additionally, an ultrasonic probe can be incorporated into the sieving apparatus to improve material flow and minimize clogging of the screens during processing.

[0075] In some embodiments, the raw ibuprofen can be sieved using a screen size of 30 pm to 500 pm, 50 pm to 450 pm, 100 pm to 400 pm, 150 pm to 350 pm, or 200 pm to 300 pm. In some embodiments, the raw ibuprofen can be sieved using a screen size of less than 500 pm, less than 450 pm, less than 400 pm, less than 350 pm, less than 300 pm, less than 250 pm, less than 200 pm, less than 150, or less than 100 pm. In some embodiments, the raw ibuprofen can be sieved using a screen size of greater than 30 pm, greater than 50 pm, greater than 100 pm, greater than 150 pm, greater than 200 pm, greater than 250 pm, greater than 300 pm, greater than 350 pm, or greater than 400 pm.

[0076] Once the ibuprofen has been coated with the coating material to produce coated ibuprofen, the coated ibuprofen can be sieved to remove excess coating material and residual fine ibuprofen, which can be uncoated, partially coated, or coated. Excess coating material can include any coating material particles that are not associated with the coated ibuprofen. Upon storage of the final drug product, any excess coating material can agglomerate. For example, fusion can occur between excess coating particles and coated particles that have already associated with the ibuprofen, thereby preventing the ingress of a medium that would otherwise aid in the disintegration of the unit or tablet or the dissolution of the coated ibuprofen. Thus, agglomeration of excess coating material can result in increased disintegration times and / or decreased dissolution rates upon administration.

[0077] However, it has been determined that a process to sieve excess coating material from the coated ibuprofen can minimize agglomeration of the coating material and maintain the original disintegration times and / or dissolution rates of the final product. The sieving process can be batch or continuous. Additionally, this sieving process can be performed in addition to or in place of the sieving process performed on the raw ibuprofen described above. In some embodiments, the sieving process parameters for the uncoated raw ibuprofen can be different than the sieving process parameters for the coated ibuprofen.

[0078] In some embodiments, the coated ibuprofen can be sieved to remove coating material particles having an average particle size that is less than the desired average coated ibuprofen particle size. In some embodiments, more than one sieve can be used to remove certain particles. For example, the sieving apparatus can include a series of two or more sieves to remove particles of a particular size depending on the size of the sieve. The sieves can be incorporated into a vacuum transfer system to deliver the particles to the series of sieves in the apparatus. Additionally, an ultrasonic probe can be incorporated into the sieving apparatus to improve material flow and minimize plugging of the sieves during processing. A flow aid, such as silicon dioxide, can be included to facilitate movement through the sieves. For example, the coating material used to coat the ibuprofen can include a flow aid. In contrast, the raw ibuprofen can not be cohesive and can not require the assistance of a flow aid during sieving. The sieving process can be a batch process or a continuous process.

[0079] In some embodiments, the raw ibuprofen can be sieved using a mesh size of 30 pm to 500 pm, 50 pm to 450 pm, 100 pm to 400 pm, 150 pm to 350 pm, or 200 pm to 300 pm. In some embodiments, the raw ibuprofen can be sieved using a mesh size of less than 500 pm, less than 450 pm, less than 400 pm, less than 350 pm, less than 300 pm, less than 250 pm, less than 200 pm, less than 150, or less than 100 pm. In some embodiments, the raw ibuprofen can be sieved using a mesh size of greater than 30 pm, greater than 50 pm, greater than 100 pm, greater than 150 pm, greater than 200 pm, greater than 250 pm, greater than 300 pm, greater than 350 pm, or greater than 400 pm.

[0080] The coating ratio (i.e., the ratio of the amount of coating material to the amount of uncoated ibuprofen) can be optimized to minimize and / or prevent agglomeration of excess coating material. For example, in some embodiments, the coating ratio can be in the range of 5-85% or 10-50% w / w coating material to 15-95% or 50-90% w / w uncoated ibuprofen. In some embodiments, the amount of coating material can 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 can be 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, more than 50% w / w, more than 60% w / w, or more than 70% w / w. In some embodiments, the amount of uncoated ibuprofen can 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 can be more than 20% w / w, more than 30% w / w, 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.

[0081] The feed ratio (i.e., the ratio of the amount of coated ibuprofen to the amount of the matrix solution / suspension comprising all non-active ingredients) can be optimized to minimize and / or prevent agglomeration of excess coating material. For example, in some embodiments, the feed ratio can be in the range of 5-60% w / w coated ibuprofen to 40-95% w / w matrix solution / suspension. In some embodiments, the feed ratio can 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 coated ibuprofen. In some embodiments, the feed ratio can 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 coated ibuprofen. In some embodiments, the feed ratio can include 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 matrix solution / suspension. In some embodiments, the feed ratio can include 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 matrix solution / suspension.

[0082] Maintaining functional coated ibuprofen produced by dry solvent-free mixing process and mixed into suspension

[0083] The pharmaceutical compositions and methods of making pharmaceutical compositions provided herein can include the addition of a hydrophobic fumed silica in the coating process to provide a functional coating (or "first coating") that surrounds the functional coated ibuprofen and / or a protective layer in which it is partially or completely embedded. The addition of such a hydrophobic fumed silica layer (or "second layer") can provide a protective layer to the first coating layer of functional coated ibuprofen and can minimize the erosion of the first coating layer to the shear forces required to mix the functional coated ibuprofen into a pharmaceutical suspension.

[0084] Generally, the solvent-free mixing process for coating ibuprofen includes mixing a coating material with ibuprofen to produce functionally coated ibuprofen. The functionally coated ibuprofen is then subjected to mechanical and / or thermal stress to deform the deformable coating material, thereby producing a continuous film that surrounds the ibuprofen. The functionally coated ibuprofen is then mixed with a matrix solution or suspension to form a drug suspension. The drug suspension comprising the functionally coated ibuprofen can be incorporated into a preformed mold (e.g., a blister pack) and further processed to produce a dispensable pharmaceutical composition (e.g., a lyophilizate, wafer, tablet, etc.). In some embodiments, the dispensable pharmaceutical composition can be an orally dispersible product. Ideally, the minimum amount of ibuprofen, if any, in the final dispensable pharmaceutical composition dissolves within the first few minutes of oral administration. This delay or significant reduction in ibuprofen release allows the taste of ibuprofen to be masked while the orally dispersible product is in the patient's mouth. Conversely, once the pharmaceutical composition passes through the gastrointestinal tract, ibuprofen can be released.

[0085] However, when the functionally coated ibuprofen is mixed into the matrix solution / suspension, the shear force required to mix the granules into the matrix solution / suspension can erode the functionally coating of the ibuprofen. Erosion of the coating can destroy or compromise the properties of the functionally coating. For example, erosion of the functionally coating can destroy or compromise any taste-masking properties of the functionally coating and allow ibuprofen to experience dissolution in the oral cavity.

[0086] Accordingly, it has been discovered that hydrophobic fumed silica, as well as serving as a glidant for the functionally coated ibuprofen to aid in downstream processing, can also be used to provide a hydrophobic barrier layer that surrounds and / or partially or completely embeds the functionally coated ibuprofen. Specifically, the hydrophobic barrier layer formed from the hydrophobic fumed silica can protect one or more underlying coatings of the functionally coated ibuprofen during the preparation of the drug suspension and other downstream processing of the functionally coated ibuprofen. Thus, ibuprofen according to some embodiments described herein can have a first functionally coating and a second protective coating.

