Process for preparing drug-containing particles coated with a laminated alumina coating and a silica coating

Abstract

The present disclosure relates to a coated particle having a drug-containing core and laminated alumina and silica coatings and a method of making the same. The coated particle has a modified drug release profile compared to the uncoated drug-containing core.

Description

Technical Field

[0001] This disclosure relates to a method for preparing coated particles comprising a drug-containing core and a laminate comprising alternating layers of alumina and silica. The laminated coating can be applied by vapor deposition. The coated particles have a modified drug release profile compared to uncoated drug-containing cores. Background Technology

[0002] The pharmaceutical industry is of great interest in developing improved formulations of active pharmaceutical ingredients (APIs). Formulations can affect the stability and bioavailability of APIs, among other characteristics. Formulations can also influence various aspects of pharmaceutical product (DP) manufacturing, such as ease of manufacturing and safety.

[0003] The drug release rate (dissolution rate) of a drug formulation is crucial because it can affect the rate and extent of drug absorption and its bioavailability. Controlled-release formulations can offer numerous benefits, including: 1) lower dosing frequency, 2) reduced side effects, 3) increased stability of blood drug levels, and 4) better patient compliance. While controlled-release formulations offer significant advantages, they may also have disadvantages, including the potential toxicity or biocompatibility of the materials used to control drug release and lower drug loading. There is a need for inert, biocompatible, mechanically strong controlled-release formulations that can achieve high drug loading. Summary of the Invention

[0004] This disclosure relates to a method for preparing a pharmaceutical composition by applying laminated alumina and silica coatings to a drug-containing core. The drug-containing core includes or is composed of a pharmaceutical product (i.e., an active pharmaceutical ingredient (API) as an organic compound). This disclosure also relates to coated particles comprising a drug-containing core encapsulated by laminated alumina and silica coatings.

[0005] This article describes a coated particle comprising a drug-containing core encapsulated by (1) one or more alumina encapsulation layers and (2) one or more silica encapsulation layers, wherein the drug-containing core contains an organic active pharmaceutical ingredient (API), the alumina encapsulation layers and the silica encapsulation layers alternate, and at least three encapsulation layers are present.

[0006] In various embodiments: each alumina coating layer independently has a thickness of about 1 nm to 5 nm or 1 nm to 10 nm; each silicon oxide coating layer independently has a thickness of about 1 nm to 5 nm or 1 nm to 10 nm; the drug-containing core has a Dv50 between 0.1 μm and 100 μm on a volume average; the outermost coating layer is an alumina coating layer; the outermost coating layer is a silicon oxide coating layer; the first coating layer adjacent to the drug-containing core is an alumina coating layer; the first coating layer adjacent to the drug-containing core is an alumina coating layer. The device comprises: a silicon dioxide coating layer; one or more alumina coating layers being continuous and conformal; one or more silicon dioxide coating layers being continuous and conformal; a drug-containing core having a Dv50 between 0.1 μm and 50 μm on a volume average; a drug-containing core having a Dv50 between 1 μm and 30 μm on a volume average; the alumina coating layer and the silicon dioxide coating layer together constituting 2 wt% to 10 wt% of the coated particles; the alumina coating layer and the silicon dioxide coating layer together constituting 1% to 5% of the coated particles. wt / wt; the coated particles comprise two or more alumina coating layers and two or more silica coating layers; the total thickness of the alumina and silica coating layers is approximately 1 nm to 50 nm; at least two silica coating layers are present; at least two alumina coating layers are present; at least three silica coating layers are present; at least three alumina coating layers are present; the total thickness of all coating layers is 5 nm to 50 nm; the coated particles have a slower API release rate compared to the API core containing the coated particles; the API release rate of the coated particles is at least 100% slower than the API release rate of the API core containing the coated particles; the API release rate of the coated particles is at least 100% slower than the API release rate of the API core containing the coated particles, wherein the drug release rate is determined by dissolving 100 mg of coated particles at 50 rpm in 900 ml of pH 6.8 solution at 37°C. The API release rate was measured in PBS buffer; the API release rate of the coated particles was at least 100% slower than that of the drug-containing core, wherein the API release rate was measured by dissolving 65 mg of coated particles in 900 ml of pH 7.2 PBS buffer at 37°C with stirring at 50 rpm; the coated particles had increased fluidity compared to the drug-containing core; the coated particles had increased wettability compared to the drug-containing core; the coated particles had an API release rate of approximately 30% to 90% of the API within 30 minutes; the coated particles had an API release rate of approximately 30% to 40% of the API within 30 minutes; and the coated particles had an API release rate of approximately 70% to 90% of the API within 30 minutes.

[0007] A method for preparing coated particles comprising a drug-containing core coated with (1) one or more alumina coating layers and (2) one or more silica coating layers is also described, wherein the drug-containing core contains an API, the method comprising the following sequential steps:

[0008] (a) Loading particles containing API into the chamber of the reactor;

[0009] (b) Apply the alumina coating by performing the following steps:

[0010] (b1) Applying vapor or gaseous aluminum precursor to particles in a reactor;

[0011] (b2) Use an inert gas to perform one or more pump-purge cycles;

[0012] (b3) Applying a vapor or gaseous oxidant to the particles in the reactor;

[0013] (b4) Using an inert gas to perform one or more pump-purge cycles; and

[0014] (b5) Repeat steps (b1) through (b4) at least once to provide an alumina coating;

[0015] (c) Apply the silicon oxide coating by performing the following steps:

[0016] (c1) Applying vapor or gaseous silicon precursor to particles in the reactor;

[0017] (c2) Use an inert gas to perform one or more pump-purge cycles;

[0018] (c3) Applying a vapor or gaseous oxidant to the particles in the reactor;

[0019] (c4) Using an inert gas to perform one or more pump-purge cycles; and

[0020] (c5) Repeat steps (c1) to (c4) at least once to provide a silicon oxide coating; and

[0021] (d) Repeat step (b) at least once after step (c).

[0022] A method for preparing coated particles comprising a drug-containing core coated with (1) one or more alumina coating layers and (2) one or more silica coating layers is also described, wherein the drug-containing core contains an API, the method comprising the following sequential steps:

[0023] (a) Loading particles containing API into the chamber of the reactor;

[0024] (b) Apply the silicon oxide coating by performing the following steps:

[0025] (b1) Applying vapor or gaseous silicon precursor to particles in a reactor;

[0026] (b2) Use an inert gas to perform one or more pump-purge cycles;

[0027] (b3) Applying a vapor or gaseous oxidant to the particles in the reactor;

[0028] (b4) Using an inert gas to perform one or more pump-purge cycles; and

[0029] (b5) Repeat steps (b1) to (b4) at least once to provide a silicon oxide coating;

[0030] (c) Apply the alumina coating by performing the following steps:

[0031] (c1) Applying vapor or gaseous aluminum precursor to particles in the reactor;

[0032] (c2) Use an inert gas to perform one or more pump-purge cycles;

[0033] (c3) Applying a vapor or gaseous oxidant (e.g., ozone) to the particles in the reactor;

[0034] (c4) Using an inert gas to perform one or more pump-purge cycles; and

[0035] (c5) Repeat steps (c1) to (c4) at least once to provide an alumina coating; and

[0036] (d) Repeat step (b) at least once after step (c).

[0037] In various embodiments of any method: step (c) is repeated after step (b); each of steps (b) and (c) is repeated two or more times to produce alternating silicon oxide and aluminum oxide coatings; at least two silicon oxide coatings and at least two aluminum oxide coatings are produced; steps (b1) to (b4) are performed at least four times to provide a first cycle, a second cycle, a third cycle, and a fourth cycle; some or all of the residual vapor or gaseous aluminum precursor is pumped out of the reactor before step (b3); some or all of the residual vapor or gaseous oxidant is pumped out of the reactor before step (c). Each alumina layer and each silicon oxide layer has a thickness ranging from 0.1 nm to 50 nm; steps (b1) to (b4) are performed at a temperature ranging from 25°C to 80°C; the oxidant is water or ozone; the particles are agitated during some or all of steps b1 to b5 and c1 to c5; the silicon oxide precursor is SiCl4 or 1,2-bis(diisopropylamino)disilane, and the alumina precursor is trimethylaluminum; the silicon oxide precursor is SiCl4, and water is the oxidant of the silicon oxide precursor; and the silicon oxide precursor is 1,2-bis(diisopropylamino)disilane, and ozone is the oxidant of the silicon oxide precursor.

[0038] A coated particle prepared by any of the aforementioned methods is also described.

