Methods for preparing drug containing particles enclosed by a laminated aluminum oxide and silicon oxide coating

Abstract

This disclosure pertains to a coated particle that has a drug-containing core and laminated aluminum oxide and silicon oxide coatings and methods of preparing thereof. The coated particle has a modified drug release profile comparing to the uncoated drug-containing core.

Description

[0001]Attorney Docket No.: 44021852WO01 / 05542-1585WO1 METHODS FOR PREPARING DRUG CONTAINING PARTICLES ENCLOSED BY A LAMINATED ALUMINUM OXIDE AND SILICON OXIDE COATING TECHNICAL FIELD This disclosure pertains to methods for preparing coated particles comprising a drug- containing core and a laminated coating comprising alternating aluminum oxide and silicon oxide layers. The laminated coating can be applied by vapor phase deposition. The coated particles have a modified drug release profile comparing to the uncoated drug-containing core. BACKGROUND It is of great interest to the pharmaceutical industry to develop improved formulations of active pharmaceutical ingredients (APIs). Formulation can influence the stability and bioavailability of the APIs as well as other characteristics. Formulation can also influence various aspects of drug product (DP) manufacture, for example, the ease and safety of the manufacturing process. The drug release rate (dissolution rate) for a dosage form of a drug is critically important as it can impact the rate and extent of drug absorption and its bioavailability. Controlled release formulations can have many benefits including: 1) lesser frequency of administration, 2) reduced side effects, 3) increased stability of drug plasma level, and 4) better patient compliance. While controlled release formulations can provide meaningful advantages, there can be disadvantages, including potential toxicity or non-biocompatibility of the materials used to control release of the drug and lower drug loading. There is a need for controlled release formulations that are inert, biocompatible, mechanically strong and capable of achieving high drug loading. SUMMARY This disclosure pertains to methods of preparing pharmaceutical compositions by applying a laminated aluminum oxide and silicon oxide coatings to a drug-containing core. The drug-containing core comprises or consists of a drug (i.e., an active pharmaceutical ingredient (API) that is an organic compound). The disclosure also pertains to a coated particle comprising a drug-containing core enclosed by a laminated aluminum oxide and silicon oxide coating. Described herein is a coated particle comprising a drug-containing core enclosed by (1) one or more aluminum oxide coating layers, and (2) one or more silicon oxide coating layers, wherein the drug-containing core comprises an organic active pharmaceutical Attorney Docket No.: 44021852WO01 / 05542-1585WO1 ingredient (API), the aluminum oxide coating layers and the silicon oxide coating layers alternate and there are at least three coating layers. In various embodiments: each aluminum oxide coating layer independently has a thickness of about 1 nm - 5 nm or 1 nm – 10 nm; each silicon oxide coating layer independently has a thickness of about 1 nm - 5 nm or 1 nm – 10 nm; the drug-containing core has a Dv50, on a volume average basis, between 0.1 ^m and 100 ^m; the outermost coating layer is an aluminum oxide coating layer; the outermost coating layer is a silicon oxide coating layer; the first coating layer adjacent to the drug-containing core is an aluminum oxide coating layer; the first coating layer adjacent to the drug-containing core is a silicon oxide coating layer; the one or more aluminum oxide coating layers are continuous and conformal; the one or more silicon oxide coating layers are continuous and conformal; the drug-containing core has a Dv50, on a volume average basis, between 0.1 μm and 50 μm; the drug-containing core has a Dv50, on a volume average basis, between 1 μm and 30 μm; the aluminum oxide coating layers and the silicon oxide coating layers collectively constitute 2%-10% wt / wt of the coated particle; the aluminum oxide coating layers and the silicon oxide coating layers collectively constitute 1%-5% wt / wt of the coated particle; the coated particle comprises two or more aluminum oxide coating layers and two or more silicon oxide coating layers; the collective thickness of the aluminum oxide coating layers and silicon oxide coating layers is about 1 nm to 50 nm; there are at least two silicon oxide coating layers; there are at least two aluminum oxide coating layers; there are at least three silicon oxide coating layers; there are at least three aluminum oxide coating layers; the collective thickness of all of the coating layers is 5 – 50 nm; the coated particle has a slower API release rate comparing to API-containing core; the API release rate of the coated particle is at least 100% slower than that of the API-containing core; the API release rate of the coated particle is at least 100% slower than that of the API-containing core, wherein the drug release rate is measured by dissolving 100 mg coated particles in 900 ml pH 6.8 PBS buffer at 37 °C, with a stirring of 50 revolutions per minute (RPM); the API release rate of the coated particle is at least 100% slower than that of the drug-containing core, wherein the API release rate is measured by dissolving 65 mg coated particles in 900 ml PBS buffer of pH 7.2 at 37 °C, with a stirring of 50 revolutions per minute (RPM); the coated particles have increased flowability compared to the API-containing core; the coated particles have increased wettability compared to the drug-containing core; the coated particle has an API release rate of about 30-90% API release in 30 minutes; the coated particle has a API release rate of about 30-40% API release in 30 Attorney Docket No.: 44021852WO01 / 05542-1585WO1 minutes; and the coated particle has an API release rate of about 70-90% API release in 30 minutes. Also described is a method of preparing coated particles comprising a drug-containing core enclosed by (1) one or more aluminum oxide coating layers, and (2) one or more silicon oxide coating layers, wherein the drug-containing core comprises an API, the method comprising the sequential steps of: (a) loading particles comprising an API into a chamber of a reactor; (b) applying an aluminum oxide coating layer by performing the following steps: (b1) applying a vaporous or gaseous aluminum precursor to the particles in the reactor; (b2) performing one or more pump-purge cycles using an inert gas; (b3) applying a vaporous or gaseous oxidant to the particles in the reactor; (b4) performing one or more pump-purge cycles using an inert gas; and (b5) repeating steps (b1) – (b4) at least once to provide an aluminum oxide coating layer; (c) applying a silicon oxide coating layer by performing the following steps: (c1) applying a vaporous or gaseous silicon precursor to the particles in the reactor; (c2) performing one or more pump-purge cycles using an inert gas; (c3) applying a vaporous or gaseous oxidant to the particles in the reactor; (c4) performing one or more pump-purge cycles using an inert gas; and (c5) repeating steps (c1) – (c4) at least once to provide an silicon oxide coating layer; and (d) repeating step (b) at least once after step (c). Also described is method of preparing coated particles comprising an drug-containing core enclosed by (1) one or more aluminum oxide coating layers, and (2) one or more silicon oxide coating layers, wherein the drug-containing core comprises an API, the method comprising the sequential steps of: (a) loading particles comprising an API into a chamber of a reactor; (b) applying a silicon oxide coating layer by performing the following steps: (b1) applying a vaporous or gaseous silicon precursor to the particles in the reactor; (b2) performing one or more pump-purge cycles using an inert gas; (b3) applying a vaporous or gaseous oxidant to the particles in the reactor; Attorney Docket No.: 44021852WO01 / 05542-1585WO1 (b4) performing one or more pump-purge cycles using an inert gas; and (b5) repeating steps (b1) – (b4) at least once to provide an silicon oxide coating layer; (c) applying an aluminum oxide coating layer by performing the following steps: (c1) applying a vaporous or gaseous aluminum precursor to the particles in the reactor; (c2) performing one or more pump-purge cycles using an inert gas; (c3) applying a vaporous or gaseous oxidant (e.g., ozone) to the particles in the reactor; (c4) performing one or more pump-purge cycles using an inert gas; and (c5) repeating steps (c1) – (c4) at least once to provide an aluminum oxide coating layer; and (d) repeating step (b) at least once after step (c). In various embodiments of either method: step (c) is repeated after step (b) is repeated; each of step (b) and step (c) are repeated two or more times to produced alternating silicon oxide an aluminum oxide coating layers; at least two silicon oxide coating layers are produced and at least two aluminum oxide coating layers are produced; steps (b1)-(b4) are performed at least four times, providing a first cycle, a second cycle, a third cycle, and a fourth cycle; some or all of the residual vaporous or gaseous aluminum precursor