Minimizing aeration of suspensions during in-line mixing

Abstract

A pharmaceutical composition and a method for preparing the pharmaceutical composition are provided that can minimize aeration of pharmaceutical suspensions during the production process. The pharmaceutical composition includes a plurality of API particles, a coating material encapsulating each API particle of the plurality of API particles, and a matrix solution / suspension including a matrix-forming agent, a structure-forming agent, and an anti-aeration agent.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 809,293, filed February 22, 2019, the entire contents of which are incorporated herein by reference.

[0002] This relates to compositions and methods for preparing compositions that can minimize aeration of pharmaceutical suspensions of hydrophobic particles, and more particularly to compositions and methods for preparing compositions that can minimize aeration of pharmaceutical suspensions of coated active pharmaceutical ingredients (APIs) for improved dose weight accuracy while maintaining the integrity of the functional coating on the API particles. [Background technology]

[0003] A pharmaceutical composition typically contains both an active pharmaceutical ingredient as well as one or more inactive ingredients. The active pharmaceutical ingredient (API) is biologically active and is designed to directly affect a patient's symptoms, disease, disorder, and / or illness. On the other hand, the inactive ingredient(s) of a pharmaceutical composition are pharmacologic inactive and may be used for a variety of purposes, including, but not limited to, improving long-term stability, filling or diluting solid formulations, promoting drug absorption, adjusting the viscosity of liquid formulations, improving solubility, and / or aiding in the manufacture of the pharmaceutical composition.

[0004] One type of pharmaceutical composition is an orally disintegrating tablet (ODT). ODTs are pharmaceutical compositions targeted at pediatric patients, geriatric patients, veterinary patients, and / or other types of patients who may have difficulty swallowing. For these types of orally administered pharmaceutical compositions, inactive ingredients can be used to mask the taste of the API.

[0005] Coatings can be used to mask the taste of pharmaceutical compositions by coating tablets containing the API or by directly coating the API particles themselves. Inactive ingredients may be used to mask the taste of the API by wet or dry coating the API to produce a functional coating that surrounds the API particles and prevents their release in the oral cavity. In wet particle coating, the inactive ingredients (polymers and additives) are dissolved or dispersed in a solvent or water to form a suspension or solution. This suspension or solution can be sprayed onto the surface of the API particles and a coating film is formed by evaporation of the solvent or water. Examples of techniques for wet particle coating include microencapsulation, fluid bed coating, solvent evaporation, spray drying, pan coating, etc. In dry particle coating (also called solventless coating), API particles are mechanically coated with fine particles of inactive ingredients (polymers and additives) to form a particle composite. Examples of dry particle coating include hot melt coating, supercritical coating, impaction coating, electrostatic coating, etc. API particles coated with taste-masking inactive ingredients can provide a more comfortable experience for patients who have difficulty swallowing or have taste sensitivities that would otherwise result in a negative patient experience and poor compliance, especially for pharmaceutical compositions that dissolve or disintegrate in the oral cavity. However, many of the materials used to coat APIs are hydrophobic. Thus, coated API particles are hydrophobic.

[0006] To accurately dispense a pharmaceutical composition into small administrable forms, hydrophobically coated API particles can be placed in a matrix solution / suspension to form a pharmaceutical suspension. Mixing the API to form a pharmaceutical suspension allows for improved dosing accuracy. Often, this pharmaceutical suspension containing hydrophobically coated API particles is dosed into a mold, dried, and the molded article can then be transferred, for example, to a bottle. However, handling such pharmaceutical compositions can increase the risk of damage and contamination.

[0007] Therefore, many API suspensions today are instead dosed into preformed blister packs. Preformed blister packs eliminate one of the handling steps mentioned above. Instead of dosing into a mold and then transferring the molded part to a bottle for packaging, the pharmaceutical suspension can be dosed into a preformed blister pack that the manufacturer can dry and then seal and package. Thus, the preformed blister pack functions as both a mold and a package in which the pharmaceutical composition can be stored.

[0008] Compositions and methods for preparing compositions are provided that can minimize aeration of hydrophobic API particles in pharmaceutical suspensions. For example, hydrophobic coated API particles can be mixed into a matrix solution / suspension to form a pharmaceutical suspension that can be accurately dosed into a mold to form a solid pharmaceutical composition (i.e., an article, tablet, etc.) for administration to a patient. However, due to the hydrophobicity of the coated API particles, the coated API particles resist dispersion into the matrix solution / suspension. This can therefore cause air to be entrained with the pharmaceutical suspension, also known as aeration. Entrapped air, or aeration of the pharmaceutical suspension, can cause phase separation of the coated API particles in the pharmaceutical suspension, resulting in a non-homogeneous pharmaceutical suspension. Aeration and non-homogeneous pharmaceutical suspensions can result in poor dose weight accuracy of pharmaceutical suspensions containing hydrophobic API particles administered into preformed blister packs and poor content uniformity in the finished product (i.e., pharmaceutical composition). Summary of the Invention [Problem to be solved by the invention]

[0009] Conventional anti-aeration and / or mechanical means to minimize aeration have not been found to be successful due to the high viscosity of pharmaceutical suspensions. For example, minimizing aeration can be achieved by applying a vacuum to pharmaceutical suspensions, but depending on the composition and further processing requirements, this approach may not be appropriate. In particular, viscous suspensions "hold" trapped air, so applying a vacuum to pharmaceutical suspensions may cause the suspension to rise. Volatile formulation components may also be lost during vacuum processing. Furthermore, conventional anti-aeration agents such as ethanol or simethicone emulsions are similarly ineffective in preventing suspension aeration. [Means for solving the problem]

[0010] Thus, the compositions and methods provided herein minimize aeration of pharmaceutical suspensions containing hydrophobically coated API particles, improve pharmaceutical suspension homogeneity, and increase dose weight accuracy. Specifically, provided embodiments can include matrix solutions / suspensions that include chemical compounds that include terpenes and / or terpinols. In some embodiments, the matrix solutions / suspensions can include the terpene limonene. By introducing chemical compounds that include terpenes such as limonene, the hydrophobically coated API particles can be more easily incorporated into the matrix solution / suspension, minimizing overall aeration of the pharmaceutical suspension.