[0039] Coated Particles

[0040] This disclosure provides coated particles comprising a drug core and laminated (e.g., alternating) alumina and silica coatings. The coated particles comprise a drug core, one or more alumina coatings, and one or more silica coatings. The coated particles are at least 70%, 80%, 90%, or 99% wt / wt API. Each alumina coating and each silica coating may be a continuous and conformal coating that completely encapsulates the particles. The elemental composition of the coated particles can be assessed by energy-dispersive X-ray spectroscopy (EDS) analysis. The coated particles may contain laminated alumina and silica coatings.

[0041] Each alumina coating may be approximately 1 nm to 5 nm or 1 nm to 10 nm thick. Each silicon oxide coating may be approximately 1 nm to 5 nm or 1 nm to 10 nm thick. In some cases, there are at least two (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) silicon oxide coatings and at least two (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) alumina coatings. For example, there may be: two silicon oxide coatings and two alumina coatings; two silicon oxide coatings and three alumina coatings; three silicon oxide coatings and two alumina coatings; three silicon oxide coatings and three alumina coatings; three silicon oxide coatings and four alumina coatings; four silicon oxide coatings and three alumina coatings; four silicon oxide coatings and four alumina coatings. The coating may have either silicon oxide or alumina as the innermost coating layer. The coating may have silicon dioxide or aluminum oxide as the outermost coating layer.

[0042] Each alumina coating may have a thickness in the range of 0.1 nm to 100 nm, 0.1 nm to 50 nm, 0.1 nm to 10 nm, 0.1 nm to 5 nm, 1 nm to 50 nm, 1 nm to 10 nm, or 1 nm to 5 nm. Each alumina coating may have a thickness greater than 0.1 nm, greater than 0.2 nm, greater than 0.3 nm, greater than 0.4 nm, greater than 0.5 nm, greater than 0.6 nm, greater than 0.7 nm, greater than 0.8 nm, greater than 0.9 nm, greater than 1 nm, greater than 2 nm, greater than 3 nm, greater than 4 nm, greater than 5 nm, greater than 6 nm, greater than 7 nm, greater than 8 nm, greater than 9 nm, greater than 10 nm, greater than 15 nm, greater than 20 nm, greater than 30 nm, greater than 40 nm, greater than 50 nm, or greater than 100 nm. Each alumina coating may have a thickness of less than 0.1 nm, less than 0.2 nm, less than 0.3 nm, less than 0.4 nm, less than 0.5 nm, less than 0.6 nm, less than 0.7 nm, less than 0.8 nm, less than 0.9 nm, less than 1 nm, less than 2 nm, less than 3 nm, less than 4 nm, less than 5 nm, less than 6 nm, less than 7 nm, less than 8 nm, less than 9 nm, less than 10 nm, less than 15 nm, less than 20 nm, less than 30 nm, less than 40 nm, less than 50 nm, or less than 100 nm. Each alumina coating may have a thickness between 1 nm and 10 nm. Each alumina coating may have a thickness between 1 nm and 5 nm.

[0043] Each silicon oxide coating may have a thickness in the range of 0.1 nm to 100 nm, 0.1 nm to 50 nm, 0.1 nm to 10 nm, 0.1 nm to 5 nm, 1 nm to 50 nm, 1 nm to 10 nm, or 1 nm to 5 nm. Each silicon oxide coating may have a thickness greater than 0.1 nm, greater than 0.2 nm, greater than 0.3 nm, greater than 0.4 nm, greater than 0.5 nm, greater than 0.6 nm, greater than 0.7 nm, greater than 0.8 nm, greater than 0.9 nm, greater than 1 nm, greater than 2 nm, greater than 3 nm, greater than 4 nm, greater than 5 nm, greater than 6 nm, greater than 7 nm, greater than 8 nm, greater than 9 nm, greater than 10 nm, greater than 15 nm, greater than 20 nm, greater than 30 nm, greater than 40 nm, greater than 50 nm, or greater than 100 nm. Each silicon oxide coating may have a thickness of less than 0.1 nm, less than 0.2 nm, less than 0.3 nm, less than 0.4 nm, less than 0.5 nm, less than 0.6 nm, less than 0.7 nm, less than 0.8 nm, less than 0.9 nm, less than 1 nm, less than 2 nm, less than 3 nm, less than 4 nm, less than 5 nm, less than 6 nm, less than 7 nm, less than 8 nm, less than 9 nm, less than 10 nm, less than 15 nm, less than 20 nm, less than 30 nm, less than 40 nm, less than 50 nm, or less than 100 nm. Each silicon oxide coating may have a thickness between 1 nm and 10 nm. Each silicon oxide coating may have a thickness between 1 nm and 5 nm.

[0044] The entire laminated alumina and silica coatings may have a thickness ranging from 0.1 nm to 100 nm, 0.1 nm to 50 nm, 0.1 nm to 10 nm, 0.1 nm to 5 nm, 1 nm to 50 nm, 1 nm to 10 nm, or 1 nm to 5 nm. The entire laminated alumina and silica coatings may have a thickness greater than 0.1 nm, greater than 0.2 nm, greater than 0.3 nm, greater than 0.4 nm, greater than 0.5 nm, greater than 0.6 nm, greater than 0.7 nm, greater than 0.8 nm, greater than 0.9 nm, greater than 1 nm, greater than 2 nm, greater than 3 nm, greater than 4 nm, greater than 5 nm, greater than 6 nm, greater than 7 nm, greater than 8 nm, greater than 9 nm, greater than 10 nm, greater than 15 nm, greater than 20 nm, greater than 30 nm, greater than 40 nm, greater than 50 nm, or greater than 100 nm. The entire laminated alumina and silicon oxide coatings can have thicknesses of less than 0.1 nm, less than 0.2 nm, less than 0.3 nm, less than 0.4 nm, less than 0.5 nm, less than 0.6 nm, less than 0.7 nm, less than 0.8 nm, less than 0.9 nm, less than 1 nm, less than 2 nm, less than 3 nm, less than 4 nm, less than 5 nm, less than 6 nm, less than 7 nm, less than 8 nm, less than 9 nm, less than 10 nm, less than 15 nm, less than 20 nm, less than 30 nm, less than 40 nm, less than 50 nm, or less than 100 nm. The entire laminated alumina and silicon oxide coatings can have thicknesses between 1 nm and 50 nm. The entire laminated alumina and silicon oxide coatings can have thicknesses between 1 nm and 25 nm.

[0045] The total amount of coating material (e.g., alumina and silica content) can be determined by thermogravimetric analysis (TGA). The coating structure and thickness can be determined by cross-sectional transmission electron microscopy (cross-sectional TEM) and energy-dispersive X-ray spectroscopy (EDS). The drug release profile (dissolution rate) of the coated particles can be determined by in vitro dissolution assays. The release curve (dissolution) of the coated particles can be determined by high-performance liquid chromatography (HPLC) analysis.

[0046] The composition of the coated particles can be assessed by thermogravimetric analysis (TGA%). The amount of inorganic residue components can be greater than 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, or 20% wt / wt of the coated particles. The amount of inorganic residue components may be less than 0.1%, less than 0.2%, less than 0.3%, less than 0.4%, less than 0.5%, less than 0.6%, less than 0.7%, less than 0.8%, less than 0.9%, less than 1%, less than 1.2%, less than 1.4%, less than 1.6%, less than 1.8%, less than 2%, less than 2.2%, less than 2.4%, less than 2.6%, less than 2.8%, less than 3%, less than 3.2%, less than 3.4%, less than 3.6%, less than 3.8%, less than 4%, less than 4.2%, less than 4.4%, less than 4.6%, less than 4.8%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 12%, less than 14%, less than 16%, less than 18%, or less than 20% wt / wt of the coated particles. The amount of inorganic residue components may be 0.1% to 20%, 0.5% to 10%, 1% to 10%, 1% to 5%, 2% to 5%, 1% to 4%, 1% to 3% or 2% to 4% wt / wt of the coated particles.

[0047] Wettability can be measured by measuring the contact angle. A smaller contact angle (less than 90°) indicates higher wettability, while a larger contact angle (greater than 90°) indicates lower wettability. The wettability of coated particles relative to uncoated particles (containing drug cores) can be at least 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 100%, greater than 110%, greater than 120%, greater than 130%, greater than 140%, greater than 150%, greater than 200%, greater than 300%, greater than 400%, and greater than 500%. The wettability of coated granules can be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 200%, 300%, 400%, or 500% lower than that of uncoated granules (including drug cores).