is pumped out of the reactor prior to step (b3); some or all of the residual vaporous or gaseous oxidant is pumped out of the reactor prior to step (c); each aluminum oxide layer and each silicon oxide layer has a thickness in the range of 0.1 nm to 50 nm; steps (b1)-(b4) take place at a temperature between 25°C and 80°C; the oxidant is water or ozone; the particles are agitated during some or all of steps b1 – b5 and c1 – c5; the silicon oxide precursor is SiCl4 or 1,2- Bis(diisopropylamino) disilane and the aluminum oxide precursor is trimethylaluminum; the silicon oxide precursor is SiCl4 and water is the oxidant for the silicon oxide precursor; and the silicon oxide precursor is ,2-Bis(diisopropylamino)disilane and ozone is the oxidant for the silicon oxide precursor. Also described is a coated particle prepared by any of the forgoing methods. Coated particles The disclosure provides coated particles comprising a drug-containing core, and laminated (e.g., alternating) aluminum oxide and silicon oxide coating layers. The disclosure provides coated particles comprising a drug-containing core, one or more aluminum oxide Attorney Docket No.: 44021852WO01 / 05542-1585WO1 coating layers, and one or more silicon oxide coating layers. The coated particles be at least 70%, 80%, 90% or 99% wt / wt API. Each aluminum oxide coating layer and each silicon oxide coating layer can be a continuous and conformal coating layer that completely encloses the particle. The elemental composition of the coated particles can be assessed by^energy- dispersive X-ray spectroscopy (EDS) analysis. The coated particles may contain laminated aluminum oxide and silicon oxide coatings. Each aluminum oxide coating may be about 1-5 or 1-10 nm thick. Each silicon oxide coating may be about 1-5 or 1-10 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 coating layers and at least two (e.g., 1, 2, 3, 4 , 5, 6, 7, 8, 9, or 10) aluminum oxide coating layers. For example there can be: two silicon oxide coating layers and at two aluminum oxide coating layers; two silicon oxide coating layers and three aluminum oxide coating layers; three silicon oxide coating layers and two aluminum oxide coating layers; three silicon oxide coating layers and three aluminum oxide coating layers; three silicon oxide coating layers and four aluminum oxide coating layers; four silicon oxide coating layers and three aluminum oxide coating layers; four silicon oxide coating layers and four aluminum oxide coating layers. The coating can have either silicon oxide or aluminum oxide as the innermost coating layer. The coating can have either silicon oxide or aluminum oxide as the outermost coating layer. Each aluminum 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 to 5 nm, 1 nm to 50 nm, 1 nm to 10 nm, or 1 nm to 5 nm. Each aluminum oxide coating may have a thickness of more than 0.1 nm, more than 0.2 nm, more than 0.3 nm, more than 0.4 nm, more than 0.5 nm, more than 0.6 nm, more than 0.7 nm, more than 0.8 nm, more than 0.9 nm, more than 1 nm, more than 2 nm, more than 3 nm, more than 4 nm, more than 5 nm, more than 6 nm, more than 7 nm, more than 8 nm, more than 9 nm, more than 10 nm, more than 15 nm, more than 20 nm, more than 30 nm, more than 40 nm, more than 50 nm, or more than 100 nm. Each aluminum 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 aluminum oxide coating may have a thickness of between 1 nm and 10 nm. Each aluminum oxide coating may have a thickness of between 1 nm and 5 nm. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 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 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 of more than 0.1 nm, more than 0.2 nm, more than 0.3 nm, more than 0.4 nm, more than 0.5 nm, more than 0.6 nm, more than 0.7 nm, more than 0.8 nm, more than 0.9 nm, more than 1 nm, more than 2 nm, more than 3 nm, more than 4 nm, more than 5 nm, more than 6 nm, more than 7 nm, more than 8 nm, more than 9 nm, more than 10 nm, more than 15 nm, more than 20 nm, more than 30 nm, more than 40 nm, more than 50 nm, or more 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 of between 1 nm and 10 nm. Each silicon oxide coating may have a thickness of between 1 nm and 5 nm. The entirety of the laminated aluminum oxide and silicon oxide coatings 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 to 5 nm, 1 nm to 50 nm, 1 nm to 10 nm, or 1 nm to 5 nm. The entirety of the laminated aluminum oxide and silicon oxide coatings may have a thickness of more than 0.1 nm, more than 0.2 nm, more than 0.3 nm, more than 0.4 nm, more than 0.5 nm, more than 0.6 nm, more than 0.7 nm, more than 0.8 nm, more than 0.9 nm, more than 1 nm, more than 2 nm, more than 3 nm, more than 4 nm, more than 5 nm, more than 6 nm, more than 7 nm, more than 8 nm, more than 9 nm, more than 10 nm, more than 15 nm, more than 20 nm, more than 30 nm, more than 40 nm, more than 50 nm, or more than 100 nm. The entirety of the laminated aluminum oxide and silicon oxide coatings 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. The entirety of the laminated aluminum oxide and silicon oxide coatings may have a thickness of between 1 nm and 50 nm. The entirety of the laminated aluminum oxide and silicon oxide coatings may have a thickness of between 1 nm and 25 nm. The total coating amount (e.g., aluminum oxide and silicon oxide content) can be determined by thermogravimetric analysis (TGA). The coating structure and thickness can be Attorney Docket No.: 44021852WO01 / 05542-1585WO1 determined by Cross-sectional transmission electron microscopy (Cross-sectional TEM) and energy-dispersive X-ray spectroscopy (EDS) mapping. The drug release profile (dissolution rate) of the coated particles can be determined by an in vitro dissolution test. The release profile (dissolution) of the coated particles can be determined by high-performance liquid chromatography (HPLC) analysis. The composition of the coated particles can be assessed by thermogravimetric Analysis (TGA%) analysis. The amount of inorganic residue component may constitute more than 0.1%, more than 0.2%, more than 0.3%, more than 0.4%, more than 0.5%, more than 0.6%, more than 0.7%, more than 0.8%, more than 0.9%, more than 1%, more than 1.2%, more than 1.4%, more than 1.6%, more than 1.8%, more than 2%, more than 2.2%, more than 2.4%, more than 2.6%, more than 2.8%, more than 3%, more than 3.2%, more than 3.4%, more than 3.6%, more than 3.8%, more than 4%, more than 4.2%, more than 4.4%, more than 4.6%, more than 4.8%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 12%, more than 14%, more than 16%, more than 18%, or more than 20% wt / wt of the coated particles. The amount of inorganic residue component may constitute 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 component may constitute 0.1%-20%, 0.5%-10%, 1%-10%, 1%-5%, 2%-5%, 1%-4%, 1%-3%, or 2%-4% wt / wt of the coated particles. Wettability can be measured by measuring the contact angle. A lower contact angle (less than 90 °) may indicate greater wettability, whereas a higher contact angle (greater 90 °) may indicate lower wettability. The wettability of the coated particles may be at least more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 110%, more than 120%, more than 130%, more than 140%, more than 150%, more than 200%, more than 300%, more than 400%, more than 500% higher, relative to that of the uncoated particles (drug containing core). The wettability of the coated particles may be at least more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 110%, more than 120%, Attorney Docket No.: 44021852WO01 / 05542-1585WO1 more than 130%, more than 140%, more than 150%, more than 200%, more than 300%, more than 400%, more than 500% lower, compared to that of the uncoated particles (drug containing core). Dispersibility in water may be measured by measuring the zeta potential of particle suspensions. Dispersibility in water may be measured by particle size distributions in water, as measured by laser diffraction. The dispersibility of the coated particles may be at least more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 110%, more than 120%, more than 130%, more than 140%, more than 150%, more than 200%, more than 300%, more than 400%, more than 500% higher, compared to that of the uncoated particles (drug containing core). The dispersibility of the coated particles may be at least more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 110%, more than 120%, more than 130%, more than 140%, more than 150%, more than 200%, more than 300%, more than 400%, more than 500% lower, compared to that of the uncoated particles (drug containing core). The coated particles may have an improved flowability comprising to uncoated drug- containing cores. There may be no significant structural change in the API after the coating process. The API may be intact after the coating process. The coating process may not damage the API. The structure of the API may be assessed by nuclear magnetic resonance (NMR) spectrum analysis. There may be no significant changes in NMR signals before and after the coating process. The structure of the API can be assessed by X-Ray Diffraction (XRD) analysis. There may be no significant changes in XRD signals before and after the coating process. 