RU2826068C2 - Minimization of agglomeration, aeration and preservation of coating of pharmaceutical compositions containing ibuprofen - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to a pharmaceutical composition containing: 75–90 wt./wt.% of active pharmaceutical ingredient (API) with coating, wherein the API coating contains a first coating material containing wax and 0.5–5 wt./wt.% of second coating material containing silicon dioxide, attached, partially included and/or completely included in the first coating material; 3–7 wt./wt.% of matrix-forming substance; 2–6 wt./wt.% of structure-forming substance; 0.1–2 wt./wt.% of anti-aeration agent; and 0.01–0.2 wt./wt.% of a viscosity modifier, as well as to a method for preparing a pharmaceutical composition, comprising: coating of ibuprofen with a first coating material to form coated ibuprofen, where the first coating material contains one or more deformable components containing wax; application of mechanical stress to coated ibuprofen for deforming one or more deformable components; coating of ibuprofen with a second coating material containing silicon dioxide; applying mechanical stress to embed a second coating material on the first coated ibuprofen coating material; after introducing the second coating material onto the first coated ibuprofen coating material, sieving the coated ibuprofen to remove excess material of the first coating, wherein the excess first coating material comprises a first coating material not bonded to the coated ibuprofen; forming a pharmaceutical suspension containing double-coated ibuprofen and a matrix solution or suspension; dosing the pharmaceutical suspension into a form; and freeze-drying the dosed pharmaceutical suspension in the form to form a pharmaceutical composition.

EFFECT: group of inventions provides minimizing the agglomeration of the coating material for the coated active pharmaceutical ingredient in order to improve the stability of the pharmaceutical product during storage and increase its storage life.

21 cl, 27 dwg, 9 tbl, 10 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

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

FIELD OF TECHNICAL INVENTION

[2] This invention relates to methods for coating ibuprofen, and in particular to processes that minimize excess coating material to prevent agglomeration of coated ibuprofen in a lyophilized orally disintegrating dosage form during storage, processes that minimize aeration of pharmaceutical suspensions containing ibuprofen to improve dose weight accuracy while maintaining the integrity of the functional shell of ibuprofen, and processes that preserve the coating of coated ibuprofen obtained by solvent-free mixing processes and formulated to delay the release of ibuprofen upon oral administration.

LEVEL TECHNIQUES

[3] Pharmaceutical compositions typically include both an active pharmaceutical ingredient and one or more inactive ingredients. An active pharmaceutical ingredient (API) is biologically active and is intended to directly affect the symptoms, diseases, disorders, and/or ailments of a patient. One example of an active pharmaceutical ingredient is ibuprofen. On the other hand, the inactive ingredient(s) of a pharmaceutical composition is pharmaceutically inert and can be used for a variety of purposes, including, but not limited to, improving long-term stabilization, bulking or diluting a solid formulation, facilitating absorption of the drug, changing the viscosity of liquid formulations, increasing solubility, and/or facilitating the manufacture of the pharmaceutical composition.

[4] Additionally, some inactive ingredients may be used to mask the taste of an API such as ibuprofen. Many APIs are known to exhibit unpleasant organoleptic properties when dissolved in the mouth, such as bitterness, burning sensation, and numbness. For example, some orally administered pharmaceutical compositions are designed to be orodispersible to allow administration without water and are targeted at pediatric patients, geriatric patients, animal patients, and/or other types of patients who may have difficulty swallowing. For these types of orally administered pharmaceutical compositions, an inactive ingredient may be used to form a “functional coating” that masks the taste of the API or ibuprofen.

[5] For example, an inactive ingredient can be used to mask the taste of an API by wet coating or dry coating the API particle to create a functional coating surrounding the API particle so that it prevents the release of the API in the mouth. In wet particle coating, the inactive ingredients (polymer and additives) are dissolved or dispersed in a solvent or water to form a suspension or solution. This suspension or solution can then be sprayed onto the surface of the API particle to form a film by evaporation of the solvent or water. Examples of wet particle coating technologies include microencapsulation, fluidized bed coating, spray drying, pan coating, etc. In dry particle coating (also called solvent-free coating), the API particles are physically coated with fine particles of the inactive ingredients (polymer and additives) to form particle composites. Examples of dry particle coating include melt coating, supercritical coating, impact coating, electrostatic coating. API particles coated with a taste-masking inactive ingredient may provide a more pleasant experience for a patient who has difficulty swallowing or has taste sensitivity that would otherwise result in a negative patient experience and poor treatment compliance.

[6] In addition, one type of pharmaceutical composition is an orally-disintegrating tablet (ODT). ODTs are pharmaceutical compositions intended for pediatric patients, elderly patients, animal patients, and/or other types of patients who may have difficulty swallowing.

[7] In order to accurately distribute a pharmaceutical composition in a small injectable form, a hydrophobic coated API particle can be placed in a matrix solution/suspension to form a pharmaceutical suspension. Mixing to form a pharmaceutical suspension can improve dosing accuracy. Often, this pharmaceutical suspension containing hydrophobic coated API particles can be dosed into molds, dried, and then the molded product can be transferred, for example, to a vial. However, such processing of the pharmaceutical composition may increase risks such as damage and contamination.

[8] Accordingly, many API suspensions are now dispensed into preformed blister packs. Preformed blister packs eliminate one of the processing steps described above. Instead of dispensing into a mold and then transferring the formed product into a vial for packaging, preformed blister packs allow the manufacturer to dispense the pharmaceutical suspension into a preformed blister pack that can be dried and then sealed and packaged. In this way, the preformed blister pack serves as both a mold and a container in which the pharmaceutical composition can be stored.

ESSENCE OF THE INVENTION

[9] Methods are provided for minimizing the agglomeration of a coating material for coated ibuprofen obtained by various mixing processes. Agglomeration of the coating material can reduce the stability of the pharmaceutical product over time. For example, the disintegration time of a pharmaceutical product can increase over time if it contains an agglomerated coating material. An increased disintegration time and/or a decreased dissolution rate imply an unstable pharmaceutical product. An unstable pharmaceutical product can result in a shorter shelf life than desired. Accordingly, the present embodiments can help minimize the agglomeration of the coating material for coated ibuprofen in order to improve the stability of the pharmaceutical product during storage and increase its shelf life.

[10] For example, the disclosed methods include removing excess coating material from the coated ibuprofen to minimize the potential for agglomeration of coating material particles. In particular, the disclosed methods include sieving the coated ibuprofen such that the final pharmaceutical product is properly surrounded by a dry matrix, minimizing any agglomeration of coating material particles during storage. The disclosed pharmaceutical compositions provide disintegration times and dissolution rates that remain relatively stable over time.

[11] Compositions and methods for preparing compositions that can minimize aeration of hydrophobic coated ibuprofen in a suspension are also provided. For example, hydrophobic coated ibuprofen can be mixed with a matrix solution/suspension to form a pharmaceutical suspension for accurate dosing into forms to form solid pharmaceutical compositions (e.g., articles, tablets, etc.) for administration to a patient. However, the hydrophobicity of the coated ibuprofen contributes to the stability of the coated ibuprofen to disperse in the solution/suspension. Therefore, this can cause air entrapment in the pharmaceutical suspension, which is also called aeration. The entrained air or aeration of the pharmaceutical suspension can cause phase separation of the coated ibuprofen in the pharmaceutical suspension, forming an inhomogeneous pharmaceutical suspension. Aeration and non-homogeneous pharmaceutical suspensions may result in low dosing accuracy of a pharmaceutical suspension containing hydrophobic ibuprofen dosed into preformed blister packs and low content uniformity in the finished product (i.e., pharmaceutical composition).

[12] Traditional mechanical means of preventing and/or minimizing aeration have proven ineffective due to the high viscosity of pharmaceutical suspensions. For example, minimizing aeration can be achieved by applying a vacuum to a pharmaceutical suspension, but depending on the formulation and downstream processing requirements, this approach may not be suitable. In particular, applying a vacuum to a pharmaceutical suspension can cause the suspension to rise as the viscous suspension “holds” the entrapped air. Volatile components of the formulation may also be lost during vacuum processing. Additionally, traditional anti-aerating agents such as ethanol or simethicone emulsion are similarly ineffective in preventing suspension aeration.

[13] Accordingly, the compositions and methods provided herein minimize aeration of a pharmaceutical suspension comprising ibuprofen with a hydrophobic coating to improve the homogeneity of the suspension and improve the accuracy of dose weighing. In particular, the embodiments provided herein may include matrix solutions/suspensions comprising chemical compounds containing terpene and/or terpinol. In some embodiments, the matrix solution/suspension may comprise the terpene limonene. By incorporating a chemical compound containing terpene, such as limonene, the ibuprofen with a hydrophobic coating may be more easily incorporated into the matrix solution/suspension while minimizing overall aeration of the pharmaceutical suspension.

[14] The present invention also provides pharmaceutical compositions and methods for preparing pharmaceutical compositions that are formulated to maintain the functional coating of ibuprofen with a functional coating during the manufacturing process. Ibuprofen with a functional coating is often mixed to form a pharmaceutical suspension. The pharmaceutical suspension allows for accurate dosing of the pharmaceutical product for administration. Typically, the shear forces required to incorporate ibuprofen with a functional coating into a pharmaceutical suspension can cause erosion of the functional coating. Erosion of this coating can destroy or damage the properties of the functional coating. Accordingly, ibuprofen with a functional coating and an eroded coating can exhibit an increased dissolution rate and reduced taste-masking properties when orally administered to a patient.

[15] However, the pharmaceutical compositions and methods for preparing pharmaceutical compositions provided herein include maintaining a coating of functionally coated ibuprofen in a pharmaceutical suspension using hydrophobic colloidal silicon dioxide. In particular, the hydrophobic colloidal silicon dioxide can provide a protective layer surrounding and/or incorporated into a particle of functionally coated ibuprofen. In some embodiments, solvent-free processes for producing functionally coated ibuprofen can produce ibuprofen comprising a first coating. According to some embodiments, the hydrophobic colloidal silicon dioxide can be added during a solvent-free mixing process to produce a second protective coating surrounding and/or partially or fully incorporated into the functionally coated ibuprofen.

[16] In addition, the second protective coating can limit the interaction between the functionally coated ibuprofen and the matrix solution/suspension, so that the influence of the functionally coated ibuprofen on the performance of the matrix is minimized.

[17] In some embodiments, the pharmaceutical composition comprises: 65-85% by weight of ibuprofen; 15-30% by weight of a coating material coating the ibuprofen; and 3-15% by weight of a matrix surrounding the ibuprofen. In some embodiments, the pharmaceutical composition comprises 50-400 mg of ibuprofen. In some embodiments, the coating material comprises a first coating material and a second coating material, and the pharmaceutical composition comprises 10-30% by weight of the first coating material and 0.5-10% by weight of the 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% by weight of an anti-aerating agent. In some embodiments, the first coating material comprises one or more of the following: carnauba wax, synthetic wax, or candelilla wax. In some embodiments, the matrix comprises a matrix-forming agent and a structure-forming agent. In some embodiments, the matrix-forming agent comprises one or more of the following agents: a water-soluble material, a water-dispersible material, a polypeptide, a polysaccharide, polyvinyl alcohol, polyvinylpyrrolidone, and gum arabic. In some embodiments, the matrix-forming agent comprises a polypeptide. In some embodiments, the polypeptide comprises gelatin. In some embodiments, the structure-forming agent comprises one or more of the following agents: mannitol, dextrose, lactose, galactose, and cyclodextrin. In some embodiments, the structure-forming agent comprises mannitol. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month when stored at a temperature of at least 25°C and a relative humidity of at least 60%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months when stored at a temperature of at least 25°C and a relative humidity of at least 60%. In some embodiments, said pharmaceutical composition has a disintegration time of 3 seconds or less for at least two months when stored at a temperature of at least 25°C and a relative humidity of at least 60%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month when stored at a temperature of at least 30°C and a relative humidity of at least 65%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months when stored at a temperature of at least 30°C and a relative humidity of at least 65%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least one month when stored at a temperature of at least 40°C and a relative humidity of at least 75%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least two months when stored at a temperature of at least 40°C and a relative humidity of at least 75%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months when stored at a temperature of at least 25°C and a relative humidity of at least 60%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months when stored at a temperature of at least 30°C and a relative humidity of at least 65%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least three months when stored at a temperature of at least 40°C and a relative humidity of at least 75%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months when stored at a temperature of at least 25°C and a relative humidity of at least 60%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months when stored at a temperature of at least 30°C and a relative humidity of at least 65%. In some embodiments, said pharmaceutical composition has a disintegration time of 4 seconds or less for at least six months when stored at a temperature of at least 40°C and a relative humidity of at least 75%. In some embodiments, said 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, said viscosity modifier comprises xanthan gum. In some embodiments, the anti-aerating agent comprises one or more of the following: terpene or terpinol. In some embodiments, the anti-aerating agent comprises a liquid flavoring agent. In some embodiments, the anti-aerating agent comprises a liquid flavoring agent containing limonene. In some embodiments, the anti-aerating agent comprises one or more of the following: orange flavor, lemon flavor, grapefruit flavor, lime flavor, strawberry flavor, or peppermint flavor. In some embodiments, said pharmaceutical composition from 3-10% by weight of a matrix-forming substance. In some embodiments, said pharmaceutical composition from 3-10% by weight of a structure-forming substance.