[0048] Dispersibility in water can be measured by measuring the zeta potential of the particle suspension. Dispersibility in water can also be measured by particle size distribution in water, such as by laser diffraction. The dispersibility of coated particles compared to uncoated particles (including drug cores) can be at least 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 100%, greater than 110%, greater than 120%, greater than 130%, greater than 140%, greater than 150%, greater than 200%, greater than 300%, greater than 400%, and greater than 500%. The dispersibility of coated particles can be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 200%, 300%, 400%, or 500% lower than that of uncoated particles (including drug cores).

[0049] Coated particles can have improved flowability compared to uncoated drug-containing cores.

[0050] Following the coating process, there may be no significant structural changes in the API. The API may remain intact after the coating process. The coating process may not damage the API. The structure of the API can be evaluated using nuclear magnetic resonance (NMR) spectroscopy. The nmR signal may not change significantly before and after the coating process. The structure of the API can be evaluated using X-ray diffraction (XRD) analysis. The XRD signal may not change significantly before and after the coating process.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Methods and materials used in this invention are described herein; other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative and not restrictive in nature. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, this specification (including definitions) shall prevail. Attached Figure Description

[0052] Figure 1 A schematic diagram of an exemplary reactor system is shown.

[0053] Figures 2A to 2B This is a TEM image of ultrafine acetaminophen particles (LAM-1). The image shows the laminated alumina and silicon oxide layers. Figure 1 As shown in B, each alumina coating is approximately 4.6 nm thick, and each silicon oxide coating is approximately 1.5 nm thick.

[0054] Figures 3A to 3B The dissolution curves are shown when 325 mg of coated particles (LAM-1) are dissolved in 900 mL of pH 5.8 PBS solution at 37 °C with or without surfactants (A) and (B).

[0055] Figure 4 TEM images of ultrafine acetaminophen particles (LAM-2) are shown.

[0056] Figure 5 The dissolution curve is shown when 325 mg of coated particles (LAM-2) is dissolved in 900 ml of pH 5.8 PBS solution at 37 °C with stirring at 50 rpm.

[0057] Figures 6A to 6C A TEM image of ultrafine acetaminophen particles (LAM-3) is shown. The results show laminated alumina and silica coatings. Figure 6C As shown, each alumina coating and silicon oxide coating is approximately 2.5 nm to 2.8 nm thick. The entire laminated alumina and silicon oxide coating is approximately 15.3 nm thick.

[0058] Figures 7A to 7C The results of EDS analysis of LAM-3 particles are shown. The results show the laminated alumina coating and silica coating.

[0059] Figure 8The dissolution curve is shown when 100 mg of coated particles (LAM-3) dispersed in 3 mL of 0.5% polysorbate-80 solution at 37 °C is dissolved in 900 mL of pH 6.8 PBS buffer with stirring at 50 rpm.

[0060] Figures 9A to 9B TEM images of micronized indomethacin particles (LAM-4) are shown. The results show laminated alumina and silica coatings. Figure 9B As shown, each alumina coating and silicon oxide coating is approximately 1 nm to 2.5 nm thick. The entire laminated alumina and silicon oxide coating is approximately 18.8 nm thick.

[0061] Figures 10A to 10C The EDS analysis results of the API-coated particles (LAM-4) are shown. The results show the laminated alumina and silica coatings.

[0062] Figure 11 The dissolution curve is shown when 65 mg of coated particles (LAM-4) dispersed in 3 mL of 0.5% polysorbate-80 solution at 37 °C is dissolved in 900 mL of pH 7.2 PBS buffer with stirring at 50 rpm.

[0063] Figure 12 TEM images of micronized indomethacin particles (RAOK-166H) coated with alternating layers of alumina and silica are shown.

[0064] Figure 13 The dissolution curves of uncoated micronized indomethacin particles and four different coated particle formulations are shown. Detailed Implementation

[0065] This disclosure provides a method for preparing coated particles comprising a drug-containing core and a laminated coating consisting of alternating layers of alumina and silica, wherein the innermost layer may be alumina or silica, and the outermost layer may also be alumina or silica. The laminated coating can be applied by vapor deposition (also known as atomic layer coating) by alternately exposing the particles to a precursor compound and an oxidant. The coating forms on the surface of the particles (i.e., the core or the previously applied coating layer), and both conform to and completely cover (encapsulate) the particles. Compared to an uncoated drug-containing core, the coated particles have a modified drug release profile (improved dissolution rate). The laminated coating offers several advantages compared to a coating composed entirely of alumina or silica. The alumina coating layer can slowly release the drug from the core. Depending on its thickness, the silica coating layer does not significantly slow down the release of the drug from the core, but it can offer other advantages. For example, a silica coating produced using 1,2-bis(diisopropylamino)disilane (BDIPADS) as a precursor and ozone as an oxidant provides a relatively hydrophobic surface. Conversely, both alumina and silica coatings produced using SiCl4 as a precursor and water as an oxidant provide relatively hydrophilic surfaces. By adjusting the number, thickness, and type of coatings in a laminated coating (including how the silica layer is formed), the release rate of the drug in the drug-containing core can be controlled, and other desired properties, such as improved handling characteristics and improved flowability, can be provided. While it is generally desirable to provide slow release with a relatively thin coating, it may also be desirable to limit the amount of alumina present in the drug product. Therefore, by providing a coating comprising a laminate of alternating alumina and silica coatings, a coating that reduces the drug release rate and has a lower amount of alumina than a coating consisting entirely of alumina can be provided. Because particle dispersion generally increases dissolution rate and uniformity, a relatively hydrophilic outer layer may be desired. Finally, the type of the innermost layer can affect ease of manufacture. Depending on the surface properties of the drug-containing core, applying a silicon oxide layer as the innermost layer can provide a more consistent and easier-to-apply layer. In some cases, the opposite is true, and applying an aluminum oxide layer as the innermost layer can provide a more consistent and easier-to-apply layer.

[0066] Method for preparing a pharmaceutical composition comprising a drug substance coated with laminated alumina and silica coatings

[0067] In one aspect, this disclosure provides a method for preparing a pharmaceutical composition (e.g., coated particles) comprising a drug-containing core encapsulated by a laminated (alternating layer) alumina coating and a silica coating.

[0068] The drug-containing core can be first coated with an alumina coating layer, followed by a silicon oxide coating layer. The process can stop there, or additional alternating coating layers can be applied, ending with either an alumina or silicon oxide coating layer.

[0069] The final coating layer can be alumina, and the outer surface of the coated particles can be an alumina coating layer. Alternatively, the final coating layer can be silicon oxide, and the outer surface of the coated particles can be a silicon oxide coating layer.

[0070] The first coating layer can be alumina, and the alumina coating can be applied directly to the uncoated particles (including the drug core). The first coating layer can be silicon dioxide, and the silicon dioxide coating can be applied directly to the uncoated particles (including the drug core).

[0071] The aluminum precursor may be trimethylaluminum (TMA). The silicon precursor may be 1,2-bis(diisopropylamino)disilane (BDIPADS), and the oxidant may be ozone; alternatively, the silicon precursor may be silicon tetrachloride, and the oxidant may be water.

[0072] The drug release rate of coated particles can be adjusted by changing the chemical composition of the outer layer of the coated particles (e.g., alumina versus silica). The drug release rate of coated particles can also be adjusted by changing the thickness or number of alumina layers and the thickness or number of silica layers.

[0073] Methods for aluminum oxide coating

[0074] Each alumina coating can be applied using vapor deposition as described herein. The aluminum precursor can be trimethylaluminum (TMA). The oxidant can be ozone or water.

[0075] A first exemplary alumina coating method includes the following sequential steps: (a) loading particles comprising a pharmaceutical agent into a reactor; (b) applying a vapor or gaseous aluminum precursor (e.g., TMA) to the particles in the reactor; (c) performing one or more pump-purge cycles on the reactor using an inert gas; (d) applying a vapor or gaseous oxidant (e.g., ozone or water) to a substrate in the reactor; and (e) performing one or more pump-purge cycles on the reactor using an inert gas. The precursor and oxidant can be applied by pulsed into the reactor. Sequential steps (b) through (e) can be repeated once or more to increase the total thickness of the alumina layer. The reactor pressure can be stabilized after steps (a), (b), and / or (d). The reactor contents can be agitated before and / or during steps (b), (c), and / or (e). A portion or substantially all of the vapor or gaseous contents can be pumped out before steps (c) and / or (e). The same method can be used (step (a) is usually omitted because the particles can remain in the reactor) to apply an alumina coating to pharmaceutical particles with a silica outer coating. The particles may be stirred during some or all of the steps to help provide a uniform coating.