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 belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 shows a schematic illustration of an exemplary reactor system. FIGs.2A-2B are TEM images of coated superfine acetaminophen particles (LAM-1). The images show laminated aluminum oxide and silicon oxide layers. As shown in FIG.1B, each aluminum oxide coating is about 4.6 nm thick, and each silicon oxide coating is about 1.5 nm thick. FIGs.3A-3B show the dissolution curve when 325 mg coated particles (LAM-1) were dissolved in 900 ml pH 5.8 pbs solution at 37 °C, with a stirring of 50 revolutions per minute (RPM) without (A) and with (B) surfactant FIG.4 shows TEM images of the coated superfine acetaminophen particles (LAM-2) FIG.5 shows the dissolution curve when 325 mg coated particles (LAM-2) were dissolved in 900 ml pH 5.8 PBS solution at 37 °C, with a stirring of 50 revolutions per minute (RPM). FIGs.6A-6C show TEM images of the coated superfine acetaminophen particles (LAM-3). The results show laminated aluminum oxide and silicon oxide coatings. As shown in FIG.6C, each aluminum oxide or silicon oxide coating is about 2.5-2.8 nm thick. The entirety of the laminated aluminum oxide and silicon oxide coating is about 15.3 nm thick. FIGs.7A-7C show the results of EDS analysis results of LAM-3 particles. The results show laminated aluminum oxide and silicon oxide coatings. FIG.8 shows the dissolution curve when 100 mg coated particles (LAM-3) dispersed in 3 ml of 0.5% polysorbate-80 solution) were dissolved in 900 ml PBS buffer of pH6.8 at 37 °C, with a stirring of 50 revolutions per minute (RPM). TMAO3-12 is luminum oxide only coating with same metal oxide wt% as LAM-3. FIGs.9A-9B show TEM images of the coated micronized indomethacin particles (LAM-4). The results show laminated aluminum oxide and silicon oxide coatings. As shown in FIG.9B, each aluminum oxide or silicon oxide coating layer is about 1-2.5 nm thick. The entirety of the laminated aluminum oxide and silicon oxide coating layers is about 18.8 nm thick. FIGs.10A-10C show the EDS analysis results of the coated API particles (LAM-4_. The results show laminated aluminum oxide and silicon oxide coatings. FIG.11 shows the dissolution curve when 65 mg coated particles (LAM-4) dispersed in 3 ml of 0.5% polysorbate-80 solution) were dissolved in 900 ml PBS buffer of pH 7.2 at 37 °C, with a stirring of 50 revolutions per minute (RPM). Attorney Docket No.: 44021852WO01 / 05542-1585WO1 FIG.12 shows TEM images of, coated micronized indomethacin particles )RAOK- 166H) having alternating aluminum oxide and silicon oxide layers. FIG.13 shows the dissolution curves for uncoated micronized indomethacin particles and four different coated particle preparations. DETAILED DESCRIPTION This disclosure provides methods for preparing coated particles comprising a drug- containing core and a laminated coating composed of alternating aluminum oxide and silicon oxide layers in which the innermost layer can be either aluminum oxide or silicon oxide and the outermost layer can likewise be either aluminum oxide or silicon oxide. The laminated coating can be applied by vapor phase deposition (also referred to 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 an earlier applied coating layer) and both conforms to and completely covers (encloses) the particle. The coated particles have a modified drug release profile (modified dissolution rate) compared to the uncoated drug- containing core. The laminated coating can provide several advantages compared to a coating that is composed entirely of aluminum oxide or a coating that is composed entirely of silicon oxide. An aluminum oxide coating layer can slow release of the drug in the core. A silicon oxide coating layer, depending on its thickness, does not appreciably slow release of the drug in the core, but it can provide other advantages. For example, a silicon oxide coating layer produced using 1,2-Bis(diisopropylamino)disilane (BDIPADS) as the precursor and ozone as the oxidant provides a relatively hydrophobic surface. In contrast, both an aluminum oxide coating layer and a silicon oxide coating layer produced using SiCl4as the precursor and water as the oxidant provide a relatively hydrophilic surface. By adjusting the number, thickness and type of coating layers (including the manner in which a silicon oxide layer is created) in a laminated coating, it is possible to the control release rate of the drug in the drug containing core and provide other desirable attributes, for example improved handling characteristics such as improved flowability. While it is often desirable to provide slow release with having relatively thin coating, it can also be desirable to limit the amount of aluminum oxide present in a drug product. Thus, by providing a laminated coating comprising alternating aluminum oxide and silicon oxide coating layers, it is possible to provide a coating that reduces the release rate of the drug and has lower amount of aluminum oxide than a coating entirely composed of aluminum oxide. Because particle dispersion generally increases dissolution rate and uniformity, it can be desirable to have an outer layer Attorney Docket No.: 44021852WO01 / 05542-1585WO1 that is relatively hydrophilic. Finally, the type of innermost layer can impact the 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 easily applied layer. In some cases, the opposite is true and applying an aluminum oxide layer as the innermost layer can provide a more consistent and easily applied layer. Methods for Preparing Pharmaceutical Compositions Comprising Drugs Encapsulated by Laminated Aluminum Oxide Coating and Silicon Oxide Coating In one aspect, the disclosure provides methods for preparing pharmaceutical compositions (e.g., coated particles) comprising a drug-containing core encapsulated by a laminated (alternating layers) aluminum oxide coating and silicon oxide coating. A drug-containing core can be first coated with an aluminum oxide coating layer, and then coated with silicon oxide coating layer. The process can stop there or additional alternating coating layers can be applied ending with either an aluminum oxide coating layer or silicon oxide coating layer. A drug-containing core can be first coated with silicon oxide coating layer, and then coated with an aluminum oxide coating layer. The process can stop there or additional alternating coating layers can be applied ending with either an aluminum oxide coating layer or silicon oxide coating layer. The last coating layer applied can be aluminum oxide, and the outer surface of the coated particles can be an aluminum oxide coating. The last coating layer applied can be silicon oxide, and the outer surface of the coated particles can be a silicon oxide coating. The first coating layer applied can be aluminum oxide, and an aluminum oxide coating can be directly applied to uncoated particles (drug containing core). The first coating layer applied can be silicon oxide, and a silicon oxide coating can be directly applied to uncoated particles (drug containing core). The aluminum precursor can be trimethylaluminum (TMA). The silicon precursor can be 1,2-Bis(diisopropylamino)disilane (BDIPADS) and the oxidant can be ozone or the silicon precursor can be silicon tetrachloride and the oxidant can be water. The drug release rate of the coated particles may be adjusted by changing the chemical composition (e.g., aluminum oxide vs. silicon oxide) of the outer layer of the coated particles. The drug release rate of the coated particles may be adjusted by changing the thickness or number of the aluminum oxide layers and thickness or number of the silicon oxide layers. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 Methods for Aluminum Oxide Coating Each aluminum oxide coating layer can be applied using vapor phase deposition as described herein. The aluminum precursor can be trimethylaluminum (TMA). The oxidant can be ozone or water. A first exemplary aluminum oxide coating method includes the sequential steps of: (a) loading the particles comprising the drug into a reactor, (b) applying a vaporous or gaseous aluminum precursor (e.g., TMA) to the particles in the reactor, (c) performing one or more pump-purge cycles of the reactor using inert gas, (d) applying a vaporous or gaseous oxidant (e.g., ozone or water) to the substrate in the reactor, and (e) performing one or more pump- purge cycles of the reactor using inert gas. The precursor and the oxidant can be applied by pulsing the precursor or oxidant into the reactor. The sequential steps (b)-(e) may be repeated one or more times to increase the total thickness of the aluminum oxide layer. The reactor pressure may be allowed to stabilize following step (a), step (b), and / or step (d). The reactor contents may be agitated prior to and / or during step (b), step (c), and / or step (e). A portion or essentially all of the vapor or gaseous content may be pumped out prior to step (c) and / or step (e). The same method (usually omitting step (a) since the particles can remain in the reactor) can be used to apply an aluminum oxide coating layer to a drug-containing particle that has a silicon oxide outer coating layer. The particles can be agitated during some or all of the steps to