[0011] The solutions, suspensions, and compositions provided herein are described with respect to hydrophobic coated API particles.However, the solutions, suspensions, and compositions provided herein, and the methods for preparing the solutions, suspensions, and compositions, can be used to minimize the aeration of any hydrophobic material that may be mixed into pharmaceutical suspension.For example, other types of compositions may be mixed into suspension compositions according to some embodiments.

[0012] In some embodiments, a method of making a pharmaceutical composition is provided, the method comprising: providing a matrix solution / suspension comprising a matrix forming agent, a structure forming agent, an anti-aeration agent, and a solvent; mixing a plurality of hydrophobic particles into the matrix solution / suspension to form a pharmaceutical suspension; and administering the pharmaceutical suspension into a preformed blister pack, wherein the dispensed or dosed weight of the administered pharmaceutical suspension is within 10.0 percent of the target dose weight. In some embodiments of the method, the dispensed weight percentage of the administered pharmaceutical suspension is within 5.0 percent of the target dose weight. In some embodiments of the method, the dispensed weight of the administered pharmaceutical suspension is within 2.5 percent of the target dose weight. In some embodiments of the method, the dispensed weight of the administered pharmaceutical suspension is within 1.0 percent of the target dose weight. In some embodiments of the method, the plurality of hydrophobic particles comprises a coated active pharmaceutical ingredient (API). In some embodiments of the method, the coated API comprises one or more of an anti-inflammatory agent, an analgesic agent, an antipsychotic agent, an antiemetic agent, a laxative agent, an antidiarrheal agent, an antihistamine agent, or an antidepressant agent. In some embodiments of the method, the composition of the functionally coated API comprises 30-90% w / w of the API. In some embodiments of the method, the matrix solution / suspension comprises a viscosity modifier. In some embodiments of the method, the viscosity modifier comprises xanthan gum. In some embodiments of the method, mixing the plurality of hydrophobic particles in the matrix solution / suspension comprises in-line mixing at 15-20 degrees Celsius. In some embodiments of the method, the anti-aeration agent comprises one or more of a terpene or a terpinol. In some embodiments of the method, the anti-aeration agent comprises a liquid flavor. In some embodiments of the method, the anti-aeration agent comprises a liquid flavor comprising limonene. In some embodiments of the method, the anti-aeration agent comprises one or more of an orange flavor, a lemon flavor, a grapefruit flavor, a lime flavor, a strawberry flavor, or a peppermint flavor. In some embodiments of the method, the matrix solution / suspension or pharmaceutical suspension comprises 0.1-1.5% w / w anti-aeration agent.In some embodiments of the method, the matrix solution / suspension or pharmaceutical suspension comprises 2.0-5.0% w / w of a matrix-forming agent. In some embodiments of the method, the matrix solution / suspension or pharmaceutical suspension comprises 1.0-5.0% w / w of a structure-forming agent.

[0013] In some embodiments, a pharmaceutical composition is provided, the pharmaceutical composition being prepared by a process comprising providing a matrix solution / suspension comprising a matrix forming agent, a structure forming agent, an anti-aeration agent, and a solvent, mixing a plurality of hydrophobic particles into the matrix solution / suspension to form a pharmaceutical suspension, and administering the pharmaceutical suspension into a preformed blister pack, wherein the dispensed weight percentage of the administered pharmaceutical suspension is within 10.0 percent of the target dose weight. In some embodiments of the pharmaceutical composition, the dispensed weight of the administered suspension is within 5.0 percent of the target dose weight. In some embodiments of the pharmaceutical composition, the dispensed weight of the administered suspension is within 2.5 percent of the target dose weight. In some embodiments of the pharmaceutical composition, the dispensed weight of the administered suspension is within 1.0 percent of the target dose weight. In some embodiments of the pharmaceutical composition, the plurality of hydrophobic particles comprises a coated active pharmaceutical ingredient (API). In some embodiments of the pharmaceutical composition, the coated API comprises one or more of one or more of an anti-inflammatory agent, an analgesic agent, an antipsychotic agent, an antiemetic agent, a laxative agent, an antidiarrheal agent, an antihistamine agent, or an antidepressant agent. In some embodiments of the pharmaceutical composition, the composition of the functionally coated API comprises 30-90% w / w of the API. In some embodiments of the pharmaceutical composition, the matrix solution / suspension comprises a viscosity modifier. In some embodiments of the pharmaceutical composition, the viscosity modifier comprises xanthan gum. In some embodiments of the pharmaceutical composition, mixing the plurality of hydrophobic particles in the matrix solution / suspension comprises in-line mixing at 15-20 degrees Celsius. In some embodiments of the pharmaceutical composition, the anti-aeration agent comprises one or more of a terpene or a terpinol. In some embodiments of the pharmaceutical composition, the anti-aeration agent comprises a liquid flavoring. In some embodiments of the pharmaceutical composition, the anti-aeration agent comprises a liquid flavoring comprising limonene. In some embodiments of the pharmaceutical composition, the anti-aerators include one or more of orange flavor, lemon flavor, grapefruit flavor, lime flavor, strawberry flavor, or peppermint flavor.In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises 1-5% w / w of an anti-aeration agent. In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises 3-10% w / w of a matrix forming agent. In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises 3-10% w / w of a structure forming agent.

