Coated drug compositions and methods of preparing the same

Abstract

To provide tablets or capsules comprising coated particles comprising an active pharmaceutical ingredient (API)-containing core enclosed by one or more metal oxide layers and one or more polymer layers, and methods of preparing the same.SOLUTION: A tablet or capsule comprises individual particles comprising an active pharmaceutical ingredient (API)-containing core enclosed by an inner metal oxide layer and a polymer layer adjacent to the metal oxide layer, where the core has a median particle size between 0.1 μm and 20 μm on a volume average basis, and where the inner metal oxide layer has an average thickness of 0.1 nm to 30 nm and the polymer layer has an average thickness of 0.1 nm to 400 nm.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present disclosure relates to coated drug compositions and methods for preparing the coated drugs. [Background technology]

[0002] Developing improved formulations of active pharmaceutical ingredients (APIs) is of great importance to the pharmaceutical industry. Formulations can affect the stability and bioavailability of APIs, as well as other properties. Formulations can also affect various aspects of drug product (DP) manufacturing, such as the ease and safety of the manufacturing process.

[0003] Many techniques have been developed to encapsulate or coat both APIs and DPs, including polymer mesh coating, pan coating, aerosol coating, fluidized bed reactor coating, and atomic layer deposition coating. Summary of the Invention

[0004] In one aspect, a method for preparing coated particles is provided having an active pharmaceutical ingredient (API)-containing core surrounded by one or more metal oxide or inorganic oxide layers and one or more polymer layers. A metal oxide layer is first applied to the core by atomic layer deposition (ALD). After the metal oxide layer is deposited, a polymer layer is applied by molecular layer deposition (MLD) or hybrid ALD / MLD deposition. These steps can be repeated to produce particles having an API-containing core surrounded by multiple layers (e.g., multiple alternating layers) of metal oxide and polymer. The method can be applied to particles of APIs or particles comprising one or more APIs and one or more excipients.

[0005] The metal oxide layer is thin and conforms to the API-containing core. This layer can significantly improve the flowability and other processing properties of the API-containing core. It can also change the stability and dissolution rate of the API. The polymer layer can adjust the dissolution rate of the API in sustained release coatings, enteric coatings, etc., and can increase the stability of the API, for example, increasing resistance to oxidation and / or changes in crystalline form. Thus, the coating layer can reduce the transition of the API from an amorphous form to a crystalline form. The coating layer can provide bulking and / or improve compressibility, thereby reducing the need for excipients. By reducing the need for additional excipients, the coated particles can be used to produce dosage forms with high drug loading.

[0006] Described herein are compositions comprising discrete particles comprising an API-containing core surrounded by an inner metal oxide layer and a polymer layer adjacent to the metal oxide layer, the core having a median particle size, on a volume average basis, between 0.1 μm and 10 or 20 μm, the inner metal oxide layer having an average thickness of 0.01 or 0.1 nm to 30 nm, and the polymer layer having an average thickness of 0.1 nm to 400 nm.

[0007] In various embodiments: the inner metal oxide layer conforms to the core and is substantially free of pinholes, and the outer polymer layer conforms to the inner metal oxide layer and is substantially free of pinholes; the core has a median particle size, on a volume average basis, of between 0.1 μm and 10 or 20 μm; the core further comprises one or more pharma- ceutically acceptable excipients; the core comprises a first API and a second API; the core consists of an API; the core comprises a first API and a second API; the particle comprises an outer metal oxide layer adjacent to the polymer layer; the metal oxide layer comprises aluminum oxide, titanium oxide, iron oxide, silicon dioxide, magnesium oxide, or zinc oxide; the polymer layer comprises a polyamide, polyimide, polyurea, polyurethane, polythiourea, polyester, or polyimine.

[0008] Also described herein are pharmaceutical compositions comprising coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers, prepared by a method comprising the following sequence of steps: (a) performing atomic layer deposition to apply a metal oxide layer to the API-containing particle, thereby preparing a particle comprising the API surrounded by a metal oxide layer; and, thereafter, (b) performing molecular layer deposition to apply a polymer layer to the drug-containing particle surrounded by the metal oxide layer, thereby preparing a coated particle comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers.

[0009] In various embodiments, the steps of performing atomic layer deposition include: (A1) loading particles including an API into a reactor; (a2) applying a metal precursor in vapor or gaseous form to the particles in the reactor; (a3) ​​performing one or more pump-purge cycles of the reactor using an inert gas; (a4) applying an oxidant in vapor or gaseous form to the particles in the reactor; and (a5) performing one or more pump-purge cycles of the reactor using an inert gas.

[0010] In various embodiments: steps (a2)-(a5) are performed two or more times to increase the total thickness of the metal oxide layer before step (b) is performed; steps (a2)-(a5) are performed 5-50 times to increase the total thickness of the metal oxide layer before step (b) is performed;

[0011] In various embodiments: the steps of performing molecular layer deposition include: (b1) applying a vaporous polymer precursor A to particles including API inclusions surrounded by an oxide layer in a reactor; (b2) performing one or more pump-purge cycles of the reactor using an inert gas; (b3) applying a vaporous polymer precursor B to the particles in the reactor; and (b4) performing one or more pump-purge cycles of the reactor using an inert gas.