[0087] However, some of the pharmaceutical compositions and methods of making pharmaceutical compositions provided herein can include not only a first coating and a second coating. For example, some of the pharmaceutical compositions and methods of making thereof can include three, four, five, six, or more coatings. Thus, the terms "first coating" and "second coating" as used herein should not be interpreted narrowly. As used herein, the term "first coating" refers to the functional coating of ibuprofen, and the "second coating" refers to the protective coating comprising silicon dioxide. In some embodiments, the functionally coated ibuprofen can have one or more coating layers between the "first coating" and the "second coating." In some embodiments, the functionally coated ibuprofen can have one or more coating layers between the ibuprofen and the "first coating." In some embodiments, the functionally coated ibuprofen can have one or more coating layers on top of the "second coating."

[0088] Once the functionally coated ibuprofen is prepared, it can be mixed into the matrix / suspension solution to form the pharmaceutical suspension for administration. Mixing the functionally coated ibuprofen into the matrix solution / suspension can erode the functional coating of the functionally coated ibuprofen. In some embodiments, to minimize this erosion, a hydrophobic fumed silicon dioxide can be used to form a second coating layer that surrounds and / or partially embeds and / or embeds the functionally coated ibuprofen.

[0089] However, it is not naturally intuitive to coat the functionally coated ibuprofen (i.e., the ibuprofen comprising at least the first coating, as described above) that will later be mixed into the matrix solution / suspension with a hydrophobic fumed silicon dioxide. As described above, to produce an orally dispersible pharmaceutical composition according to the embodiments described herein, the functionally coated ibuprofen is mixed into a matrix solution / suspension comprising a matrix former, a structure former, and a solvent, typically water, to form the pharmaceutical suspension. However, hydrophobic materials naturally resist mixing into the matrix solution / suspension. Thus, it can be assumed that a hydrophobic fumed silicon dioxide would increase the interfacial tension between the functionally coated ibuprofen and the matrix solution / suspension, thereby increasing the difficulty of incorporating the functionally coated ibuprofen into the matrix solution / suspension and potentially causing phase separation of the pharmaceutical suspension.

[0090] Interestingly, it has been determined that a hydrophobic fumed silicon dioxide can be used to coat the functionally coated ibuprofen to preserve the first functional coating without substantially interfering with the incorporation of the functionally coated ibuprofen into the matrix solution / suspension. As described above, a hydrophobic substance in a matrix solution / suspension, such as the functionally coated ibuprofen coated with a hydrophobic fumed silicon dioxide in the matrix solution / suspension described above, characteristically exhibits a relatively high surface tension between the hydrophobic substance and the matrix solution / suspension. Thus, the surface tension between the hydrophobic functionally coated ibuprofen and the matrix solution / suspension can also be relatively high.

[0091] However, as discussed below, the matrix solution / suspension can include a matrix forming agent, such as gelatin. Some matrix forming agents, including gelatin, are mild surfactants, meaning that they can reduce the surface tension between two substances. Thus, it is believed that matrix forming agents that exhibit surfactant-like behavior can reduce the surface tension between the functionally coated ibuprofen and the matrix solution / suspension, which in turn allows the functionally coated ibuprofen to be incorporated into the matrix solution / suspension while at the same time maintaining the protective properties of the first functional coating of the functionally coated ibuprofen by the hydrophobic aerosol silica coating layer. This second coating layer comprising hydrophobic aerosol silica can provide a hydrophobic barrier to the underlying first coating of the functionally coated ibuprofen to protect the underlying first coating from the shear forces required to mix the functionally coated ibuprofen into the drug suspension. By coating the functionally coated ibuprofen with a hydrophobic barrier comprising hydrophobic aerosol silica, the underlying (first) coating can be protected from erosion. Furthermore, the use of hydrophobic aerosol silica according to the described method can prevent the matrix solution / suspension from penetrating the coating to reach the ibuprofen.

[0092] Under normal handling conditions, without the hydrophobic aerosol silica coating layer, the coating of the functionally coated ibuprofen can erode over time under the shear forces required to mix the functionally coated ibuprofen into the matrix solution / suspension. However, from the time the functionally coated ibuprofen is first mixed into the matrix solution / suspension, there can be a "handling window" of two or more hours in which the coating can remain intact and its functionality can remain unimpaired. The exact time of this "handling window" can vary and can depend on the composition of the various components of the functionally coated ibuprofen, the composition of the matrix solution / suspension, the amount of material used to prepare the coating of the functionally coated ibuprofen, and / or the physicochemical properties of the ibuprofen. However, with the functionally coated ibuprofen having a second coating comprising aerosol silica, this "handling window" can be extended.

[0093] In some embodiments, the pharmaceutical composition or coated ibuprofen can comprise 0.5 to 35% w / w hydrophobic fumed silica. In some embodiments, the pharmaceutical composition or coated ibuprofen can comprise 0.5 to 20% w / w, 0.5 to 10% w / w, or 0.5 to 5% w / w hydrophobic fumed silica. In some embodiments, the pharmaceutical composition or coated ibuprofen can comprise more than 0.5% w / w, more than 1.0% w / w, more than 1.5% w / w, more than 2.0% w / w, more than 2.5% w / w, more than 3.0% w / w, more than 4.0% w / w, more than 5.0% w / w, more than 10% w / w, more than 15% w / w, more than 20% w / w, more than 25% w / w, or more than 30% w / w hydrophobic fumed silica. In some embodiments, the pharmaceutical composition or coated ibuprofen can comprise 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 hydrophobic fumed silica. The hydrophobic fumed silica can be any of Aerosil R972 silica (Degussa), CAB-O-SIL EH-5 silica (Cabot), OX-50 silica (Degussa), COSMO 55 (Catalyst & Chemical Ind. Co. Ltd (Japan)), TS5 silica (Cabot), and / or other suitable types of silica.

[0094] The effectiveness of the protective layer comprising hydrophobic fumed silica can be determined by measuring the particle size of the functional coated ibuprofen in the pharmaceutical suspension over time. If the hydrophobic fumed silica is effective at preserving the coating, the particle size of the functional coated ibuprofen can remain constant or decrease very little over time. If not, the particle size of the functional coated ibuprofen can decrease more significantly over time. The particle size of the functional coated particles can be measured using laser diffraction, a particle analyzer (e.g., Malvern Mastersizer), or any other suitable means for analyzing fine particles.

[0095] The effectiveness of the protective layer comprising hydrophobic fumed silica can also be determined by performing a dissolution test on the functional coated ibuprofen. If the hydrophobic fumed silica is effective at keeping the coating, then the amount of functional coated ibuprofen released (e.g., percent released) over time in the dissolution test will be slower. If not, then the amount of functional coated ibuprofen released over time will be greater. The amount of functional coated particles released can be measured using a dissolution test, a spectrophotometer (e.g., Pion MicroDISS Profiler), or any other suitable means for performing a dissolution test.

[0096] Minimizing aeration of ibuprofen-containing suspensions

[0097] Embodiments provided herein can include the addition of a chemical compound comprising a terpene and / or terpineol to the base solution / suspension. In particular, embodiments of the pharmaceutical suspensions provided herein can include a liquid flavoring comprising a terpene and / or terpineol. In some embodiments, the liquid flavoring can include the terpene limonene. The addition of specific chemical compounds and, in particular, liquid flavorings comprising limonene, can minimize aeration of the suspension, increase the homogeneity of the suspension, and improve dose weight accuracy when the suspension is injected into a mold. As used herein, "dose weight accuracy" and related terms refer to the ability to accurately dispense a pharmaceutical suspension into a preformed mold. The dose weight accuracy of the incorporated pharmaceutical suspension can depend on a number of variables, including but not limited to homogeneity, viscosity, chemical components, dosing equipment, and the like.