[18] In some embodiments, said pharmaceutical composition may be prepared by a method comprising the following steps: coating 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; coating the coated ibuprofen with a second coating material comprising silicon dioxide; applying a mechanical stress to pour 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 not associated with the coated ibuprofen; forming a pharmaceutical suspension comprising the dual-coated ibuprofen and a matrix solution or suspension; dispensing the pharmaceutical suspension into a mold; and freeze-drying the dispensed pharmaceutical 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 μm or greater. In some embodiments, sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 200 μm or less. In some embodiments, the weight of the dosed pharmaceutical suspension is within 10 percent of the weight of the target dose. In some embodiments, the weight of the dosed pharmaceutical suspension is consistent within 5 percent of the weight of the target dose. In some embodiments, the weight of the dosed pharmaceutical suspension is consistent within 2.5 percent of the weight of the target dose. In some embodiments, the weight of the dosed pharmaceutical suspension is consistent within 1 percent of the weight of the target dose. In some embodiments, mixing the coated ibuprofen into the matrix solution or suspension comprises in-line mixing at a temperature of 15-20°C degrees Celsius. In some embodiments, the coated ibuprofen loses less than 40% of its particle size within the first 2 hours after mixing into the matrix solution. In some embodiments, the coated ibuprofen loses less than 30% of its particle size within the first 2 hours after mixing into the matrix solution. In some embodiments, the coated ibuprofen loses less than 20% of its particle size within the first 2 hours after mixing into the matrix solution.

[19] In some embodiments, a method of treating a patient comprises administering to the patient a pharmaceutical composition of any of the substances described herein. In some embodiments, the patient is a human.

[20] In some embodiments, a method of preparing 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 pour 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 not associated with the coated ibuprofen; forming a pharmaceutical suspension comprising the dual-coated ibuprofen and a matrix solution or suspension; dispensing the pharmaceutical suspension into a mold; and freeze-drying the dispensed pharmaceutical suspension in the mold to form the pharmaceutical composition.

Brief description of graphic materials

[21] Embodiments of the present invention will now be described by way of example only with reference to the accompanying drawings in which:

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

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

[24] Fig. 1C shows an API particle coated with a continuous film layer of a deformable coating material (i.e., a first coating layer) with silica particles (i.e., a second coating layer) partially incorporated and/or embedded in the surface of the first coating layer according to some embodiments;

[25] Fig. 2 shows a scanning electron microscope (SEM) image of an uncoated API particle according to some embodiments;

[26] Fig. 3 shows a scanning electron microscope (SEM) image of a coated API particle according to some embodiments;

[27] Figs. 4A-4J are a series of photomicrographs of screened coated ibuprofen for Examples 1-4;

[28] Fig. 5 is a graph providing an estimate of the d10 particle size of a functionally coated ibuprofen containing a second protective coating with varying concentrations of silica, according to some embodiments;

[29] Fig. 6 shows a graph providing an estimate of the d50 particle size of a functionally coated ibuprofen containing a second protective coating with varying concentrations of silica, according to some embodiments;

[30] Fig. 7 shows a graph providing an estimate of the d90 particle size of a functionally coated ibuprofen containing a second protective coating with varying concentrations of silica, according to some embodiments;

[31] Fig. 8 shows a low volume dissolution graph of carnauba wax coated ibuprofen with varying levels of hydrophobic colloidal silicon dioxide according to some embodiments;

[32] Fig. 9 shows a low volume dissolution graph of ibuprofen coated with Sasol wax (synthetic wax) with varying levels of hydrophobic colloidal silicon dioxide according to some embodiments;

[33] Fig. 10 shows a graph giving an estimate of the particle size d10 of ibuprofen with a hydrophobic coating with different concentrations of liquid flavoring;

[34] Fig. 11 shows a graph giving an estimate of the d50 particle size of ibuprofen with a hydrophobic coating with different concentrations of liquid flavoring;

[35] Fig. 12 shows a graph giving an estimate of the d90 particle size of ibuprofen with a hydrophobic coating with different concentrations of liquid flavoring;

[36] Fig. 13 shows a graph giving an estimate of the d10 particle size of ibuprofen with a hydrophobic coating with different concentrations of pure limonene;

[37] Fig. 14 shows a graph giving an estimate of the d50 particle size of ibuprofen with a hydrophobic coating with different concentrations of pure limonene;

[38] Fig. 15 shows a graph giving an estimate of the d90 particle size of ibuprofen with a hydrophobic coating with different concentrations of pure limonene; and

[39] Fig. 16 shows a graph comparing the results of various particle size analyses of hydrophobically coated ibuprofen with strawberry and orange liquid flavors.

DETAILED DESCRIPTION OF THE ENTITY INVENTIONS

[40] Described herein are exemplary embodiments of methods for minimizing and/or preventing agglomeration of a coating material of 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 methods described herein. Each of these methods and pharmaceutical compositions is described in detail below. Pharmaceutical compositions containing ibuprofen can be prepared using any combination of characteristics of the preparation methods described below.

[41] Figs. 1A, 1B, and 1C illustrate various phases of a coated API particle (e.g., ibuprofen) according to some embodiments. In some embodiments, the API particles may be combined with one or more coating materials to form a coated API. The coating may comprise materials including a water-soluble and/or water-swellable material and a water-insoluble material (described in detail below).

[42] For example, FIG. 1A shows an API particle 102 surrounded by particles of a coating material 104. To produce the coated API particle shown in FIG. 1A, the combined API (i.e., the API particle 102) and one or more coating materials (e.g., the particles of the coating material 104) can be exposed to mechanical and/or thermal energy to produce an ordered mixture of API particles 102 comprising a discrete layer of particles of the coating material 104 lying on the surface of the API particle 102. The API particle 102 in FIG. 1A is shown with a single layer of discrete particles of the coating material(s). However, the API particle 102 can have two or more discrete layers of coating particles. Additionally, FIG. 2 shows an SEM image of an uncoated API particle.

[43] Fig. 1B shows an API particle 102 surrounded by a continuous deformed film layer 104. In particular, Fig. 1B shows that all of the particles of the coating material 104 may be deformable and may deform under the influence of mechanical stress and/or elevated temperature. Thus, since all of the coating materials have deformable characteristics, the coating material 104 in Fig. 1B 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, the term “continuous film” may refer to a layer surrounding the API particle that is formed by melting/softening or otherwise breaking up one or more deformable components of the individual particles of the coating material so that they constitute a single continuous layer surrounding the API particle. Fig. 3 also shows an SEM image of a coated API particle according to some embodiments;

[44] In some embodiments, one or more coating materials may not be deformable, but may be included in a deformable coating layer. Thus, a continuous film may comprise solid particles of a non-deformable material included in a deformable coating material. In Fig. 1C, it is shown that a continuous film 104 may comprise solid non-deformable particles 108 of one or more non-deformable materials partially included and/or included in a deformed coating material of the continuous film 104. This continuous film 104 of Fig. 1B or 1C may provide a coating (e.g., a coating that masks the taste of the API) and a delayed release of the API. In some embodiments, the API particle 102 may have two or more continuous coating layers partially included and/or included with the particles of the non-deformable coating material. Fig. 3 also shows an SEM image of a functionally coated API, according to some embodiments.

[45] In this context, the terms “deformable,” “deformable components,” “deformable components of the coating material,” and other related terms refer to one or more components of water-soluble, water-swellable, and/or water-insoluble materials that can be destroyed by mechanical action and/or elevated temperature.

[46] In some embodiments, the coated API particles may comprise ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may comprise from 30.0 to 90.0 wt. % ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may comprise from 40.0 to 85.0 wt. %, from 50.0 to 80.0 wt. %, or from 70.0 to 80.0 wt. % ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may comprise greater than 40.0 wt. %, greater than 50.0 wt. %, greater than 60.0 wt. %, greater than 65 wt. %, greater than 70.0 wt. %, greater than 75.0 wt. %, greater than 80.0 wt. %, or greater than 85.0 wt. % ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may comprise less than 90.0 wt.%, less than 85.0 wt.%, less than 80.0 wt.%, less than 75.0 wt.%, less than 70.0 wt.%, less than 60.0 wt.%, less than 50.0 wt.%, or less than 40.0 wt.% ibuprofen.

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

[48] The water-swellable material of the coating material may be a particle having an average particle size of from about 0.5 μm to about 20 μm or from about 1 μm to about 10 μm. In some embodiments, the water-swellable material may be about ten times smaller than the ibuprofen material to ensure orderly mixing and coating. The water-swellable material may swell upon absorption of water such that the diameter of the water-swellable particles increases by at least about 120-600%. The coating material or pharmaceutical composition may comprise from 0 to 8 wt. % or from 0.1 to 0.9 wt. % of the water-swellable materials. In some embodiments, the coating material or pharmaceutical composition may comprise from 0.5 to 6.0 wt. %, from 1.0 to 4.0 wt. %, from 1.5 to 3.5 wt. %, or from 2.0 to 3.0 wt. %. water-swellable materials. In some embodiments, the coating material or pharmaceutical composition may comprise less than 8.0 wt.%, less than 6.0 wt.%, less than 4.0 wt.%, less than 2.0 wt.%, less than 1.0 wt.%, or less than 0.5 wt.% water-swellable materials. In some embodiments, the coating material or pharmaceutical composition may comprise greater than 0.1 wt.%, greater than 0.5 wt.%, greater than 1.0 wt.%, greater than 2.0 wt.%, greater than 3.0 wt.%, greater than 5.0 wt.%, or greater than 6.0 wt.% water-swellable materials. The water-swellable material of the coating material may deform under mechanical stress and/or elevated temperature (described in detail below). The water-swellable material may be one or more of the following: crospovidone, croscarmellose, sodium starch glycolate or any other suitable disintegrant used in the pharmaceutical industry as an additive or mixture prepared for tabletting.