[0076] A second exemplary alumina coating method includes the following sequential steps: (a) loading particles containing a pharmaceutical product into a reactor; (b) reducing the reactor pressure to less than 50 mTorr; (c) stirring the reactor contents until the reactor contents have the desired moisture content; (d) pressurizing the reactor to at least 2 Torr by adding a vapor or gaseous aluminum precursor (e.g., TMA); (e) stabilizing the reactor pressure; (f) stirring the reactor contents; (g) pumping out a portion or substantially all of the vapor or gaseous contents and determining when to stop pumping based on analysis of the contents in the reactor; (h) performing a series of pump-purge cycles of the reactor using an inert gas; (i) pressurizing the reactor to 2 Torr by adding a vapor or gaseous oxidant (e.g., water or ozone); (j) stabilizing the reactor pressure; (k) stirring the reactor contents; (l) pumping out a portion or substantially all of the vapor or gaseous contents and determining when to stop pumping based on analysis of the contents in the reactor; and (m) performing a series of pump-purge cycles of the reactor using an inert gas. Precursors and oxidants can be applied by pulsed into the reactor. Sequential steps (b) through (m) can be repeated once or multiple times to increase the total thickness of the alumina layer. The alumina coating can be applied to the pharmaceutical-containing particles with a silica outer coating using the same method (step (a) is usually omitted because the particles can remain in the reactor). The particles can be stirred during some or all of the steps to help provide a uniform coating.

[0077] Methods for silica coatings

[0078] Each silica coating can be applied using vapor deposition as described herein. The silicon precursor can be SiCl4 or 1,2-bis(diisopropylamino)disilane (BDIPADS). When using SiCl4, water is the oxidant. When using BDIPADS, ozone is the oxidant.

[0079] Silica coatings can be applied directly to uncoated particles or to the alumina-coated particles described herein. The drug-containing core can be first coated with an alumina layer, followed by a silica layer.

[0080] A first exemplary silica coating method includes the following sequential steps: (a) loading particles comprising a pharmaceutical ingredient into a reactor; (b) applying a vapor or gaseous silica precursor (BDIPADS) to a substrate in the reactor; (c) performing one or more pump-purge cycles of the reactor using an inert gas; (d) applying a vapor or gaseous oxidant (e.g., ozone) to the substrate in the reactor; and (e) performing one or more pump-purge cycles of the reactor using an inert gas. The precursor and oxidant can be applied by pulsed into the reactor. Sequential steps (b) through (e) can be repeated once or more to increase the total thickness of the silica layer. The reactor pressure can be stabilized after steps (a), (b), and / or (d). The reactor contents can be agitated before and / or during steps (b), (c), and / or (e). A portion or substantially all of the vapor or gaseous contents can be pumped out before steps (c) and / or (e). The same method can be used (step (a) is usually omitted because the particles can remain in the reactor) to apply a silica layer to the drug-containing particles with an alumina outer coating. The particles may be stirred during some or all of the steps to help provide a uniform coating.

[0081] A second exemplary silica coating method includes the following sequential steps: (a) loading particles comprising a pharmaceutical ingredient into a reactor; (b) reducing the reactor pressure to less than 50 mTorr; (c) stirring the reactor contents until the reactor contents have the desired moisture content; (d) pressurizing the reactor to at least 0.3 Torr by adding vapor or gaseous silica precursor BDIPADS; (e) stabilizing the reactor pressure; (f) stirring the reactor contents; (g) pumping out a subset of the vapor or gaseous contents and determining when to stop pumping based on analysis of the contents in the reactor; (h) performing a series of pump-purge cycles of the reactor using an insertion gas; (i) pressurizing the reactor to 8 Torr by adding a gaseous oxidant (e.g., ozone); (j) stabilizing the reactor pressure; (k) stirring the reactor contents; (l) pumping out a portion or substantially all of the vapor or gaseous contents and determining when to stop pumping based on analysis of the contents in the reactor; and (m) performing a series of pump-purge cycles of the reactor using an inert gas. The precursor and oxidant can be applied by pulsed into the reactor. Sequential steps (b) through (m) can be repeated once or multiple times to increase the total thickness of the silica layer. The silica layer can be applied to pharmaceutical particles with an alumina outer coating using the same method (step (a) is usually omitted because the particles can remain in the reactor). The particles can be stirred during some or all of the steps to help provide a uniform coating.

[0082] A third exemplary silica coating method comprises the following sequential steps: (a) loading particles including a pharmaceutical product into a reactor; (b) reducing the reactor pressure to less than 50 m Torr; (c) stirring the reactor contents until the reactor contents have the desired moisture content; (d) pressurizing the reactor to at least 20 Torr by adding a vapor or gaseous silicon precursor, silicon tetrachloride; (e) stabilizing the reactor pressure; (f) stirring the reactor contents; (g) pumping out a subset of the vapor or gaseous contents and determining when to stop pumping based on analysis of the contents in the reactor; (h) performing a series of pump-purge cycles of the reactor using an insert gas; (i) pressurizing the reactor to 4 Torr by adding steam (oxidant); (j) stabilizing the reactor pressure; (k) stirring the reactor contents; (l) pumping out a portion or substantially all of the vapor or gaseous contents and determining when to stop pumping based on analysis of the contents in the reactor; and (m) performing a series of pump-purge cycles of the reactor using an insert gas. The precursor and oxidant can be applied by pulsed into the reactor. Sequential steps (b) through (m) can be repeated once or multiple times to increase the total thickness of the silica layer. The silica layer can be applied to pharmaceutical particles with an alumina outer coating using the same method (step (a) is usually omitted because the particles can remain in the reactor). The particles can be stirred during some or all of the steps to help provide a uniform coating.

[0083] Uncoated granules (including drug cores)

[0084] Uncoated particles (including drug cores) may consist of a drug substance (API). Uncoated particles (including drug cores) may further contain one or more pharmaceutically acceptable excipients.

[0085] As used herein, the terms “drugs” and “APIs” include all small molecule APIs, particularly organic molecule APIs. Drugs may be selected from analgesics, anesthetics, anti-inflammatory agents, anthelmintics, antiarrhythmic agents, antiasthmatic agents, antibiotics, anticancer agents, anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antihistamines, antitussives, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antitumor agents, antioxidants, antipyretics, immunosuppressants, immunostimulants, antithyroid agents, antiviral agents, anxiolytic sedatives, hypnotics, tranquilizers, astringents, antibacterial agents, beta-adrenergic receptor blockers, blood products, blood substitutes, and bronchodilators. Buffers, cardiac systolic agents, chemotherapeutic agents, contrast agents, corticosteroids, cough suppressants, expectorants, mucolytics, diuretics, dopaminergic agents, anti-Parkinson's agents, free radical scavengers, growth factors, hemostatic agents, immunomodulators, lipid regulators, muscle relaxants, parasympathomimetic drugs, parathyroid calcitonin, bisphosphonates, prostaglandins, radiopharmaceuticals, hormones, sex hormones, antihistamines, appetite stimulants, anorexia nervosa, steroids, sympathomimetic drugs, thyroid preparations, vaccines, vasodilators, and xanthine.

[0086] This method can be used to coat particles containing biomolecules, such as proteins (e.g., antibodies) or nucleic acids (e.g., DNA or RNA).

[0087] APIs can be crystalline or amorphous.

[0088] Uncoated particles may contain at least 50% wt / wt of API. Uncoated particles may contain at least 70%, 80%, 90%, 99%, or 100% wt / wt of API.

[0089] On a volume average basis, uncoated particles (including drug cores) may have a Dv10 of less than 0.1 μm, less than 0.2 μm, less than 0.5 μm, less than 1 μm, less than 2 μm, less than 5 μm, less than 10 μm, less than 20 μm, or less than 50 μm. On a volume average basis, uncoated particles may have a Dv10 of greater than 0.1 μm, greater than 0.2 μm, greater than 0.5 μm, greater than 1 μm, greater than 2 μm, greater than 5 μm, greater than 10 μm, greater than 20 μm, or greater than 50 μm. On a volume average basis, uncoated particles may have a Dv10 of approximately 2 μm.

[0090] On a volume average basis, uncoated particles may have a Dv50 of less than 0.1 μm, less than 0.2 μm, less than 0.5 μm, less than 1 μm, less than 2 μm, less than 5 μm, less than 10 μm, less than 20 μm, or less than 50 μm. On a volume average basis, uncoated particles may have a Dv50 of greater than 0.1 μm, greater than 0.2 μm, greater than 0.5 μm, greater than 1 μm, greater than 2 μm, greater than 5 μm, greater than 10 μm, greater than 20 μm, or greater than 50 μm. On a volume average basis, uncoated particles may have a Dv50 of 0.1 μm to 200 μm, 0.1 μm to 1 μm, 0.1 μm to 10 μm, or 0.1 μm to 50 μm. On a volume average basis, uncoated particles may have a D50 of approximately 0.1–50, 10–50, or 10–30 μm.