[0098] As noted above, traditional mechanical means of preventing and / or minimizing aeration have not been found to be successful due to the high viscosity of the pharmaceutical suspension. For example, applying a vacuum to the pharmaceutical suspension can cause the suspension to rise in height as the viscous suspension "grabs" onto the entrained air. Volatile formulation components can also be lost during the vacuuming process. Further, traditional anti-aerating agents (e.g., ethanol or simethicone emulsion) similarly fail to effectively prevent aeration of the suspension.

[0099] Accordingly, it has been found that when hydrophobic coated ibuprofen is mixed into the base solution / suspension, certain chemical compounds and, in particular, liquid flavorings comprising a terpene and / or terpineol (e.g., limonene) can minimize aeration of the pharmaceutical suspension. By minimizing aeration, the hydrophobic coated ibuprofen is more effectively and efficiently dispersed throughout the pharmaceutical suspension. This increased dispersion can increase the homogeneity of the pharmaceutical suspension, the dose weight accuracy, and the content uniformity of the final product.

[0100] As described above, mixing hydrophobic coated ibuprofen into the matrix solution / suspension can create entrained air or bubbles in the liquid. Since the coated ibuprofen is hydrophobic, it generally has a low affinity for the matrix solution / suspension. Thus, rather than readily associating with and dispersing into the matrix solution / suspension, the hydrophobic coated ibuprofen preferentially associates with the entrained air. In many fluids, bubbles generally travel to the surface of the fluid and disappear into the air above. However, since the hydrophobic coated ibuprofen has an affinity for the entrained air, the hydrophobic coated ibuprofen "grabs" onto the bubble, preventing it from traveling to the surface and releasing into the air above the fluid. This causes the drug suspension to become aerated. Aeration of the drug suspension can cause phase separation, and thus a heterogeneous suspension. Phase separation can also become exacerbated upon exposure to shear forces introduced by the dosing pump. The heterogeneous drug suspension can cause pump hang-ups when passing through the dosing pump, resulting in inaccurate dose weights and lack of uniformity in the overall finished product, as well as poor production efficiency due to stoppages.

[0101] Additionally, due to the high loading of hydrophobic coated ibuprofen (i.e., up to 50 wt.% hydrophobic coated ibuprofen), the drug suspension comprising the hydrophobic coated ibuprofen can have a high viscosity. As described above, the entrainment of air into the drug suspension during the inline mixing of the hydrophobic coated ibuprofen into the suspension can even further increase the viscosity of the drug suspension. Thus, not only does the phase separation and heterogeneity of the suspension adversely affect the dose weight accuracy and uniformity of the finished product, but the increased viscosity also adversely affects the dose weight accuracy and uniformity of the finished product.

[0102] Interestingly, certain chemical compounds have been found to minimize the aeration of a drug suspension comprising hydrophobic coated ibuprofen when added to the base solution / suspension. In particular, chemical compounds comprising terpenes and / or terpineols according to some embodiments provided herein can minimize the amount of air entrained in a drug suspension resulting from the inline mixing of hydrophobic coated ibuprofen into a base solution / suspension. For example, suspensions comprising liquid flavorants containing terpenes and / or terpineols can minimize the aeration of a drug suspension even at relatively low concentrations. Specifically, it has been found that base solutions / suspensions comprising one or more liquid flavorants comprising limonene can minimize the aeration in a drug suspension during the inline mixing of hydrophobic coated ibuprofen. Other chemical compounds including terpenes and terpineols have also been shown to be successful in minimizing the aeration of a drug suspension. For example, chemical compounds including terpenes (e.g., limonene, carvyl ketone, ocimene, taxadiene, and squalene) can be suitable for minimizing the aeration of a drug suspension. Terpineols can also be suitable anti-aerators. In some embodiments, pure terpenes and / or pure terpineols can be used as anti-aerators. In some embodiments, liquid flavorants comprising terpenes and / or terpineols can be used as anti-aerators. In some embodiments, other suitable chemical compounds comprising terpenes and / or terpineols can be used as anti-aerators.

[0103] One challenge faced by some chemical compounds comprising terpenes and / or terpineols, such as some liquid flavorants, is that they tend to be relatively oily. Like regular oils and water, these oily chemical compounds can not be easily dispersed into a base solution / suspension. However, as discussed below, a base solution / suspension according to embodiments herein can include gelatin as a base-forming agent. Gelatin is a mild surfactant on its own. Surfactants can lower the surface tension between two materials. Thus, in some embodiments, the gelatin of a base solution / suspension can lower the surface tension between an oily chemical compound and the base solution / suspension. This can allow for the sufficient incorporation of an oily compound (e.g., a liquid flavorant) into a base solution / suspension.

[0104] Under normal handling conditions, without the presence of a chemical compound comprising a terpene and / or a terpenoid, the coating of the hydrophobically coated ibuprofen is eroded over time due to the shear forces required to mix the hydrophobically coated ibuprofen into the matrix solution / suspension to form the drug suspension. However, there exists a "handling window" of two or more hours in which the coating remains significantly functional. The exact time of this "handling window" can vary for each product and can depend on the composition of the components of the hydrophobically coated ibuprofen, the composition of the matrix solution / suspension, the amount of material used to make the hydrophobically coated ibuprofen, the physicochemical properties of the ibuprofen, and / or the mixing conditions. Unfortunately, in the presence of a chemical compound comprising a terpene and / or a terpenoid, this "handling window" can be significantly reduced due to the interactions between these chemical compounds and the coating of the hydrophobically coated ibuprofen. These interactions can impair the functional properties of the coating. For example, the interactions between the liquid flavoring and the coating of the hydrophobically coated ibuprofen can impair any taste-masking functionality of the coating. That is, it has been found that there is a threshold chemical compound (i.e., liquid flavoring) concentration below which the chemical compound does not significantly impair the coating, but the "handling window" is not reduced so much that the coating of the hydrophobically coated ibuprofen erodes significantly. Thus, this optimal amount of a chemical compound comprising a terpene and / or a terpenoid sufficiently minimizes the aeration of the drug suspension, resulting in a homogenous drug suspension that can be accurately incorporated into a mold to produce a uniform final product.

[0105] Additionally, liquid flavorings comprising a terpene and / or a terpenoid, and specifically limonene, have the potential to lower the freezing point of the drug suspension, which can result in fusion defects of the product further processed by freeze-drying. In particular, limonene has a freezing point of -74 °C. However, no fusion defects were observed during the preparation of the disclosed products, and thus at least some chemical compounds comprising a terpene and / or a terpenoid do not affect the drug suspension such that the downstream freezing and freeze-drying process steps are adversely affected. It is believed that the absence of fusion defects in the present case is due to the high solid content of the suspension, which helps to maintain the structure of the product even in the presence of a freezing point depressant (i.e., limonene).

[0106] The matrix solution / suspension composition according to the embodiments described herein can include a matrix former, a structure former, an anti-aeration agent, a viscosity modifier, and / or a solvent.