[0012] In various embodiments: steps (b1)-(b4) are performed two or more times to increase the total thickness of the polymer layer; steps (a2)-(a5) are performed 5-50 times to increase the total thickness of the metal oxide layer before step (b) is performed; the reactor contents are agitated before and / or during step (a) and / or step (b); the reactor pressure is stabilized for subsequent steps (a1), (a2), and / or (a4); the reactor contents are agitated before and / or during step (a1), step (a3), and / or step (a5); a subset of the vapor or gaseous contents is pumped out prior to step (a3) ​​and / or step (a5); the metal oxide layer is heated to a temperature of 0.01 or 0.1 nm to 20 or 30 nm; the polymer layer has a thickness in the range of 0.1 nm to 100 nm; steps (a2)-(a5) are repeated two or more times, and between each repetition, particles are not removed from the reactor; steps (a2)-(a5) are repeated two or more times, and during step (a), particles are not removed from the reactor; steps (b1)-(b4) are repeated two or more times, and between each repetition, particles are not removed from the reactor; steps (b1)-(b4) are repeated two or more times, and during step (b), particles are not removed from the reactor; the API-containing particles further comprise one or more pharma- ceutically acceptable excipients; the API-containing particles have a volume average mass of 0.1 nm to 100 nm, on a volume-average basis, prior to step (a).having a median particle size between 1 μm and 10 or 20 μm; the particles subjected to step (a) comprise a first API and a second API; the particles subjected to step (a) consist of an API; the particles subjected to step (a) consist of a first API and a second API; the particles subjected to step (a) comprise an API and one or more pharma- ceutically acceptable excipients; the particles subjected to step (a) comprise a first API, a second API, and one or more pharma-ceutically acceptable excipients; the particles subjected to step (a) comprise an API and and one or more pharma- ceutically acceptable excipients; the particles subjected to step (a) consist of a first API, a second API, and one or more pharma- ceutically acceptable excipients; the metal oxide layer comprises aluminum oxide, titanium oxide, iron oxide, silicon dioxide, magnesium oxide, or zinc oxide; the polymer layer comprises a polyamide, polyimide, polyurea, polyurethane, polythiourea, polyester, or polyimine; the polymer layer is biodegradable; the composition comprises an inner metal oxide layer, an intermediate polymer layer, and an outer metal oxide layer.

[0013] Also described herein is a method for preparing a coated particle comprising an active pharmaceutical ingredient (API)-containing core surrounded by one or more metal oxide layers and one or more polymer layers, the method comprising the following sequence of steps: (a) performing atomic layer deposition to apply a metal oxide layer to the API-containing particle, thereby preparing a particle comprising the API surrounded by a metal oxide layer; and thereafter; (b) performing molecular layer deposition to apply a polymer layer to the drug-containing particle surrounded by a metal oxide layer, thereby preparing a coated particle comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers.

[0014] In various embodiments, the steps of performing atomic layer deposition include: (a1) loading particles including an API into a reactor; (a2) applying a metal precursor in vapor or gaseous form to the particles in the reactor; (a3) ​​performing one or more pump-purge cycles of the reactor using an inert gas; (a4) applying an oxidant in vapor or gaseous form to the particles in the reactor; and (a5) performing one or more pump-purge cycles of the reactor using an inert gas.

[0015] In various embodiments: steps (a2)-(a5) are performed two or more times to increase the total thickness of the metal oxide layer before step (b) is performed; steps (a2)-(a5) are performed 5-50 times to increase the total thickness of the metal oxide layer before step (b) is performed.

[0016] In various embodiments: the steps of performing molecular layer deposition include: (b1) applying a vaporous polymer precursor A to particles including API inclusions surrounded by a metal oxide layer in a reactor; (b2) performing one or more pump-purge cycles of the reactor using an inert gas; (b3) applying a vaporous polymer precursor B to the particles in the reactor; and (b4) performing one or more pump-purge cycles of the reactor using an inert gas.

[0017] In various embodiments: steps (b1)-(b4) are performed two or more times to increase the total thickness of the polymer layer; steps (a2)-(a5) are performed 5-50 times to increase the total thickness of the metal oxide layer before step (b) is performed; the reactor contents are stirred before and / or during step (a) and / or step (b); the reactor pressure is stabilized for the following steps (a1), (a2), and / or (a4); the reactor contents are stirred for step (a1), (a3), and / or (a5) a subset of the vapor or gaseous contents is pumped out prior to step (a3) ​​and / or step (a5); the metal oxide layer has a thickness in the range of 0.01 or 0.1 nm to 10 or 20 nm; the polymer layer has a thickness in the range of 0.1 nm to 400 nm; steps (a2)-(a5) are repeated two or more times, with no particles being removed from the reactor between each repetition; steps (a2)-(a5) are repeated two or more times, with no particles being removed from the reactor during step (a); Steps (b1)-(b4) are repeated two or more times, with no particles being removed from the reactor between each repetition; Steps (b1)-(b4) are repeated two or more times, with no particles being removed from the reactor during step (b); The particles comprising the API further comprise one or more pharma- ceutically acceptable excipients; The particles comprising the API, prior to step (a), have a median particle size, on a volume-average basis, of between 0.1 μm and 20 μm; The particles, prior to step (a), have a median particle size, on a volume-average basis, of between 0.1 μm and 5 or 10 μm. the particles have, prior to step (a), a median particle size, on a volume-average basis, between 0.1 μm and 1000 μm; the particles subjected to step (a) comprise a first API and a second API; the particles subjected to step (a) consist of an API; the particles subjected to step (a) consist of a first API and a second API; the particles subjected to step (a) comprise an API and one or more pharma- ceutically acceptable excipients; the particles subjected to step (a) comprise a first API, a second API, and one or more pharma-ceutically acceptable excipients;The particles subjected to step (a) comprise an API and one or more pharma- ceutically acceptable excipients; the particles subjected to step (a) comprise a first API, a second API, and one or more pharma- ceutically acceptable excipients; the method comprises mixing the coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers with a pharma- ceutically acceptable diluent or carrier; the method further comprises treating the coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers to form a tablet or capsule; the method further comprises mixing the coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers with a pharma- ceutically acceptable diluent or carrier to form a mixture and treating the mixture to form a tablet or capsule; the method comprises performing atomic layer deposition to apply a metal oxide layer to the particles comprising an API-containing core surrounded by a metal oxide layer and a polymer layer, thereby forming an inner metal oxide layer, an intermediate polymer layer, and an outer metal oxide layer. The method further comprises performing molecular layer deposition to apply a polymer layer to the particle comprising an API surrounded by an inner metal oxide layer, an intermediate polymer layer, and an outer metal oxide layer, thereby preparing a particle comprising an API surrounded by an inner metal oxide layer, an inner intermediate polymer layer, and an outer intermediate metal oxide layer, and an outer polymer layer; the method further comprises mixing the coated particle comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers with a pharma- ceutically acceptable diluent or carrier; the method further comprises treating the coated particle comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers to form a tablet or capsule; the method further comprises mixing the coated particle comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers with a pharma- ceutically acceptable diluent or carrier to form a mixture, and treating the mixture to form a tablet or capsule;