[49] The water-soluble material of the coating material may also be a particle having an average particle size of about 0.5 μm to about 20 μm or about 1 μm to about 10 μm. In some embodiments, the water-soluble material may be about ten times smaller than the ibuprofen material to ensure orderly mixing and coating. The water-soluble material may have a water solubility of at least about 50 mg/mL in water at neutral pH and at 20 °C. In addition, the water-soluble material may have a characteristic dissolution rate of about 3-60 μg/ ^m2 s. The water-soluble material of the coating material may be deformed by mechanical energy and/or thermal energy. The coating material or pharmaceutical composition may contain from 0 to 35% by weight of water-soluble materials. In some embodiments, the coating material or pharmaceutical composition may comprise 0.5 to 25 wt.%, 1.0 to 15 wt.%, 1.5 to 10 wt.%, or 2.0 to 3.0 wt.% of water-soluble materials. In some embodiments, the coating material or pharmaceutical composition may comprise less than 35 wt.%, less than 30 wt.%, less than 25 wt.%, less than 20 wt.%, less than 15 wt.%, less than 10 wt.%, less than 5.0 wt.%, less than 4.5 wt.%, less than 4.0 wt.%, less than 3.5 wt.%, less than 3.0 wt.%, less than 2.5 wt.%, less than 2.0 wt.%, less than 1.5 wt.%, less than 1.0 wt.%, or less than 0.5 wt.% of water-soluble materials. In some embodiments, the coating material or pharmaceutical composition may comprise more than 0.1 wt.%, more than 0.5 wt.%, more than 1.0 wt.%, more than 1.5 wt.%, more than 2.0 wt.%, more than 2.5 wt.%, more than 3.0 wt.%, more than 4.0 wt.%, more than 5.0 wt.%, more than 8.0 wt.%, more than 10 wt.%, more than 15 wt.%, more than 20 wt.%, more than 25 wt.%, or more than 30 wt.% of water-soluble materials. The water-soluble material may be one or more of the following: sucrose, mannitol, sorbitol, polyvinylpyrrolidone, hydroxypropyl cellulose, lactose, poly(ethylene oxide), and any other suitable micronizable materials or polyols.

[50] In addition to the characteristic dissolution rate of 3-60 μg/ ^m2 s described above, the proposed methods may use water-soluble and/or water-swellable materials which also have a higher characteristic dissolution rate of about 60-300 μg/ ^m2 s. However, ibuprofen with coating materials having a higher characteristic dissolution rate must be coated with dry hydrophobic silica. The dry coating of ibuprofen, if it contains water-soluble and/or water-swellable materials having higher characteristic dissolution rates, may prolong the dissolution time of ibuprofen, so that it will not be possible to effectively mask the taste of ibuprofen. Accordingly, dry coating of ibuprofen with silica as a second coating material to slow down the dissolution rate can improve the taste-masking properties of the coating in vivo. The coated ibuprofen may contain from 0.5 to 35% by weight of silica. In some embodiments, the coated ibuprofen or pharmaceutical composition may comprise from 0.5 to 20 wt.%, from 0.5 to 10 wt.%, or from 0.5 to 5 wt.% hydrophobic colloidal silicon dioxide. In some embodiments, the coated ibuprofen or pharmaceutical composition may comprise more than 0.5 wt.%, more than 1.0 wt.%, more than 1.5 wt.%, more than 2.0 wt.%, more than 2.5 wt.%, more than 3.0 wt.%, more than 4.0 wt.%, more than 5.0 wt.%, more than 10 wt.%, more than 15 wt.%, more than 20 wt.%, more than 25 wt.%, or more than 30 wt.% hydrophobic colloidal silicon dioxide. In some embodiments, the coated ibuprofen or pharmaceutical composition may comprise less than 35 wt.%, less than 25 wt.%, less than 15 wt.%, less than 10 wt.%, less than 5.0 wt.%, less than 4.0 wt.%, less than 3.5 wt.%, less than 3.0 wt.%, less than 2.5 wt.%, less than 2.0 wt.%, less than 1.5 wt.%, or less than 1.0 wt.% hydrophobic colloidal silicon dioxide. Examples of silica that can be used include, but are not limited to, Aerosil R972 silica (Degussa), CAB-O-SIL EH-5 silica (Cabot), OX-50 silica (Degussa), COSM055 (Catalyst & Chemical Ind. Co. Ltd (Japan)), P-500 hydrophilic silica (Catalyst & Chemical Ind. Co. Ltd (Japan)) and TS5 silica (Cabot). Furthermore, suitable devices that can be used for drying silica include, but are not limited to, Comil (U3 Quadro Comil, Quadro, Pennsylvania, USA), LabRAM (Resodyne, Minnesota, USA), Magnetically Enhanced Coater (MAIC, Aveka, Minnesota, USA) and Jet Mill (Fluid Energy Mill, FEM, Qualification Micronizer of Sturtevant Massachusetts, USA).

[51] The pharmaceutical composition can be prepared by dispensing the pharmaceutical suspension into preformed blister packs. In some embodiments, the lyophilized orally disintegrating tablet can be prepared by dispensing the suspension into blister packs. In some embodiments, the dispensing pumps pump by volume, but the process is controlled by weight. Thus, in order to ensure uniformity of content from one dosage form to another, the dispensing process can be controlled so that the volume to weight percentage of the dosed suspension is constant. For example, the volume to weight percentage can be constant within 10 percent, within 8 percent, within 6 percent, within 5 percent, within 4 percent, within 3 percent, within 2 percent, within 1.5 percent, within 1 percent, within 0.5 percent, or within 0.25 percent. In some embodiments, the weight of the dosed pharmaceutical suspension is within 10 percent, 8 percent, 6 percent, 5 percent, 4 percent, 2.5 percent, 2 percent, 1.5 percent, 1 percent, 0.5 percent, or within 0.25 percent of the target weight. In addition, the viscosity of the pharmaceutical suspension should be low enough to facilitate dosing. As described above, high viscosity of the pharmaceutical suspension can cause the pump to seize during dosing.

[52] The water-insoluble material of the coating materials may also be a particle having an average particle size smaller than that of ibuprofen. For example, the water-insoluble materials may have an average particle size of from about 1 to 20 μm, from about 1 to 12 μm, from about 2 to 10 μm, from about 5 to 12 μm, or from about 5 to 6 μm. In some embodiments, the water-insoluble material may be about ten times smaller than the ibuprofen material to ensure orderly mixing and coating. The water-insoluble material of the coating material may be deformed under mechanical stress and/or elevated temperature. The coating material or pharmaceutical composition may comprise from 5 to 70 wt. %, from 10 to 60 wt. %, from 10 to 50 wt. %, from 10 to 40 wt. %, from 10 to 35 wt. %, or from 15 to 30 wt. %. water-insoluble materials. In some embodiments, the coating material or pharmaceutical composition may comprise greater than 5 wt.%, greater than 10 wt.%, greater than 15 wt.%, greater than 20 wt.%, greater than 25 wt.%, greater than 30 wt.%, greater than 35 wt.%, or greater than 40 wt.% water-insoluble materials. In some embodiments, the coating material or pharmaceutical composition may comprise less than 70 wt.%, less than 60 wt.%, less than 50 wt.%, less than 45 wt.%, less than 40 wt.%, less than 35 wt.%, or less than 30 wt.% water-insoluble materials. Examples of suitable water-insoluble materials include, but are not limited to, ethylcellulose, polyethylene, polypropylene, polytetrafluoroethylene, carnauba wax, candelilla wax, castor wax, polyamide wax, and/or synthetic wax.

[53] In some embodiments, mechanical and/or thermal energy may be applied to deform one or more of the following: water-insoluble materials, water-swellable materials, and/or water-insoluble materials. For example, mechanical stress may be applied to the functionally coated ibuprofen using a PharmaRAM II acoustic mixer, a RAM 5 Pharma mixer, or a RAM 55 Pharma mixer (Resodyn Mixers). The coated ibuprofen may be subjected to up to 100 times the force of gravity (100G acceleration) during this acoustic mixing process. These high forces cause particle-particle collisions, which generate energy in the form of heat, which may be applied to deform one or more of the following: water-insoluble materials, water-swellable materials, and/or water-insoluble materials on the API.

[54] However, the above-described coating process may also result in the formation of "loose" or "free" particles of coating material. Fig. 2 is an SEM image of an uncoated API particle. Fig. 3 is an SEM image of a coated API 312 particle. The "loose" or "free" particles 314 of coating material are not associated with the coated API 312 particles.

[55] After screening, the coated ibuprofen may be mixed with the matrix solution/suspension to form a pharmaceutical suspension (e.g., coated ibuprofen plus matrix solution/suspension) and dispensed by weight into preformed blister packs to form aliquots of the pharmaceutical suspension. After dispensing, the blister packs containing the aliquots of the pharmaceutical suspension are frozen at sub-zero temperatures. The frozen aliquots of the dosed pharmaceutical suspension are kept frozen until they are ready for freeze-drying, during which the solvent of the pharmaceutical suspension is removed to form the pharmaceutical composition.

[56] 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 with respect to the functionally coated ibuprofen. In some embodiments, the matrix former may be a polypeptide, such as gelatin. The gelatin may be at least partially hydrolyzed (by heating in water). Other suitable materials for forming the matrix include, but are not limited to, polysaccharides such as hydrolyzed dextran, dextrin and alginates, polyvinyl alcohol, polyvinylpyrrolidone, and/or gum arabic. In some embodiments, the amount of matrix in the pharmaceutical composition (e.g., an orally disintegrating tablet) may be 1-30% by weight. In some embodiments, the amount of matrix may be less than 30 wt.%, less than 25 wt.%, less than 20 wt.%, less than 15 wt.%, less than 10 wt.%, less than 5 wt.%, or less than 3 wt.% In some embodiments, the amount of matrix may be greater than 1 wt.%, greater than 3 wt.%, greater than 5 wt.%, greater than 10 wt.%, greater than 15 wt.%, greater than 20 wt.%, or greater than 25 wt.%.

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

[58] The structurant or matrix filler may include a sugar. For example, suitable structurants include, but are not limited to, mannitol, dextrose, lactose, galactose, glycine, cyclodextrin, or combinations thereof. The structurant may be used in freeze-drying as a filler because it crystallizes to provide structural strength to the freeze-dried dosage form. In some embodiments, the amount of structurant in the matrix solution/suspension may be from about 0.1 to 10 wt.%, or from 1.5 to 5.0 wt.%, or from 1.5 to 5.0 wt.%, in some embodiments. In some embodiments, the amount of structurant in the matrix solution/suspension or pharmaceutical suspension can be greater than 0.1 wt.%, greater than 0.5 wt.%, greater than 1.0 wt.%, greater than 2.0 wt.%, greater than 3.0 wt.%, greater than 4.0 wt.%, greater than 4.0 wt.%, greater than 5.0 wt.%, or greater than 8.0 wt.% In some embodiments, the amount of structurant in the matrix solution/suspension or pharmaceutical suspension can be less than 10 wt.%, less than 8.0 wt.%, less than 6.0 wt.%, less than 5.0 wt.%, less than 4.0 wt.%, less than 3.0 wt.%, less than 2.5 wt.%, less than 2.0 wt.%, less than 1.5 wt.%, or less than 1.0 wt.%. In some embodiments, the amount of the structuring agent in the pharmaceutical composition may be about 3-15 wt.%, about 4-10 wt.%, or about 4-7 wt.% In some embodiments, the amount of the structuring agent in the pharmaceutical composition may be greater than 0.1 wt.%, greater than 0.5 wt.%, greater than 1.0 wt.%, greater than 2.0 wt.%, greater than 3.0 wt.%, greater than 4.0 wt.%, greater than 5.0 wt.%, greater than 6.0 wt.%, greater than 7.0 wt.%, greater than 8.0 wt.%, greater than 9.0 wt.%, greater than 10.0 wt.%, greater than 11.0 wt.%, greater than 12.0 wt.%, greater than 13.0 wt.%, or greater than 14.0 wt.%. In some embodiments, the amount of structure-forming substance in the pharmaceutical composition may be less than 15% by weight, less than 14.0% by weight, less than 13.0% by weight, less than 12.0% by weight, less than 10.0% by weight, less than 9.0% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, or less than 4.0% by weight.