[0107] In some embodiments, the amount of a chemical compound comprising a terpene and / or a terpineol (i.e., an anti-aeration agent) in the matrix solution / suspension, drug suspension, or pharmaceutical composition can be 0.001 to 5.0% w / w. In some embodiments, the amount of a chemical compound comprising a terpene and / or a terpineol (i.e., an anti-aeration agent) in the matrix solution / suspension, drug suspension, or pharmaceutical composition can be 1-5% w / w, 1-4% w / w, 1-3% w / w, 1-2% w / w, 0.05 to 3.0% w / w, 0.1 to 2.0% w / w, or 0.5 to 1.0% w / w. In some embodiments, more than 0.001% w / w, more than 0.01% w / w, more than 0.05% w / w, more than 0.1% w / w, more than 0.3% w / w, more than 0.5% w / w, more than 0.8% w / w, more than 1.0% w / w, more than 1.5% w / w, more than 2.0% w / w, more than 2.5% w / w, more than 3.0% w / w, more than 3.5% w / w, more than 4.0% w / w, or more than 4.5% w / w of a chemical compound comprising a terpene and / or a terpineol (i.e., an anti-aeration agent) is in the matrix solution / suspension, drug suspension, or pharmaceutical composition. In some embodiments, 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, less than 0.8% w / w, less than 0.6% w / w, less than 0.3% w / w, or less than 0.1% w / w of a chemical compound comprising a terpene and / or a terpineol (i.e., an anti-aeration agent) is in the matrix solution / suspension, drug suspension, or pharmaceutical composition. In some embodiments, a suitable anti-aeration agent can include an orange flavoring, a strawberry flavoring, a mint flavoring, a raspberry flavoring, a licorice flavoring, an orange flavoring, a lemon flavoring, a lime flavoring, a grapefruit flavoring, a caramel flavoring, a vanilla flavoring, a cherry flavoring, a grape flavoring, a mixed fruit flavoring, a medley fruit flavoring, or any combination thereof.

[0108] Minimizing agglomeration embodiments

[0109] Several experiments were conducted to evaluate the effectiveness of removing excess coating material from coated ibuprofen by sieving, and to optimize the coating ratio and feed ratio. The disintegration times of pharmaceutical compositions containing various coated ibuprofen were measured under various conditions to investigate the effect of sieving excess coating material. It is reasonable to assume that removing excess coating material can minimize the agglomeration of coating material. Optimizing the coating and feed ratios can also help to minimize the agglomeration of coating material. Minimizing the amount of agglomeration in turn can help to maintain the desired disintegration times and / or dissolution rates of the pharmaceutical compositions and coated ibuprofen. Thus, in the following examples, disintegration times were used as a measure to evaluate the amount of agglomeration. In some embodiments, 50°C accelerated dissolution data can indicate the presence of excess coating material that was not sieved.

[0110] In addition, coating ratio and feed ratio information is provided for the following examples. The coating ratio refers to the ratio of the amount of coating material to the amount of uncoated ibuprofen. The feed ratio refers to the ratio of the amount of coated ibuprofen to the amount of matrix solution / suspension containing all inactive ingredients.

[0111] Example 1: Ibuprofen was coated with carnauba wax at a coating ratio of 26:74. Freeze-dried tablets were prepared using a feed ratio of 40:60. Tablets from four separate batches were tested - batches 1-3 were tested at 2 month intervals, and batch 4 was tested at 6 month intervals. Tablets from these batches were each tested at 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, and samples were taken from batches 1, 2, and 3 at one month and two months. In addition, each batch was exposed to 50°C stress conditions to provide accelerated data at two weeks and four weeks for each study. Table 1 below provides disintegration time data for batches 1-3 of the two month study of coated ibuprofen.

[0112]

[0113] Table 1. Carnauba wax (feed ratio 40:60) (2 month study)

[0114] Sieving of coated ibuprofen from batch 2 was poor after ibuprofen coating. Microscopic examination of sieved coated ibuprofen from batch 2 showed that the coated ibuprofen was not well sieved, and that there was a significant amount of agglomeration of the coated ibuprofen. Microscopic examination of sieved coated ibuprofen from batch 3 showed that the coated ibuprofen was well sieved, and that there was a minimal amount of agglomeration of the coated ibuprofen. Figure 4B) showed the presence of excess unbound coating material. Microscopic examination of the sieved coated ibuprofen also showed poor coating of ibuprofen. As shown in the last column of Table 1, this batch exhibited a significantly longer disintegration time after two months under 40°C / 75% RH stability test conditions. (The initial disintegration time was less than two seconds, and the disintegration time at two months was almost 15 seconds.) Thus, this result supports the hypothesis that the presence of excess unbound coating material in the drug product leads to an increase in disintegration time over time (as the drug product ages) due to agglomeration of unbound coating material during storage.

[0115] In contrast, the coated ibuprofen of batch 3 was sufficiently sieved after ibuprofen coating. Microscopic examination of the sieved coated ibuprofen Figure 4C ) showed that ibuprofen was sufficiently coated because there was no unbound coating material present. The disintegration time of this batch sample changed very little over the two-month period for any ICH stability condition. (The disintegration time fluctuated between about one second and about three seconds throughout the two-month study.) This supports the hypothesis that minimizing the presence of excess unbound coating material, through, for example, sieving, will help prevent agglomeration of coating material in the drug product over time when placed in storage, particularly at higher temperatures.

[0116] The coated ibuprofen of batch 1 was sieved after ibuprofen coating. For the initial time data point, batch 1 exhibited a similar disintegration time of less than 2 seconds compared to batches 2 and 3. However, after two months under 40°C / 75% RH stability test conditions, the disintegration time increased to about 7 seconds or less. When stored at 50°C for 4 weeks, the disintegration time increased to about 10 seconds or less. This indicates that the sieving process of this batch did not significantly remove excess coating material, and thus, residual unbound coating material was present. Batch 2 experienced even more unbound coating material, and agglomerated to a greater extent when stored than batch 1. Microscopic examination of the sieved coated ibuprofen Figure 4A ) showed that ibuprofen particles were moderately well coated by the residual amount of unbound coating material present.

[0117] The following Table 2 shows the disintegration time data for a six-month study of coated ibuprofen (i.e., batch 4).

[0118]

[0119] Table 2. Camauba Wax (feed ratio 40:60) (6-month study)

[0120] The coated ibuprofen of Batch 4 was sieved after ibuprofen coating. Batch 4 of Table 2 showed no great change in disintegration time throughout the duration of the six-month study. The initial disintegration time of Batch 4 was about five seconds and the final disintegration time of the 25°C / 60% RH sample was about two seconds; the 30°C / 65% RH sample was about two seconds and the 40°C / 75% RH sample was about two seconds. However, an increase was observed when stored at 50°C. Since no increase was observed in tablets stored at 40°C and lower temperatures, this indicates that the sieving has removed most of the unbound excess coating material, but there is a sufficient residual amount that, when the tablets are placed at 50°C, the residual amount agglomerates. Microscopic examination Figure 4D ) of the sieved coated ibuprofen showed that the ibuprofen was moderately well coated with a residual amount of unbound coating material.

[0121] Example 2: Ibuprofen was coated with Sasol (synthetic) wax at a theoretical coating ratio of 26:74. After coating, the coated ibuprofen was sieved. The 40:60 feed ratio was used to produce the freeze-dried tablets and tested over two months. The ibuprofen 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 50°C stress conditions to provide accelerated data at two weeks and four weeks during the study. Table 3 below provides the disintegration time data for the two-month study of the 40:60 feed ratio of coated ibuprofen. Microscopic examination Figure 4E ) of the sieved coated ibuprofen showed that the ibuprofen was moderately well coated with a small amount of unbound coating material.

[0122]

[0123] Table 3. Sasol wax (feed ratio 40:60) ibuprofen strength: 200 mg

[0124] Batch 5 of Table 3 did not show a significant change in disintegration time over the two month period of the study nor under accelerated conditions at 50°C. Specifically, the initial disintegration time for Batch 5 was about three seconds and the disintegration time at two months for all three ICH stability conditions (25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH) was about four seconds. The disintegration time at two weeks under 50°C accelerated conditions was about three seconds and at 4 weeks was about four seconds. Based on the 50°C data, there can be a small amount of residual unbound excess coating material. If present, this small amount of unbound excess coating material would not cause a significant amount of agglomeration upon storage because the disintegration time would not increase much even if it did increase. This is comparable to Batch 3 in Example 1 which used a different wax. These 2 examples demonstrate that if the unbound excess coating material is effectively removed by sieving, then agglomeration of the coating material in the drug product upon storage, particularly at higher temperatures and after extended storage periods, can be minimized or prevented.