assist in providing a uniform coating layer. A second exemplary aluminum oxide coating method includes the sequential steps of (a) loading the particles comprising the drug into a reactor, (b) reducing the reactor pressure to less than 50 mTorr, (c) agitating the reactor contents until the reactor contents have a desired moisture content, (d) pressurizing the reactor to at least 2 Torr by adding a vaporous or gaseous aluminum precursor (e.g., TMA), (e) allowing the reactor pressure to stabilize, (f) agitating the reactor contents, (g) pumping out a portion or essentially all of the vapor or gaseous content and determining when to stop pumping based on analysis of content in reactor, (h) performing a sequence of pump-purge cycles of the reactor using inert gas, (i) pressuring the reactor to 2 Torr by adding a vaporous or gaseous oxidant (e.g., water or ozone), (j) allowing the reactor pressure to stabilize, (k) agitating the reactor contents, (l) pumping out a portion or essentially all of the vapor or gaseous content and determining when to stop pumping based on analysis of content in reactor and (m) performing a sequence of pump-purge cycles of the reactor using inert gas. The precursor and the oxidant can be applied by pulsing the precursor or oxidant into the reactor. The sequential steps (b)-(m) may Attorney Docket No.: 44021852WO01 / 05542-1585WO1 be repeated one or more times to increase the total thickness of the aluminum oxide layer, The same method (usually omitting step (a) since the particles can remain in the reactor) can be used to apply an aluminum oxide coating layer to a drug-containing particle that has a silicon oxide outer coating layer. The particles can be agitated during some or all of the steps to assist in providing a uniform coating layer. Methods for Silicon Oxide Coating Each silicon oxide coating can be applied using vapor phase deposition as described herein. The silicon precursors can be SiCl4 or 1,2-Bis(diisopropylamino)disilane (BDIPADS). Where When SiCl4 is used, water is the oxidant. When BDIPAS is used, ozone is the oxidant. The silicon oxide coating may be applied directly to uncoated particles or may be applied to the aluminum oxide coated particles described herein. The drug-containing core may be first coated with an aluminum oxide layer and then coated with a silicon oxide layer. A first exemplary silicon oxide coating method includes the sequential steps of: (a) loading the particles comprising the drug into a reactor, (b) applying a vaporous or gaseous silicon precursor (BDIPADS) to the substrate in the reactor, (c) performing one or more pump-purge cycles of the reactor using inert gas, (d) applying a vaporous 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 inert gas. The precursor and the oxidant can be applied by pulsing the precursor or oxidant into the reactor. The sequential steps (b)-(e) may be repeated one or more times to increase the total thickness of the silicon oxide layer. The reactor pressure may be allowed to stabilize following step (a), step (b), and / or step (d). The reactor contents may be agitated prior to and / or during step (b), step (c), and / or step (e). A portion or essentially all of the vapor or gaseous content may be pumped out prior to step (c) and / or step (e). The same method (usually omitting step (a) since the particles can remain in the reactor) can be used to apply an silicon oxide layer to a drug-containing particle that has an aluminum oxide outer coating layer. The particles can be agitated during some or all of the steps to assist in providing a uniform coating layer. A second exemplary silicon oxide coating method includes the sequential steps of (a) loading the particles comprising the drug into a reactor, (b) reducing the reactor pressure to less than 50 mTorr, (c) agitating the reactor contents until the reactor contents have a desired moisture content, (d) pressurizing the reactor to at least 0.3 Torr by adding a vaporous or gaseous silicon precursor, BDIPADS, (e) allowing the reactor pressure to stabilize, (f) Attorney Docket No.: 44021852WO01 / 05542-1585WO1 agitating the reactor contents, (g) pumping out a subset of vapor or gaseous content and determining when to stop pumping based on analysis of content in reactor, (h) performing a sequence of pump-purge cycles of the reactor using insert gas, (i) pressuring the reactor to 8 Torr by adding gaseous oxidant (e.g., ozone), (j) allowing the reactor pressure to stabilize, (k) agitating the reactor contents, (l) pumping out a portion or essentially all of the vapor or gaseous content and determining when to stop pumping based on analysis of content in reactor and (m) performing a sequence of pump-purge cycles of the reactor using inert gas. The precursor and the oxidant can be applied by pulsing the precursor or oxidant into the reactor. The sequential steps (b)-(m) may be repeated one or more times to increase the total thickness of the silicon oxide layer. The same method (usually omitting step (a) since the particles can remain in the reactor) can be used to apply an silicon oxide layer to a drug- containing particle that has an aluminum oxide outer coating layer. The particles can be agitated during some or all of the steps to assist in providing a uniform coating layer. A third exemplary silicon oxide coating method includes the sequential steps of (a) loading the particles comprising the drug into a reactor, (b) reducing the reactor pressure to less than 50m Torr, (c) agitating the reactor contents until the reactor contents have a desired moisture content, (d) pressurizing the reactor to at least 20 Torr by adding a vaporous or gaseous silicon precursor, silicon tetrachloride, (e) allowing the reactor pressure to stabilize, (f) agitating the reactor contents, (g) pumping out a subset of vapor or gaseous content and determining when to stop pumping based on analysis of content in reactor, (h) performing a sequence of pump-purge cycles of the reactor using insert gas, (i) pressuring the reactor to 4 Torr by adding a water vapor (oxidant), (j) allowing the reactor pressure to stabilize, (k) agitating the reactor contents, (l) pumping out a portion or essentially all of the vapor or gaseous content and determining when to stop pumping based on analysis of content in reactor and (m) performing a sequence of pump-purge cycles of the reactor using insert gas. The precursor and the oxidant can be applied by pulsing the precursor or oxidant into the reactor. The sequential steps (b)-(m) may be repeated one or more times to increase the total thickness of the silicon oxide layer. The same method (usually omitting step (a) since the particles can remain in the reactor) can be used to apply an silicon oxide layer to a drug- containing particle that has an aluminum oxide outer coating layer. The particles can be agitated during some or all of the steps to assist in providing a uniform coating layer. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 Uncoated particles (drug-containing core) The uncoated particles (drug-containing core) may consist of the drug (API). The uncoated particles (drug-containing core) may further contain one or more pharmaceutically acceptable excipients. The terms “drug” and “API” as used herein include all small molecule APIs, in particular APIs that are organic molecules. The drug can be selected from the group consisting of an analgesic, an anesthetic, an anti-inflammatory agent, an anthelmintic, an anti- arrhythmic agent, an antiasthma agent, an antibiotic, an anticancer agent, an anticoagulant, an antidepressant, an antidiabetic agent, an antiepileptic, an antihistamine, an antitussive, an antihypertensive agent, an antimuscarinic agent, an antimycobacterial agent, an antineoplastic agent, an antioxidant agent, an antipyretic, an immunosuppressant, an immunostimulant, an antithyroid agent, an antiviral agent, an anxiolytic sedative, a hypnotic, a neuroleptic, an astringent, a bacteriostatic agent, a beta-adrenoceptor blocking agent, a blood product, a blood substitute, a bronchodilator, a buffering agent, a cardiac inotropic agent, a chemotherapeutic, a contrast media, a corticosteroid, a cough suppressant, an expectorant, a mucolytic, a diuretic, a dopaminergic, an antiparkinsonian agent, a free radical scavenging agent, a growth factor, a haemostatic, an immunological agent, a lipid regulating agent, a muscle relaxant, a parasympathomimetic, a parathyroid calcitonin, a biphosphonate, a prostaglandin, a radio-pharmaceutical, a hormone, a sex hormone, an anti-allergic agent, an appetite stimulant, an anoretic, a steroid, a sympathomimetic, a thyroid agent, a vaccine, a vasodilator and a xanthine. The method can be used to coat particles containing a biological molecule, e.g., a protein (for example an antibody) or a nucleic acid (for example, DNA or RNA). The API may be crystalline or amorphous. The uncoated particles may contain at least 50% wt / wt API. The uncoated particles may contain at least 70%, 80%, 90%, 99% or 100% wt / wt API. The uncoated particles (drug-containing core) 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. The uncoated particles may have a D10 of more than 0.1 μm, more than 0.2 μm, more than 0.5 μm, more than 1 μm, more than 2 μm, more than 5 μm, more than 10 μm, more than 20 μm, or more than 50 μm, on a volume average basis. The uncoated particles may have a Dv10 of 0.1 μm to 200 μm, 0.1 ^m to 1 ^m, 0.1 ^m to 10 ^m, or 0.1 ^m to 50 ^m on a volume average basis. The uncoated particles may have a Dv10 of about 2 ^m on a volume average basis. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 The 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. The uncoated particles may have a Dv50 of more than 0.1 μm, more than 0.2 μm, more than 0.5 μm, more than 1 μm, more than 2 μm, more than 5 μm, more than 10 μm, more than 20 μm, or more than 50 μm, on a volume average basis. The uncoated particles may have a Dv50 of 0.1 μm to 200 μm, 0.1 ^m to 1 ^m, 0.1 ^m to 10 ^m, or 0.1 ^m to 50 ^m on a volume average basis. The uncoated particles may have a D50 of about 0.1 - 50, 10 - 50 or 10 – 30 ^m on a volume average basis. The 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. The uncoated particles may have a D90 of more than 0.1 μm, more than 0.2 μm, more than 0.5 μm, more than 1 μm, more than 2 μm, more than 5 μm, more than 10 μm, more than 20 μm, or more than 50 μm, on a volume average basis. The uncoated particles may have a Dv90 of 200 μm to 2000 μm on a volume average basis. The uncoated particles may have a Dv50 of 0.1 μm to 200 μm, 0.1 ^m to 1 ^m, 0.1 ^m to 10 ^m, or 0.1 ^m to 50 ^m on a volume average basis. The uncoated particles may have a Dv90 of about 9.2 ^m on a volume average basis. Vapor Phase Deposition The coatings are applied by vapor phase deposition using a precursor molecule (e.g., ,2-Bis(diisopropylamino)disilane (BDIPADS), SiCl4or 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 an earlier applied coating layer) and both conforms to and completely covers the particle. Vapor phase deposition of metal oxides and metalloid oxides is sometimes referred to as atomic layer deposition (ALD). However, depending on a number of factors, including the surface being coated, each cycle of the deposition reaction does not necessarily deposit one atomic layer during each reaction cycle. Thus, the process is sometimes referred to as atomic layer coating. Reactor System The term “reactor system” in its broadest sense includes all systems that could be used to perform vapor phase deposition or atomic layer deposition. An exemplary reactor system is illustrated in FIG.1 and further described below. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 The reactor system 10 can perform vapor phase deposition or atomic layer deposition. The reactor system 10 permits the process to be performed at higher (above 50 ºC, e.g., 50- 100 ºC or higher) or lower operating temperature, e.g., below 50 ºC, e.g., at or below 25 ºC. For example, the reactor system 10 can form thin-film aluminum oxide or silicon oxide on the particles primarily at temperatures of 40-80 ºC, e.g., 40 ºC or 80 ºC. In general, the particles can remain or be maintained at such temperatures. This can be achieved by having the reactants and / or the interior surfaces of the reactor chamber (e.g., the chamber 20 and drum 40 discussed below) remain or be maintained at such temperatures. Again, illustrating a vapor phase deposition or atomic layer deposition process, the reactor system 10 includes a stationary vacuum chamber 20 which is coupled to a vacuum pump 24 by vacuum tubing 22. The vacuum pump 24 can be an industrial vacuum pump sufficient to establish pressures less than 1 Torr, e.g., 1 to 100 mTorr, e.g., 50 mTorr. The vacuum pump 24 permits the chamber 20 to be maintained at a desired pressure and permits removal of reaction byproducts and unreacted process gases. In operation, the reactor 10 performs the vapor phase deposition or atomic layer deposition process by introducing a gaseous oxidant and aluminum (or silicon) precursor into the chamber 20. The gaseous oxidant and aluminum (or silicon) precursor are introduced alternatively into the reactor. In addition, the reaction can be performed at low temperature conditions, such as below 80 ºC, e.g., below 50 ºC, below 30 ºC, or below 25 ºC. The operating temperature may be about 50 °C. The operating temperature may be above 5 °C, above 10 °C, 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. The operating temperature may 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. The 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 by respective delivery lines 34a, 34b, 34c and controllable valves 36a, 36b, 36c to the vacuum chamber 20. The chemical delivery system 30 can include a combination of restrictors, gas flow controllers, pressure transducers, and ultrasonic flow meters to provide controllable flow rate of the various gasses into the chamber 20. The chemical delivery system 30 can also include one or more temperature control components, e.g., a heat exchanger, resistive heater, heat lamp, etc., to heat or cool the various gasses before they flow into the chamber 20. Although FIG.1 illustrates separate gas lines extending in parallel to the chamber for each gas source, Attorney Docket No.: 44021852WO01 / 05542-1585WO1 two or more of the gas lines could be joined, e.g., by one or more three-way valves, before the combined line reaches the chamber 20. One of the gas sources can provide an oxidant. In particular, a gas source can provide a vaporous or gaseous oxidant. For example, the oxidant can be ozone. As another example, the oxidant can be water vapor. One of the gas sources can be an aluminum (or silicon) precursor. In particular, a gas source can provide a vaporous 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. One of the gas sources can provide a purge gas. In particular, the third gas source can provide a gas that is chemically inert to the oxidant and aluminum (or silicon) precursor, the coating, and the particles being processed. For example, the purge gas can be N2, or a noble gas, such as argon. A rotatable coating drum 40 is held inside the chamber 20. The drum 40 can be connected by a drive shaft 42 that extends through a sealed port in a side wall of the chamber 20 to a motor 44. The motor 44 can rotate the drum at speeds of 1 to 100 rpm. Alternatively, the drum can be directly connected to a vacuum source through a rotary union. The particles to be coated, shown as a particle bed 50, are placed in an interior volume 46 of the drum 40. The drum 40 and chamber 20 can include sealable ports (not illustrated) to permit the particles to be placed into and removed from the drum 40. The body of the drum 40 is provided by one or more of a porous material, a solid metal, and a perforated metal. The pores through the cylindrical side walls of the drum 40 can have a dimension of 1-10 μm. In operation, one of the gasses flows into chamber 20 from the chemical delivery system 30 as the drum 40 rotates. A combination of pores (1-100 um), holes (0.1-10 mm), or large openings in the coating drum 40 serve to confine the particles in the coating drum 40 while allowing rapid delivery of precursor chemistry and the pumping of byproducts or unreacted species. Due to the pores in the drum 40, the gas can flow between the exterior of the drum 40, i.e., the reactor chamber 20, and the interior of the drum 40. In addition, rotation of the drum 40 agitates the particles to expose new surfaces of the powder bed, ensuring a large surface area of the particles remains exposed to the process gas. This permits fast, uniform interaction of the particle surface with the process gas. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 One or more temperature control components can be integrated into the drum 40 to permit control of the temperature of the drum 40. For example, a resistive heater, a thermoelectric cooler, or other component can be in or on the side walls of the drum 40. The reactor system 10 also includes a controller 60 coupled to the various controllable components, e.g., vacuum pump 24, gas delivery system 30, motor 44, a temperature control system, etc., to control operation of the reactor system 10. The controller 60 can also be coupled to various sensors, e.g., pressure sensors, flow meters, etc., to provide closed loop control of the pressure of the gasses in the chamber 20. In general, the controller 60 can operate the reactor system 10 in accord with a “recipe.” The recipe specifies an operating value for each controllable element as a function of time. For example, the recipe can specify the times during which the vacuum pump 24 is to operate, the times of and flow rate for each gas source 32a, 32b, 32c, the rotation rate of the motor 44, etc. The controller 60 can receive the recipe as computer-readable data (e.g., that is stored on a non-transitory computer readable medium). The controller 60 and other computing device parts of systems described herein can be implemented in digital electronic circuitry, or in computer software, firmware, or hardware. For example, the controller can include a processor to execute a computer program as stored in a computer program product, e.g., in a non-transitory machine-readable storage medium. Such a computer program (also known as a program, software, software application, or code) can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a standalone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. The controller 