[0014] In some embodiments, a method of treating a patient is provided, the method comprising administering to the patient a pharmaceutical composition. In some embodiments of the method, the patient is a human.

[0015] In some embodiments, a pharmaceutical composition is provided, the pharmaceutical composition comprising a plurality of API particles, a coating material encapsulating each API particle of the plurality of API particles, a matrix forming agent, a structure forming agent, and an anti-aeration agent. In some embodiments of the pharmaceutical composition, the pharmaceutical composition is formed by creating a matrix solution / suspension comprising a matrix forming agent, a structure forming agent, and an anti-aeration agent. In some embodiments of the pharmaceutical composition, the plurality of API particles comprises one or more of one or more of an anti-inflammatory agent, an analgesic agent, an antipsychotic, an antiemetic agent, a laxative, an antidiarrheal agent, an antihistamine, or an antidepressant. In some embodiments of the pharmaceutical composition, the matrix solution / suspension comprises a viscosity modifier. In some embodiments of the pharmaceutical composition, the viscosity modifier comprises xanthan gum. In some embodiments of the pharmaceutical composition, the anti-aeration agent comprises one or more of a terpene or a terpinol. In some embodiments of the pharmaceutical composition, the anti-aeration agent comprises a liquid flavor. In some embodiments of the pharmaceutical composition, the anti-aeration agent comprises a liquid flavor comprising limonene. In some embodiments of the pharmaceutical composition, the anti-aeration agent comprises one or more of orange flavor, lemon flavor, grapefruit flavor, lime flavor, strawberry flavor, or peppermint flavor. In some embodiments of the pharmaceutical composition, the functionally coated API composition comprises 30-90% w / w of the API. In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises 1-5% w / w of an anti-aeration agent. In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises 3-10% w / w of a matrix forming agent. In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises 3-10% w / w of a structure forming agent.

[0016] The invention will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0017]

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[0018] Exemplary embodiments of compositions formulated to minimize aeration of pharmaceutical suspensions comprising hydrophobically coated API particles are described herein. Methods of minimizing aeration of pharmaceutical suspensions comprising hydrophobically coated API particles are also provided. In some embodiments, the embodiments provided herein may include adding a chemical compound comprising a terpene and / or terpinol to the matrix solution / suspension. Specifically, the suspension embodiments provided herein may include a liquid flavor comprising a terpene and / or terpinol. In some embodiments, the liquid flavor(s) may include the terpene limonene. The addition of certain chemical compounds, specifically liquid flavors comprising limonene, can minimize aeration of the pharmaceutical suspension, increase the homogeneity of the pharmaceutical suspension, and improve dose weight accuracy when the pharmaceutical suspension is poured into a mold. As used herein, "dose weight accuracy" and related terms refer to the ability to accurately dispense a pharmaceutical suspension into a preformed mold. The dose weight accuracy of a pharmaceutical suspension may depend on several variables, including, but not limited to, uniformity, viscosity, chemical components, dosing equipment, etc.

[0019] As mentioned above, conventional anti-aeration and / or mechanical means to minimize aeration have not been found to be successful due to the high viscosity of pharmaceutical suspensions. For example, when a vacuum is applied to a suspension, the suspension height may increase because the viscous suspension "holds" the trapped air. Volatile formulation components may also be lost during vacuum processing. Furthermore, conventional anti-aeration agents such as ethanol or simethicone emulsions are similarly ineffective in preventing suspension aeration.

[0020] Thus, it has been discovered that some chemical compounds, particularly liquid flavors containing terpenes such as limonene and / or terpinol, can minimize aeration of pharmaceutical suspensions when hydrophobically coated API particles are mixed into the matrix solution / suspension. By minimizing aeration, the hydrophobically coated API particles are more efficiently and effectively dispersed throughout the pharmaceutical suspension. This increased dispersion can increase suspension homogeneity, dose weight accuracy, and content uniformity of the finished product.

[0021] In some embodiments, the coated API particles or pharmaceutical compositions may comprise 30.0-90.0% w / w of API. In some embodiments, the coated API particles or pharmaceutical compositions may comprise 40.0-85.0% w / w, 50.0-80.0% w / w, or 70.0-80.0% w / w of API. In some embodiments, the coated API particles or pharmaceutical compositions may comprise more than 40.0% w / w, more than 50.0% w / w, more than 60.0% w / w, more than 65% w / w, more than 70.0% w / w, more than 75.0% w / w, more than 80.0% w / w, or more than 85.0% w / w of API. In some embodiments, the coated API particles or pharmaceutical compositions may comprise less than 90.0% w / w, less than 85.0% w / w, less than 80.0% w / w, less than 75.0% w / w, less than 70.0% w / w, less than 60.0% w / w, less than 50.0% w / w, or less than 40.0% w / w of the API.