[59] In some embodiments, the matrix solution/suspension and the pharmaceutical suspension may include a viscosity modifier. For example, the viscosity modifier according to the embodiments provided herein may include plant gums such as xanthan gum, alginin, guar gum, or locust bean gum, proteins such as collagen or gelatin, sugars such as agar, carboxymethylcellulose, pectin, or carrageenan, starches such as arrowroot, corn starch, katakuri starch, potato starch, sago, or tapioca, and/or other suitable viscosity modifiers. In some embodiments, the amount of viscosity modifier in the matrix solution/suspension, pharmaceutical suspension, or pharmaceutical composition may be from 0 to 0.2% by weight or from 0.01 to 0.1% by weight. In some embodiments, the amount of viscosity modifier in the matrix solution/suspension, pharmaceutical suspension, or pharmaceutical composition can be greater than 0.01 wt.%, greater than 0.03 wt.%, greater than 0.05 wt.%, greater than 0.07 wt.%, greater than 0.1 wt.%, greater than 0.12 wt.%, greater than 0.15 wt.%, or greater than 0.17 wt.% In some embodiments, the amount of viscosity modifier in the matrix solution/suspension, pharmaceutical suspension, or pharmaceutical composition can be less than 0.2 wt.%, less than 0.18 wt.%, less than 0.15 wt.%, less than 0.12 wt.%, less than 0.1 wt.%, less than 0.08 wt.%, less than 0.06 wt.%, or less than 0.03 wt.%.

[60] The solvent of the matrix solution/suspension and the pharmaceutical suspension may be water, but the suspension solution may also include a co-solvent. In some embodiments, the solvent may be ethanol, alcohol, isopropanol, other lower alkanols, water (e.g., purified water), or combinations thereof. For example, a suitable solvent and/or co-solvent may be an alcohol, such as tert-butyl alcohol. In some embodiments, the remainder of the pharmaceutical suspension is the solvent (i.e., Q.S. 100%).

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

Minimizing and/or preventing agglomeration of the coating material of coated ibuprofen

[62] The following describes methods for preparing pharmaceutical compositions containing ibuprofen that minimize the amount of excess coating material and/or the degree of agglomeration of excess coating material during storage.

[63] Methods according to some embodiments include removing excess coating material particles to minimize and/or prevent agglomeration of the coating material in the pharmaceutical product. In some embodiments, the methods may include sieving untreated ibuprofen and/or coated ibuprofen. In particular, the disclosed methods may include sieving ibuprofen and/or coated ibuprofen to remove any unwanted particles, such as excess coating material particles. The sieving processes according to the described embodiments may help prevent and/or minimize the possibility of agglomeration of the coating material, which may adversely affect the disintegration time and/or dissolution rate of the final product. The methods may also include optimizing the coating and/or dosing ratios in said process.

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

[65] Typically, a solvent-free mixing process for coating ibuprofen involves mixing coating materials with ibuprofen to form coated ibuprofen. The coated ibuprofen is then subjected to mechanical and/or thermal action to deform the deformable coating material to form a continuous film surrounding the ibuprofen. The coated ibuprofen is then mixed with a matrix solution/suspension to form a pharmaceutical suspension. The pharmaceutical suspension containing the coated ibuprofen may be dosed into preformed forms such as blister packs and further processed to form a pharmaceutical composition for dispensing (e.g., a lyophilisate, wafer, tablet, etc.).

[66] However, during storage of the final product (i.e., the pharmaceutical composition), any particles of excess coating material not associated with the coated ibuprofen may agglomerate. The amount and/or degree of agglomeration may increase over time. Agglomeration of excess coating material may increase the disintegration time and/or decrease the dissolution rate of the pharmaceutical product and adversely affect any functional properties of the coating material. Increased disintegration time may also result in unacceptable dispersion and mouthfeel characteristics in vivo .

[67] Accordingly, it has been found that by sieving the coated ibuprofen, excess coating material can be removed, thereby minimizing the amount of agglomeration of said excess coating material during storage. In addition, some embodiments include optimizing the coating ratio (the ratio of the amount of coating materials to the amount of uncoated ibuprofen) and optimizing the dosing ratio (the ratio of the amount of coated ibuprofen to the aqueous solution matrix containing all other inactive ingredients), which can also minimize the agglomeration of particles of excess coating material.

[68] The embodiments provided herein can be applied to coated ibuprofen produced by dry, solvent-free processes. Some of the mixing processes of the embodiments described herein include coating the ibuprofen with a taste-masking coating. Such coatings can control the disintegration time and/or dissolution rate of the orodispersible pharmaceutical composition such that the release of ibuprofen upon oral administration is delayed or significantly reduced during the first few minutes it is in the mouth, while a satisfactory amount of ibuprofen is released within 30 minutes of ingestion following ingestion. (For example, a satisfactory amount of ibuprofen may be 90% of the amount of ibuprofen that is released without the coating.) U.S. Patent No. 9,107,851 (the '851 patent) describes an example of a dry, solvent-free process for coating pharmaceutical ingredients, which is incorporated herein in its entirety.

[69] However, other variations of coating/encapsulation methods may also be used. For example, sugar coating, film coating, other microencapsulation variations, compression coating, other dry coating variations, melt coating, dip coating, rotary die coating, electrostatic coating, and/or other suitable types of coating may be used.

[70] In addition, the specific data presented herein relates to disintegration time. However, disintegration time is inversely proportional to dissolution rate. Thus, the data inherently also provides information on dissolution rates. Disintegration time can be measured according to the methods set forth in the United States Pharmacopeia (Disintegration 701). In some embodiments, the disintegration time can be from 2-30 seconds to 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, the dissolution rate can also be tested according to the methods set forth in the United States Pharmacopeia (Dissolution 711).

[71] In some embodiments, the crude ibuprofen may be screened prior to the coating process to achieve a narrower particle size range. For example, the crude ibuprofen may be screened to remove larger particles and/or to remove smaller particles. In some embodiments, more than one mesh may be used to remove certain particles. For example, the screening device may comprise a series of two or more meshes to remove particles of a certain size according to the mesh size. The screen may comprise a vacuum transfer system to transport the particles through a series of meshes in the device. In addition, ultrasonic sensors may be integrated into the screening device to improve material flow and minimize mesh clogging during processing.

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

[73] After the ibuprofen has been coated with a coating material to produce coated ibuprofen, the coated ibuprofen may be sieved to remove excess coating material and residual finely divided ibuprofen, either uncoated, partially coated, or coated. Excess coating material may include any particles of coating material not associated with the coated ibuprofen. During storage of the final pharmaceutical product, any excess coating material may agglomerate. For example, excess coating particles may coalesce with coating particles that are already associated with ibuprofen, thereby preventing the penetration of a medium that would otherwise promote disintegration of the unit or tablet or dissolution of the coated ibuprofen. Accordingly, agglomeration of excess coating material may cause an increase in disintegration time and/or a decrease in the dissolution rate upon administration.

[74] However, it has been determined that methods for screening excess coating material from coated ibuprofen can minimize agglomeration of the coating material and maintain the original disintegration time and/or dissolution rate of the final product. The screening process can be batch or continuous. Furthermore, this screening process can be performed in addition to or instead of the screening process performed for uncoated ibuprofen described above. In some embodiments, the parameters of the screening process can be different for uncoated uncoated ibuprofen and coated ibuprofen.

[75] In some embodiments, the coated ibuprofen may be sieved to remove particles of the coating material that have an average size smaller than the desired average particle size of the coated ibuprofen. In some embodiments, more than one mesh may be used to remove certain particles. For example, the sieving device may comprise a series of two or more meshes to remove particles of a certain size according to the mesh size. The sieve may comprise a vacuum transfer system to transport particles through a series of meshes in the device. In addition, ultrasonic sensors may be integrated into the sieving device to improve material flow and minimize mesh clogging during processing. A flow enhancing agent (e.g., silicon dioxide) may be added to promote movement through the sieve. For example, the coating material used to coat ibuprofen may comprise a flow enhancing agent. Conversely, untreated ibuprofen may not be cohesive and may not require the addition of a flow aid during sieving. The sieving process may be batch or continuous.

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

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

[78] The dosing ratio (i.e., the ratio of the amount of coated ibuprofen to the amount of matrix solution/suspension containing all inactive ingredients) can be optimized to minimize and/or prevent agglomeration of excess coating materials. For example, in some embodiments, the dosing ratio can range from 5-60% by weight of coated ibuprofen to 40-95% by weight of matrix solution/suspension. In some embodiments, the dosing ratio can include less than 60% by weight, less than 50% by weight, less than 40% by weight, less than 30% by weight, less than 20% by weight, or less than 10% by weight of coated ibuprofen. In some embodiments, the dosing ratio can include more than 5% by weight, more than 10% by weight, more than 20% by weight, more than 30% by weight, more than 40% by weight, or more than 50% by weight of coated ibuprofen. In some embodiments, the dosing ratio may comprise less than 95 wt%, less than 90 wt%, less than 80 wt%, less than 70 wt%, less than 60 wt%, or less than 50 wt% of the matrix solution/suspension. In some embodiments, the dosing ratio may comprise greater than 40 wt%, greater than 50 wt%, greater than 60 wt%, greater than 70 wt%, greater than 80 wt%, or greater than 90 wt% of the matrix solution/suspension.

Preservation of functionally coated ibuprofen obtained by solvent-free dry mixing and mixed in suspension

[79] The pharmaceutical compositions and methods for preparing the pharmaceutical compositions provided herein may include the addition of hydrophobic colloidal silicon dioxide during the coating process to provide a protective layer surrounding and/or partially or completely incorporated into the functional layer (or "first coating") of the functionally coated ibuprofen. The addition of this hydrophobic colloidal silicon dioxide layer (or "second layer") may provide a protective layer for the first coating layer of the functionally coated ibuprofen and may minimize erosion of the first coating layer due to the shear forces required to mix the functionally coated ibuprofen in the pharmaceutical suspension.

[80] Typically, a solvent-free mixing process for coating ibuprofen includes mixing coating materials with ibuprofen to form functionally coated ibuprofen. The functionally coated ibuprofen is then subjected to mechanical and/or thermal action to deform the deformable coating material to form a continuous film surrounding the ibuprofen. The functionally coated ibuprofen is then mixed with a matrix solution/suspension to form a pharmaceutical suspension. The pharmaceutical suspension containing the functionally coated ibuprofen can be dosed into preformed forms, such as blister packs, and further processed to form a pharmaceutical composition to be dispensed (e.g., a lyophilisate, wafer, tablet, etc.). In some embodiments, the pharmaceutical composition to be dispensed can be an orodispersible product. Ideally, the minimal amount of ibuprofen in the final pharmaceutical composition, if any, is dissolved within the first few minutes after oral administration. This delay or significant slowing of the release of ibuprofen allows the taste of ibuprofen to be masked when the orodispersible product is in the patient's mouth. Instead, the ibuprofen may be released after the pharmaceutical composition has entered the gastrointestinal tract.

[81] However, when ibuprofen with a functional coating is mixed with a matrix solution/suspension, the shear forces required to mix the particles in the matrix solution/suspension can cause erosion of the functional coating of the ibuprofen. Erosion of this coating can destroy or damage the properties of the functional coating. For example, erosion of the functional coating can destroy or damage any taste-masking properties of the functional coating and allow the ibuprofen to dissolve in the oral cavity.

[82] Accordingly, it has been found that hydrophobic colloidal silicon dioxide, as well as its use as a flow enhancing agent for functionally coated ibuprofen to facilitate subsequent processing, can also be used to create a hydrophobic barrier layer surrounding and/or partially or completely incorporated into the functionally coated ibuprofen. In particular, the hydrophobic barrier layer formed by the hydrophobic colloidal silicon dioxide can protect one or more underlying coatings of the functionally coated ibuprofen during the preparation of a pharmaceutical suspension and other subsequent processing of the functionally coated ibuprofen. Thus, ibuprofen according to some embodiments described herein can have a first functional coating and a second protective coating.

[83] However, some pharmaceutical compositions and methods for preparing pharmaceutical compositions provided herein may include more than a first coating and a second coating. For example, some pharmaceutical compositions and methods for preparing the same may include three, four, five, six or more coatings. Thus, as used herein, the terms "first coating" and "second coating" should not be construed narrowly. As used herein, the term "first coating" refers to a functional coating of ibuprofen, and the "second coating" refers to a protective coating comprising silicon dioxide. In some embodiments, the functionally coated ibuprofen may have one or more coating layers between the "first coating" and the "second coating." In some embodiments, the functionally coated ibuprofen may have one or more coating layers between the ibuprofen and the "first coating." In some embodiments, the functionally coated ibuprofen may have one or more coating layers over the "second coating."