[0018] Thus, the metal oxide deposition method includes the successive steps of (a1) loading particles of an API or particles containing an API into a reactor, (a2) applying a vapor or gaseous metal precursor to the particles in the reactor, (a3) ​​running one or more pump-purge cycles of the reactor using an inert gas, (a4) applying a vapor or gaseous oxidant to the particles in the reactor, and (a5) running one or more pump-purge cycles of the reactor using an inert gas. This produces a pharmaceutical composition comprising an API-containing core surrounded by one or more metal oxide materials. The metal oxide coated particles are then coated with a polymer. Thus, the polymer deposition method includes the successive steps of (b1) applying a vapor or gaseous precursor A to the particles in the reactor, (b2) running one or more pump-purge cycles of the reactor using an inert gas, (b3) applying a vapor or gaseous precursor B to the particles in the reactor, and (b4) running one or more pump-purge cycles of the reactor using an inert gas. Precursor A and precursor B can react to form an ABAB type polymer. Other precursors can be used to form other types of polymers. For example, precursor A, precursor B, and precursor C.

[0019] The polymer layer can be a hybrid layer. The hybrid polymer deposition method includes the following successive steps: (b1') applying a vapor or gaseous precursor A to the particles in a reactor, (b2') performing one or more pump-purge cycles of the reactor using an inert gas, (b3') applying a vapor or gaseous metal oxide precursor to the particles in the reactor, and (b4') performing one or more pump-purge cycles of the reactor using an inert gas.

[0020] In various embodiments: the temperature inside the reactor need not exceed 100°C, 50°C, 40°C; the one or more metal oxide materials may include aluminum oxide, titanium oxide, iron oxide, gallium oxide, magnesium oxide, silicon dioxide, zinc oxide, niobium oxide, hafnium oxide, tantalum oxide, lanthanum oxide, and / or zirconium dioxide; the one or more metal oxide materials consist of aluminum oxide and / or titanium oxide; the oxidizing agent may be selected from the group consisting of water, ozone, and organic peroxides; the one or more polymer layers may include polymer amides, polyesters, polyurethanes, polyureas, polyimides; the MLD precursors may be selected from any organic molecule containing a difunctional group, such as diols, diamines, diisocyanates, dichlorides, dialdehydes, etc.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0022] Other features and advantages of the invention will become apparent from the following detailed description and drawings, and from the claims. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 is a schematic diagram of a rotating reactor for ALD and / or CVD coating of particles, e.g., particles of an API or particles comprising an API and an excipient. [Diagram 2] Schematic diagram of the MLD coating process [Diagram 3] SEM image of coated API particles and TEM cross section of coated API particles [Figure 4]Graph showing dissolution of uncoated acetaminophen particles, acetaminophen particles coated with a metal oxide, and acetaminophen particles coated with both a metal oxide layer and a polymer (polyamide) layer. [Diagram 5] TEM image of a cross section of an API particle coated with alternating metal oxide and polyamide coating layers. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] There are various methods for encapsulating API particles in polymers, for example, hot melt extrusion. Often these methods result in a relatively thick polymer coating. While such polymer coatings can impart desirable properties, the high ratio of polymer to API can make it difficult to produce a drug product with a desired high volume fraction of API. In addition, the layer of polymer encapsulating the API can be non-uniform, making it difficult to provide a formulation with consistent properties. There remains a need for improved coating techniques that can impart desirable properties to both the active pharmaceutical ingredient and the drug product.

[0025] The present disclosure provides a method for preparing a pharmaceutical composition comprising API (drug)-containing particles encapsulated by one or more metal oxide layers and one or more polymer layers. The coating layers are conformal and have a controlled total thickness of a few nanometers to a few micrometers. The coated article can consist of API alone or API in combination with one or more excipients. The coating process described herein can provide API with increased glass transition temperature compared to uncoated API, reduced crystallization rate of amorphous form API compared to uncoated API, and reduced surface mobility of API molecules within the particle compared to uncoated API. Importantly, the dissolution of API particles can be modified by controlling the thickness, composition, and functional groups of the conformal polymer layer. High drug loading can be achieved due to the relatively thin coating. Finally, multiple coatings can be applied in the same reactor, which has advantages in terms of cost and ease of manufacturing.