[0125] Example 3: Ibuprofen coated with Sasol (synthetic) wax at a theoretical coating ratio of 26:74. After coating, the coated ibuprofen was then sieved. The 50:50 feed ratio was used to produce the freeze-dried tablets and tested over three 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 50°C stress conditions to provide accelerated data at two weeks and four weeks during each study. Table 4 below provides the data for the three month study of the 50:50 Sasol wax coated ibuprofen. Microscopic examination of the sieved coated API for Batch 6 of Table 4 showed that the ibuprofen was sufficiently coated and had some unbound coating material. Figure 4F ) showed that the ibuprofen was sufficiently coated and had some unbound coating material.

[0126]

[0127] Table 4. Sasol wax (feed ratio 50:50) ibuprofen strength: 200 mg

[0128] Neither Batch 6 nor Batch 7 showed a significant change in disintegration time over the course of the three month study. Specifically, the initial disintegration time for the samples of Batch 6 was about one second and the final three month disintegration time for each of the three ICH stability conditions (25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH) was about two seconds. The disintegration time under the two weeks and four weeks accelerated 50°C conditions for Batch 6 was about two seconds.

[0129] The initial disintegration time of the samples of Batch 7 was about two seconds, and the last three month disintegration times at 25°C / 60% RH and 30°C / 65% RH ICH stability conditions were about two seconds. The disintegration time for the last three months at 40°C / 75% RH ICH stability condition was about three seconds. The disintegration times at two weeks and four weeks accelerated 50°C conditions were both about five seconds. The high coating ratio of 50:50 can increase the amount of excess unbound coating material when unsieved. Despite the use of a higher feed ratio of 50:50 for both batches, which means a high load of coated ibuprofen and any unbound excess coating material, these data infer that the sieving process of coated ibuprofen is effective in removing unbound excess coating material to minimize agglomeration.

[0130] Example 4: Ibuprofen coated with Carnauba Wax at theoretical coating ratios of 22.5:77.5 and 30:70. Freeze-dried tablets were prepared using a feed ratio of 30:70, and the study was conducted over a 2 month period. The ibuprofen strength was 200 mg. The batch was stored in an oven at 40°C. The tablets were tested for disintegration time at initial, day 25, and 2 month time points. Table 5 below provides the disintegration times for the study. Microscopic examination of un-sieved coated ibuprofen ( Figure 4G and Figure 4H ) and sieved coated ibuprofen ( Figure 4I and Figure 4J ) is provided. The ibuprofen was fully coated.

[0131] There was no unbound coating material present for the sieved samples.

[0132]

[0133] Table 5. Carnauba Wax (feed ratio 30:70) Ibuprofen Strength: 200 mg

[0134] Batches 8-11 show that for coated ibuprofen that was either unsieved (Batches 8 and 10) or sieved (Batches 9 and 11), the disintegration time of tablets stored at 40°C did not increase over time using a feed ratio of 30:70. This supports the hypothesis that by reducing the feed ratio, for example to 30:70, the amount of excess unbound wax is reduced enough to minimize agglomeration of the excess unbound material over time when stored at higher temperatures.

[0135] A general summary of the results of the above examples is tabulated in Table 6.

[0136]

[0137]

[0138] Table 6. General Summary of Results for Batches 1-11.

[0139] Maintaining Functional Coating Ibuprofen

[0140] Example 5: According to the embodiments described herein, functional coating ibuprofen was coated with hydrophobic fumed silica. Specifically, the hydrophobic fumed silica used was Aerosil R972 ("Aerosil"). Two different concentrations of Aerosil R972 were tested— 1.5% w / w and 1.0% w / w. The size of the functional coating ibuprofen was evaluated over a 6 hour holding period, during which it was subjected to low shear mixing.

[0141] Figure 5 , Figure 6 and Figure 7 provide an evaluation of the d10 particle size, d50 particle size, and d90 particle size, respectively, over a 6 hour period. Generally, a particle size denoted by its d10 means that 10% of the particles in a given amount of sample are below a given particle size. Thus, a particle size denoted by its d50 means that 50% of the particles in a given amount of sample are below a given particle size, and a particle size denoted by its d90 means that 90% of the particles in a given amount of sample are below a given particle size.

[0142] As shown in Figure 5 , a larger concentration of silica (1.5% w / w) was more effective at maintaining the initial particle size, and thus the coating, than a lower concentration of silica (1.0% w / w). Specifically, during the 6 hour period, functional coating ibuprofen containing 1.5% w / w Aerosil lost about 30% of its initial size, while functional coating ibuprofen containing 1.0% w / w Aerosil lost about 80% of its initial particle size.

[0143] Figure 6 It was further shown that a larger concentration of silica (1.5% w / w Aerosil) was more effective at maintaining the initial functional coating ibuprofen particle size, and thus the functional coating, than a lower concentration of silica (1.0% w / w Aerosil). Specifically, during the 6 hour period, functional coating ibuprofen containing 1.5% w / w Aerosil lost almost 20% of its initial size, while functional coating ibuprofen containing 1.0% w / w Aerosil lost about 45% of its initial functional coating API particle size.

[0144] Figure 7It was also shown that a larger concentration of silicon dioxide (1.5% w / w Aerosil) was more effective than a lower concentration of silicon dioxide (1.0% w / w Aerosil) in maintaining the initial functional coating ibuprofen particle size, and thus the functional coating of the functional coating ibuprofen. Specifically, during the 6 hour period, the functional coating ibuprofen comprising 1.5% w / w Aerosil lost almost 15% of its initial size, while the functional coating ibuprofen comprising 1.0% w / w Aerosil lost about 35% of its initial particle size.

[0145] Furthermore, as the particle size of the functional coating ibuprofen decreased, a separate population of particles comprising a particle size of 5 μιη to 20 μιη appeared and increased over time. These particles are believed to be non-deformable coating material particles that were embedded in the deformed continuous coating material prior to the erosion of the coating due to shear forces. Thus, as the coating erodes, and the particle size of the functional coating ibuprofen decreases, the population size of these smaller particles increases as the deformed coating material surrounding them erodes, resulting in the release of these non-deformable particles from the functional coating ibuprofen.

[0146] In summary, these experiments show that the 1.5% w / w Aerosil coating of the functional coating ibuprofen can increase the "handling window" to about 4 hours, as opposed to the 2 hour "handling window" that exists without silicon dioxide. The functional coating ibuprofen exhibits little, if any, coating erosion for the first four hours of handling in suspension and comprising a second outer coating comprising 1.5% w / w Aerosil.

[0147] Example 6: According to the embodiments described herein, the functional coating ibuprofen was coated with hydrophobic fumed silicon dioxide. Specifically, the hydrophobic fumed silicon dioxide used was Aerosil R972 ("Aerosil"). Five different concentrations of Aerosil R972 were tested— 0.0% w / w, 1.5% w / w, 2.5% w / w, 5.0% w / w, and 10.0% w / w. The amount of release of the functional coating ibuprofen was evaluated using a dissolution test (i.e., 0.01% SDS in a pH 7.2 phosphate buffer dissolution media, the media temperature was 37°C, and the media volume was 10 ml (ibuprofen)).