[84] Once the functionally coated ibuprofen is obtained, it can be mixed with the matrix solution/suspension to form a pharmaceutical suspension for dosing. Mixing the functionally coated ibuprofen with the matrix solution/suspension can cause erosion of the functional coating of the functionally coated ibuprofen. In some embodiments, in order to minimize this erosion, hydrophobic colloidal silicon dioxide can be used to form a second coating layer surrounding and/or partially included and/or included in the functionally coated ibuprofen.

[85] However, coating ibuprofen with a functional coating (i.e., ibuprofen comprising at least a first coating as described above) that will later be mixed with a matrix solution/suspension with a hydrophobic colloidal silicon dioxide is not self-evident. As described above, to create an orodispersible pharmaceutical composition according to the embodiments described herein, the functionally coated ibuprofen is mixed with a matrix solution/suspension comprising a matrix former, a structure former, and a solvent (often water), thereby forming a pharmaceutical suspension. However, the hydrophobic material is inherently resistant to mixing with the matrix solution/suspension. Accordingly, it can be expected that hydrophobic colloidal silica will increase the interfacial tension between the functionally coated ibuprofen and the matrix solution/suspension, increasing the difficulty of incorporating the functionally coated ibuprofen into the matrix solution/suspension and potentially causing phase separation of the pharmaceutical suspension.

[86] Of interest is the determination that a hydrophobic colloidal silica can be used to coat ibuprofen with a functional coating contained to maintain a first functional coating without significantly interfering with the incorporation of the functionally coated ibuprofen into a matrix solution/suspension. As described above, a hydrophobic material in a matrix solution/suspension, such as ibuprofen with a functional coating coated with a hydrophobic colloidal silica in the matrix solution/suspension described above, typically exhibits a relatively high surface tension between the hydrophobic material and the matrix solution/suspension. Accordingly, the surface tension between ibuprofen with a hydrophobic functional coating and the matrix solution/suspension is likely to be also relatively high.

[87] However, as discussed below, the matrix solution/suspension may contain a matrix former, such as gelatin. Some matrix formers, including gelatin, are mild surfactants, meaning that they can reduce the interfacial tension between two materials. Accordingly, it is believed that matrix formers that exhibit surfactant-like characteristics can reduce the interfacial 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 maintaining the protective properties of the hydrophobic colloidal silica coating layer compared to the first functional coating of the functionally coated ibuprofen. This second coating layer containing hydrophobic colloidal silicon dioxide can provide a hydrophobic barrier for the underlying first coating of ibuprofen with a functional coating to protect the underlying first coating from the shear forces required to mix the ibuprofen with the functional coating into a pharmaceutical suspension. By coating the ibuprofen with a functional coating with a hydrophobic barrier containing hydrophobic colloidal silicon dioxide, the underlying (first) coating can be protected from erosion. In addition, the use of hydrophobic colloidal silicon dioxide in accordance with the disclosed methods can prevent the matrix solution/suspension from penetrating through the coating to the ibuprofen.

[88] Under normal processing conditions, without the hydrophobic colloidal silica coating layer, the functionally coated ibuprofen coating may erode over time due to the shear forces required to mix the functionally coated ibuprofen with the matrix solution/suspension. However, there may be a "processing window" of two or more hours from the time the functionally coated ibuprofen is first mixed with the matrix solution/suspension, during which time the functionally coated ibuprofen coating may remain intact and its functionality may remain intact. The exact timing of this "processing window" varies and may 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 functionally coated ibuprofen coating, and/or the physicochemical properties of the ibuprofen. However, with functional coated ibuprofen, which has a second coating containing colloidal silicon dioxide, this "treatment window" can be extended.

[89] In some embodiments, the pharmaceutical composition or coated ibuprofen may comprise from 0.5 to 35 wt. % hydrophobic colloidal silicon dioxide. In some embodiments, the pharmaceutical composition or coated ibuprofen may comprise from 0.5 to 20 wt. %, from 0.5 to 10 wt. %, or from 0.5 to 5 wt. % hydrophobic colloidal silicon dioxide. In some embodiments, the pharmaceutical composition or coated ibuprofen may comprise greater than 0.5 wt. %, greater than 1.0 wt. %, greater than 1.5 wt. %, greater than 2.0 wt. %, greater than 2.5 wt. %, greater than 3.0 wt. %, greater than 4.0 wt. %, greater than 5.0 wt. %, greater than 10 wt. %, greater than 15 wt. %, greater than 20 wt. %, greater than 25 wt. %, or greater than 30 wt. hydrophobic colloidal silicon dioxide. In some embodiments, the pharmaceutical composition or coated ibuprofen may comprise less than 35 wt.%, less than 25 wt.%, less than 15 wt.%, less than 10 wt.%, less than 5.0 wt.%, less than 4.0 wt.%, less than 3.5 wt.%, less than 3.0 wt.%, less than 2.5 wt.%, less than 2.0 wt.%, less than 1.5 wt.%, or less than 1.0 wt.% hydrophobic colloidal silicon dioxide. The hydrophobic colloidal silica may be any of the following: Aerosil R972 silica (Degussa), CAB-O-SIL EH-5 silica (Cabot), OX-50 silica (Degussa), COSM055 (Catalyst & Chemical Ind. Co. Ltd (Japan)), TS5 silica (Cabot), and/or other suitable types of silica.

[90] The effectiveness of the hydrophobic colloidal silicon dioxide-containing backing layer can be determined by measuring the particle size of the functionally coated ibuprofen in the pharmaceutical suspension over time. If the hydrophobic colloidal silicon dioxide is effective in maintaining the coating, the particle size of the functionally coated ibuprofen may remain constant or decrease very slightly over time. If the hydrophobic colloidal silicon dioxide is ineffective, the particle size of the functionally coated ibuprofen may decrease more significantly over time. The particle size of the functionally coated particles can be measured using laser diffraction, a particle analyzer such as the Malvern Mastersizer, or any other suitable fine particle analysis instrument.

[91] The effectiveness of the hydrophobic protective layer containing colloidal silicon dioxide can also be determined by conducting dissolution tests on the functionally coated ibuprofen. If the hydrophobic colloidal silicon dioxide is effective in maintaining the coating, the amount of release (e.g., percentage release) of the functionally coated ibuprofen over time will be slower in the dissolution test. If the colloidal silicon dioxide is ineffective, the amount of functionally coated ibuprofen released over time will be greater. The amount of released functionally coated particles can be measured by a dissolution test, a spectrophotometric analyzer such as the Pion MicroDISS Profiler, or any other suitable dissolution test instrument.

Minimizing aeration of ibuprofen-containing suspensions

[92] Embodiments provided herein may include the addition of a chemical compound containing a terpene and/or terpinol to the matrix solution/suspension. In particular, embodiments of the pharmaceutical suspensions provided herein may include liquid flavors containing a terpene and/or terpinols. In some embodiments, the liquid flavor(s) may include the terpene limonene. Certain chemical compounds, and in particular the addition of liquid flavors containing limonene, may minimize suspension aeration, enhance suspension homogeneity, and improve dose weight accuracy when the suspension is injected into molds. As used herein, the term "dose weight accuracy" and related terms refer to the ability to accurately dispense a pharmaceutical suspension into a preformed mold. The weight accuracy of the dosed pharmaceutical suspension may depend on a number of variables, including, but not limited to, homogeneity, viscosity, chemical components, dosing tool, etc.

[93] As described above, traditional mechanical means of preventing and/or minimizing aeration have proven ineffective due to the high viscosity of the pharmaceutical suspension. For example, applying a vacuum to a pharmaceutical suspension can cause the suspension to rise because the viscous suspension “holds” the entrapped air. Volatile components of the formulation can also be lost during vacuum processing. Additionally, traditional anti-aerating agents such as ethanol or simethicone emulsion are similarly ineffective in preventing suspension aeration.

[94] Accordingly, it has been found that certain chemical compounds, and in particular liquid flavors containing terpenes and/or terpinols such as limonene, can minimize aeration of the pharmaceutical suspension when the hydrophobically coated ibuprofen is mixed with the matrix solution/suspension. By minimizing aeration, the hydrophobically coated ibuprofen is more efficiently and effectively dispersed throughout the pharmaceutical suspension. This increased dispersion can improve the uniformity of the pharmaceutical suspension, the accuracy of the dose weight, and the uniformity of the content of the finished product.

[95] As described above, when the hydrophobic coated ibuprofen is mixed with the matrix solution/suspension, entrapped air or air bubbles may form in the liquid. Because the ibuprofen coatings are hydrophobic, they typically have low affinity for the matrix solution/suspension. Thus, instead of readily binding and dispersing in the matrix solution/suspension, the hydrophobic coated ibuprofen preferentially binds to the entrapped air. In many liquids, air bubbles typically migrate to the surface of the liquid and disappear into the air above it. However, because the hydrophobic coated ibuprofen has affinity for entrapped air, the hydrophobic coated ibuprofen “traps” the air bubbles, preventing them from migrating to the surface and becoming trapped in the air above the liquid. This causes aeration of the pharmaceutical suspension. Aeration of the pharmaceutical suspension can cause phase separation and thus produce a non-uniform suspension. Phase separation can also be increased by the shear forces created by metering pumps. Heterogeneous pharmaceutical suspensions can cause pump seizure as they pass through metering pumps, resulting in inaccurate dose weights and lack of homogeneity throughout the finished product, as well as reduced manufacturing efficiency due to stoppages.

[96] In addition, pharmaceutical suspensions containing hydrophobic-coated ibuprofen may have high viscosity due to the high loading of hydrophobic-coated ibuprofen (i.e., up to 50% by weight of hydrophobic-coated ibuprofen). The ingress of air into the pharmaceutical suspension during the in-line mixing of hydrophobic-coated ibuprofen into the suspension as described above may further increase the viscosity of the pharmaceutical suspension. Accordingly, not only phase separation and suspension inhomogeneity adversely affect the dosing accuracy and uniformity of the final product, but also the increased viscosity.

[97] It is of interest to discover that certain chemical compounds, when added to a matrix solution/suspension, can minimize aeration of pharmaceutical suspensions containing hydrophobically coated ibuprofen. In particular, chemical compounds containing terpene and/or terpinol, according to some embodiments provided herein, can minimize the amount of entrapped air in pharmaceutical suspensions caused by in-line mixing of hydrophobically coated ibuprofen into matrix solutions/suspensions. For example, suspensions comprising liquid flavors containing terpenes and/or terpinols, even at relatively low concentrations, can minimize aeration of pharmaceutical suspensions. In particular, it has been discovered that matrix solutions/suspensions containing one or more liquid flavors containing limonene can minimize aeration of pharmaceutical suspensions during in-line mixing of hydrophobically coated ibuprofen into the suspension. It has been demonstrated that other chemical compounds, including terpenes and terpinols, also successfully reduce aeration of pharmaceutical suspensions. For example, chemical compounds, including terpenes, such as limonene, carvone, humulene, taxadiene and squalene, can be useful for minimizing aeration of a pharmaceutical suspension. Terpinol can also be a useful anti-aerating agent. In some embodiments, pure terpenes and/or pure terpinols can be used as an anti-aerating agent. In some embodiments, a liquid flavor containing a terpene and/or terpinol can be used as an anti-aerating agent. In some embodiments, other suitable chemical compounds containing a terpene and/or terpinol can be used as an anti-aerating agent.