60 can be a general-purpose programmable computer. The controller can be implemented using special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit). Operation Initially, uncoated particles are loaded into the drum 40 in the reactor system 10. The uncoated particles can be purely particles of a drug (or a combination of particles of a first drug and a second drug) or a mixture of particles of a drug (or a combination of particles of a first drug and a second drug) and particles of an excipient. The uncoated particles can be composed of one or more drugs (e.g., one of the drugs discussed above) and one or more excipients. Once any access ports are sealed, the controller 60 operates the reactor system 10 Attorney Docket No.: 44021852WO01 / 05542-1585WO1 according to the recipe in order to form the thin-film aluminum (or silicon) oxide on the particles. In particular, the oxidant and the aluminum (or silicon) precursor can be alternately supplied to the chamber 20, with each step of supplying an oxidant or the aluminum (or silicon) precursor followed by a purge cycle in which the inert gas is supplied to the chamber 20 to force out the excessive oxidant or aluminum (or silicon) precursor and by-products used in the prior step. Moreover, one or more of the gases (aluminum (or silicon) precursor gases and / or the inert gas and / or oxidant gas) can be supplied in pulses in which the chamber 20 is filled with the gas to a specified pressure, a holding time is permitted to pass, and the chamber is evacuated by the vacuum pump 24 before the next pulse commences. In particular, the controller 60 can operate the reactor system 10 as follows. In an aluminum (or silicon) precursor half-cycle, while the motor 44 rotates the drum 40 to agitate the particles 50: i) The gas delivery system 30 is operated to flow the aluminum (or silicon) precursor gas, e.g., trimethylaluminum (TMA), silicon tetrachloride or 1,2- Bis(diisopropylamino)disilane (BDIPADS), from the source 32a into the chamber 20 until a first specified pressure is achieved. The specified pressure can be 0.1 Torr to half of the saturation pressure of the aluminum (or silicon) precursor gas (e.g., 0.3-20 torr). ii) Flow of the aluminum (or silicon) precursor is halted, and a specified holding time (e.g., 60 seconds) is permitted to pass, e.g., as measured by a timer in the controller. This permits the aluminum (or silicon) precursor to flow through the particle bed in the drum 40 and react with the surface of the particles 50 inside the drum 40. iii) The vacuum pump 50 evacuates the chamber 20, e.g., down to pressures below 1 Torr, e.g., to 1 to 100 mTorr, e.g., 50 mTorr. Next, in a first purge cycle, while the motor 44 rotates the drum to agitate the particles 50: iv) The gas delivery system 30 is operated to flow the inert gas, e.g., N2, from the source 32c into the chamber 20 until a second specified pressure is achieved. The second specified pressure can be 1 to 100 Torr. v) Flow of the inert gas is halted, and a specified delay time is permitted to pass, e.g., as measured by the timer in the controller. This permits the inert gas to flow through the pores in the drum 40 and diffuse through the particles 50 to displace the aluminum (or silicon) precursor gas and any vaporous by-products. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 vi) The vacuum pump 50 evacuates the chamber 20, e.g., down to pressures below 1 Torr, e.g., to 1 to 500 mTorr, e.g., 50 mTorr. These steps (iv)-(vi) can be repeated a number of times set by the recipe, e.g., six to twenty times, e.g., sixteen times. In an oxidant half-cycle, while the motor 44 rotates the drum 40 to agitate the particles 50: vii) The gas delivery system 30 is operated to flow the oxidant (e.g., water or ozone), from the source 32a into the chamber 20 until a third specified pressure is achieved. The third pressure can be 0.1 Torr to half of the saturation pressure of the oxidant gas (e.g., 2-8 torr). viii) Flow of the oxidant is halted, and a specified holding time is permitted to pass, e.g., as measured by the timer in the controller. This permits the oxidant to flow through the pores in the drum 40 and react with the surface of the particles 50 inside the drum 40. ix) The vacuum pump 50 evacuates the chamber 20, e.g., down to pressures below 1 Torr, e.g., to 1 to 500 mTorr, e.g., 50 mTorr. Next, a second purge cycle is performed. This second purge cycle can be identical to the first purge cycle, or can have a different number of repetitions of the steps (iv)-(vi) and / or different delay time and / or different pressure. The cycle of the aluminum (or silicon) precursor half-cycle, first purge cycle, oxidant half cycle and second purge cycle can be repeated a number of times set by the recipe, e.g., one to ten times. As noted above, the coating process can be performed at a low operating temperature, e.g., below 80 ºC, e.g., at or below 50 ºC, at or below 35 ºC, or at or below 25 ºC. The operating temperature 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. The operating temperature can be about 50 °C. The operating temperature can be: 20 °C to 100 °C, 80 °C 70 °C, 60 °C or 50 °C. The operating temperature 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. In particular, the particles can remain or be maintained at such temperatures during all of steps (i)-(ix) noted above. In general, the temperature of the interior of the reactor chamber does not exceed 80°C during of steps (i)-(ix). This can be achieved by having the oxidant gas, aluminum (or silicon) precursor gas and inert gas be injected into the chamber at such temperatures during the respective cycles. In addition, Attorney Docket No.: 44021852WO01 / 05542-1585WO1 physical components of the chamber can remain or be maintained at such temperatures, e.g., using a cooling system, e.g., a thermoelectric cooler, if necessary. Pharmaceutical Compositions Also provided herein are pharmaceutical compositions that contain the coated particles. The pharmaceutical compositions can be formulated in any suitable manner known in the art. The pharmaceutical compositions can be in the form of tablets, capsules, powders, microparticles, granules, syrups, suspensions, solutions, nasal spray, transdermal patches, injectable solutions, or suppositories. Pharmaceutical compositions are formulated to be compatible with their intended route of administration (e.g., oral, intravenous, intraarterial, intramuscular, intradermal, subcutaneous, or intraperitoneal). The compositions can include a sterile diluent (e.g., sterile water or saline), a fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvents, antibacterial or antifungal agents (e.g., benzyl alcohol or methyl parabens, 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), polyalcohols (e.g., mannitol or sorbitol), and salts (e.g., sodium chloride)), or any combination thereof. Liposomal suspensions can also be used as pharmaceutically acceptable carriers.Preparations of the compositions can be formulated and enclosed in ampules, disposable syringes, or multiple dose vials. Where required (as in, for example, injectable formulations), proper fluidity can be maintained by, for example, the use of a coating (e.g., lecithin) or a surfactant. Controlled release can be achieved by implants and microencapsulated delivery systems, which can include biodegradable, biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid). Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present disclosure include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine), sorbic acid, potassium sorbate, partial glyceride mixtures 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, polyvinyl pyrrolidone, cellulose-based substances, Attorney Docket No.: 44021852WO01 / 05542-1585WO1 polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol, and wool fat. The compositions or dosage forms can contain the coated particles described herein in the range of 0.001% to 100% (e.g., 0.1-95%, 20-80%, or 75-85%) with the balance made up from the suitable pharmaceutically acceptable excipients. The methods described herein may simply the formulation process or other manufacturing process of a pharmaceutical composition. The methods described herein may eliminate the need to include additional detergents in the final formulation. EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Example 1: AlOx / SiOx / AlOx / SiOx laminated coating on semi-fine acetaminophen (LAM-1) Alternating aluminum oxide (AlOx) and silicon oxide (SiOx) coating layers were applied to uncoated particles (drug-containing core) using the parameters listed in the table below. As shown Table 1, the method entailed: (1) applying an aluminum oxide coating layer; (2) applying a silicon oxide coating layer; (3) applying an aluminum oxide coating layer; and (4) applying a silicon oxide coating layer. The operating temperature was 50 °C. Table 1 Coating Parameters for LAM-1 To evaluate if encapsulation of API with laminated aluminum oxide and silicon oxide coating layers altered the structure of the API or changed the properties of the API particles, the coated particles were subjected to various analysis. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 Thermogravimetric Analysis (TGA%) analysis Table 1 shows the TGA analysis results of the coated API particles. As shown in Table 1, the total inorganic material constitutes about 1.49% of the coated particles. Transmission Electron Microscopy (TEM) analysis FIGs.2A-2B show the TEM images of the coated API particles. The results show laminated aluminum oxide and silicon oxide coatings. As shown in FIG.2B, each aluminum oxide coating is about 4.6 nm thick, and each silicon oxide coating is about 1.5 nm thick. Release over time (dissolution) analysis FIG.3A shows the dissolution curve when 325 mg of coated particles (LAM-1) was added to 900 ml of a pH 6.8 phosphate buffered saline (PBS) solution at 37 °C, stirred at 50 RPM. FIG 3A shows the API coated with laminated film with an outer SiO2coating layer. The outer layer was produced using BDIPAS as the precursor and ozone as the oxidant. The outer surface is hydrophobic surface, thus, in the absence of surfactant, the particles do not disperse in the buffer. This limits release. FIG.3B shows the release after adding 0.5% surfactant Polysorbate-80 in the dissolution media. Table 2 Dissolution Test Results Example 2: AlOx / SiOx / AlOx / SiOx / AlOx laminated coating on semi-fine acetaminophen (LAM-2) Alternating aluminum oxide coating and silicon oxide coating layers were applied to uncoated particles (drug-containing core) using the parameters listed in Table 3. As shown in Table 3, the method entailed: (1) applying an aluminum oxide coating layer; (2) applying a silicon oxide coating layer; (3) applying an aluminum oxide coating layer; (4) applying a silicon oxide coating layer; and (5) applying an aluminum oxide coating layer. The operating temperature was 50 °C. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 Table 3 Coating Parameters for LAM-2 To evaluate if encapsulation of API by laminated aluminum oxide and silicon oxide coating layers altered the structure of the API or changed the properties of the API particles, the coated particles were subjected to various analysis. Thermogravimetric Analysis (TGA%) analysis Table 3 shows the TGA analysis results of the coated API particles. As shown in Table 3, the total inorganic material constitutes about 1.63% of the coated particles. Transmission Electron Microscopy (SEM) analysis FIG.4 shows a SEM image of the coated API particles. The results show laminated aluminum oxide and silicon oxide coatings. As shown in FIG.4, each aluminum oxide or silicon oxide coating is about 2-6 nm thick. The entirety of the laminated aluminum oxide and silicon oxide coating is about 23 nm thick. Release over time (dissolution) analysis FIG.5 shows the dissolution curve when 325 mg of coated particles (LAM-2) was added to 900 ml pH 5.8 PBS solution at 37 °C and stirred at 50 rpm. Example 3: AlOx / SiOx / AlOx / SiOx on semi-fine acetaminophen (LAM-3) Alternating aluminum oxide coating and silicon oxide coating layers were applied to uncoated particles (drug-containing core) using the parameters listed in the table below. As shown in Table 4, the method entailed: (1) applying an aluminum oxide coating layer; (2) Attorney Docket No.: 44021852WO01 / 05542-1585WO1 applying a silicon oxide coating layer; (3) applying an aluminum oxide coating layer; and (4) applying a silicon oxide coating layer. The operating temperature was 50 °C. Table 4 Coating Parameters for LAM-3 To evaluate if encapsulation of API by laminated aluminum oxide and silicon oxide coatings altered the structure of the API or changed the properties of the API particles, the coated particles were subjected to various analysis. Thermogravimetric Analysis (TGA%) analysis Table 4 shows the TGA analysis results of the coated API particles. As shown in Table 5, the total inorganic material constitutes about 1.6% of the coated particles. Transmission Electron Microscopy (TEM) analysis FIGs.6A-6C show TEM images of the coated API particles. The results show laminated aluminum oxide and silicon oxide coatings. As shown in FIG.6C, each aluminum oxide or silicon oxide coating layer is about 2.5-2.8 nm thick. The entirety of the laminated aluminum oxide and silicon oxide coating is about 15.3 nm thick. Energy Dispersive Spectroscopy (EDS) analysis FIGs.7A-7C show the EDS analysis results of the coated API particles. The results show laminated aluminum oxide and silicon oxide coatings. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 Release over time (dissolution) analysis FIG.8 shows the dissolution curve when 100 mg coated particles (LAM-3 dispersed in 3 ml of 0.5% polysorbate-80 solution) were add to 900 ml PBS buffer (pH 6.8) at 37 °C and stirred at 50 RPM. TMAO3-12 is aluminum oxide coated semi-fine acetaminophen with same TGA wt% as LAM-3. The detailed dissolution test results are shown in Table 5 and Table 6, below. With similar oxide content wt%, the laminated film shows slower release compared with aluminum oxide only film on semi-fine acetaminophen . Table 5 Dissolution Test Results for LAM-3 Table 6 Dissolution Test Results for TMAO3-12 Example 4: AlOx / SiOx / AlOx / SiOx / AlOx / SiOx / AlOx on micronized indomethacin (LAM-4) Alternating aluminum oxide coating and silicon oxide coating layers were applied to uncoated particles (drug-containing core) using the parameters listed in Table 7. As shown in the Table 7, the method included: (1) applying an aluminum oxide coating layer; (2) applying a silicon oxide coating layer; (3) applying an aluminum oxide coating layer; (4) applying a silicon oxide coating layer; (5) applying an aluminum oxide coating layer; (6) applying a Attorney Docket No.: 44021852WO01 / 05542-1585WO1 silicon oxide coating layer; (7) applying an aluminum oxide coating layer. The operating temperature was 50 °C. Table 7 Coating Parameters for LAM-4 To evaluate if encapsulation of API by laminated aluminum oxide and silicon oxide coatings altered the structure of the API or changed the properties of the API particles, the coated particles were subjected to various analysis. Thermogravimetric Analysis (TGA%) analysis Table 7 shows the TGA analysis results of the coated API particles. As shown in Table 7, the total inorganic material constitutes about 4.5% of the coated particles. Transmission Electron Microscopy (TEM) analysis FIGs.9A-9B show TEM images of the coated API particles. The results show laminated aluminum oxide and silicon oxide coatings. As shown in FIG.9B, each aluminum oxide or silicon oxide coating is about 1-2.5 nm thick. The entirety of the laminated aluminum oxide and silicon oxide coating is about 18.8 nm thick. Attorney Docket No.: 44021852WO01 / 05542-1585WO1 Energy Dispersive Spectroscopy (EDS) analysis FIGs.10A-10C show the EDS analysis results of the coated API particles. The results show laminated aluminum oxide and silicon oxide coatings. As shown in FIG.10B, each aluminum oxide or silicon oxide coating is about 1-2.5 nm thick. Release over time (dissolution) analysis FIG.11 shows the dissolution curve when 65 mg of coated particles (LAM-4 dispersed in 3 ml of 0.5% polysorbate-80 solution) were added to 900 ml PBS buffer of pH 7.2 at 37 °C and stirred at 50 RPM.The detailed dissolution results are shown in the table below. Slow release is demonstrated with laminated film on m-IMC. Table 8 Dissolution Test Results for LAM-4 Example 5: SiOx / AlOx / SiOx / AlOx / SiOx / AlOx on on micronized indomethacin compared with Aluminum oxide only coated on micronized indomethacin FIG.12 shows TEM images of RAOK-166H, micronized indomethacin particles having alternating aluminum oxide and silicon oxide layers (six total layers with a silicon oxide innermost layer and an aluminum oxide outermost layer; silicon oxide layers formed using SiCl4 as the precursor and water as the oxidant). As shown in FIG.12, each aluminum oxide or silicon oxide coating layer is about 4-5 nm thick. The entirety of the laminated aluminum oxide and silicon oxide coating is about 28.2 nm thick (3.88 wt% AlOx; 3.22 wt% SiOx). ROAK-166F was prepared in the same manner is expect that each coating layer is thinner resulting in a lower wt% of aluminum oxide and silicon oxide (2.57 wt% AlOx; 1.89 wt% SiOx). Two different aluminum oxide only coated particles were created: ROA-074A (4.91 wt% AlOx) and ROAK-074B (7.06 wt% AlOx) Attorney Docket No.: 44021852WO01 / 05542-1585WO1 FIG. 13 shows the dissolution curves for each of the four particle preparations. The release profile shows that uncoated particles have essentially instant release. While the laminated and aluminum oxide only coated particles have extended-release profiles. The higher the oxide content, the slower the release profile. With the same oxide content, the laminated aluminum oxide and silicon oxide coated exhibit faster release then aluminum oxide only coated particles. This is in contrast to the comparison of on aluminum oxide only and laminated aluminum oxide and silicon oxide particles where the silicon oxide particles were created using a BDIPAS / O3process on semi-fine acetaminophen where the laminated particles exhibited slower release than the aluminum oxide only coated particles. OTHER EMBODIMENTS It is to be understood that while the invention has been described in conjunction with the detailed description thereof, 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 following claims.