[0148] Figure 8 and Figure 9 The evaluation of the amount of release performed on the functional coating ibuprofen over a 5 or 30 minute period is provided. In general, a low volume dissolution result expressed in % of its release means that "x" weight % of the added material has dissolved into solution.

[0149] Figure 8Release data for ibuprofen coated with carnauba wax and various amounts of hydrophobic silica are shown. As shown in the accompanying figures, greater concentrations of silica (up to 10.0% w / w) are more effective than lower concentrations of silica in providing a slower release rate in the dissolution test, and therefore maintaining the coating. Specifically, during the 5 minute test period, the functional coated ibuprofen comprising 10.0% w / w Aerosil (i.e., ibuprofen coated with carnauba wax) exhibited 1.5% release after 5 minutes, while the functional coated ibuprofen comprising 0.0% w / w Aerosil exhibited 24.9% release. The functional coated ibuprofen comprising intermediate levels of Aerosil (i.e., 1.5% w / w, 2.5% w / w, and 5.0% w / w) showed dissolution results of 12.1% release, 7.4% release, and 2.3% release, respectively, after 5 minutes.

[0150] Figure 9 Release data are presented for ibuprofen coated with Sasol (synthetic) wax and various levels of hydrophobic silica. Figure 10 It was also shown that greater concentrations of silicon dioxide (up to 10.0% w / w) were more effective than lower concentrations of silicon dioxide in providing a slower release rate in the dissolution test, and thus maintaining the coating. Specifically, during the 5-minute test period, the functionalized coated ibuprofen containing 10.0% w / w Aerosil (i.e., ibuprofen coated with synthetic wax) exhibited a 2.8% release after 5 minutes, while the functionalized coated ibuprofen containing 0.0% w / w Aerosil showed an 8.5% release. The functionalized coated ibuprofen containing intermediate levels of Aerosil (i.e., 1.5% w / w, 2.5% w / w, and 5.0% w / w) produced dissolution results of 4.3% release, 3.6% release, and 2.4% release, respectively, after 5 minutes.

[0151] Minimized Aeration Example

[0152] The effectiveness of the chemical compound comprising a terpene and / or terpineol in minimizing aeration can be determined in part by measuring the particle size of the hydrophobically coated ibuprofen in the pharmaceutical suspension over time. If the chemical compound is effective, the aeration of the suspension will be sufficiently low, and the particle size of the hydrophobically coated ibuprofen will remain constant or barely decrease over time. If it is ineffective, the amount of aeration of the suspension will be higher than the desired amount of aeration, and the particle size of the hydrophobically coated ibuprofen may decrease more significantly over time. The degree of aeration of the suspension is evaluated by measuring the height of the foam in the mixing vessel. The particle size of the functional coated particles can be measured using laser diffraction, a particle analyzer (e.g., a Malvern Mastersizer), or any other suitable means for analyzing fine particles.

[0153] Example 7: A series of suspension mixtures were made by mixing coated ibuprofen into base solution / suspensions containing different levels of limonene, orange flavoring, and strawberry flavoring. The heights of the foams from these suspensions are summarized in Tables 7, 8, and 9, respectively.

[0154] Concentration of limonene (% w / w) Foam height (mm) 0 5 0.15 2 0.30 1 0.6 1

[0155] Table 7: Heights of foams from mixtures containing different levels of limonene.

[0156] Concentration of orange flavorant (% w / w) Foam height (mm) 0 5 0.15 1 0.30 0 0.6 0

[0157] Table 8: Heights of foams from mixtures containing different levels of orange flavoring.

[0158] Concentration of strawberry flavorant (% w / w) Foam height (mm) 0 5 0.15 3 0.30 3 0.6 3

[0159] Table 9: Heights of foams from mixtures containing different levels of strawberry flavoring.

[0160] The results in Tables 7 and 8 show that the addition of limonene and orange flavoring at levels of 0.15% w / w and above minimizes aeration. For strawberry (Table 9), it also reduces aeration, but not to the same extent.

[0161] Example 8: Figure 10 , Figure 11 and Figure 12 show the decrease in particle size (d10, d50, and d90, respectively) of hydrophobic coated ibuprofen in pharmaceutical suspensions containing various concentrations of liquid orange flavoring. Particle size expressed in its d10 means that 10% of the particles in a given volume of sample are below a given particle size. Thus, a d50 particle size means that 50% of the particles in a given volume of sample are below a given particle size, and a d90 particle size means that 90% of the particles in a given volume of sample are below a given particle size. Specifically, Figures 3-5 show the results of testing of suspension formulations containing hydrophobic coated ibuprofen and liquid orange flavoring at concentrations including 0.0%, 0.15%, 0.45%, and 0.60% w / w, under low shear mixing for periods of up to 6 hours.

[0162] At concentrations of orange flavoring up to 0.45% w / w, including 0.15% w / w, the reduction in d10, d50, and d90 particle size within the first 2 hours "handling window" is largely similar to the reduction of the drug suspension comprising hydrophobic coated ibuprofen without any liquid flavoring (0% liquid flavoring). However, at a concentration of 0.6% w / w liquid orange flavoring, the coating of the hydrophobic coated ibuprofen is easily removed, and a rapid reduction in particle size is observed. Further, at a concentration of 0.3% w / w liquid orange flavoring, the aeration of the suspension is low enough that there is minimal, if any, damage to the coating of the hydrophobic coated ibuprofen, and there is only a minimal reduction in the particle size of the hydrophobic coated ibuprofen.

[0163] Example 9: Figure 13 , Figure 14 and Figure 15 provide data for the reduction in d10, d50, and d90 particle size of hydrophobic coated ibuprofen for the particular component limonene (which is found in some liquid flavorings). These tests were performed to explore the behavior of the particular component limonene of the liquid flavoring on the hydrophobic coated ibuprofen in the suspension. Note that the concentrations of limonene shown in the figures are significantly greater than the concentrations of limonene that would be present if a liquid flavoring were used. In Figures 13-15 pure limonene was used at concentrations of 0.25% w / w, 0.45% w / w, and 0.75% w / w, and the tests were performed over a 24 hour period. As shown in all three figures, the detrimental impact on the particle size of the hydrophobic coated ibuprofen coating was much less at a limonene concentration of 0.25% w / w compared to the 0.45% w / w and 0.75% w / w limonene concentrations. Further, the drug suspensions tested with 0.25% w / w limonene contained a low enough amount of aeration. Thus, these tests demonstrate that Figures 3-5 the limonene of the liquid orange flavoring tested in

[0164] Example 10: Figure 16 shows test data for two different liquid flavorings (strawberry and orange). The d10, d50, and d90 particle size of hydrophobic coated ibuprofen was tested for both the strawberry and orange liquid flavorings. Both the strawberry and orange liquid flavorings contained limonene. As shown in the figures, the performance of both flavorings with respect to the particle size of the hydrophobic coated ibuprofen was similar. The d10 particle sample showed a greater amount of particle size reduction within the first two hours of the test than the d50 and d90 particle samples. The d50 and d90 particle samples exhibited less particle size reduction within the same two hour period. However, this observation is consistent with the data for the d10, d50, and d90 particle sizes of the previously discussed examples.

[0165] In addition, it was observed that in all trials, as the particle size of the hydrophobic coated API (ibuprofen) granules decreased, a population of individual particles comprising a particle size of 5 to 20 μιη appeared and increased over time. These particles are believed to be non-deformable coating material particles that are embedded in the deformed continuous coating material prior to the coating being eroded due to shear forces. Thus, as the coating erodes, and the particle size of the hydrophobic coated ibuprofen decreases, the population size of these smaller particles increases as the deformed coating material surrounding them erodes, resulting in the release of these non-deformable particles from the hydrophobic coated ibuprofen.