[0026] The term "drug" in its broadest sense includes all small molecule (e.g., non-biological) APIs. Drugs may be any of the following: analgesics, anesthetics, anti-inflammatory agents, anthelmintics, antiarrhythmic agents, antiasthmatic agents, antibiotics, anticancer agents, anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antihistamines, antitussives, antihypertensive agents, antimuscarinics, antimycobacterial agents, antineoplastic agents, antioxidants, antipyretics, immunosuppressants, immunostimulants, antithyroid agents, antivirals, anxiolytics, sedatives, hypnotics, neuroleptics, astringents, bacteriostatic agents, beta-adrenergic receptor blocking agents, blood products, blood substitutes, bronchodilators, buffers, cardiac inotropes, chemotherapeutic agents, imaging agents, etc. , corticosteroids, cough suppressants, expectorants, mucolytics, diuretics, dopamine agonists, anti-Parkinson's drugs, free radical scavengers, growth factors, hemostatic agents, immune agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, bisphosphonates, prostaglandins, radiopharmaceuticals, hormones, sex hormones, antiallergic agents, appetite stimulants, appetite suppressants, steroids, sympathomimetics, thyroid agents, vaccines, vasodilators, and xanthines.

[0027] Exemplary types of small molecule drugs include, but are not limited to, acetaminophen, clarithromycin, azithromycin, ibuprofen, fluticasone propionate, salmeterol, pazopanib HCl, palbociclib, and amoxicillin-clavulanate potassium.

[0028] The term "metal oxide material" in its broadest sense includes all materials formed from the reaction of elements considered to be metals with an oxygen-based oxidizing agent. Exemplary metal oxide materials include, but are not limited to, aluminum oxide, titanium oxide, iron oxide, gallium oxide, magnesium oxide, zinc oxide, niobium oxide, hafnium oxide, tantalum oxide, lanthanum oxide, and zirconium dioxide. Exemplary oxidizing agents include, but are not limited to, water, ozone, and inorganic peroxides.

[0029] Atomic layer deposition is a thin film deposition technique that allows the deposition of films with controlled thickness and uniformity down to the atomic or molecular monolayer level by the sequential addition of self-limiting monolayers of elements or compounds. Self-limiting means that only a single atomic layer is formed at a time, and a subsequent process step is required to regenerate the surface to allow further deposition.

[0030] Molecular layer deposition is similar to atomic layer deposition, but uses organic precursors to form fully organic thin films. During a typical MLD process, two homobifunctional precursors are used (Figure 2). A first precursor is introduced into the chamber. Molecules of the first precursor react with reactive groups on the substrate surface via corresponding linking chemistry to add a molecular layer of the first precursor on the substrate surface with new reactive sites. After purging, a second precursor is introduced and the molecules of the second precursor react with the new reactive sites provided by the first precursor to generate a molecular layer of the first precursor linked to the second precursor. This is followed by another purse cycle. The chemistry can be represented as follows, using adipoyl chloride (AC) and 1,6-hexanediamine (HD) as precursors: First Precursor Reaction TIFF2025011147000002.tif13170 Second precursor reaction TIFF2025011147000003.tif13170

[0031] Succinyl chloride and 1,3-diaminopropane is another suitable first and second precursor combination.

[0032] MLD can be used to produce a variety of biocompatible polymer coatings, including: hydrophobic polymer coatings (e.g., poly(caprolactone), poly(lactic acid), poly(glycolide) and their copolymers); hydrophilic polymers (e.g., poly(ether esters)); and pH-responsive polymers (e.g., poly(ether amides) and poly(ether esters) with pendant carboxylic acid groups). Precursors that can be used in the first precursor reaction include: acid chlorides (e.g., succinyl chloride, glutaryl chloride, and adipoyl chloride). Precursors that can be used in the second precursor reaction include: diols (e.g., diethylene glycol); hydrophobic diamines (e.g., ethylenediamine); hydrophilic diamines (2,2'-(ethylenedioxy)bis(ethylamine)). Crosslinking acid chlorides (e.g., trimesoyl chloride (1,3,5-benzenetricarbonyl trichloride) can also be incorporated.

[0033] Hybrid MLD / ALD layer deposition is similar to atomic layer deposition and molecular layer deposition, using one MLD precursor and one metal oxide precursor to form a hybrid layer with both organic-inorganic compositions. During a typical MLD / ALD hybrid process, two homobifunctional precursors are used. A first precursor is introduced into the chamber. Molecules of the first precursor react with reactive groups on the substrate surface via corresponding linking chemistry to add a molecular layer of the first precursor on the substrate surface with new reactive sites. After purging, a second precursor, a metal oxide precursor, is introduced and the molecules of the second precursor react with the new reactive sites provided by the first precursor to produce a hybrid layer composed of the first precursor linked to the second precursor. This is followed by another purge cycle. Using TMA and 1,2 ethylanediol as precursors, the chemistry can be represented as follows: TIFF2025011147000004.tif34170

[0034] Other useful precursor combinations include: succinyl chloride and 1,3-diaminopropane.

[0035] The term "reactor system" in its broadest sense includes any system that can be used to perform ALD or mixed ALD / CVD or CVD. An exemplary reactor system is shown in FIG. 1 and is further described below in the context of ALD reactions. The same or similar reactor systems can be used to perform MLD, hybrid MLD / ALD reactions.

[0036] FIG. 1 illustrates a reactor system 10 for performing coating of particles with a thin film coating. The reactor system 10 can perform coating using ALD, and / or hybrid, and / or MLD coating conditions. The reactor system 10 allows the coating process (ALD or MLD or hybrid) to be performed at higher (greater than 50° C., e.g., 50-100° C.) or lower processing temperatures, e.g., below 50° C., e.g., 35° C. or less. For example, the reactor system 10 can form thin film metal oxides on particles by ALD at temperatures primarily between 22-35° C., e.g., 25-35° C., 25-30° C., or 30-35° C. Generally, the particles can remain or be maintained at such temperatures. This can be accomplished by leaving or maintaining the reactant gases and / or the interior surfaces of the reactor chamber (e.g., chamber 20 and drum 40, discussed below) at such temperatures.

