Minimizing agglomeration of drug particle coating material during storage to stabilize disintegration times of pharmaceutical products

Abstract

This document provides pharmaceutical compositions and methods for preparing pharmaceutical compositions using solvent-free mixing methods. Excess coating material unbound to coated API particles can be removed by a sieving process. The coating and stoichiometric ratios can also be optimized to minimize the amount of excess unbound coating material. Specifically, the coating ratio and / or stoichiometric ratio can be used to minimize the residual amount of excess unbound coating material, thereby minimizing the aggregation of the coating material during storage. In some embodiments, a pharmaceutical composition is provided comprising: 65-85% w / w API particles; 15-30% w / w coating material coating the API particles; and 3-15% w / w matrix surrounding the coated API particles, wherein the pharmaceutical composition has a disintegration time of less than 10 seconds for at least six months under storage conditions of at least 25°C and at least 60% relative humidity.

Description

[Technical Field] This invention relates to a method for coating active pharmaceutical ingredient (API) particles, and more specifically to a method for minimizing excess coating material to prevent the coated material from agglomerating during storage in a lyophilized orally disintegrating form. [Previous Technology] Pharmaceutical compositions typically comprise both an active pharmaceutical ingredient (API) and one or more inactive ingredients. The active API is biologically active and designed to directly affect a patient's symptoms, diseases, conditions, and / or pain. Conversely, the inactive ingredients of a pharmaceutical composition are pharmaceutically inert and can be used for various purposes, including but not limited to improving long-term stability, filling or diluting solid formulations, promoting drug absorption, adjusting the viscosity of liquid formulations, enhancing solubility, and / or aiding in the manufacture of the pharmaceutical composition. Additionally, some inactive ingredients can be used to mask the taste of APIs. Many APIs are known to exhibit unpleasant sensory properties when allowed to dissolve in the mouth, such as bitterness, burning, and numbness. For example, some orally administered pharmaceutical compositions are designed to disperse in the mouth for administration without water and are targeted at pediatric patients, elderly patients, animal patients, and / or other types of patients with swallowing difficulties. For these types of orally administered pharmaceutical compositions, inactive ingredients can be used to form a "functional coating" to mask the taste of the API. For example, inactive ingredients can be used to mask the taste of APIs by creating a functional coating surrounding the API particles through wet or dry coating, thereby preventing the API from being released in the mouth. In wet particle coating, 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 then be sprayed onto the surface of the API particles to form a film coating by the evaporation of the solvent or water. Examples of wet particle coating techniques include microencapsulation, fluidized bed coating, spray drying, and pan coating. In dry particle coating (also known as solvent-free coating), API particles are physically coated with fine particles of inactive ingredients (polymers and additives) to form a particle complex. Examples of dry particle coating include thermal melt coating, supercritical coating, compression coating, and electrostatic coating. API particles coated with taste-masking inactive ingredients can provide a more pleasant experience for patients with swallowing difficulties or those sensitive to tastes that would otherwise lead to a negative patient experience and poor compliance. For example, dry, solvent-free mixing methods can use high-energy vibration or acoustic resonance to mix APIs with inactive ingredients. Furthermore, coating API particles with a functional coating can temporarily delay the release of the API into the patient's mouth during the dispersion of the pharmaceutical composition, while still allowing at least 90% of the API that would be released without the coating to be released from the functionally coated API for absorption within an appropriate amount and time. Coating APIs with taste-masking inactive ingredients allows control over the dissolution rate of the coated API particles, ensuring that most of the API is not released until after the coated API particles have passed through the patient's stomach. [Summary of the Invention] Methods are provided for minimizing the aggregation of coating materials for coated API particles prepared using various mixing methods. API particles coated using conventional mixing methods often experience excessive aggregation of the coating material, particularly during storage. Aggregation of the coating material can reduce the stability of pharmaceutical products over time. For example, if a pharmaceutical product contains agglomerated coating material, its disintegration time can increase over time. Increased disintegration time and / or decreased dissolution rate imply an unstable pharmaceutical product. An unstable pharmaceutical product can lead to a shorter shelf life than desired. Therefore, the provided embodiments can help minimize the aggregation of coating materials in coated API particles to improve the stability of pharmaceutical products during storage and increase their shelf life. For example, the method includes removing excess coating material from the coated API particles to minimize the possibility of particle agglomeration. Specifically, the provided method includes sieving the coated API particles so that the final pharmaceutical product is adequately surrounded by a dry matrix, thereby minimizing any agglomeration of the coating particles during storage. The pharmaceutical composition provides a relatively stable disintegration time and dissolution rate over time. In some embodiments, a pharmaceutical composition is provided comprising: 65-85% w / w API particles; 15-30% w / w coating material coating the API particles; and 3-15% w / w matrix surrounding the coated API particles, wherein the pharmaceutical composition has a disintegration time of less than 10 seconds for at least six months under storage conditions of at least 25°C and at least 60% relative humidity. In some embodiments, the coating material comprises a first coating material and a second coating material, and the pharmaceutical composition comprises 10-30% w / w of the first coating material and 0.5-10% w / w of the second coating material. In some embodiments, the first coating material comprises wax. In some embodiments, the second coating material comprises silicon dioxide. In some embodiments of the pharmaceutical composition, the pharmaceutical composition has a disintegration time of less than 10 seconds for at least six months under storage conditions of at least 30°C and at least 65% relative humidity. In some embodiments of the pharmaceutical composition, the pharmaceutical composition has a disintegration time of less than 10 seconds for at least six months under storage conditions of at least 40°C and at least 75% relative humidity. In some embodiments of the pharmaceutical composition, the API particles comprise one or more of an anti-inflammatory drug, analgesic, antipsychotic, antiemetic, laxative, antidiarrheal, antihistamine, or antidepressant. In some embodiments of the pharmaceutical composition, the coating material comprises one or more of silicon dioxide as a protectant or flow aid. In some embodiments of the pharmaceutical composition, the coating material comprises wax. In some embodiments of the pharmaceutical composition, the coating material comprises one or more of carnauba wax, candelilla wax, or a synthetic wax. In some embodiments of the pharmaceutical composition, the coating ratio for combining API particles and coating material comprises 5-85% w / w coating material and 15-95% w / w uncoated API particles. In some embodiments of the pharmaceutical composition, the matrix comprises a matrix forming agent and a structure forming agent. In some embodiments of the pharmaceutical composition, the matrix forming agent comprises one or more of a water-soluble material, a water-dispersible material, a polypeptide, a polysaccharide, polyvinyl