[0091] On a volume average basis, uncoated particles may have a Dv90 of less than 0.1 μm, less than 0.2 μm, less than 0.5 μm, less than 1 μm, less than 2 μm, less than 5 μm, less than 10 μm, less than 20 μm, or less than 50 μm. On a volume average basis, uncoated particles may have a Dv90 of greater than 0.1 μm, greater than 0.2 μm, greater than 0.5 μm, greater than 1 μm, greater than 2 μm, greater than 5 μm, greater than 10 μm, greater than 20 μm, or greater than 50 μm. On a volume average basis, uncoated particles may have a Dv90 of 200 μm to 2000 μm. On a volume average basis, uncoated particles may have a Dv50 of 0.1 μm to 200 μm, 0.1 μm to 1 μm, 0.1 μm to 10 μm, or 0.1 μm to 50 μm. On a volume average basis, uncoated particles can have a Dv90 of approximately 9.2 μm.

[0092] vapor deposition

[0093] A coating is applied via vapor deposition using precursor molecules (e.g., 2-bis(diisopropylamino)disilane (BDIPADS), SiCl4, or trimethylaluminum (TMA)) and an oxidant (e.g., ozone or water vapor). The coating forms on the surface of the particles (i.e., the core or the previously applied coating layer), and both conform to and completely cover the particles. Vapor deposition of metal oxides and quasi-metal oxides is sometimes referred to as atomic layer deposition (ALD). However, depending on many factors, including the surface being coated, not every cycle of the deposition reaction necessarily deposits one atomic layer during each reaction cycle. Therefore, this process is sometimes referred to as atomic layer coating.

[0094] reactor system

[0095] The term "reactor system," in its broadest sense, includes all systems that can be used to perform vapor phase deposition or atomic layer deposition. Exemplary reactor systems are shown in... Figure 1 It is shown in the figure and described further below.

[0096] Reactor system 10 can perform vapor deposition or atomic layer deposition. Reactor system 10 allows the method to be carried out at higher (above 50°C, e.g., 50-100°C or higher) or lower operating temperatures, e.g., below 50°C, such as at 25°C or below. For example, reactor system 10 can form thin films of alumina or silica on particles primarily at temperatures of 40-80°C, e.g., 40°C or 80°C. Typically, the particles can be held or maintained at such temperatures. This can be achieved by maintaining or sustaining the reactants and / or the inner surfaces of the reactor chambers (e.g., chamber 20 and roller 40 discussed below) at such temperatures.

[0097] Again, a vapor phase deposition or atomic layer deposition process is illustrated, wherein reactor system 10 includes a stationary vacuum chamber 20 coupled to a vacuum pump 24 via a vacuum tube 22. The vacuum pump 24 may be an industrial vacuum pump sufficient to establish a pressure of less than 1 torr, for example 1 to 100 millitors, such as 50 millitors. The vacuum pump 24 allows chamber 20 to be maintained at the desired pressure and allows for the removal of reaction byproducts and unreacted process gases.

[0098] In operation, reactor 10 performs a vapor phase deposition or atomic layer deposition process by introducing a gaseous oxidant and an aluminum (or silicon) precursor into chamber 20. The gaseous oxidant and aluminum (or silicon) precursor are introduced alternately into the reactor. Furthermore, the reaction can be carried out at low temperatures, such as below 80°C, or below 50°C, below 30°C, or below 25°C. The operating temperature can be approximately 50°C. Operating temperatures can be higher than 5°C, higher than 10°C, higher than 15°C, higher than 20°C, higher than 25°C, higher than 30°C, higher than 35°C, higher than 40°C, higher than 45°C, higher than 50°C, higher than 56°C, higher than 60°C, higher than 65°C, higher than 70°C, higher than 75°C, or higher than 80°C. The operating temperature can be below 20℃, below 25℃, below 30℃, below 35℃, below 40℃, below 45℃, below 50℃, below 56℃, below 60℃, below 65℃, below 70℃, below 75℃, or below 80℃.

[0099] Chamber 20 is also coupled to a chemical delivery system 30. The chemical delivery system 30 includes three or more gas sources 32a, 32b, 32c coupled to the vacuum chamber 20 via corresponding delivery lines 34a, 34b, 34c and controllable valves 36a, 36b, 36c. The chemical delivery system 30 may include a combination of flow restrictors, airflow controllers, pressure sensors, and ultrasonic flow meters to provide controllable flow rates of various gases entering chamber 20. The chemical delivery system 30 may also include one or more temperature control components, such as heat exchangers, resistance heaters, heating lamps, etc., to heat or cool various gases before they flow into chamber 20. Although Figure 1 A separate gas line is shown extending parallel to the chamber for each gas source, but two or more gas lines may be connected, for example, via one or more three-way valves, before the combined line reaches chamber 20.

[0100] One of the gas sources can provide an oxidant. In particular, the gas source can provide a vapor or gaseous oxidant. For example, the oxidant can be ozone. As another example, the oxidant can be water vapor.

[0101] One of the gas sources can be an aluminum (or silicon) precursor. In particular, the gas source can provide a vapor or gaseous aluminum (or silicon) precursor. For example, the aluminum precursor can be TMA, and the oxidant can be ozone or water. The silicon precursor can be silicon tetrachloride or 1,2-bis(diisopropylamino)disilane, and the oxidant can be water or ozone.

[0102] One of the gas sources can provide a purging gas. In particular, a third gas source can provide a gas that is chemically inert to the oxidant and the aluminum (or silicon) precursor, the coating, and the particles being treated. For example, the purging gas can be N2 or a rare gas, such as argon.

[0103] A rotatable coating roller 40 is held within the chamber 20. The roller 40 is connected to a motor 44 via a drive shaft 42 extending through a sealed port in the side wall of the chamber 20. The motor 44 can rotate the roller at speeds from 1 to 100 RPM. Alternatively, the roller can be directly connected to a vacuum source via a rotary joint.

[0104] The particles to be coated (shown as particle bed 50) are placed in the inner volume 46 of the roller 40. The roller 40 and the chamber 20 may include sealable ports (not shown) to allow particles to be placed into and removed from the roller 40.

[0105] The main body of roller 40 is provided with one or more of porous materials, solid metal, and perforated metal. The holes through the cylindrical sidewalls of roller 40 can have a size of 1-10 μm.

[0106] During operation, as the roller 40 rotates, one of the gases flows from the chemical delivery system 30 into the chamber 20. A combination of orifices (1-100 μm), holes (0.1-10 mm), or large openings in the coating roller 40 is used to confine particles within the coating roller 40 while allowing rapid delivery of precursor chemicals and pumping of byproducts or unreacted substances. Due to the orifices in the roller 40, gas can flow between the outside of the roller 40 (i.e., reactor chamber 20) and the inside of the roller 40. Furthermore, the rotation of the roller 40 agitates the particles to expose new surfaces to the powder bed, thereby ensuring that a large surface area of ​​the particles remains exposed to the process gas. This allows the particle surface to interact rapidly and uniformly with the process gas.

[0107] One or more temperature control components may be integrated into the drum 40 to allow for temperature control of the drum 40. For example, a resistance heater, thermoelectric cooler, or other components may be in or on the sidewall of the drum 40.

[0108] The reactor system 10 also includes a controller 60 coupled to various controllable components (e.g., vacuum pump 24, gas delivery system 30, motor 44, temperature control system, etc.) to control the operation of the reactor system 10. The controller 60 may also be coupled to various sensors, such as pressure sensors, flow meters, etc., to provide closed-loop control of the gas pressure in the chamber 20.

[0109] Typically, controller 60 operates reactor system 10 according to a "recipe" that specifies the operating values ​​of each controllable element as a function of time. For example, the recipe may specify the operating time of vacuum pump 24, the time and flow rate of each gas source 32a, 32b, 32c, the rotational speed of motor 44, etc. Controller 60 may receive the recipe as computer-readable data (e.g., stored on a non-transitory computer-readable medium).