[0037] Again illustrating the ALD process, reactor system 10 includes a stationary vacuum chamber 20 coupled to a vacuum pump 24 by a vacuum tube 22. Vacuum pump 24 can be an industrial vacuum pump sufficient to establish a pressure of less than 1 Torr, such as between 1 and 100 mTorr, e.g., 50 mTorr. Vacuum pump 24 allows chamber 20 to be maintained at a desired pressure and allows removal of reaction by-products and unreacted process gases.

[0038] During operation, the reactor 10 performs an ALD thin film coating process by introducing gaseous precursors of the coating into the chamber 20. The gaseous precursors are alternately spiked into the reactor. This allows the ALD process to be a solvent-free process. The half-reactions of the ALD process are self-limiting and can provide angstrom-level control of the deposition. In addition, the ALD reaction can be carried out at low temperature conditions, such as below 50° C., e.g., below 35° C.

[0039] The chamber 20 is also coupled to a chemical supply system 30. The chemical supply system 20 includes three or more gas sources 32a, 32b, 32c coupled to the vacuum chamber 20 by respective supply tubes 34a, 34b, 34c and controllable valves 36a, 36b, 36c. The chemical supply system 30 may include a combination of restrictors, gas flow controllers, pressure transducers, and ultrasonic flow meters to provide a controllable flow rate of the various gases into the chamber 20. The chemical supply system 30 may also include one or more temperature control components, such as, for example, heat exchangers, resistive heaters, heat lamps, etc., to heat or cool the various gases before they flow into the chamber 20. Although FIG. 1 shows separate gas lines running parallel to the chamber for each gas source, two or more gas lines may be combined, for example, with one or more three-way valves, before the combined lines reach the chamber 20. Additionally, although three gas sources are shown in FIG. 1, four gas sources can be used to enable in situ formation of a laminated structure having alternating layers of two different metal oxides.

[0040] The two gas sources supply two chemically distinct gaseous reactants for the coating process to the chamber 20. Suitable reactants for the ALD process include any of the following or a combination thereof: monomer vapor, metal organics, metal halides, oxidizers such as ozone or water vapor, and polymer or nanoparticle aerosols (dry or wet). For example, the first gas source 32a can supply gaseous trimethylaluminum (TMA) or titanium tetrachloride (TiCl4), while the second gas source 32b can supply water vapor.

[0041] 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 reactants, coatings, and particles being processed. For example, the purge gas can be N2, or a noble gas such as argon.

[0042] A rotatable coating drum 40 is held within chamber 20. Drum 40 may be connected to a motor 44 by a drive shaft 42 that extends through a sealed port in the side wall of chamber 20. Motor 44 may rotate the drum at speeds between 1 and 100 rpm. Alternatively, the drum may be directly connected to a vacuum source via a rotary union.

[0043] The particles to be coated, shown as a particle bed 50, are disposed within the interior volume 46 of the drum 40. The drum 40 and chamber 20 may include a sealable port (not shown) that allows particles to be disposed within and removed from the drum 40.

[0044] 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 wall of the drum 40 may have dimensions of 10 μm.

[0045] During operation, as the drum 40 rotates, one of the gases flows from the chemical delivery system 30 into the chamber 20. The combination of pores (1-100 μm), holes (0.1-10 mm), or large openings in the coating drum serve to confine the particles within the coating drum while allowing for rapid delivery of precursor chemicals and pumping out by-products or unreacted species. The pores in the drum 40 allow gas to flow between the exterior of the drum 40, i.e., the reactor chamber 20, and the interior of the drum 40. In addition, the rotation of the drum 40 agitates the particles to keep them separated and ensures that a large surface area of ​​the particles remains exposed. This allows for rapid and uniform interaction of the particle surfaces with the process gas.

[0046] In some implementations, one or more temperature control components are incorporated into the drum 40 to allow for control of the temperature of the drum 40. For example, resistive heaters, thermoelectric coolers, or other components may be present in or on the sidewalls of the drum 40.

[0047] The reactor system 10 also includes a controller 60 coupled to various controllable components, such as the vacuum pump 24, the gas distribution system 30, the motor 44, the 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 pressure of the gases in the chamber 20.

[0048] Generally, the controller 60 can operate the reactor system 10 according to a "recipe," which specifies the operating values ​​of each controllable element as a function of time. For example, the recipe can specify the times that the vacuum pump 24 operates, the times and flow rates of each gas source 32a, 32b, 32c, the rotational speed of the motor 44, etc. The controller 60 can receive the recipe as computer-readable data (e.g., stored on a non-transitory computer-readable medium).

[0049] The controller 60 and other computing devices that are part of the systems described herein can be implemented in digital electronic circuitry, or computer software, firmware, or hardware. For example, the controller can include a processor that executes a computer program stored in a computer program product, such as a non-transitory machine-readable storage medium. Such computer programs (also known as programs, software, software applications, or code) can be written in any type of programming language, including compiled or interpreted languages, and can be deployed in any form, such as as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. In some implementations, the controller 60 is a general-purpose programmable computer. In some implementations, the controller can be implemented using special purpose logic circuitry, such as a field programmable gate array (FPGA) or an application specific integrated circuit (ASIC).