alcohol, polyvinylpyrrolidone, and gum arabic. In some embodiments of the pharmaceutical composition, the matrix forming agent comprises a polypeptide. In some embodiments of the pharmaceutical composition, the polypeptide comprises gelatin. In some embodiments of the pharmaceutical composition, the structural forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin. In some embodiments of the pharmaceutical composition, the structural forming agent comprises mannitol. In some embodiments, a pharmaceutical composition is provided, which is prepared by a method comprising the following steps: coating API particles with a first coating material to form coated API particles, wherein the coating material comprises one or more deformable components; applying mechanical stress to the coated API particles to deform the one or more deformable components; coating the coated API particles with silicon dioxide; applying mechanical stress to embed the silicon dioxide in the coated API particles; sieving the coated API particles to remove excess coating material, wherein the excess coating material includes coating material not bound to the coated API particles; mixing the coated API particles into a matrix solution / suspension to form a pharmaceutical suspension; and metering the pharmaceutical suspension into a mold, wherein the pharmaceutical composition has a disintegration time of less than 10 seconds for at least six months under storage conditions of at least 25°C and at least 60% relative humidity. In some embodiments of the pharmaceutical composition, the stoichiometric ratio of coated API particles to matrix solution / suspension comprises 5-60% w / w coated API particles to 40-95% w / w matrix solution / suspension. In some embodiments of the pharmaceutical composition, the coating ratio of API particles to coating material comprises 5-85% w / w coating material and 15-95% w / w uncoated API particles. In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises freezing a stoichiometric suspension at sub-zero conditions and freeze-drying to form a lyophilized pharmaceutical composition. In some embodiments of the pharmaceutical composition, the pharmaceutical composition has a disintegration time of less than 10 seconds for at least six months under storage conditions of at least 30°C and at least 65% relative humidity. In some embodiments of the pharmaceutical composition, the pharmaceutical composition has a disintegration time of less than 10 seconds for at least six months under storage conditions of at least 40°C and at least 75% relative humidity. In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises 65-85% w / w API particles. In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises 15-30% w / w coating material. In some embodiments of the pharmaceutical composition, the pharmaceutical composition comprises 3-15% w / w matrix. In some embodiments of the pharmaceutical composition, the method for preparing the pharmaceutical composition comprises sieving uncoated API particles. In some embodiments of the pharmaceutical composition, sieving coated API particles comprises passing the coated API particles through a device comprising two or more sieves. In some embodiments of the pharmaceutical composition, sieving coated API particles comprises sieving the coated API particles to an average particle size of 75 µm or larger. In some embodiments of the pharmaceutical composition, sieving coated API particles comprises sieving the coated API particles to an average particle size of 200 µm or smaller.In some embodiments of the pharmaceutical composition, the API particles comprise one or more of an anti-inflammatory drug, analgesic, antipsychotic, antiemetic, laxative, antidiarrheal, antihistamine, or antidepressant. In some embodiments of the pharmaceutical composition, the coating material comprises one or more of silicon dioxide as a protective coating or flow aid. In some embodiments of the pharmaceutical composition, one or more deformable components of the coating material comprise wax. In some embodiments of the pharmaceutical composition, the wax comprises one or more of carnauba wax, candelilla wax, or synthetic wax. In some embodiments of the pharmaceutical composition, the matrix comprises a matrix forming agent and a structure forming agent. In some embodiments of the pharmaceutical composition, the matrix forming agent comprises one or more of a water-soluble material, a water-dispersible material, a polypeptide, a polysaccharide, polyvinyl alcohol, polyvinylpyrrolidone, and gum arabic. In some embodiments of the pharmaceutical composition, the matrix forming agent comprises a polypeptide. In some embodiments of the pharmaceutical composition, the polypeptide comprises gelatin. In some embodiments of the pharmaceutical composition, the structure forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin. In some embodiments of the pharmaceutical composition, the structural forming agent comprises mannitol. In some embodiments, a method of treating a patient is provided, the method comprising administering a therapeutic amount of a pharmaceutical composition to the patient. In some embodiments of the method, the patient is a human. In some embodiments, a method for preparing a pharmaceutical composition is provided, the method comprising: coating API particles with a first coating material to form coated API particles, wherein the coating material comprises one or more deformable components; applying mechanical stress to the coated API particles to deform the one or more deformable components of the coating material to form a continuous film layer on the surface of the API particles; coating the coated API particles with silicon dioxide to form a second coating by applying mechanical stress to partially embed or embed the silicon dioxide in a deformable coating; sieving the coated API particles to remove excess coating material; mixing the coated API particles into a matrix solution / suspension to form a pharmaceutical suspension; and metering the pharmaceutical suspension into a mold. In some embodiments of the method, the metering ratio for combining the coated API particles to the matrix solution / suspension comprises 5-60% w / w coated API particles to 40-95% w / w matrix solution / suspension. In some embodiments of the method, the coating ratio for combining API particles with a coating material comprises 5-85% w / w coating material and 15-95% w / w uncoated API particles. In some embodiments of the method, the method comprises freezing a metered suspension at sub-zero temperatures and freeze-drying it to form a lyophilized pharmaceutical composition. In some embodiments of the method, the method comprises sieving uncoated API particles. In some embodiments of the method, sieving coated API particles comprises passing the coated API particles through a device comprising two or more sieves. In some embodiments of the method, sieving coated API particles comprises sieving the coated API particles to an average particle size of 75 µm or larger. In some embodiments of the method, sieving coated API particles comprises sieving the coated API particles to an average particle size of 200 µm or smaller. In some embodiments of the method, the API particles comprise one or more of an anti-inflammatory drug, analgesic, antipsychotic, antiemetic, laxative, antidiarrheal, antihistamine, or antidepressant. In some embodiments of the method, the coating material comprises silicon dioxide as one or more of a protective coating or flow aid. In some embodiments of the method, one or more deformable components of the coating material comprise wax. In some embodiments of the method, the wax comprises one or more of carnauba wax, candelilla wax, or synthetic wax. In some embodiments of the method, the matrix comprises a matrix forming agent and a structure forming agent. In some embodiments of the method, the matrix forming agent comprises one or more of a water-soluble material, a water-dispersible material, a polypeptide, a polysaccharide, polyvinyl alcohol, polyvinylpyrrolidone, and gum arabic. In some embodiments of the method, the matrix forming agent comprises a polypeptide. In some embodiments of the method, the polypeptide comprises gelatin. In some embodiments of the method, the structure forming agent comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin. In some embodiments of the method, the structure forming agent comprises mannitol.