[98] One problem with some terpene and/or terpinol-containing chemical compounds, such as some liquid flavors, is that they tend to be relatively oily. As with typical oils and water, these oily chemical compounds may not disperse easily in the matrix solution/suspension. However, as discussed below, matrix solutions/suspensions according to embodiments described herein may include gelatin as a matrix-forming substance. Gelatin is a mild surfactant by nature. Surfactants can reduce the surface tension between two materials. Accordingly, in some embodiments, gelatin in the matrix solution/suspension may reduce the surface tension between the oily chemical compounds and the matrix solution/suspension. This can ensure proper incorporation of oily chemical compounds such as liquid flavors into the matrix solution/suspension.

[99] Under normal processing conditions, without the use of terpene and/or terpinol-containing chemicals, the hydrophobic-coated ibuprofen coating erodes over time due to the shear forces required to mix the hydrophobic-coated ibuprofen with the matrix solution/suspension to form the pharmaceutical suspension. However, there is a “processing window” of two or more hours during which the coating retains significant functionality. The exact time of this “processing window” varies for each product and may depend on the composition of the hydrophobic-coated ibuprofen components, the composition of the matrix solution/suspension, the amount of material used to prepare the hydrophobic-coated ibuprofen, the physicochemical properties of ibuprofen, and/or the mixing conditions. Unfortunately, in the presence of terpene and/or terpinol-containing chemicals, this “processing window” may be significantly shortened due to interactions between these chemicals and the hydrophobic-coated ibuprofen coating. These interactions may compromise the functional properties of the coating. For example, interactions between liquid flavors and the hydrophobic-coated ibuprofen coating may compromise any taste-masking functionality of the coating. However, it has been found that there is a threshold concentration of chemicals (e.g., liquid flavor) below which the chemical does not significantly affect the coating, but the "processing window" is not shortened to such an extent that the hydrophobic-coated ibuprofen coating is significantly eroded. Accordingly, this optimal amount of terpene and/or terpinol-containing chemical compound adequately minimizes aeration of the pharmaceutical suspension, resulting in a uniform pharmaceutical suspension that can be accurately dispensed into molds to produce a uniform final product.

[100] Furthermore, terpene and/or terpinol containing chemical compounds, and in particular limonene containing liquid flavourings, may depress the freezing point of the pharmaceutical suspension, which may result in melting defects in products that are subsequently freeze-dried. In particular, limonene has a freezing point of -74 °C. However, no melting defects were observed during the preparation of the described product, and thus at least some of the terpene and/or terpinol containing chemical compounds do not affect the pharmaceutical suspension, so that the freezing and freeze-drying process steps located lower in the process hierarchy are adversely affected. It is believed that the absence of melting defects in these circumstances is due to the high solids content of the suspension, which helps maintain the structure of the product even in the presence of a freezing point depressant (e.g. limonene).

[101] Matrix solution/suspension compositions according to embodiments described herein may include a matrix-forming agent, a structure-forming agent, an anti-aerating agent, a viscosity modifier, and/or a solvent.

[102] In some embodiments, the amount of terpene and/or terpinol (i.e., anti-aerating agent)-containing chemical compounds in the matrix solution/suspension, pharmaceutical suspension, or pharmaceutical composition can be from 0.001 to 5.0 wt%. In some embodiments, the amount of terpene and/or terpinol (i.e., anti-aerating agent)-containing chemical compounds in the matrix solution/suspension, pharmaceutical suspension, or pharmaceutical composition can be 1-5 wt%, 1-4 wt%, 1-3 wt%, 1-2 wt%, 0.05 to 3.0 wt%, 0.1 to 2.0 wt%, or 0.5 to 1.0 wt%. In some embodiments, more than 0.001 wt.%, more than 0.01 wt.%, more than 0.05 wt.%, more than 0.1 wt.%, more than 0.3 wt.%, more than 0.5 wt.%, more than 0.8 wt.%, more than 1.0 wt.%, more than 1.5 wt.%, more than 2.0 wt.%, more than 2.5 wt.%, more than 3.0 wt.%, more than 3.5 wt.%, more than 4.0 wt.%, or more than 4.5 wt.% of the terpene and/or terpinol (i.e., anti-aerating agent)-containing chemical compounds are present in the matrix solution/suspension, pharmaceutical suspension, or pharmaceutical composition. In some embodiments, less than 5.0 wt.%, less than 4.5 wt.%, less than 4.0 wt.%, less than 3.5 wt.%, less than 3.0 wt.%, less than 2.5 wt.%, less than 2.0 wt.%, less than 1.5 wt.%, less than 1.0 wt.%, less than 0.8 wt.%, less than 0.6 wt.%, less than 0.3 wt.%, or less than 0.1 wt.% of the terpene and/or terpinol (i.e., anti-aerating agent)-containing chemical compounds are present in the matrix solution/suspension, pharmaceutical suspension, or pharmaceutical composition. In some embodiments, a suitable anti-aeration agent may include orange flavor, strawberry flavor, mint flavor, raspberry flavor, licorice flavor, orange flavor, lemon flavor, lime flavor, grapefruit flavor, caramel flavor, vanilla flavor, cherry flavor, grape flavor, mixed fruit flavor, tutti-frutti flavor, or any combination thereof.

EXAMPLES OF AGGLOMERATION MINIMIZATION

[103] Several studies have been conducted to evaluate the effectiveness of removing excess coating material from coated ibuprofen by sieving and optimizing the coating ratio and dosing ratio. The disintegration times of pharmaceutical compositions containing ibuprofen coated with different coatings were measured under various conditions to study the effect of sieving the excess coating material. It can be reasonably assumed that removing excess coating material can minimize the agglomeration of the coating material. Optimizing the coating and dosing ratios can also help minimize the agglomeration of the coating material. In turn, minimizing the amount of agglomeration can help maintain the desired disintegration time and/or dissolution rates of the pharmaceutical composition and the coated ibuprofen. Accordingly, the disintegration time is used as an indicator to evaluate the degree of agglomeration in the following examples. In some embodiments, the accelerated disintegration data at 50°C may indicate the presence of unsieved excess coating material.

[104] In addition, the following Examples provide information on the coating ratio and the dosing ratio. The coating ratio is the ratio of the amount of coating materials to the amount of uncoated ibuprofen. The dosing ratio is the ratio of the amount of coated ibuprofen to the amount of matrix solution/suspension containing all inactive ingredients.

[105] Example 1: Ibuprofen was coated with carnauba wax at a coating ratio of 26:74. A dosing ratio of 40:60 was used to produce tablets by freeze drying. Four separate lots of tablets were tested - Lots 1-3 for 2 months and Lot 4 for 6 months. Each lot of tablets was tested according to ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) principles under stability conditions of 25 °C/60% RH, 30 °C/65% RH and 40 °C/75% RH and samples were collected after one and two months for Lots 1, 2 and 3. In addition, each lot was subjected to a stress condition of 50 °C to obtain accelerated data at both two weeks and four weeks for each study. Table 1 below presents disintegration time data for Batches 1-3 of the two-month study of coated ibuprofen.

Party Batch No. No. Dosage Original VR Week 2 Week 4 Month 1 Month 1 Month 1 Month 2 Month 2 Month 2 50°C 50°C 25°C/ 60% RH 30°C/
65%OV 40°C/
75%OV 25°C/
60%OV 30°C/
65%OV 40°C/
75%OV 1 Z3876/128 400 mg < 2 s < 4 s < 10 s < 4 s < 4 s < 4 s < 3 s < 4 s < 7 s 2 Z4630/97 50 mg < 2 s < 4 s < 7 s < 2 s < 2 s < 2 s < 2 s < 2 s < 15 sec 3 Z4630/101 50 mg < 3 s < 3 s < 4 s < 1 s < 2 s < 3 s < 2 s < 2 s < 2 s

Table 1. Carnauba Wax (40:60 Dosage Ratio) (2-Month Study)

[106] The coated ibuprofen for Batch 2 did not screen well after coating the ibuprofen. Microscopic examination (Figure 4B) of the screened coated ibuprofen demonstrated the presence of excess unbound coating material. Microscopic examination of the screened coated ibuprofen also demonstrated that the ibuprofen was insufficiently coated. As can be seen from the last column of Table 1, this batch demonstrated a significantly longer disintegration time in the stability tests at 40°C and 75% relative humidity after two months. (The initial disintegration time was less than two seconds, and the disintegration time after two months was almost 15 seconds.) Accordingly, this result supports the hypothesis that the presence of excess unbound coating material in the pharmaceutical product is the cause of the increased disintegration time over time (as the pharmaceutical product ages) due to agglomeration of the unbound coating material during storage.

[107] In contrast, the coated ibuprofen for Lot 3 was sieved after the ibuprofen had been coated. Microscopic examination (Figure 4C) of the sieved coated ibuprofen demonstrated that the ibuprofen was well coated, as there was no unbound coating material. The disintegration times of the samples from this lot changed very little over the two-month period for any of the ICH stability conditions. (Disintegration times ranged from approximately one second to approximately three seconds over the two-month study.) This supports the hypothesis that minimizing the presence of excess unbound coating material by sieving, for example, will help prevent agglomeration of the coating material in the pharmaceutical product during storage, particularly at higher temperatures over time.

[108] The coated ibuprofen for Batch 1 was sieved after coating the ibuprofen. Batch 1 demonstrated a similar disintegration time of less than 2 seconds compared to Batches 2 and 3 for the initial time points. However, under stability testing conditions at 40°C and 75% relative humidity, after two months the disintegration time increased to approximately 7 seconds or less. When stored for 4 weeks at 50°C, the disintegration time increased to approximately 10 seconds or less. This may indicate that the sieve process for this batch did not sufficiently remove excess coating material, and therefore residual unbound coating material was present. Batch 2 had even more unbound coating material and more agglomeration during storage than Batch 1. Microscopic examination (Figure 4A) of the sieved coated ibuprofen demonstrated that the ibuprofen particles were relatively well coated by the residual amount of unbound coating material present.

[109] Table 2 below presents disintegration time data for the six-month study of coated ibuprofen (i.e., Batch 4).

Party Batch No. No. Dosage Initial level Week 2 4
Week Month 1 Month 1 Month 1 Month 3 Month 3 Month 3 Month 6 Month 6 Month 6 50°C 50°C 25°C/60%
OV 30°C/65%
OV 40°C/75%
OV 25°C/60%
OV 30°C/65%
OV 40°C/75%
OV 25°C/60%
OV 30°C/65%RH 40°C/75%
OV 4 Z3876/131 200 mg <5 sec < 20 sec < 13 s < 5 sec < 4 s < 5 sec < 4 s < 3 s < 4 s < 2 s < 2 s < 2 s

Table 2. Carnauba Wax (40:60 Dosage Ratio) (6-Month Study)

[110] The coated ibuprofen for Batch 4 was sieved after coating the ibuprofen. Batch 4 from Table 2 did not show a significant change in disintegration time over the six month study. The initial disintegration time of Batch 4 was approximately five seconds, and the final disintegration time of the samples at 25°C/60% RH was approximately two seconds; the disintegration time of the samples at 30°C/65% RH was approximately two seconds, and the disintegration time of the samples at 40°C/75% RH was approximately two seconds. However, an increase was observed upon storage at 50°C. Since no increase was observed in tablets stored at 40°C and below, this may indicate that sieving removed most of the unbound excess coating material, but left enough residue that agglomerated when the tablets were placed at 50°C. Microscopic examination (Fig. 4D) demonstrated that the sieved coated ibuprofen was relatively well coated with residual unbound coating material present.

[111] Example 2: Ibuprofen was coated with Sasol wax (synthetic) with a theoretical coating ratio of 26:74. The coated ibuprofen was sieved after coating. A dosing ratio of 40:60 was used to prepare freeze-dried tablets and tested for two months. The ibuprofen strength was 200 mg. Each lot was tested under ICH stability conditions of 25°C/60% RH, 30°C/65% RH, and 40°C/75% RH. In addition, samples were stressed at 50°C to obtain accelerated data at two and four weeks during the study. Table 3 below presents the data for the 40:60 dosing ratio in the two-month study of coated ibuprofen. Microscopic examination (Fig. 4E) demonstrated that the screened coated ibuprofen was relatively well coated with a small amount of unbound coating material.