[0166] In summary, these trials show that by optimizing the amount of terpene limonene added to the drug suspension comprising hydrophobic coated ibuprofen, the amount of aeration in the suspension can be minimized to allow for downstream processing, while at the same time having no adverse effect on the coating of the hydrophobic coated ibuprofen (as determined by the particle size of the hydrophobic coated ibuprofen).

[0167] The foregoing description has been set forth in terms of specific embodiments for purposes of explanation. However, the above description is not intended to be exhaustive or to limit the application to the precise form disclosed. Many modifications and variations are possible in light of the above teaching. Embodiments were chosen and described in order to best explain the principles of the technology and its practical application. Thus, others skilled in the art can best adapt and utilize the various embodiments with various modifications as their applications require.

[0168] While the present disclosure and examples have been fully described with reference to the accompanying drawings, it is to be noted that various changes and modifications will become apparent to those skilled in the art. Such changes and modifications are to be understood as included within the scope of the present disclosure and examples as defined by the claims.

Claims

1. A pharmaceutical composition comprising: More than 75% w / w of a coated API, wherein the coated API comprises a first coating material and the coated API comprises 0.5 to less than 2.5% w / w of hydrophobic fumed silica; and 3-7% w / w matrix forming agent; More than 2-less than 6% w / w structure-forming agents; 0.1-2% w / w of an anti-aerator comprising limonene; and 0.01-0.2% w / w viscosity modifier; wherein the API is ibuprofen, and the pharmaceutical composition comprises 50-400 mg of ibuprofen; and The pharmaceutical composition is prepared by a method comprising the following steps: coating the ibuprofen with a first coating material to form coated ibuprofen, wherein the first coating material comprises one or more deformable components; applying a mechanical stress to the coated ibuprofen to deform the one or more deformable components; dry coating the coated ibuprofen with a second coating material comprising silicon dioxide to provide a protective hydrophobic barrier to the first coating material; applying mechanical stress to embed the second coating material onto the first coating material coated with ibuprofen; After embedding the second coating material onto the first coating material of the coated ibuprofen, sieving the coated ibuprofen to remove excess first coating material, wherein the excess first coating material comprises first coating material that is not bound to the coated ibuprofen; forming a drug suspension comprising twice-coated ibuprofen and a matrix solution or suspension, wherein the drug suspension comprises 0.15-0.6% w / w limonene and a feed ratio ranging from 5-60% w / w coated ibuprofen to 40-95% w / w matrix solution or suspension; as well as incorporating the drug suspension into a mold; as well as The drug suspension in the mold is freeze-dried to form a pharmaceutical composition.

2. The pharmaceutical composition of claim 1, wherein the first coating material comprises wax.

3. The pharmaceutical composition of claim 2, wherein the first coating material comprises one or more of carnauba wax, synthetic wax, or candelilla wax.

4. The pharmaceutical composition of claim 1, wherein the matrix forming agent comprises one or more water-soluble materials.

5. The pharmaceutical composition of claim 1, wherein the matrix forming agent comprises one or more water-dispersible materials. The pharmaceutical composition of claim 1 , wherein the matrix-forming agent comprises one or more of a polypeptide, a polysaccharide, polyvinyl alcohol, polyvinyl pyrrolidone, and gum arabic.

7. The pharmaceutical composition of claim 6, wherein the matrix forming agent comprises a polypeptide.

8. The pharmaceutical composition of claim 7, wherein the polypeptide comprises gelatin.

9. The pharmaceutical composition of claim 1, wherein the structure forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin.

10. The pharmaceutical composition of claim 9, wherein the structure forming agent comprises mannitol.

11. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition continues to have a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 25°C and at least 60% relative humidity.

12. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

13. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 3 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

14. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 30°C and at least 65% relative humidity.

15. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 30°C and at least 65% relative humidity.

16. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 40°C and at least 75% relative humidity.

17. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 40°C and at least 75% relative humidity.

18. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 25°C and at least 60% relative humidity.

19. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 30°C and at least 65% relative humidity.

20. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 40°C and at least 75% relative humidity.

21. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 25°C and at least 60% relative humidity.

22. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 30°C and at least 65% relative humidity.

23. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 40°C and at least 75% relative humidity.

24. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dissolution test result of 10% or less after 5 minutes.

25. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dissolution test result of 5% or less after 5 minutes.

26. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dissolution test result of 3% or less after 5 minutes.

27. The pharmaceutical composition of claim 1, wherein the viscosity modifier comprises xanthan gum.

28. A pharmaceutical composition prepared by a method comprising the following steps: coating the ibuprofen with a first coating material to form coated ibuprofen, wherein the first coating material comprises one or more deformable components; applying a mechanical stress to the coated ibuprofen to deform the one or more deformable components; dry coating the coated ibuprofen with a second coating material comprising silicon dioxide to provide a protective hydrophobic barrier to the first coating material; applying mechanical stress to embed the second coating material onto the first coating material of the coated ibuprofen, wherein the coated ibuprofen comprises 0.5 to less than 2.5% w / w hydrophobic fumed silica; After embedding the second coating material onto the first coating material of the coated ibuprofen, sieving the coated ibuprofen to remove excess first coating material, wherein the excess first coating material comprises first coating material that is not bound to the coated ibuprofen; forming a pharmaceutical suspension comprising twice-coated ibuprofen and a matrix solution or suspension comprising an anti-aeration agent, the anti-aeration agent comprising limonene, wherein the pharmaceutical suspension comprises 0.15-0.6% w / w limonene and a feed ratio ranging from 5-60% w / w coated ibuprofen to 40-95% w / w matrix solution or suspension; as well as incorporating the drug suspension into a mold; as well as freeze-drying the drug suspension in the mold to form a pharmaceutical composition; wherein the pharmaceutical composition comprises 65-85% w / w ibuprofen.

29. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition comprises 50-400 mg ibuprofen.

30. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition comprises 15-30% w / w of the first coating material and the second coating material.

31. The pharmaceutical composition of claim 28, wherein the first coating material is configured to mask the taste of ibuprofen.

32. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition comprises 3-15% w / w base.

33. The pharmaceutical composition of claim 28, comprising sieved uncoated ibuprofen.

34. The pharmaceutical composition of claim 28, wherein sieving the coated ibuprofen comprises passing the coated ibuprofen through a device comprising two or more sieves.

35. The pharmaceutical composition of claim 28, wherein sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 75 μm or greater.

36. The pharmaceutical composition of claim 28, wherein sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 200 μm or less.

37. The pharmaceutical composition of claim 28, wherein the first coating material comprises wax.

38. The pharmaceutical composition of claim 37, wherein the wax comprises one or more of carnauba wax, candelilla wax, or a synthetic wax.

39. The pharmaceutical composition of claim 28, wherein the matrix solution or suspension comprises a matrix forming agent and a structure forming agent.

40. The pharmaceutical composition of claim 39, wherein the matrix forming agent comprises one or more water-soluble materials.

41. The pharmaceutical composition of claim 39, wherein the matrix forming agent comprises one or more water-dispersible materials.

42. The pharmaceutical composition of claim 39, wherein the matrix forming agent comprises one or more of a polypeptide, a polysaccharide, polyvinyl alcohol, polyvinyl pyrrolidone, and gum arabic.

43. The pharmaceutical composition of claim 39, wherein the matrix forming agent comprises a polypeptide.

44. The pharmaceutical composition of claim 43, wherein the polypeptide comprises gelatin.

45. The pharmaceutical composition of claim 39, wherein the structure forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin.