[0022] The compositions and methods provided for minimizing aeration of pharmaceutical suspensions according to the embodiments described herein may be used with hydrophobically coated API particles prepared by a solvent-free mixing process. Thus, some embodiments provided below are described below in the context of pharmaceutical suspensions comprising one or more hydrophobically coated API particles prepared by a solvent-free mixing process. However, one skilled in the art can readily recognize other applications of the disclosed methods for minimizing aeration of suspensions. For example, different mixing processes that can be used to coat or encapsulate APIs with inactive ingredients include 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.

[0023] As mentioned above, mixing hydrophobically coated API particles into a matrix solution / suspension can generate air trapped in the liquid, or bubbles. Because the coated API particles are hydrophobic, they generally have a low affinity for the matrix solution / suspension. Thus, instead of readily associating with and dispersing in the matrix solution / suspension, the hydrophobically coated API particles preferably associate with the trapped air. In many fluids, the air bubbles typically migrate to the surface of the fluid and disappear into the air above. However, because the hydrophobically coated API particles have an affinity for the trapped air, the hydrophobically coated API particles "hold" the air bubbles, thus preventing them from migrating to the surface and releasing into the air above the fluid. This causes the pharmaceutical suspension to be aerated. Aeration of the suspension can cause phase separation and therefore a non-homogeneous pharmaceutical suspension. Phase separation can also be exaggerated when exposed to shear forces introduced by a dosing pump. A non-homogeneous pharmaceutical suspension when passed through a dosing pump can cause the pump to seize, potentially leading to inaccurate dose weights, lack of uniformity across the finished product, and poor production efficiency due to stoppages.

[0024] Furthermore, pharmaceutical suspensions containing hydrophobically coated API particles may have high viscosity due to high loading of hydrophobically coated API particles (i.e., as much as 50% by weight of hydrophobically coated API particles). As mentioned above, entrapment of air in the suspension during in-line mixing of hydrophobically coated API particles into the suspension may further increase the viscosity of the suspension. Thus, phase separation and non-homogeneity of pharmaceutical suspensions not only adversely affect the dose weight accuracy and uniformity of the final product (i.e., pharmaceutical composition), but also adversely affect the increase in viscosity.

[0025] Interestingly, it has been found that certain chemical compounds can minimize the aeration of pharmaceutical suspensions containing hydrophobically coated API particles when added to a matrix solution / suspension. In particular, according to some embodiments provided herein, chemical compounds containing terpenes and / or terpinol can minimize the amount of trapped air in the suspension caused by in-line mixing of hydrophobically coated API particles into a matrix solution / suspension. For example, even at relatively low concentrations, a matrix solution / suspension containing a liquid flavor containing terpenes and / or terpinol can minimize the aeration of pharmaceutical suspensions. Specifically, it has been found that a matrix solution / suspension containing one or more liquid flavors including limonene can minimize the aeration in pharmaceutical suspensions during in-line mixing of hydrophobically coated API particles. Other chemical compounds containing terpenes and terpinol have also been shown to be successful in minimizing the aeration of suspensions. For example, chemical compounds containing terpenes such as limonene, carvone, humulene, taxadiene, and squalene may be suitable for minimizing the aeration of suspensions. Terpinol may also be a suitable anti-aeration agent. In some embodiments, pure terpenes and / or pure terpinol may be used as anti-aeration agents. In some embodiments, liquid flavors containing terpenes and / or terpinol may be used as anti-aeration agents. In some embodiments, other suitable chemical compounds containing terpenes and / or terpinol may be used as anti-aeration agents.

[0026] As used herein, "active pharmaceutical ingredient" or "API" refers to a pharmaceutical product that can be used in the diagnosis, cure, mitigation, treatment, or prevention of disease. Any API can be used for the purposes of this disclosure. Suitable APIs include, but are not limited to, analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigouts, antihypertensives, antimalarials, antimigraine, antimuscarinics, antineoplastics and immunosuppressants, antiprotamines, antipsychotics, antiemetics, antirheumatics, antithyroids, antivirals, anxiolytics, irritants, sedatives, hypnotics and neuroleptics, beta-blockers, antispasmodics ... These APIs include sedatives, cardiac inotropes, corticosteroids, cough suppressants, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonians, gastrointestinal agents, histamine receptor antagonists, laxatives, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritional agents, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, laxatives, sex hormones and contraceptives, spermicides, and stimulants, and combinations thereof. A list of specific examples of these APIs can be found in U.S. Pat. No. 6,709,669, which is incorporated herein by reference. If present, the API is present in the pharmaceutical formulation in an amount necessary to exhibit the required physiological effect established by clinical studies. One of ordinary skill in the art can easily determine the appropriate amount of API to include in a dosage form made according to the present disclosure. Furthermore, the compositions provided herein, and the methods of preparing the compositions, are not limited to the APIs listed above. The ventilation behavior described herein is independent of the API since the matrix solution / suspension interacts with the coating of the API and not with the API itself.

[0027] One challenge posed by some chemical compounds containing terpenes and / or terpinols, such as some liquid flavors, is that they tend to be relatively oily. As with traditional oil and water, these oily chemical compounds may not be easily dispersed in a matrix solution / suspension. However, as discussed below, a matrix solution / suspension according to an embodiment herein may include gelatin as a matrix forming agent. Gelatin is inherently a mild surfactant. A surfactant may reduce the surface tension between two materials. Thus, in some embodiments, the gelatin of the matrix solution / suspension may reduce the surface tension between the oily chemical compounds and the matrix solution / suspension. This allows the oily chemical compounds, such as liquid flavors, to be properly incorporated into the matrix solution / suspension.