[0050] operation Although the operation is shown using an ALD process, the operation is similar for MLD or hybrid. Initially, particles are loaded into the drum 40 of the reactor system 10. The particles may have a solid core containing a drug, such as one of the drugs mentioned above. Once the access ports are sealed, the controller 60 operates the reactor system 10 according to a recipe to form a thin film metal oxide layer on the particles.

[0051] In particular, two reactant gases are alternately supplied to the chamber 20, and each step of supplying a reactant gas is followed by a purge cycle in which an inert gas is supplied to the chamber 20 to drive out the reactant gas and by-products used in the previous step. Additionally, one or more gases (e.g., reactant gas and / or inert gas) can be supplied in pulses, where the chamber 20 is filled with gas to a specified pressure, a delay time is allowed to elapse, and the chamber is evacuated by the vacuum pump 24 before the next pulse begins.

[0052] In particular, the controller 60 can operate the reactor system 10 as follows.

[0053] In the first reactant half-cycle, the motor 44 rotates the drum 40 to agitate the particles 50 while i) The gas delivery system 30 is operated to flow a first reactant gas, e.g., TMA, from a gas source 32a into the chamber 20 until a first specified pressure is achieved. The specified pressure can be from 0.1 Torr to half the saturation pressure of the reactant gas. ii) The flow of the first reactant is stopped and a specified delay time is allowed to elapse, for example as measured by a timer in the controller, to allow the first reactant to flow through the bed of particles in the drum 40 and react with the surfaces of the particles 50 in the drum 40. iii) The vacuum pump 50 evacuates the chamber 20, for example to a pressure below 1 Torr, for example 1-100 mTorr, for example 50 mTorr.

[0054] These steps (i) to (iii) may be repeated a number of times set by the recipe, for example 2 to 10 times, for example 6 times.

[0055] Next, in a first purge cycle, the motor 44 rotates the drum to agitate the particles 50 while: iv) The gas distribution system 30 is operated to flow an inert gas, such as N2, from the gas source 32c into the chamber 20 until a second specified pressure is achieved. The second specified pressure can be between 1 and 100 Torr. v) The flow of inert gas is stopped and a specified delay time is allowed to elapse, for example as measured by a timer in the controller, to allow the inert gas to flow through the pores in drum 40 and diffuse through particles 50 to displace the reactant gases and any vapor by-products. vi) The vacuum pump 50 evacuates the chamber 20, for example to a pressure less than 1 Torr, for example 1-500 mTorr, for example 50 mTorr.

[0056] These steps (iv)-(vi) may be repeated a number of times set by the recipe, for example 6 to 20 times, for example 16 times.

[0057] In the second reactant half-cycle, motor 44 rotates drum 40 to agitate particles 50 while vii) The gas delivery system 30 is operated to flow a second reactant gas, e.g., HO, from the gas source 32a into the chamber 20 until a third designated pressure is achieved. The third pressure may be from 0.1 Torr to half the saturation pressure of the reactant gas. viii) The flow of the second reactant is stopped and a specified delay time is allowed to elapse, for example as measured by a timer in the controller, to allow the second reactant to flow through the pores in the drum 40 and react with the surfaces of the particles 50 within the drum 40. ix) The vacuum pump 50 evacuates the chamber 20, for example to a pressure below 1 Torr, for example 1-500 mTorr, for example 50 mTorr.

[0058] These steps (vii) to (ix) may be repeated a number of times set by the recipe, for example 2 to 10 times, for example 6 times.

[0059] A second purge cycle is then performed which may be identical to the first purge cycle or may have a different number of repetitions of steps (iv)-(vi) and / or a different delay time and / or a different pressure.

[0060] The cycle of a first reactant half cycle, a first purge cycle, a second reactant half cycle, and a second purge cycle can be repeated a number of times set by the recipe, for example, from 1 to 10 times.

[0061] As mentioned above, the coating process can be carried out at low processing temperatures, e.g., below 50°C, e.g., below 35°C. In particular, the particles can remain or be maintained at such temperatures during all of steps (i)-(ix) above. Generally, the temperature inside the reactor chamber does not exceed 35°C during steps (i)-(ix). This can be achieved by injecting the first reactant gas, the second reactant gas, and the inert gas into the chamber at such temperatures during each cycle. In addition, the physical components of the chamber can remain or be maintained at such temperatures, as needed, e.g., using a cooling system, e.g., a thermoelectric cooler.

[0062] Process for preparing a pharmaceutical composition comprising a drug encapsulated by one or more layers of a metal oxide Two exemplary methods are provided for pharmaceutical compositions comprising a drug-containing core surrounded by one or more metal oxide materials. The first exemplary method includes the following sequence of steps: (a) loading a drug-containing particle into a reactor, (b) applying a vapor or gaseous metal precursor to the substrate in the reactor, (c) running one or more pump-purge cycles of the reactor using an inert gas, (d) applying a vapor or gaseous oxidant to the substrate in the reactor, and (e) running one or more pump-purge cycles of the reactor using an inert gas. In some embodiments of the first exemplary method, the sequence of steps (b)-(e) is optionally repeated one or more times to increase the overall thickness of the one or more metal oxide materials surrounding the solid core of the coated particle. In some embodiments, the reactor pressure can be stabilized during the following steps (a), (b), and / or (d). In some embodiments, the contents of the reactor are stirred before and / or during steps (b), (c), and / or (e). In some embodiments, a subset of the vapor or gaseous contents is pumped out prior to step (c) and / or step (e).