Party Batch No. No. Original VR Week 2 Week 4 Month 1 Month 1 Month 1 Month 2 Month 2 Month 2 50°C 50°C 25°C/ 60% RH 30°C/ 65% RH 40°C/75%RH 25°C/ 60%RH 30°C/65%RH 40°C/75%RH 5 Z3876/138 < 3 s < 3 s < 4 s < 2 s < 2 s < 5 sec < 4 s < 4 s < 4 s

Table 3. Sasol Wax (dosage ratio 40:60) Ibuprofen dosage: 200 mg

[112] Batch 5 of Table 3 did not exhibit significant change in disintegration time over the two month study period, nor under the accelerated conditions at 50°C. Specifically, the initial disintegration time of Batch 5 was approximately three seconds, and the disintegration time after two months for all three ICH stability conditions (25°C/60% RH, 30°C/65% RH, and 40°C/75% RH) was approximately four seconds. The disintegration time under the accelerated conditions at 50°C was approximately three seconds after two weeks, and approximately four seconds after four weeks. Based on the data obtained at 50°C, a small amount of unbound excess coating material may be present. If so, this small amount of unbound excess coating material does not cause significant agglomeration during storage, since the disintegration time does not increase much, if at all. These data compare well with Batch 3 in Example 1, which used a different wax. These 2 examples demonstrate that if unbound excess coating material is effectively removed by sieving, agglomeration of the coating material in the pharmaceutical product during storage can be minimized or prevented, particularly at higher temperatures and over extended storage periods.

[113] Example 3: Ibuprofen was coated with Sasol wax (synthetic) with a theoretical coating ratio of 26:74. The coated ibuprofen was sieved after coating. A 50:50 dosing ratio was used to prepare freeze-dried tablets and tested for three months. The ibuprofen strength was 200 mg. As described in Examples 1 and 2 above, each lot was tested under the ICH stability conditions of 25°C/60% RH, 30°C/65% RH, and 40°C/75% RH. Samples were also subjected to stress conditions at 50°C to obtain accelerated data at two and four weeks during each study. Table 4 below presents the data from the three-month study of ibuprofen coated with Sasol 50:50 wax. Microscopic examination (Figure 4F) of the sieved coated API for Batch 6 demonstrated that the ibuprofen was well coated, with some unbound coating material remaining.

Party Batch No. No. Original VR Week 2 Week 4 Month 1 Month 1 Month 1 Month 2 Month 2 Month 2 Month 3 Month 3 Month 3 50°C 50°C 25°C/60% 30°C/65%RH 40°C/75%RH 25°C/60%RH 30°C/65%RH 40°C/75%RH 25°C/60%RH 30°C/65%RH 40°C/75%RH 6 Z3876/142 < 1 s < 2 s < 2 s < 2 s < 2 s < 2 s < 2 s < 1 s < 2 s < 2 s < 2 s < 2 s 7 Z3876/141/1 < 2 s < 5 sec < 5 sec < 2 s < 3 s < 3 s < 2 s < 2 s < 3 s < 2 s < 2 s < 3 s

Table 4. Sasol Wax (50:50 Dosage Ratio) Ibuprofen Dosage: 200 mg

[114] Neither Lot 6 nor Lot 7 demonstrated significant change in disintegration time over the three-month study. Specifically, the initial disintegration time of Lot 6 samples was approximately 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 approximately two seconds. The disintegration times for both the two-week and four-week accelerated conditions at 50°C for Lot 6 were approximately two seconds.

[115] The initial disintegration times for Lot 7 samples were approximately two seconds and the final three-month disintegration times for ICH stability conditions at 25°C/60% RH and 30°C/65% RH were approximately two seconds. The final three-month disintegration times for ICH stability conditions at 40°C/75% RH were approximately three seconds. The disintegration times for both the two-week and four-week accelerated conditions at 50°C were approximately five seconds. The high 50:50 coating ratio may increase the amount of excess unbound coating material if not screened. Although both lots used the higher 50:50 dosing ratio, which means there was a high loading of coated ibuprofen and any unbound excess coating material, these data suggest that the screening process of the coated ibuprofen was effective in removing unbound excess coating materials to minimize agglomeration.

[116] Example 4: Ibuprofen was coated with carnauba wax at theoretical coating ratios of 22.5:77.5 and 30:70. The 30:70 dosing ratio was used to prepare freeze-dried tablets and tested for two months. The ibuprofen strength was 200 mg. The batches were stored in an oven at 40°C. The tablets were tested for disintegration times at the following time points: baseline, Day 25, and Month 2. Table 5 below provides the disintegration times for the study. Microscopic examination of unscreened coated ibuprofen (Figures 4G and 4H) and screened coated ibuprofen (Figures 4I and 4J). The ibuprofen was well coated. The screened samples did not contain any unbound coating material.

Party Batch No. No. API Covered Coverage ratio Initial level Day 24
At 40°C Month 2
At 40°C 8 Z4750/186/2a Unsifted 22.5:77.5 5 s 2 s 2 s 9 Z4750/186/4a Sieved 22.5:77.5 4 s 3 s 3 s 10 Z4750/186/6a Unsifted 30:70 1 s 2 s 2 s 11 Z4750/186/8a Sieved 30:70 2 s 3 s 3 s

Table 5. Carnauba wax (dosage ratio 30:70) Ibuprofen dosage: 200 mg

[117] Batches 8-11 demonstrate that when using a 30:70 dosing ratio for coated ibuprofen, either unscreened (Banks 8 and 10) or screened (Banks 9 and 11), the disintegration time of tablets stored at 40°C did not increase over time. This supports the hypothesis that by decreasing the dosing ratio; for example to 30:70, the amount of excess unbound wax is significantly reduced to a level that can minimise agglomeration of excess unbound material when stored at higher temperatures over time.

[118] A general summary of the results of the above examples is presented in Table 6.

Party Batch No. No. Preparation Dosage (mg) Coverage ratio Dosage ratio Screening of covered API Coating assessment (microscopy) Unbound excess wax (microscopy) Disintegration time at 40°C/75%RH at time points 1/2/3/6 months Disintegration time at 50 °C at 2/4 weeks 1 Z3876/128 Ibuprofen 400 26:74 40:60 Sieved Average In stock < 4-7 sec < 4-10 sec 2 Z4630/97 Ibuprofen 50 26:74 40:60 Sifted (bad) Bad In stock < 2-15 sec < 4-7 sec 3 Z4630/101 Ibuprofen 50 26:74 40:60 Sieved
(good) Good Absent < 2-3 sec < 3-4 sec 4 Z3876/131 Ibuprofen 200 26:74 40:60 Sieved Average In stock < 2-5 sec < 13-20 sec 5 Z3876/138 Ibuprofen 200 26:74 40:60 Sieved Good In stock < 4-5 sec < 3-4 sec 6 Z3876/142 Ibuprofen 200 26:74 50:50 Sieved Good In stock < 2 s < 2 s 7 Z3876/141/1 Ibuprofen 200 25:75 50:50 Sieved No photo No photo < 3 s < 5 sec 8 Z4750/186/2a Ibuprofen 200 22.5:77.5 30:70 Unsifted Good In stock < 2 s No data 9 Z4750/186/4a Ibuprofen 200 22.5:77.5 30:70 Sieved
(good) Good Absent < 3 s No data 10 Z4750/186/6a Ibuprofen 200 30:70 30:70 Unsifted Good In stock < 2 s No data 11 Z4750/186/8a Ibuprofen 200 30:70 30:70 Sieved Good Absent < 3 s No data

Table 6. Overall summary of results for Games 1-11.

Examples of preserving ibuprofen with a functional coating

[119] Example 5: A hydrophobic colloidal silica was used to coat functionally coated ibuprofen in accordance with the embodiments described herein. In particular, the hydrophobic colloidal silica used was Aerosil R972 (“Aerosil”). Two different concentrations of Aerosil R972 were tested: 1.5 wt% and 1.0 wt%. The size of the functionally coated ibuprofen was evaluated over a 6-hour exposure period during which they were subjected to low-shear mixing.

[120] Figs. 5, 6 and 7 show the d10 particle size, d50 particle size and d90 particle size estimates, respectively, over a 6 hour period. In general, a d10 particle size means that 10 percent of the particles in a given sample volume are detected below the given size. Accordingly, a d50 particle size means that 50 percent of the particles in a given sample amount are detected below the given size, and a d90 particle size means that 90 percent of the particles in a given sample amount are detected below the given size.

[121] As demonstrated in Fig. 5, the higher silica concentration (1.5 wt.%) was more effective in maintaining the original particle size and thus maintaining the coating, compared to the lower silica concentration (1.0 wt.%). In particular, over a 6-hour period, the functionally coated ibuprofen containing 1.5 wt.% Aerosil lost approximately 30% of its original particle size, whereas the functionally coated ibuprofen containing 1.0 wt.% Aerosil lost approximately 80% of its original particle size.

[122] As demonstrated in Fig. 6, again, the higher silica concentration (1.5 wt.% Aerosil) was more effective in maintaining the original particle size of the functionally coated ibuprofen, and thus maintaining the functional coating, compared to the lower silica concentration (1.0 wt.% Aerosil). Specifically, over a 6 hour period, the functionally coated ibuprofen containing 1.5 wt.% Aerosil lost nearly 20% of its original particle size, whereas the functionally coated ibuprofen containing 1.0 wt.% Aerosil lost approximately 45% of its original particle size of the functionally coated API.

[123] As demonstrated in Fig. 7, again, the higher concentration of silica (1.5 wt.% Aerosil) was more effective in maintaining the original particle size of the functionally coated ibuprofen, and thus maintaining the functional coating of the functionally coated ibuprofen, compared to the lower concentration of silica (1.0 wt.% Aerosil). Specifically, over a 6-hour period, the functionally coated ibuprofen containing 1.5 wt.% Aerosil lost nearly 15% of its original particle size, whereas the functionally coated ibuprofen containing 1.0 wt.% Aerosil lost approximately 35% of its original particle size.

[124] In addition, as the particle size of the functionally coated ibuprofen decreased, a distinct population of particles ranging in size from 5 to 20 μm appeared and increased over time. These particles are believed to represent particles of non-deformable coating material incorporated into the deformed continuous coating material prior to erosion of the coating due to shear forces. Accordingly, as the coating degrades and the particle size of the functionally coated ibuprofen increases, the population size of these smaller particles increases as the deformed coating material surrounding them erodes, causing the release of these non-deformable particles from the functionally coated ibuprofen.

[125] Overall, the results of these tests suggest that 1.5% Aerosil coating functionally coated ibuprofen may extend the "processing window" to approximately 4 hours, instead of the 2 hour "processing window" that exists without silica. During the first four hours of processing in a suspension containing a second outer coating containing 1.5% by weight Aerosil functionally coated ibuprofen, little or no coating erosion occurs.

[126] Example 6: A hydrophobic colloidal silica was used to coat functionally coated ibuprofen according to the embodiments described herein. In particular, the hydrophobic colloidal silica used was Aerosil R972 (“Aerosil”). Five different concentrations of Aerosil R972 were tested: 0.0 wt.%, 1.5 wt.%, 2.5 wt.%, 5.0 wt.%, and 10.0 wt.%. The amount of functionally coated ibuprofen released was evaluated in a dissolution test (i.e., with a dissolution medium of 0.01% SDS in a phosphate buffer with a pH of 7.2, a medium temperature of 37°C, and a medium volume of 10 ml (ibuprofen)).

[127] Figures 8 and 9 show release rate estimates for functionally coated ibuprofen over 5 or 30 minutes. In general, the small volume dissolution result, expressed as a percentage of its release, means that "x" percent of the weight of the added material has dissolved in the solution.