[0028] Under normal processing conditions, without the use of chemical compounds containing terpenes and / or terpinol, the coating of the hydrophobically coated API particles will erode over time due to the shear forces required to mix the hydrophobically coated API particles into the matrix solution / suspension. However, there is a "processing window" of 2 hours or more during which the coating retains significant functionality. The exact time of this "processing window" varies from product to product and may depend on the composition of the components of the hydrophobically coated API particles, the composition of the matrix solution / suspension, the amount of materials used to prepare the hydrophobically coated API particles, the physicochemical properties of the API, and / or the mixing conditions. Unfortunately, in the presence of chemical compounds containing terpenes and / or terpinol, this "processing window" may be significantly reduced due to interactions between these chemical compounds and the coating of the hydrophobically coated API particles. These interactions may impair the functional properties of the coating. For example, interactions between liquid flavors and the coating of the hydrophobically coated API particles may impair any taste masking function of the coating. However, it has been discovered that there is a threshold chemical compound (i.e., liquid flavor) concentration below which the chemical compound will not significantly impair the coating, but will not reduce the "processing window" so much that the coating of the hydrophobically coated API particles is significantly eroded. Thus, this optimal amount of chemical compound, including terpenes and / or terpinols, sufficiently minimizes aeration of the suspension and results in a homogenous pharmaceutical suspension that can be accurately dosed into molds to obtain a uniform end product.

[0029] Furthermore, chemical compounds containing terpenes and / or terpinol, and specifically liquid flavors containing limonene, have the potential to lower the freezing point of the pharmaceutical suspension, which may result in melting defects in the product that is further processed by freeze-drying. In particular, limonene has a freezing point of -74°C. However, no melting defects have been observed during the preparation of the disclosed products, and therefore, at least some chemical compounds containing terpenes and / or terpinol do not affect the suspension, thereby adversely affecting downstream freezing and freeze-drying process steps. The absence of melting defects under the current circumstances is believed to be due to the high solids content of the pharmaceutical suspension, which helps to maintain the structure of the product, even in the presence of a freezing point depressant (i.e., limonene).

[0030] The matrix solutions / suspensions according to embodiments described herein may include matrix forming agents, structure forming agents, anti-aeration agents, viscosity modifiers, and / or solvents.

[0031] In some embodiments, the amount of the chemical compound containing terpene and / or terpinol (i.e., anti-aeration agent) in the matrix solution / suspension, pharmaceutical suspension, or pharmaceutical composition can be 0.001 - 5.0% w / w. In some embodiments, the amount of the chemical compound containing terpene and / or terpinol (i.e., anti-aeration agent) in the matrix solution / suspension, pharmaceutical suspension, or pharmaceutical composition can be 1 - 5% w / w, 1 - 4% w / w, 1 - 3% w / w, 1 - 2% w / w, 0.05 - 3.0% w / w, 0.1 - 2.0% w / w, or 0.5 - 1.0% w / w. In some embodiments, there is a chemical compound containing terpene and / or terpinol (i.e., anti-aeration agent) in the matrix solution / suspension, pharmaceutical suspension, or pharmaceutical composition that is more than 0.001% w / w, more than 0.01% w / w, more than 0.05% w / w, more than 0.1% w / w, more than 0.3% w / w, more than 0.5% w / w, more than 0.8% w / w, more than 1.0% w / w, more than 1.5% w / w, more than 2.0% w / w, more than 2.5% w / w, more than 3.0% w / w, more than 3.5% w / w, more than 4.0% w / w, or more than 4.5% w / w. In some embodiments, there is a chemical compound containing terpene and / or terpinol (i.e., anti-aeration agent) in the matrix solution / suspension, pharmaceutical suspension, or pharmaceutical composition that is less than 5.0% w / w, less than 4.5% w / w, less than 4.0% w / w, less than 3.5% w / w, less than 3.0% w / w, less than 2.5% w / w, less than 2.0% w / w, less than 1.5% w / w, less than 1.0% w / w, less than 0.8% w / w, less than 0.6% w / w, less than 0.3% w / w, or less than 0.1% w / w. In some embodiments, suitable anti-aeration agents 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.

[0032] The matrix former of the matrix solution / suspension according to some embodiments may comprise any water-soluble or water-dispersible material that is pharmacologically acceptable or inert towards the hydrophobically coated API particles. In some embodiments, the matrix former may be a polypeptide such as gelatin. Gelatin may be at least partially hydrolyzed (by heating in water). Other suitable matrix former materials include, but are not limited to, hydrolyzed dextrans, dextrins, and polysaccharides such as alginates, polyvinyl alcohols, polyvinylpyrrolidones, and / or acacia. In some embodiments, the amount of matrix former in the matrix solution / suspension or pharmaceutical suspension may be about 0.1-10% w / w. In some embodiments, the amount of matrix former in the matrix solution / suspension or pharmaceutical suspension may comprise 1.0-8.0% w / w or 2.0-5.0% w / w. In some embodiments, the amount of matrix in the matrix solution / suspension or pharmaceutical suspension may comprise more than 0.1% w / w, more than 0.5% w / w, more than 1.0% w / w, more than 2.0% w / w, more than 3.0% w / w, more than 4.0% w / w, more than 4.5% w / w, more than 5.0% w / w, or more than 8.0% w / w. In some embodiments, the amount of matrix forming agent in the matrix solution / suspension or pharmaceutical suspension may comprise less than 10% w / w, less than 8.0% w / w, less than 6.0% w / w, less than 5.0% w / w, less than 4.0% w / w, less than 3.0% w / w, less than 2.5% w / w, less than 2.0% w / w, less than 1.5% w / w, or less than 1.0% w / w. In some embodiments, the amount of matrix forming agent in the pharmaceutical composition can be about 3-15% w / w, about 4-10% w / w, or about 4-7% w / w. In some embodiments, the amount of matrix forming agent in the pharmaceutical composition may include greater than 0.1% w / w, greater than 0.5% w / w, greater than 1.0% w / w, greater than 2.0% w / w, greater than 3.0% w / w, greater than 4.0% w / w, greater than 5.0% w / w, greater than 6.0% w / w, greater than 7.0% w / w, greater than 8.0% w / w, greater than 9.0% w / w, greater than 10.0% w / w, greater than 11.0% w / w, greater than 12.0% w / w, greater than 13.0% w / w, or greater than 14.0% w / w.In some embodiments, the amount of the matrix former in the pharmaceutical composition may be less than 15% w / w, less than 14.0% w / w, less than 13.0% w / w, less than 12.0% w / w, less than 10.0% w / w, less than 9.0% w / w, less than 8% w / w, less than 7% w / w, less than 6% w / w, less than 5% w / w, or less than 4.0% w / w.