46. ​​The pharmaceutical composition of claim 39, wherein the structure forming agent comprises mannitol.

47. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition comprises a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 25°C and at least 60% relative humidity.

48. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

49. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 3 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

50. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 30°C and at least 65% relative humidity.

51. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 30°C and at least 65% relative humidity.

52. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 40°C and at least 75% relative humidity.

53. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 40°C and at least 75% relative humidity.

54. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 25°C and at least 60% relative humidity.

55. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 30°C and at least 65% relative humidity.

56. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 40°C and at least 75% relative humidity.

57. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 25°C and at least 60% relative humidity.

58. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 30°C and at least 65% relative humidity.

59. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 40°C and at least 75% relative humidity.

60. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a dissolution test result of 10% or less after 5 minutes.

61. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a dissolution test result of 5% or less after 5 minutes.

62. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition has a dissolution test result of 3% or less after 5 minutes.

63. The pharmaceutical composition of claim 28, wherein the weight of the incorporated drug suspension is within 10% of the target weight.

64. The pharmaceutical composition of claim 28, wherein the weight of the incorporated drug suspension is within 5% of a set target weight.

65. The pharmaceutical composition of claim 28, wherein the matrix solution or suspension comprises a viscosity modifier.

66. The pharmaceutical composition of claim 65, wherein the viscosity modifier comprises xanthan gum.

67. The pharmaceutical composition of claim 28, wherein mixing the coated ibuprofen into the base solution or suspension comprises in-line mixing at 15-20 degrees Celsius.

68. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition comprises 1-5% w / w anti-aeration agent.

69. The pharmaceutical composition of claim 28, wherein the coated ibuprofen undergoes less than 40% particle size loss within the first 2 hours after mixing into the matrix solution or suspension.

70. The pharmaceutical composition of claim 28, wherein the coated ibuprofen undergoes less than 30% particle size loss within the first 2 hours after mixing into the matrix solution or suspension.

71. The pharmaceutical composition of claim 28, wherein the coated ibuprofen undergoes less than 20% particle size loss within the first 2 hours after mixing into the matrix solution or suspension.

72. Use of the pharmaceutical composition according to any one of claims 28 to 71 in the preparation of a medicament.

73. The use of claim 72, wherein the medicament is for use in humans.

74. A method for preparing a pharmaceutical composition, the method comprising: coating the ibuprofen with a first coating material to form coated ibuprofen, wherein the first coating material comprises one or more deformable components; applying a mechanical stress to the coated ibuprofen to deform the one or more deformable components; dry coating the coated ibuprofen with a second coating material comprising silicon dioxide to provide a protective hydrophobic barrier to the first coating material; applying mechanical stress to embed the second coating material onto the first coating material of the coated ibuprofen, wherein the coated ibuprofen comprises 0.5 to less than 2.5% w / w hydrophobic fumed silica; After embedding the second coating material onto the first coating material of the coated ibuprofen, sieving the coated ibuprofen to remove excess first coating material, wherein the excess first coating material comprises first coating material that is not bound to the coated ibuprofen; forming a pharmaceutical suspension comprising twice-coated ibuprofen and a matrix solution or suspension comprising an anti-aeration agent, the anti-aeration agent comprising limonene, wherein the pharmaceutical suspension comprises 0.15-0.6% w / w limonene and a feed ratio ranging from 5-60% w / w coated ibuprofen to 40-95% w / w matrix solution or suspension; as well as incorporating the drug suspension into a mold; as well as The drug suspension in the mold is freeze-dried to form a pharmaceutical composition.

75. The method of claim 74, wherein the pharmaceutical composition comprises 50-400 mg ibuprofen.

76. The method of claim 74, wherein the pharmaceutical composition comprises 65-85% w / w ibuprofen.

77. The method of claim 74, wherein the pharmaceutical composition comprises 15-30% w / w of the first coating material and the second coating material.

78. The method of claim 74, wherein the pharmaceutical composition comprises 3-15% w / w base.

79. The method of claim 74, comprising sieving uncoated ibuprofen.

80. The method of claim 74, wherein the first coating material is configured to mask the taste of the ibuprofen.

81. The method of claim 74, comprising incorporating the drug suspension into a preformed mold.

82. The method of claim 74, wherein sieving the coated ibuprofen comprises passing the coated ibuprofen through an apparatus comprising two or more sieves.

83. The method of claim 74, wherein sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 75 μm or greater.

84. The method of claim 74, wherein sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 200 μm or less.

85. The method of claim 74, wherein the first coating material comprises wax.

86. The method of claim 74, wherein the first coating material comprises one or more of carnauba wax, candelilla wax, or a synthetic wax.

87. The method of claim 74, wherein the matrix solution or suspension comprises a matrix forming agent and a structure forming agent.

88. The method of claim 87, wherein the matrix forming agent comprises one or more water-soluble materials.

89. The method of claim 87, wherein the matrix forming agent comprises one or more water-dispersible materials.

90. The method of claim 87, wherein the matrix-forming agent comprises one or more of a polypeptide, a polysaccharide, polyvinyl alcohol, polyvinyl pyrrolidone, and gum arabic.

91. The method of claim 87, wherein the matrix forming agent comprises a polypeptide.

92. The method of claim 91, wherein the polypeptide comprises gelatin.

93. The method of claim 87, wherein the structure forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin.

94. The method of claim 87, wherein the structure forming agent comprises mannitol.

95. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

96. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 3 seconds or less for at least two months under storage conditions of at least 25°C and at least 60% relative humidity.

97. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 30°C and at least 65% relative humidity.

98. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 30°C and at least 65% relative humidity.

99. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 40°C and at least 75% relative humidity.

100. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months under storage conditions of at least 40°C and at least 75% relative humidity.

101. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 25°C and at least 60% relative humidity.

102. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 30°C and at least 65% relative humidity.

103. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months under storage conditions of at least 40°C and at least 75% relative humidity.

104. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 25°C and at least 60% relative humidity.

105. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 30°C and at least 65% relative humidity.

106. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months under storage conditions of at least 40°C and at least 75% relative humidity.

107. The method of claim 74, wherein the pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month under storage conditions of at least 25°C and at least 60% relative humidity.

108. The method of claim 74, wherein the pharmaceutical composition has a dissolution test result of 10% or less after 5 minutes.

109. The method of claim 74, wherein the pharmaceutical composition has a dissolution test result of 5% or less after 5 minutes.

110. The method of claim 74, wherein the pharmaceutical composition has a dissolution test result of 3% or less after 5 minutes.

111. The method of claim 74, wherein the weight of the incorporated drug suspension is within 10% of a target weight.

112. The method of claim 74, wherein the weight of the incorporated drug suspension is within 5% of a target weight.

113. The method of claim 74, wherein the matrix solution or suspension comprises a viscosity modifier.

114. The method of claim 111, wherein the viscosity modifier comprises xanthan gum.

115. The method of claim 74, wherein mixing the coated ibuprofen into the base solution or suspension comprises in-line mixing at 15-20 degrees Celsius.

116. The method of claim 74, wherein the pharmaceutical composition comprises 3-10% w / w matrix forming agent.

117. The method of claim 74, wherein the pharmaceutical composition comprises 3-10% w / w structure forming agent.

118. The method of claim 74, wherein the coated ibuprofen undergoes less than 40% particle size loss within the first 2 hours after mixing into the matrix solution or suspension.

119. The method of claim 74, wherein the coated ibuprofen experiences less than 30% particle size loss within the first 2 hours after mixing into the matrix solution or suspension.

120. The method of claim 74, wherein the coated ibuprofen undergoes less than 20% particle size loss within the first 2 hours after mixing into the matrix solution or suspension.

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