[0110] The controller 60 and other computing device portions of the system described herein may be implemented in digital electronic circuitry or in computer software, firmware, or hardware. For example, the controller may include a processor to execute a computer program stored in a computer program product (e.g., a non-transitory machine-readable storage medium). Such a computer program (also referred to as a program, software, software application, or code) may be written in any form of programming language, including compiled or interpreted languages, and may be deployed in any form, including as a standalone program or as a module, component, subroutine, or other unit suitable for a computing environment. The controller 60 may be a general-purpose programmable computer. The controller may be implemented using special-purpose logic circuitry, such as an FPGA (Field-Programmable Gate Array) or an ASIC (Application-Specific Integrated Circuit).

[0111] operate

[0112] Initially, uncoated particles are loaded into rollers 40 in reactor system 10. The uncoated particles may be pure pharmaceutical particles (or a combination of particles of a first and a second pharmaceutical product) or a mixture of pharmaceutical particles (or a combination of particles of a first and a second pharmaceutical product) and excipient particles. The uncoated particles may consist of one or more pharmaceutical products (e.g., one of the aforementioned pharmaceutical products) and one or more excipients. Once any inlet port is sealed, controller 60 operates reactor system 10 according to the formulation to form a thin film of aluminum (or silicon) oxide on the particles.

[0113] Specifically, oxidant and aluminum (or silicon) precursor may be supplied alternately to chamber 20, wherein each step of supplying oxidant or aluminum (or silicon) precursor is followed by a purging cycle, in which inert gas is supplied to chamber 20 to force out excess oxidant or aluminum (or silicon) precursor and byproducts used in the previous step. Furthermore, one or more gases (aluminum (or silicon) precursor gas and / or inert gas and / or oxidant gas) may be pulsed, wherein chamber 20 is filled with gas to a specified pressure, allowing for a holding time, and the chamber is evacuated by vacuum pump 24 before the start of the next pulse.

[0114] Specifically, the controller 60 can operate the reactor system 10 as follows.

[0115] In the aluminum (or silicon) precursor semi-circulation, when motor 44 rotates drum 40 to agitate particles 50:

[0116] i) Operate the gas delivery system 30 to allow an aluminum (or silicon) precursor gas (e.g., trimethylaluminum (TMA), silicon tetrachloride, or 1,2-bis(diisopropylamino)disilane (BDIPADS)) to flow from source 32a into chamber 20 until a first specified pressure is reached, which may be from 0.1 Torr to half the saturation pressure of the aluminum (or silicon) precursor gas (e.g., 0.3-20 Torr).

[0117] ii) Stop the flow of aluminum (or silicon) precursor and allow a specified holding time (e.g., 60 seconds), such as as measured by a timer in the controller, which allows the aluminum (or silicon) precursor to flow through the particle bed in the drum 40 and react with the surface of the particles 50 within the drum 40.

[0118] iii) Vacuum pump 50 evacuates chamber 20, for example, to a pressure below 1 tort, for example, to 1 to 100 millitors, for example, 50 millitors.

[0119] Next, in the first purge cycle, while motor 44 rotates the drum to agitate particles 50:

[0120] iv) Operate the gas delivery system 30 to allow an inert gas (e.g., N2) to flow from the source 32c into the chamber 20 until a second specified pressure is reached, which may be 1 to 100 Torr.

[0121] v) Stop the flow of inert gas and allow a specific delay time, such as that measured by a timer in the controller, which allows the inert gas to flow through the holes in the drum 40 and diffuse through the particles 50 to displace the aluminum (or silicon) precursor gas and any gaseous byproducts.

[0122] vi) Vacuum pump 50 evacuates chamber 20, for example, to a pressure below 1 tort, for example, to 1 to 500 millitors, for example, 50 millitors.

[0123] These steps (iv) to (vi) may be repeated as specified in the recipe, for example, six to twenty times, or, for example, sixteen times.

[0124] In the oxidant semi-circulation, when motor 44 rotates drum 40 to agitate particles 50:

[0125] vii) Operate the gas delivery system 30 to allow an oxidant (e.g., water or ozone) to flow from source 32a into chamber 20 until a third specified pressure is reached, which may be from 0.1 Torr to half the oxidant gas saturation pressure (e.g., 2-8 Torr).

[0126] viii) Stop the flow of the oxidant and allow a specified holding time, for example, as measured by a timer in the controller, which allows the oxidant to flow through the holes in the drum 40 and react with the surface of the particles 50 inside the drum 40.

[0127] ix) Vacuum pump 50 evacuates chamber 20, for example, to a pressure below 1 tor, for example, to 1 to 500 millitors, for example, 50 millitors.

[0128] Next, a second purging cycle is performed. This second purging cycle may be the same as the first purging cycle, or it may have different numbers of repetitions of steps (iv) to (vi) and / or different delay times and / or different pressures.

[0129] The cycles of the aluminum (or silicon) precursor half-cycle, the first purge cycle, the oxidant half-cycle, and the second purge cycle can be repeated multiple times as specified in the formulation, for example, one to ten times.

[0130] As described above, the coating process can be carried out at low operating temperatures, such as below 80°C, such as at or below 50°C, at or below 35°C, or at or below 25°C. Operating temperatures can be above 15°C, above 20°C, above 25°C, above 30°C, above 35°C, above 40°C, above 45°C, above 50°C, above 56°C, above 60°C, above 65°C, above 70°C, above 75°C, or above 80°C. Operating temperatures can be approximately 50°C. Operating temperatures can be from 20°C to 100°C, 80°C, 70°C, 60°C, or 50°C. Operating temperatures can be below 20°C, below 25°C, below 30°C, below 35°C, below 40°C, below 45°C, below 50°C, below 56°C, below 60°C, below 65°C, below 70°C, below 75°C, or below 80°C. Specifically, during all steps (i) to (ix) described above, the particles can be maintained or sustained at such a temperature. Typically, the temperature inside the reactor chamber does not exceed 80°C during steps (i) to (ix). This can be achieved by injecting oxidant gas, aluminum (or silicon) precursor gas, and inert gas into the chamber at such a temperature during the corresponding cycles. Furthermore, the physical components of the chamber can be maintained or sustained at such a temperature, for example, using a cooling system such as a thermoelectric cooler if necessary.

[0131] Pharmaceutical Composition

[0132] This document also provides pharmaceutical compositions containing coated particles. The pharmaceutical compositions can be formulated in any suitable manner known in the art. The pharmaceutical compositions may be in the form of tablets, capsules, powders, microparticles, granules, syrups, suspensions, solutions, nasal sprays, transdermal patches, injectable solutions, or suppositories.

[0133] The pharmaceutical composition is formulated to be compatible with its intended route of administration (e.g., oral, intravenous, intra-arterial, intramuscular, intradermal, subcutaneous, or intraperitoneal). The composition may include sterile diluents (e.g., sterile water or saline), fixative oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents, antibacterial or antifungal agents (e.g., benzyl alcohol or methylparaben, chlorobutanol, phenol, ascorbic acid, and thimerosal), antioxidants (e.g., ascorbic acid and sodium bisulfite), chelating agents (e.g., ethylenediaminetetraacetic acid), buffers (e.g., acetates, citrates, and phosphates), and isotonic agents (e.g., sugars (e.g., dextrose), polyols (e.g., mannitol or sorbitol), and salts (e.g., sodium chloride)) or any combination thereof. Liposome suspensions may also be used as pharmaceutically acceptable carriers. The composition may be formulated and packaged in ampoules, disposable syringes, or multi-dose vials. When needed (e.g., in injectable formulations), appropriate fluidity can be maintained by using, for example, encapsulation (e.g., lecithin) or surfactants. Controlled release can be achieved through implants and microencapsulated delivery systems that may include biodegradable, biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid).

[0134] Pharmaceutically acceptable carriers, adjuvants, and mediators that can be used in pharmaceutical compositions disclosed herein include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates, glycine), sorbic acid, potassium sorbate, mixtures of metaglycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0135] The composition or dosage form may contain 0.001% to 100% (e.g., 0.1-95%, 20-80% or 75-85%) of the coated particles described herein, with the balance consisting of suitable pharmaceutically acceptable excipients.

[0136] The methods described herein can be simply processes for formulating pharmaceutical compositions or other manufacturing processes. The methods described herein eliminate the need to include additional detergents in the final formulation.

[0137] Example

[0138] The invention is further described in the following examples, which do not limit the scope of the invention as described in the claims.

[0139] Example 1: AlOx / SiOx / AlOx / SiOx layered coating on semi-fine acetaminophen (LAM-1)

[0140] Use the parameters listed in the table below to apply alternating alumina (AlOx) and silica (SiOx) coatings to uncoated particles (containing drug cores). As shown in Table 1, the method requires: (1) applying an alumina coating; (2) applying a silica coating; (3) applying an alumina coating; and (4) applying a silica coating. The operating temperature is 50°C.