[0033] The structuring agent or bulking agent for the matrix solution / suspension according to some embodiments may contain sugar. For example, suitable structuring agents include, but are not limited to, mannitol, dextrose, lactose, galactose, glycine, cyclodextrin, or combinations thereof. The structuring agent can be used as a bulking agent in lyophilization to crystallize and provide structural robustness in the lyophilized form. In some embodiments, the amount of the structuring agent in the matrix solution / suspension or pharmaceutical suspension can be about 0.1 - 10% w / w. In some embodiments, the amount of the structuring agent in the matrix solution / suspension or pharmaceutical suspension may include 1.0 - 8.0% w / w or 2.0 - 5.0% w / w. In some embodiments, the amount of the structuring agent in the matrix solution / suspension or pharmaceutical suspension may include more than 0.1% w / w, more than 0.5% w / w, more than 1.0% w / w, more than 2.0% w / w, more than 3.0% w / w, more than 4.0% w / w, more than 4.5% w / w, more than 5.0% w / w, or more than 8.0% w / w. In some embodiments, the amount of the structuring agent in the matrix solution / suspension or pharmaceutical suspension may include less than 10% w / w, less than 8.0% w / w, less than 6.0% w / w, less than 5.0% w / w, less than 4.0% w / w, less than 3.0% w / w, less than 2.5% w / w, less than 2.0% w / w, less than 1.5% w / w, or less than 1.0% w / w. In some embodiments, the amount of the structuring agent in the pharmaceutical composition can be about 3 - 15% w / w, about 4 - 10% w / w, or about 4 - 7% w / w. In some embodiments, the amount of the structuring agent in the pharmaceutical composition may include more than 0.1% w / w, more than 0.5% w / w, more than 1.0% w / w, more than 2.0% w / w, more than 3.0% w / w, more than 4.0% w / w, more than 5.0% w / w, more than 6.0% w / w, more than 7.0% w / w, more than 8.0% w / w, more than 9.0% w / w, more than 10.0% w / w, more than 11.0% w / w, more than 12.0% w / w, more than 13.0% w / w, or more than 14.0% w / w.In some embodiments, the amount of structure forming agent in the pharmaceutical composition may comprise less than 15% w / w, less than 14.0% w / w, less than 13.0% w / w, less than 12.0% w / w, less than 10.0% w / w, less than 9.0% w / w, less than 8% w / w, less than 7% w / w, less than 6% w / w, less than 5% w / w, or less than 4.0% w / w.

[0034] In some embodiments, the matrix solution / suspension and pharmaceutical suspension may include a viscosity modifier. For example, the viscosity modifier according to the embodiments provided herein may include a vegetable gum such as xanthan gum, arginine, guar gum, or locust bean gum, a protein such as collagen or gelatin, a sugar such as agar, carboxymethylcellulose, pectin, or carrageenan, a starch such as arrowroot, corn starch, dogtooth violet starch, potato starch, sago, or tapioca, and / or other suitable viscosity modifier. In some embodiments, the amount of the viscosity modifier in the matrix solution / suspension, pharmaceutical suspension, or pharmaceutical composition may be 0-0.2% w / w or 0.01-0.1% w / w. In some embodiments, the amount of viscosity modifier in the matrix solution / suspension, pharmaceutical suspension, or pharmaceutical composition may be more than 0.01% w / w, more than 0.03% w / w, more than 0.05% w / w, more than 0.07% w / w, more than 0.1% w / w, more than 0.12% w / w, more than 0.15% w / w, or more than 0.17% w / w. In some embodiments, the amount of viscosity modifier in the matrix solution / suspension, pharmaceutical suspension, or pharmaceutical composition may be less than 0.2% w / w, less than 0.18% w / w, less than 0.15% w / w, less than 0.12% w / w, less than 0.1% w / w, less than 0.08% w / w, less than 0.06% w / w, or less than 0.03% w / w.

[0035] The solvent of the suspension / solution and the pharmaceutical suspension may be water, but the suspension / solution may also contain a co-solvent. In some embodiments, the solvent can be ethanol, alcohol, isopropanol, other lower alkanols, water (e.g., purified water), or combinations thereof. For example, suitable solvents and / or co-solvents may be alcohols such as tert-butyl alcohol. In some embodiments, the balance of the pharmaceutical formulation is the solvent (i.e., Q.S.100%).