[0063] A second exemplary method includes (a) loading the drug-containing particles into a reactor, (b) reducing the reactor pressure to less than 1 Torr, (c) pressurizing the reactor by adding a vapor or gaseous oxidant, (d) stabilizing the reactor pressure, (e) stirring the reactor contents, (f) pumping out a subset of the vapor or gaseous contents, and determining when to stop pumping based on an analysis of the reactor contents, including the metal precursor and by-products of the metal precursor reacting with exposed hydroxyl residues on the substrate or on the particle surface, and (g) a series of pump-purging of the reactor using an insert gas. The method includes (e.g., consists of) the steps of: (a) running a cycle, (b) pressurizing the reactor by adding a vapor or gaseous oxidant, (c) stabilizing the pressure of the reactor, (d) stirring the reactor contents, (e.g., mixing the reactor contents, (f) pumping out a subset of the vapor or gaseous contents, and determining when to stop pumping out based on an analysis of the reactor contents, including metal precursor reacted with exposed hydroxyl residues on the substrate or on the particle surface, by-products of the metal precursor, and unreacted oxidant, and (f) running a series of pump-purge cycles of the reactor using an insert gas. In some embodiments of the second exemplary method, the sequence of steps (b)-(m) is optionally repeated one or more times to increase the overall thickness of the one or more metal oxide materials surrounding the solid core of the coated particle.

[0064] Pharmaceutically acceptable excipients, diluents, and carriers Pharmaceutically acceptable excipients include, but are not limited to, the following: (1) Surfactants and polymers, including: polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium lauryl sulfate, polyvinyl alcohol, crospovidone, polyvinylpyrrolidone-polyvinyl acrylate copolymers, cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, carbomers and their polymers, emulsifiers, sugar gums, starches, organic acids and their salts, vinylpyrrolidone, and vinyl acetate; (2) Binders, such as cellulose, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, etc.; (3) fillers, such as lactose monohydrate, lactose anhydrous, microcrystalline cellulose, and various starches; (4) Lubricants, such as agents that affect the flowability of the powder being compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel, etc.; (5) Sweeteners, e.g., any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K; (6) Flavoring agents; (7) Preservatives, such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride; (8) Buffer; (9) Diluents, such as pharma- ceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, sugars, and / or mixtures of any of the foregoing; (10) Wetting agents, such as corn starch, potato starch, maize starch, modified starches, and mixtures thereof; (11) Disintegrants; for example, croscarmellose sodium, crospovidone, sodium starch glycolate, etc.; and (12) Effervescent agents, such as organic acids (e.g., citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid and their anhydrides and acid salts), or effervescent couples such as carbonates (e.g., sodium carbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate), or bicarbonates (e.g., sodium bicarbonate or potassium bicarbonate). EXAMPLES

[0065] In the examples described herein, the following materials and methods were used.

[0066] Example 1: Preparation of particles containing a drug encapsulated with a metal oxide and polymer layer In this example, one of the disclosed methods for preparing metal oxide and polymer encapsulated drugs is performed and data is presented. In the ALD step to apply the metal oxide coating, the vapor or gaseous metal precursor is trimethylaluminum (TMA), the by-product gaseous methane is formed after TMA reacts with exposed hydroxyl groups on the particle or on the surface of the coated particle, and the oxidant is water vapor. In the MLD step to apply the polymer coating, adipoyl chloride is introduced first, followed by ethylenediamine. A polyamide coating is formed.

[0067] How ALD Coating Works Briefly, the method consists of the following series of steps: (a) loading drug-containing particles into a reactor; (b) reducing the reactor pressure to less than 1 Torr (e.g., less than 50 mtorr); (c) pressurizing the reactor to at least 1 Torr by adding vapor or gaseous TMA; (d) stabilizing reactor pressure; (e) stirring the contents of the reactor; (f) pumping out a subset of the vapor or gaseous contents, including gaseous methane and unreacted TMA, and performing an RGA to determine when to stop pumping by monitoring the levels of gaseous methane and unreacted TMA in the reactor; (g) performing a series of pump-purge cycles on the reactor using nitrogen gas; (h) pressurizing the reactor to at least 1 Torr by adding water vapor; (i) Stabilize the reactor pressure; (j) stirring the contents of the reactor; (k) pumping out a subset of the vapor or gaseous contents, including water vapor, and determining when to stop pumping by running an RGA to monitor the level of water vapor in the reactor; (l) performing a series of pump-purge cycles on the reactor using nitrogen gas.

[0068] In addition, steps (b)-(l) were repeated multiple times to increase the total thickness of aluminum oxide surrounding the drug particle core.

[0069] Hybrid MLD / ALD Coating Method Briefly, the method consists of the following series of steps: (a) loading drug-containing particles into a reactor; (b) reducing the reactor pressure to less than 1 Torr (e.g., less than 50 mtorr); (c) pressurizing the reactor to at least 1 Torr by adding a vaporous organic precursor, such as 1,2 ethylanediol; (d) stabilizing the reactor pressure; (e) stirring the contents of the reactor; (f) pumping out a subset of the vapor or gaseous contents, including gaseous unreacted 1,2-ethylenediol, and determining when to stop pumping by running an RGA to monitor the levels of vaporous HCl and unreacted 1,2-ethylenediol in the reactor; (g) performing a series of pump-purge cycles on the reactor using nitrogen gas; (h) pressurizing the reactor to at least 1 Torr by adding a vaporous metal oxide precursor, e.g., TMA; (i) Stabilize the reactor pressure; (j) stirring the contents of the reactor; (k) pumping out a subset of the vapor or gaseous contents, including methane, and determining when to stop pumping by running an RGA to monitor the level of methane vapor in the reactor; (l) performing a series of pump-purge cycles on the reactor using nitrogen gas.

[0070] In addition, steps (b)–(l) were repeated multiple times to increase the total thickness of the hybrid layer surrounding the metal oxide-coated core.