[0141] Table 1. Coating parameters of LAM-1

[0142]

[0143] To evaluate whether coating the API with laminated alumina and silica coatings alters the API's structure or the properties of the API particles, various analyses were performed on the coated particles.

[0144] Thermogravimetric analysis (TGA%)

[0145] Table 1 shows the TGA analysis results of the API-coated particles. As shown in Table 1, the total inorganic material accounts for approximately 1.49% of the coated particles.

[0146] Transmission electron microscopy (TEM) analysis

[0147] Figures 2A to 2B TEM images of the API-coated particles are shown. The results show the laminated alumina and silica coatings. Figure 2B As shown, each alumina coating is approximately 4.6 nm thick, and each silicon oxide coating is approximately 1.5 nm thick.

[0148] Release (dissolution) analysis over time

[0149] Figure 3A The dissolution profile is shown when 325 mg of coated particles (LAM-1) is added to 900 mL of pH 6.8 phosphate-buffered saline (PBS) solution at 37 °C and stirred at 50 RPM. Figure 3A API coated with a laminated film having an outer SiO2 coating layer is shown. The outer layer is generated using BDIPAS as a precursor and ozone as an oxidant. The outer surface is hydrophobic, therefore, the particles do not disperse in the buffer solution in the absence of a surfactant. This limits release. Figure 3B The release was shown after adding 0.5% of the surfactant polysorbate-80 to the dissolution medium.

[0150] Table 2 Dissolution test results

[0151]

[0152] Example 2: Coatings of AlOx / SiOx / AlOx / SiOx / AlOx layers on semi-fine acetaminophen (LAM-2)

[0153] The parameters listed in Table 3 are used to apply alternating alumina and silica coatings to uncoated particles (containing the drug core). As shown in Table 3, the method requires: (1) applying an alumina coating; (2) applying a silica coating; (3) applying an alumina coating; (4) applying a silica coating; and (5) applying an alumina coating. The operating temperature is 50°C.

[0154] Table 3. Coating parameters of LAM-2

[0155]

[0156] To assess whether coating the API with laminated alumina and silica coatings alters the API's structure or the properties of the API particles, various analyses were performed on the coated particles.

[0157] Thermogravimetric analysis (TGA%)

[0158] Table 3 shows the TGA analysis results of the API-coated particles. As shown in Table 3, the total inorganic material accounts for approximately 1.63% of the coated particles.

[0159] Transmission electron microscopy (SEM) analysis

[0160] Figure 4 SEM images of the API-coated particles are shown. The results show the laminated alumina and silica coatings. Figure 4 As shown, each alumina coating and silicon oxide coating is approximately 2 nm to 6 nm thick. The entire laminated alumina and silicon oxide coating is approximately 23 nm thick.

[0161] Release (dissolution) analysis over time

[0162] Figure 5 The dissolution curve is shown when 325 mg of coated particles (LAM-2) is added to 900 ml of pH 5.8 PBS solution at 37 °C and stirred at 50 RPM.

[0163] Example 3: AlOx / SiOx / AlOx / SiOx (LAM-3) on semi-fine acetaminophen

[0164] Use the parameters listed in the table below to apply alternating alumina and silica coatings to uncoated particles (containing drug cores). As shown in Table 4, the method requires: (1) applying an alumina coating; (2) applying a silica coating; (3) applying an alumina coating; and (4) applying a silica coating. The operating temperature is 50°C.

[0165] Table 4. Coating parameters of LAM-3

[0166]

[0167] To assess whether coating the API with laminated alumina and silica coatings alters the API's structure or the properties of the API particles, various analyses were performed on the coated particles.

[0168] Thermogravimetric analysis (TGA%)

[0169] Table 4 shows the TGA analysis results of the API-coated particles. As shown in Table 5, the total inorganic material accounts for approximately 1.6% of the coated particles.

[0170] Transmission electron microscopy (TEM) analysis

[0171] Figures 6A to 6C TEM images of the API-coated particles are shown. The results show the laminated alumina and silica coatings. Figure 6C As shown, each alumina coating and silicon oxide coating is approximately 2.5 nm to 2.8 nm thick. The entire laminated alumina and silicon oxide coating is approximately 15.3 nm thick.

[0172] Energy dispersive spectroscopy (EDS) analysis

[0173] Figures 7A to 7C The EDS analysis results for the API-coated particles are shown. The results show the laminated alumina and silica coatings.

[0174] Release (dissolution) analysis over time

[0175] Figure 8 The dissolution curves are shown when 100 mg of coated particles (LAM-3 dispersed in 3 mL of 0.5% polysorbate-80 solution) are added to 900 mL of PBS buffer (pH 6.8) at 37 °C and stirred at 50 RPM. TMAO3-12 is alumina-coated semi-fine acetaminophen with the same TGA wt% as LAM-3. Detailed dissolution test results are shown in Tables 5 and 6 below. At similar oxide content wt%, the laminated membrane exhibits slower release of semi-fine acetaminophen compared to the alumina-only membrane.

[0176] Table 5. Dissolution test results of LAM-3

[0177]

[0178] Table 6. Dissolution test results of TMAO3-12

[0179]

[0180] Example 4: AlOx / SiOx / AlOx / SiOx / AlOx / SiOx / AlOx / AlOx / AlOx on micronized indomethacin (LAM-4)

[0181] The parameters listed in Table 7 are used to apply alternating alumina and silica coatings to uncoated particles (including drug cores). As shown in Table 7, the method includes: (1) applying an alumina coating; (2) applying a silica coating; (3) applying an alumina coating; (4) applying a silica coating; (5) applying an alumina coating; (6) applying a silica coating; and (7) applying an alumina coating. The operating temperature is 50°C.

[0182] Table 7. Coating parameters of LAM-4

[0183]

[0184] To assess whether coating the API with laminated alumina and silica coatings alters the API's structure or the properties of the API particles, various analyses were performed on the coated particles.

[0185] Thermogravimetric analysis (TGA%)

[0186] Table 7 shows the TGA analysis results of the API-coated particles. As shown in Table 7, the total inorganic material accounts for approximately 4.5% of the coated particles.

[0187] Transmission electron microscopy (TEM) analysis

[0188] Figures 9A to 9B TEM images of the API-coated particles are shown. The results show the laminated alumina and silica coatings. Figure 9B As shown, each alumina coating and silicon oxide coating is approximately 1 nm to 2.5 nm thick. The entire laminated alumina and silicon oxide coating is approximately 18.8 nm thick.

[0189] Energy dispersive spectroscopy (EDS) analysis

[0190] Figures 10A to 10C The EDS analysis results for the API-coated particles are shown. The results illustrate the laminated alumina and silica coatings. (As shown...) Figure 10BAs shown, each alumina coating and silicon oxide coating is approximately 1 nm to 2.5 nm thick.

[0191] Release (dissolution) analysis over time

[0192] Figure 11 The dissolution curves are shown when 65 mg of the coated particles (LAM-4 dispersed in 3 mL of 0.5% polysorbate-80 solution) are added to 900 mL of pH 7.2 PBS buffer at 37 °C and stirred at 50 RPM. Detailed dissolution results are shown in the table below. Slow release was demonstrated using a laminated membrane on M-IMC.

[0193] Table 8. Dissolution test results of LAM-4

[0194]

[0195] Example 5: Compared to alumina coated only on micronized indomethacin, the SiOx / AlOx / SiOx / AlOx / SiOx / AlOx / SiOx / AlOx on micronized indomethacin

[0196] Figure 12 TEM images of RAOK-166H are shown. The micronized indomethacin particles have alternating layers of alumina and silica (six layers in total, with an innermost silica layer and an outermost alumina layer; the silica layers are formed using SiCl4 as a precursor and water as an oxidant). Figure 12 As shown, each alumina and silica coating layer is approximately 4 nm to 5 nm thick. The total laminated alumina and silica coatings are approximately 28.2 nm thick (3.88 wt% AlOx, 3.22 wt% SiOx). ROAK-166F was prepared in the same manner, with thinner coating layers expected, resulting in lower wt% alumina and silica (2.57 wt% AlOx, 1.89 wt% SiOx). Two different alumina-only coated particles were produced: ROA-074A (4.91 wt% AlOx) and ROAK-074B (7.06 wt% AlOx).