[0036] 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 silicate, modified starches, preservatives, antioxidants, colorants, flavoring agents, pH adjusters, sweeteners, taste masking agents, and combinations thereof. Suitable colorants can include red, black, and yellow iron oxides, as well as FD&C dyes such as FD&C Blue No. 2 and FD&C Red No. 40, and combinations thereof. Suitable pH adjusters can 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 can include aspartame, acesulfame K, sucralose, and thaumatin, and combinations thereof. Suitable taste masking agents can include sodium bicarbonate, ion exchange resins, cyclodextrin-containing compounds, adsorbents or microencapsulating agents, and combinations thereof. Those skilled in the art can readily determine the suitable amounts of these various additional excipients as needed.

[0037] In some embodiments, pharmaceutical suspensions may be prepared by mixing the API with one or more coating materials at a temperature of 10-40, 15-25, or 15-20 degrees Celsius. In some embodiments, the materials may be mixed at a temperature of less than 40, less than 35, less than 30, less than 25, less than 20, or less than 15 degrees Celsius. In some embodiments, the materials may be mixed at a temperature of greater than 10, greater than 15, greater than 20, greater than 25, greater than 30, or greater than 35 degrees Celsius. In some embodiments, the materials may be mixed using a PharmaRAM II acoustic mixer, a RAM5 Pharma acoustic mixer, or a RAM 55 Pharma mixer (Resodyn Mixers).

[0038] The pharmaceutical composition may be prepared by dosing the pharmaceutical suspension into a preformed blister pack. In some embodiments, a freeze-dried orally disintegrating tablet may be prepared by dosing the pharmaceutical suspension into a blister pack. In some embodiments, the dosing pump pumps by volume, but the process is controlled by weight. Thus, to ensure content uniformity from one dosage form to the next, the dosing process may be controlled so that the volume-to-weight percentage of the administered pharmaceutical suspension or the weight of the dispensed pharmaceutical suspension is consistent. For example, the volume-to-weight percentage may be consistent 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 administered 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 0.25 percent of the target administered weight. Additionally, the viscosity of the suspension must be kept low enough to facilitate administration. As noted above, high viscosity suspensions can cause the pump to seize during administration.

[0039] In some embodiments, each dosage form of the pharmaceutical composition meets the content uniformity requirements of the United States Pharmacopoeia. In some embodiments, each dosage form of the pharmaceutical composition meets the product quality requirements of the United States Pharmacopoeia (e.g., volatile content, disintegration, tablet breaking force, dosage unit uniformity, etc.). EXAMPLES

[0040] The effectiveness of the chemical compounds, including terpenes and / or terpinols, in minimizing aeration can be determined in part by measuring the particle size of the hydrophobically coated API particles in the pharmaceutical suspension over time. If the chemical compounds are effective, the aeration of the suspension will be low enough that the particle size of the hydrophobically coated API particles will remain constant or will not decrease significantly over time. If they are not effective, the aeration of the pharmaceutical suspension will be higher than desired and the particle size of the hydrophobically coated API particles may decrease more substantially over time. The degree of aeration of the pharmaceutical suspension is assessed by measuring the foam height in the mixing vessel. The particle size of the functionally coated particles can be measured using laser diffraction, a particle analyzer such as a Malvern Mastersizer, or any other suitable means for analyzing particulates.

[0041] Example 1: A series of suspension mixtures were made by mixing the coated API in a matrix solution / suspension containing various levels of limonene, orange flavor, and strawberry flavor. The foam heights from these suspensions are summarized in Tables 1, 2, and 3, respectively. [Table 1] [Table 2] [Table 3]

[0042] The results in Tables 1 and 2 show that the addition of limonene and orange flavor at levels of 0.15% and above minimized aeration. Strawberry (Table 3) also reduced aeration, but not to the same extent.

[0043] Example 2: Figures 1, 2, and 3 show the particle size reduction (d10, d50, and d90, respectively) of hydrophobically coated API particles in pharmaceutical suspensions containing various concentrations of liquid orange flavor. Ibuprofen was used as a model API. A particle size expressed in terms of its d10 means that 10% of the particles in a given amount of sample are below the given particle size. Thus, the d50 particle size represents 50 percent of the particles in a given amount of sample are below the given particle size, and the d90 particle size represents 90 percent of the particles in a given amount of sample are below the given particle size. Specifically, Figures 3-5 show the test results of suspension formulations containing hydrophobically coated API and liquid orange flavor at concentrations including 0.0%, 0.15%, 0.45%, and 0.60% w / w, held for up to 6 hours with low shear mixing.

[0044] At concentrations of orange flavor up to 0.45% w / w (including 0.15% w / w), the reduction in d10, d50, and d90 particle size within the first 2 hours "processing window" is nearly similar to that of the suspension containing hydrophobically coated API particles without any liquid flavor (0% liquid flavor). However, at a concentration of 0.6% w / w liquid orange flavor, the coating of the hydrophobically coated API particles is easily removed and a rapid reduction in particle size is observed. Furthermore, at a concentration of 0.3% w / w liquid orange flavor, the aeration of the pharmaceutical suspension is low enough that there is little, if any, damage to the coating of the coated API particles and only a minimal reduction in the particle size of the hydrophobically coated API particles.