Implementation Method

Claims

1. A method for preparing a pharmaceutical composition, comprising: coating API particles with a coating material comprising wax at a coating ratio of 22.5:77.5 to 30:70 to form coated API particles, wherein the API particles comprise ibuprofen, and the coating ratio is the ratio of the amount of coating material to the amount of uncoated API; sieving the coated API particles to remove excess coating material, wherein the excess coating material comprises coating material not bound to the coated API particles; The coated API particles are mixed in a matrix solution / suspension at a stoichiometric ratio of 30:70 to 50:50 to form a pharmaceutical suspension, wherein the matrix solution / suspension contains a matrix forming agent and a structure forming agent, wherein the matrix forming agent contains one or more of gelatin, hydrolyzed polydextrose, dextrin, alginate, polyvinyl alcohol, polyvinylpyrrolidone, and gum arabic, and the structure forming agent contains one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin, and the stoichiometric ratio is the ratio of the amount of coated API to the amount of matrix solution / suspension; the pharmaceutical suspension is metered into a mold; and the metered suspension is frozen at sub-zero temperature and freeze-dried to form a lyophilized pharmaceutical composition, wherein the lyophilized pharmaceutical composition has a disintegration time of less than 15 seconds for at least one or two months under storage conditions of 40°C and 75% relative humidity.

2. The method of claim 1 further includes sieving uncoated API particles.

3. The method of claim 1, wherein sieving the coated API particles comprises passing the coated API particles through a device comprising two or more sieves.

4. The method of claim 1, wherein sieving the coated API particles comprises sieving the coated API particles to an average particle size of 75 µm or larger.

5. The method of claim 4, wherein sieving the coated API particles comprises sieving the coated API particles into an average particle size of 200 µm or less.

6. The method of claim 1, wherein the coating material comprises silicon dioxide as one or more of a protective coating or a flow aid.

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