[128] Figure 8 shows the release data of ibuprofen coated with carnauba wax and varying amounts of hydrophobic silica. As demonstrated in Figure, higher concentrations of silica (up to 10.0 wt%) were more effective in providing a slower release rate during the dissolution test and thus in maintaining the coating compared to lower concentrations of silica. In particular, over the 5 minute test period, functionally coated ibuprofen (i.e., ibuprofen coated with carnauba wax) containing 10.0 wt% Aerosil demonstrated 1.5% release after 5 minutes, whereas functionally coated ibuprofen containing 0.0 wt% Aerosil demonstrated 24.9% release. Functionally coated ibuprofen containing intermediate levels of Aerosil (i.e. 1.5% w/w, 2.5% w/w and 5.0% w/w) demonstrated dissolution results at 5 minutes with release of 12.1%, 7.4% and 2.3%, respectively.

[129] Figure 9 shows the release data for ibuprofen coated with Sasol wax (synthetic) and varying amounts of hydrophobic silica. As also demonstrated in Figure 10, higher concentrations of silica (up to 10.0 wt%) were more effective in providing a slower release rate in the dissolution test and thus in maintaining the coating compared to lower concentrations of silica. In particular, over the 5 minute test period, functionally coated ibuprofen (i.e., ibuprofen coated with synthetic wax) containing 10.0 wt% Aerosil demonstrated 2.8% release after 5 minutes, whereas functionally coated ibuprofen containing 0.0 wt% Aerosil demonstrated 8.5% release. Functionally coated ibuprofen containing intermediate levels of Aerosil (i.e. 1.5% w/w, 2.5% w/w and 5.0% w/w) demonstrated dissolution results at 5 minutes with release of 4.3%, 3.6% and 2.4%, respectively.

Examples of minimizing aeration

[130] The effectiveness of the terpene and/or terpinol containing chemical compounds in minimizing aeration can be determined in part by measuring the particle size of the hydrophobic coated ibuprofen in the pharmaceutical suspension over time. If the chemical compound is effective, aeration of the suspension will be quite low and the particle size of the hydrophobic coated ibuprofen will remain constant or decrease very slightly over time. If the compound is ineffective, aeration of the suspension will be higher than desired and the particle size of the hydrophobic coated ibuprofen may decrease more significantly over time. The degree of aeration of the suspension is assessed by measuring the height of the foam in the mixing vessel. The particle size of the functionally coated particles can be measured using laser diffraction, a particle analyzer such as the Malvern Mastersizer, or any other suitable fine particle analysis instrument.

[131] Example 7: A series of suspension mixtures were prepared by mixing coated ibuprofen with a matrix solution/suspension containing varying levels of limonene, orange flavour and strawberry flavour. The foam heights from this suspension are given in Tables 7, 8 and 9, respectively.

Limonene concentration (%wt) Foam height (mm) 0 5 0.15 2 0.30 1 0.6 1

Table 7: Foam height of mixtures containing different levels of limonene .

Orange flavor concentration (% wt.) Foam height (mm) 0 5 0.15 1 0.30 0 0.6 0

Table 8: Foam height from blends containing different levels of orange flavor.

Strawberry flavor concentration (% wt.) Foam height (mm) 0 5 0.15 3 0.30 3 0.6 3

Table 9: Foam height of blends containing different levels of strawberry flavor.

[132] The results in Tables 7 and 8 demonstrate that the addition of limonene and orange flavor at levels of 0.15% w/w and above minimized aeration. With respect to strawberry flavor (Table 9), it also reduced aeration, but not to the same extent.

[133] Example 8: Figs. 10, 11 and 12 illustrate the reduction in particle size (d10, d50 and d90, respectively) of ibuprofen with a hydrophobic coating in a pharmaceutical suspension containing different concentrations of liquid orange flavor. A particle size expressed as d10 means that 10 percent of the particles in a given sample volume are detected below a given size. Accordingly, a d50 particle size represents 50 percent of the particles in a given sample volume detected below a given particle size, and a d90 particle size represents 90 percent of the particles in a given sample volume detected below a given particle size. In particular, Figs. 3-5 illustrate test results for suspension compositions containing ibuprofen with a hydrophobic coating and liquid orange flavor at concentrations including 0.0 wt.%, 0.15 wt.%, 0.45 wt.% and 0.5 wt.%, respectively. and 0.60% wt., aged for up to 6 hours with low shear mixing

[134] At orange flavor concentrations up to 0.45 wt% (including 0.15 wt%), the reduction in d10, d50, and d90 particle sizes during the first 2 hours of the “processing window” are largely similar to those of a pharmaceutical suspension containing hydrophobically coated ibuprofen without any liquid flavor (0% liquid flavor). However, at a concentration of 0.6 wt% liquid orange flavor, the hydrophobically coated ibuprofen coating is easily removed and a rapid reduction in particle size is observed. Furthermore, at a concentration of 0.3 wt% liquid orange flavor, suspension aeration was quite low with little, if any, damage to the coating of the coated ibuprofen and only minimal reduction in the particle size of the hydrophobically coated ibuprofen.

[135] Example 9: Figures 13, 14 and 15 provide particle size reduction data d10, d50 and d90, respectively, of hydrophobically coated ibuprofen for a particular component limonene, which is present in certain liquid flavors. These tests were conducted to examine the performance of a particular component of the liquid flavor, limonene, on hydrophobically coated ibuprofen in suspension. It should be noted that the limonene concentrations shown in the Figures are significantly higher than the limonene concentration that would be present if the liquid flavor were used. In Figures 13-15, neat limonene was used at concentrations of 0.25 wt.%, 0.45 wt.% and 0.75 wt.% and tested for 24 hours. As shown in all three Figures, the limonene concentration of 0.25 wt.% had a much less negative effect on the coating of the hydrophobic-coated ibuprofen particles than 0.45 wt% and 0.75 wt% limonene. In addition, the pharmaceutical suspensions tested with 0.25 wt% limonene were characterized by a relatively low degree of aeration. Accordingly, these tests confirm that limonene from the liquid orange flavor tested in Figs. 3-5 is at least partially responsible for minimizing the aeration of the pharmaceutical suspension and the subsequent erosion of the hydrophobic-coated ibuprofen coating at relatively high levels and/or over relatively long exposure times.

[136] Example 10: Figure 16 shows test data for two different liquid flavors: strawberry and orange. The d10, d50, and d90 particle sizes of ibuprofen with a hydrophobic coating were tested with both the liquid strawberry flavor and the liquid orange flavor. Both the liquid strawberry and orange flavors contain limonene. As shown in the Figure, both flavors behave similarly with respect to the particle size of the hydrophobic coated ibuprofen. The d10 particle size samples showed a greater reduction in particle size during the first two hours of testing than the d50 and d90 particle samples. The d50 and d90 particle size samples showed a lesser reduction in particle size during the same two-hour period. However, this observation is consistent with the d10, d50, and d90 particle size data in the previously described Examples.

[137] Furthermore, in all tests, it was observed that as the particle size of the hydrophobic-coated API (ibuprofen) decreased, a distinct population of particles ranging in size from 5 to 20 μm appeared and increased over time. These particles are believed to represent particles of non-deformable coating material incorporated into the deformed continuous coating material prior to erosion of the coating due to shear forces. Accordingly, as the coating degrades and the particle size of the hydrophobic-coated ibuprofen increases, the population size of these smaller particles increases as the deformed coating material surrounding them erodes, causing the release of these non-deformable particles from the hydrophobic-coated ibuprofen.

[138] Overall, these trials demonstrate that by optimizing the amount of terpene limonene added to a pharmaceutical suspension containing hydrophobically coated ibuprofen, the degree of aeration of the suspension can be minimized to allow for further processing while not adversely affecting the coating of the hydrophobically coated ibuprofen (as determined by the particle size of the hydrophobically coated ibuprofen).

[139] The foregoing description has been given with reference to specific embodiments for purposes of explanation. However, the above illustrative discussions are not intended to be exhaustive or to limit the invention to the precise forms disclosed. In view of the above, many modifications and variations are possible. The embodiments have been selected and described to better explain the principles of the disclosed techniques for their practical application. Thus, others skilled in the art can best apply the techniques and various embodiments with various modifications that are suitable for the particular intended application.

Although the description and examples have been fully set forth above with reference to the accompanying drawings, it should be noted that various changes and modifications will become apparent to those skilled in the art. It should be understood that such changes and modifications are included within the scope of the invention and the examples defined by the claims.

Claims (34)

1. A pharmaceutical composition containing: 75-90% w/w of a coated active pharmaceutical ingredient (API), wherein the API coating comprises a first coating material comprising wax and 0.5-5% w/w of a second coating material comprising silicon dioxide attached to, partially incorporated into and/or fully incorporated into the first coating material; 3-7% w/w matrix-forming substance; 2-6% w/w structure-forming substance; 0.1-2% w/w anti-aerating agent; and 0.01-0.2% w/w viscosity modifier. 2. The pharmaceutical composition of claim 1, wherein the first coating material comprises 10-30% w/w of coated API. 3. The pharmaceutical composition according to claim 1 or 2, wherein the first coating material comprises one or more of carnauba wax, synthetic wax or candelilla wax. 4. The pharmaceutical composition according to any one of claims 1-3, wherein the matrix forming material comprises one or more of a water-soluble material, a water-dispersible material, a polypeptide, a polysaccharide, polyvinyl alcohol, polyvinylpyrrolidone and gum arabic. 5. The pharmaceutical composition according to claim 4, wherein the material for forming the matrix comprises a polypeptide. 6. The pharmaceutical composition according to claim 5, wherein the polypeptide contains gelatin. 7. A pharmaceutical composition according to any one of claims 1-6, containing a structure-forming substance containing one or more of the following components: mannitol, dextrose, lactose, galactose and cyclodextrin. 8. The pharmaceutical composition according to claim 1, wherein the viscosity modifier comprises xanthan gum. 9. The pharmaceutical composition according to claim 1, wherein the anti-aerating agent comprises one or more of a terpene or a terpinol. 10. The pharmaceutical composition according to claim 1, wherein the anti-aerating agent comprises limonene. 11. The pharmaceutical composition of claim 10, wherein the anti-aerating agent comprises one or more of the following components: orange flavor, lemon flavor, grapefruit flavor, lime flavor, strawberry flavor, or peppermint flavor. 12. A pharmaceutical composition according to any one of claims 1-11, additionally containing a sweetener. 13. The pharmaceutical composition of any one of claims 1-12, wherein the pharmaceutical composition has a disintegration time of 4 s or less for at least six months under storage conditions of at least 25 °C and at least 60% relative humidity. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the pharmaceutical composition has a disintegration time of 4 s or less for at least six months under storage conditions of at least 30 °C and at least 65% relative humidity. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein the pharmaceutical composition has a disintegration time of 4 s or less for at least six months under storage conditions of at least 40 °C and at least 75% relative humidity. 16. A pharmaceutical composition according to any one of claims 1-15, wherein the API comprises ibuprofen. 17. A method for preparing a pharmaceutical composition, comprising: coating ibuprofen with a first coating material to form coated ibuprofen, wherein the first coating material comprises one or more deformable components containing wax; applying mechanical stress to the coated ibuprofen to deform one or more deformable components; coating ibuprofen with a second coating material containing silicon dioxide; applying mechanical stress to embed the second coating material onto the first ibuprofen coated coating material; after introducing 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 the first coating material not associated with the coated ibuprofen; forming a pharmaceutical suspension containing double-coated ibuprofen and a matrix solution or suspension; dosing the pharmaceutical suspension into a form; and sublimation drying of a dosed pharmaceutical suspension in a form to form a pharmaceutical composition. 18. The method of claim 17, wherein sieving the coated ibuprofen comprises passing the coated ibuprofen through a device comprising two or more sieves. 19. The method according to claim 17 or 18, wherein sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 75 μm or more. 20. The method according to any one of claims 17-19, wherein sieving the coated ibuprofen comprises sieving the coated ibuprofen to an average particle size of 200 µm or less. 21. A pharmaceutical composition according to any one of claims 1-16, wherein silicon dioxide provides a slower release rate of API compared to the release rate of API without silicon dioxide.

Images