[0045] Example 3: Figures 4, 5, and 6 provide data on the reduction in d10, d50, and d90 particle size of hydrophobically coated API particles, respectively, for a specific component, limonene, found in several liquid flavors. These tests were performed to explore the behavior of a specific component of liquid flavors, limonene, on hydrophobically coated API particles in suspension. Ibuprofen was used as a model API. Note that the concentration of limonene shown in the figures is significantly higher than the concentration of limonene that would be present if a liquid flavor were used. In Figures 6-8, pure limonene was used at concentrations of 0.25% w / w, 0.45% w / w, and 0.75% w / w and tested over a 24 hour period. As shown in all three figures, the 0.25% w / w limonene concentration had a much less detrimental effect on the coating of hydrophobically coated API particle size than the 0.45% w / w and 0.75% w / w limonene concentrations. Additionally, pharmaceutical suspensions tested with 0.25% w / w limonene contained sufficiently low amounts of aeration. Thus, these studies confirm that the limonene in the liquid orange flavor tested in Figures 3-5 is at least partially responsible for minimizing aeration of the pharmaceutical suspensions and subsequently eroding the coating of the hydrophobic coated API particles at relatively high amounts and / or relatively high exposure times.

[0046] Example 4: Figure 7 shows the test data for two different liquid flavors (strawberry and orange). The d10, d50, and d90 particle sizes of hydrophobically coated API particles were tested for both strawberry and orange liquid flavors. Both strawberry and orange liquid flavors contain limonene. Ibuprofen was used as the model API. As shown in the figure, both flavors behave similarly with respect to hydrophobically coated API particle size. The d10 particle size sample showed a greater amount of particle size reduction within the first two hours of testing than the d50 and d90 particle size samples. The d50 and d90 particle size samples showed less particle size reduction within the same two hours. However, this observation is consistent with the d10, d50, and d90 particle size data of the examples discussed above.

[0047] Furthermore, in all studies, it was observed that as the particle size of the hydrophobically coated API (ibuprofen) particles decreased, a distinct particle population comprising particles between 5 μm and 20 μm in size appeared and increased over time. These particles are believed to be non-deformed coating material particles embedded within the continuous coating material that was deformed by shear forces prior to coating erosion. Thus, as the coating erodes and the particle size of the hydrophobically coated API particles decreases, the population size of these smaller particles increases as the deformed coating material surrounding them erodes, and these non-deformed particles are released from the hydrophobically coated API particles.

[0048] Overall, these studies demonstrate that optimizing the amount of terpene limonene added to a pharmaceutical suspension containing hydrophobically coated API particles minimizes the amount of aeration in the suspension to allow for downstream processing while not adversely affecting the coating of the hydrophobically coated API particles (as determined by the particle size of the hydrophobically coated API particles).

[0049] The foregoing description has been set forth in terms of specific embodiments for purposes of illustration. However, the illustrative discussion above is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teachings. The embodiments were chosen and described in order to best explain the principles of the techniques and their practical application. In order to enable those skilled in the art to optimally utilize the techniques and various embodiments, with various modifications suited to the particular use contemplated.

[0050] Although the present disclosure and embodiments have been fully described with reference to the accompanying drawings, it should be noted that various changes and modifications will become apparent to those skilled in the art, and such changes and modifications should be understood to be included within the scope of the present disclosure and embodiments as defined by the appended claims.

Claims

1. 1. A method for producing a pharmaceutical composition, comprising: providing a matrix solution / suspension comprising a matrix former, a structuring agent, an anti-aeration agent which is a liquid flavor consisting of limonene only, and a solvent; mixing a plurality of hydrophobic particles into said matrix solution / suspension to form a pharmaceutical suspension comprising 0.15-0.3% by weight limonene, wherein aeration of the pharmaceutical suspension is reduced by a liquid flavor consisting solely of limonene; and and administering the pharmaceutical suspension into a preformed blister pack, wherein the dose weight of the administered pharmaceutical suspension is within 10% of a target dose weight; the matrix forming agent is selected from the group consisting of polypeptides, polysaccharides, polyvinyl alcohol, and polyvinylpyrrolidone; and The method of claim 1, wherein said structure-forming agent is selected from the group consisting of sugars.

2. 10. The method of claim 1, wherein the dose weight of the administered pharmaceutical suspension is within 5% of a target dose weight.

3. 10. The method of claim 1, wherein the dose weight of the administered pharmaceutical suspension is within 2.5% of a target dose weight.

4. The method of any one of claims 1 to 3, wherein the plurality of hydrophobic particles comprises a coated active pharmaceutical ingredient (API).

5. 5. The method of claim 4, wherein the coated API comprises one or more of an anti-inflammatory agent, an analgesic agent, an antipsychotic agent, an antiemetic agent, a laxative agent, an antidiarrheal agent, an antihistamine agent, or an antidepressant agent.

6. 6. The method according to claim 4 or 5, wherein the coated API comprises 30-90% by weight of API.

7. 7. The method of claim 6, wherein the pharmaceutical composition comprises 65-85% by weight of API.

8. 8. The method of any one of claims 1 to 7, wherein the matrix solution / suspension comprises a viscosity modifier selected from the group consisting of vegetable gums, proteins, sugars (but excluding vegetable gums), and carboxymethylcellulose.

9. The method of claim 8 , wherein the viscosity modifier comprises xanthan gum.

10. 10. The method of any one of claims 1 to 9, wherein mixing a plurality of hydrophobic particles in the matrix solution / suspension comprises in-line mixing at 15-20 degrees Celsius.

11. The method according to any one of claims 1 to 10, wherein the matrix solution / suspension or pharmaceutical suspension comprises 2.0 to 5.0% by weight of a matrix forming agent.

12. The method according to any one of claims 1 to 11, wherein the matrix solution / suspension or pharmaceutical suspension comprises 1.0 to 5.0% by weight of a structure-forming agent.

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