[0197] Figure 13 Dissolution profiles for each of the four granular formulations are shown. Release profiles show that uncoated particles exhibit substantially instantaneous release. Laminated and alumina-only coated particles, however, show prolonged release profiles. Higher oxide content results in slower release profiles. At the same oxide content, coated laminated alumina and silica particles exhibit faster release than alumina-only coated particles. This contrasts with a comparison of alumina-only particles and laminated alumina and silica particles, where the silica particles were produced on semi-fine acetaminophen using the BDIPAS / O3 method, where laminated particles exhibit slower release than alumina-only coated particles.

[0198] Other examples

[0199] It should be understood that although the invention has been described in conjunction with a detailed description, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

Claims

1. A coated particle comprising a drug-containing core encapsulated by (1) one or more alumina coating layers and (2) one or more silica coating layers, wherein the drug-containing core contains an organic active pharmaceutical ingredient (API), the alumina coating layers and the silica coating layers alternate, and at least three coating layers are present.

2. The coated particles of claim 1, wherein each alumina coating layer independently has a thickness of about 1 nm to 5 nm or 1 nm to 10 nm.

3. The coated particles of claim 1, wherein each silicon oxide coating layer independently has a thickness of about 1 nm to 5 nm or 1 nm to 10 nm.

4. The coated particles of claim 1, wherein the drug-containing core has a Dv50 between 0.1 μm and 100 μm on a volume average basis.

5. The coated particles as described in claim 1, wherein the outermost coating layer is an alumina coating layer.

6. The coated particles as described in claim 1, wherein the outermost coating layer is a silicon oxide coating layer.

7. The composition of claim 1, wherein the first coating layer adjacent to the drug-containing core is an alumina coating layer.

8. The composition of claim 1, wherein the first coating layer adjacent to the drug-containing core is a silicon oxide coating layer.

9. The coated particles of claim 1, wherein the one or more alumina coating layers are continuous and conformal.

10. The coated particles of claim 1, wherein the one or more silicon oxide coating layers are continuous and conformal.

11. The coated particles of claim 1, wherein the drug-containing core has a Dv50 between 0.1 μm and 50 μm on a volume average basis.

12. The coated particles of claim 1, wherein the drug-containing core has a Dv50 between 1 μm and 30 μm on a volume average basis.

13. The coated particles of claim 1, wherein the alumina coating layer and the silicon oxide coating layer together constitute 2% to 10% wt / wt of the coated particles.

14. The coated particles of claim 1, wherein the alumina coating layer and the silicon oxide coating layer together constitute 1% to 5% wt / wt of the coated particles.

15. The coated particles of claim 1, wherein the coated particles comprise two or more alumina coating layers and two or more silicon oxide coating layers.

16. The coated particles of claim 1, wherein the total thickness of the alumina coating and the silicon oxide coating is about 1 nm to 50 nm.

17. The coated particles of claim 1, wherein at least two silicon oxide coating layers are present.

18. The coated particles of claim 1, wherein at least two alumina coating layers are present.

19. The coated particles of claim 1, wherein at least three silicon oxide coating layers are present.

20. The coated particles of claim 1, wherein at least three alumina coating layers are present.

21. The coated particles of claim 1, wherein the total thickness of all said coating layers is 5 nm to 50 nm.

22. The coated particles of claim 1, wherein the coated particles have a slower drug release rate compared to the drug-containing core.

23. The coated particles of claim 1, wherein the drug release rate of the coated particles is at least 100% slower than the drug release rate of the drug-containing core.

24. The coated particles of claim 1, wherein the drug release rate of the coated particles is at least 100% slower than the drug release rate of the drug-containing core, wherein the drug release rate is measured by dissolving 100 mg of the coated particles in 900 ml of pH 6.8 PBS buffer at 37°C with stirring at 50 rpm.

25. The coated particles of claim 1, wherein the drug release rate of the coated particles is at least 100% slower than the drug release rate of the drug-containing core, wherein the drug release rate is measured by dissolving 65 mg of the coated particles in 900 ml of pH 7.2 PBS buffer at 37°C with stirring at 50 rpm.

26. The coated particles of claim 1, wherein the coated particles have increased flowability compared to the drug-containing core.

27. The coated particles of claim 1, wherein the coated particles have increased wettability compared to the drug-containing core.

28. The coated particles of claim 1, wherein the coated particles have a drug release rate of about 30% to 90% of the drug released within 30 minutes.

29. The coated particles of claim 1, wherein the coated particles have a drug release rate of about 30% to 40% of the drug released within 30 minutes.

30. The coated particles of claim 1, wherein the coated particles have a drug release rate of approximately 70% to 90% of the drug released within 30 minutes.

31. A method for preparing coated particles comprising a drug-containing core coated with (1) one or more alumina coating layers and (2) one or more silica coating layers, wherein the drug-containing core comprises an API, the method comprising the following sequential steps: (a) Loading particles containing API into the chamber of the reactor; (b) Apply the alumina coating by performing the following steps: (b1) Applying a vapor or gaseous aluminum precursor to the particles in the reactor; (b2) Use an inert gas to perform one or more pump-purge cycles; (b3) Applying a vapor or gaseous oxidant to the particles in the reactor; (b4) Using an inert gas to perform one or more pump-purge cycles; and (b5) Repeat steps (b1) through (b4) at least once to provide an alumina coating; (c) Apply the silicon oxide coating by performing the following steps: (c1) Applying a vapor or gaseous silicon precursor to the particles in the reactor; (c2) Use an inert gas to perform one or more pump-purge cycles; (c3) Applying a vapor or gaseous oxidant to the particles in the reactor; (c4) Using an inert gas to perform one or more pump-purge cycles; and (c5) Repeat steps (c1) to (c4) at least once to provide a silicon oxide coating; and (d) Repeat step (b) at least once after step (c).

32. A method for preparing coated particles comprising a drug-containing core coated with (1) one or more alumina coating layers and (2) one or more silica coating layers, wherein the drug-containing core comprises an API, the method comprising the following sequential steps: (a) Loading particles containing API into the chamber of the reactor; (b) Apply the silicon oxide coating by performing the following steps: (b1) Applying a vapor or gaseous silicon precursor to the particles in the reactor; (b2) Use an inert gas to perform one or more pump-purge cycles; (b3) Applying a vapor or gaseous oxidant to the particles in the reactor; (b4) Using an inert gas to perform one or more pump-purge cycles; and (b5) Repeat steps (b1) to (b4) at least once to provide a silicon oxide coating; (c) Apply the alumina coating by performing the following steps: (c1) Applying a vapor or gaseous aluminum precursor to the particles in the reactor; (c2) Use an inert gas to perform one or more pump-purge cycles; (c3) Applying a vapor or gaseous oxidant (e.g., ozone) to the particles in the reactor; (c4) Using an inert gas to perform one or more pump-purge cycles; and (c5) Repeat steps (c1) to (c4) at least once to provide an alumina coating; and (d) Repeat step (b) at least once after step (c).

33. The method of claim 31 or 32, wherein step (c) is repeated after step (b) is repeated.

34. The method of claim 31 or 32, wherein each of steps (b) and (c) is repeated two or more times to produce alternating silicon oxide coatings and aluminum oxide coatings.

35. The method of claim 31 or 32, wherein at least two silicon oxide coating layers and at least two aluminum oxide coating layers are produced.

36. The method of claim 31 or 32, wherein steps (b1) to (b4) are performed at least four times, thereby providing a first cycle, a second cycle, a third cycle, and a fourth cycle.

37. The method of claim 31 or 32, wherein some or all of the residual vapor or gaseous aluminum precursor is pumped out of the reactor prior to step (b3).

38. The method of claim 31 or 32, wherein some or all of the residual vapor or gaseous oxidant is pumped out of the reactor prior to step (c).

39. The method of claim 31 or 32, wherein each alumina layer and each silicon oxide layer has a thickness in the range of 0.1 nm to 50 nm.

40. The method of claim 31 or 32, wherein steps (b1) to (b4) are performed at a temperature between 25°C and 80°C.

41. The method of claim 31 or 32, wherein the oxidant is water or ozone.

42. The method of claim 31 or 32, wherein the particles are agitated during some or all of steps b1 to b5 and c1 to c5.

43. The method of claim 31 or 32, wherein the silicon oxide precursor is SiCl4 or 1,2-bis(diisopropylamino)disilane, and the aluminum oxide precursor is trimethylaluminum.

44. The method of claim 43, wherein the silicon oxide precursor is SiCl4, and water is the oxidant of the silicon oxide precursor.

45. The method of claim 43, wherein the silicon oxide precursor is 1,2-bis(diisopropylamino)disilane, and ozone is the oxidant of the silicon oxide precursor.

46. ​​A coated particle prepared by the method of claim 30 or 31.

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