Claims

Attorney Docket No.: 44021852WO01 / 05542-1585WO1 WHAT IS CLAIMED IS:

1. A coated particle comprising a drug-containing core enclosed by (1) one or more aluminum oxide coating layers, and (2) one or more silicon oxide coating layers, wherein the drug-containing core comprises an organic active pharmaceutical ingredient (API), the aluminum oxide coating layers and the silicon oxide coating layers alternate and there are at least three coating layers.

2. The coated particle of claim 1, wherein each aluminum oxide coating layer independently has a thickness of about 1 nm - 5 nm or 1 nm – 10 nm.

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

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

5. The coated particle of claim 1, wherein the outermost coating layer is an aluminum oxide coating layer.

6. The coated particle of claim 1, wherein the outermost coating layer is a silicon oxide coating layer.

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

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

9. The coated particle of claim 1, wherein the one or more aluminum oxide coating layers are continuous and conformal.Attorney Docket No.: 44021852WO01 / 05542-1585WO1 10. The coated particle of claim 1, wherein the one or more silicon oxide coating layers are continuous and conformal.

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

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

13. The coated particle of claim 1, wherein the aluminum oxide coating layers and the silicon oxide coating layers collectively constitute 2%-10% wt / wt of the coated particle.

14. The coated particle of claim 1, wherein the aluminum oxide coating layers and the silicon oxide coating layers collectively constitute 1%-5% wt / wt of the coated particle.

15. The coated particle of claim 1, wherein the coated particle comprises two or more aluminum oxide coating layers and two or more silicon oxide coating layers.

16. The coated particle of claim 1, wherein the collective thickness of the aluminum oxide coating layers and silicon oxide coating layers is about 1 nm to 50 nm.

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

18. The coated particle of claim 1, wherein there are at least two aluminum oxide coating layers.

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

20. The coated particle of claim 1, wherein there are at least three aluminum oxide coating layers.Attorney Docket No.: 44021852WO01 / 05542-1585WO1 21. The coated particle of claim 1, wherein the total thickness of all of the coating layers is 5 – 50 nm.

22. The coated particle of claim 1, wherein the coated particle has a slower drug release rate comparing to drug-containing core.

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

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

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

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

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

28. The coated particle of claim 1, wherein the coated particle has a drug release rate of about 30-90% drug release in 30 minutes.

29. The coated particle of claim 1, wherein the coated particle has a drug release rate of about 30-40% drug release in 30 minutes.

30. The coated particle of claim 1, wherein the coated particle has a drug release rate of about 70-90% drug release in 30 minutes.Attorney Docket No.: 44021852WO01 / 05542-1585WO1 31. A method of preparing coated particles comprising a drug-containing core enclosed by (1) one or more aluminum oxide coating layers, and (2) one or more silicon oxide coating layers, wherein the drug-containing core comprises an API, the method comprising the sequential steps of: (a) loading particles comprising an API into a chamber of a reactor; (b) applying an aluminum oxide coating layer by performing the following steps: (b1) applying a vaporous or gaseous aluminum precursor to the particles in the reactor; (b2) performing one or more pump-purge cycles using an inert gas; (b3) applying a vaporous or gaseous oxidant to the particles in the reactor; (b4) performing one or more pump-purge cycles using an inert gas; and (b5) repeating steps (b1) – (b4) at least once to provide an aluminum oxide coating layer; (c) applying a silicon oxide coating layer by performing the following steps: (c1) applying a vaporous or gaseous silicon precursor to the particles in the reactor; (c2) performing one or more pump-purge cycles using an inert gas; (c3) applying a vaporous or gaseous oxidant to the particles in the reactor; (c4) performing one or more pump-purge cycles using an inert gas; and (c5) repeating steps (c1) – (c4) at least once to provide an silicon oxide coating layer; and (d) repeating step (b) at least once after step (c).

32. A method of preparing coated particles comprising an drug-containing core enclosed by (1) one or more aluminum oxide coating layers, and (2) one or more silicon oxide coating layers, wherein the drug-containing core comprises an API, the method comprising the sequential steps of: (a) loading particles comprising an API into a chamber of a reactor; (b) applying a silicon oxide coating layer by performing the following steps: (b1) applying a vaporous or gaseous silicon precursor to the particles in the reactor; (b2) performing one or more pump-purge cycles using an inert gas; (b3) applying a vaporous or gaseous oxidant to the particles in the reactor; (b4) performing one or more pump-purge cycles using an inert gas; andAttorney Docket No.: 44021852WO01 / 05542-1585WO1 (b5) repeating steps (b1) – (b4) at least once to provide an silicon oxide coating layer; (c) applying an aluminum oxide coating layer by performing the following steps: (c1) applying a vaporous or gaseous aluminum precursor to the particles in the reactor; (c2) performing one or more pump-purge cycles using an inert gas; (c3) applying a vaporous or gaseous oxidant (e.g., ozone) to the particles in the reactor; (c4) performing one or more pump-purge cycles using an inert gas; and (c5) repeating steps (c1) – (c4) at least once to provide an aluminum oxide coating layer; and (d) repeating 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 step (b) and step (c) are repeated two or more times to produced alternating silicon oxide an aluminum oxide coating layers.

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

36. The method of claim 31 or 32, wherein steps (b1)-(b4) are performed at least four times, 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 vaporous 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 vaporous or gaseous oxidant is pumped out of the reactor prior to step (c).

39. The method of claim 31 or 32, wherein each aluminum oxide layer and each silicon oxide layer has a thickness in the range of 0.1 nm to 50 nm.Attorney Docket No.: 44021852WO01 / 05542-1585WO1 40. The method of claim 31 or 32, wherein steps (b1)-(b4) take place 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 – b5 and c1 – 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 for the silicon oxide precursor.

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

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

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