[0071] MLD Coating Method Briefly, the method consists of the following series of steps: (a) loading drug-containing particles into a reactor; (b) reducing the reactor pressure to less than 1 Torr (e.g., less than 50 mtorr); (c) pressurizing the reactor to at least 1 Torr by adding vaporous adipoyl chloride; (d) stabilizing the reactor pressure; (e) stirring the contents of the reactor; (f) pumping out a subset of the vapor or gaseous contents, including HCl vapor and unreacted adipoyl chloride, and determining when to stop pumping by running an RGA to monitor the levels of gaseous HCl and unreacted adipoyl chloride in the reactor; (g) performing a series of pump-purge cycles on the reactor using nitrogen gas; (h) pressurizing the reactor to at least 1 Torr by adding vaporous ethylenediamine; (i) Stabilize the reactor pressure; (j) stirring the contents of the reactor; (k) pumping a subset of the vapor or gaseous contents, including the HCl vapor, and running an RGA to monitor the level of the HCl vapor in the reactor to determine when to stop pumping; and (l) performing a series of pump-purge cycles on the reactor using nitrogen gas.

[0072] In addition, steps (b)-(l) were repeated multiple times to increase the total thickness of the polymer surrounding the metal oxide coated core.

[0073] FIG. 2 contains typical process conditions for carrying out the MLD deposition of a polymer layer (polyamide).

[0074] FIG. 3 is an SEM image (left side) of an API particle coated essentially as described above and a TEM cross-section (right side and magnified at far right) of an API particle coated essentially as described above.

[0075] As can be seen in Figure 4, the combination of ALD and MLD coatings can significantly reduce the dissolution rate of acetaminophen particles. Herein, dissolution was tested in phosphate buffer, pH 5.8, 50 rpm, 325 mg of API in 900 ml of medium.

[0076] Figure 5 shows TEM images of cross sections of API particles coated with alternating coating layers of metal oxide and polyamide. In each case, 10 to 20 cycles were performed.

Claims

1. 1. A pharmaceutical composition comprising discrete particles comprising an API-containing core surrounded by an inner metal oxide layer and a polymer layer adjacent to the metal oxide layer, wherein the core has a median particle size, on a volume average basis, between 0.1 μm and 20 μm, the inner metal oxide layer has an average thickness of 0.1 nm to 30 nm, and the polymer layer has an average thickness of 0.1 nm to 400 nm.

2. 2. The pharmaceutical composition of claim 1, wherein the inner metal oxide layer is conformable to the core and is substantially free of pinholes, and the outer polymeric layer is conformable to the inner metal oxide layer and is substantially free of pinholes.

3. 2. The pharmaceutical composition of claim 1, wherein the core has a median particle size, on a volume average basis, between 0.1 μm and 10 μm.

4. 4. The pharmaceutical composition of claim 1, wherein the core further comprises one or more pharma- ceutically acceptable excipients.

5. 5. The pharmaceutical composition of claim 1, wherein the core comprises a first API and a second API.

6. 5. The pharmaceutical composition of claim 1, wherein the core consists of an API.

7. 5. The pharmaceutical composition of claim 1, wherein the core comprises a first API and a second API.

8. 8. The pharmaceutical composition of claim 1, wherein the particle comprises an outer metal oxide layer adjacent to the polymer layer.

9. 9. The pharmaceutical composition of claim 1, wherein the metal oxide layer comprises aluminum oxide, titanium oxide, iron oxide, silicon dioxide, magnesium oxide, or zinc oxide.

10. 10. The pharmaceutical composition of claim 1, wherein the polymer layer comprises a polyamide, a polyimide, a polyurea, a polyurethane, a polythiourea, a polyester, or a polyimine.

11. 1. A pharmaceutical composition comprising coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers, the composition comprising the steps of: (a) performing atomic layer deposition to apply a metal oxide layer to particles comprising an API, thereby preparing particles comprising an API surrounded by a metal oxide layer; and thereafter (b) performing molecular layer deposition to apply a polymer layer to said particle comprising a drug surrounded by a metal oxide layer, thereby preparing a coated particle comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers. A pharmaceutical composition prepared by a method comprising:

12. performing atomic layer deposition, (a1) loading the particles comprising the API into a reactor; (a2) applying a vapor or gaseous metal precursor to the particles in the reactor; (a3) performing one or more pump-purge cycles of the reactor using an inert gas; (a4) applying a vapor or gaseous oxidant to the particles in the reactor; and (a5) performing one or more pump-purge cycles of the reactor using an inert gas; 12. The pharmaceutical composition of claim 11, comprising:

13. 13. The pharmaceutical composition of claim 12, wherein steps (a2)-(a5) are performed two or more times to increase the total thickness of the metal oxide layer before step (b) is performed.

14. 14. The pharmaceutical composition of claim 13, wherein steps (a2)-(a5) are performed 5-20 times to increase the total thickness of the metal oxide layer before step (b) is performed.

15. 4. The method of claim 3, wherein the step of performing molecular layer deposition further comprises: (b1) applying a vaporous polymer precursor A to the particles comprising API inclusions surrounded by an oxide layer in the reactor; (b2) performing one or more pump-purge cycles of the reactor using an inert gas; (b3) applying a vaporous polymer precursor B to the particles in the reactor; and (b4) performing one or more pump-purge cycles of the reactor using an inert gas.

15. The pharmaceutical composition of any one of claims 11 to 14, comprising:

16. 15. The pharmaceutical composition of claim 14, wherein steps (b1)-(b4) are performed two or more times to increase the total thickness of the polymer layer.

17. 17. The pharmaceutical composition of claim 16, wherein steps (a2)-(a5) are performed 5-20 times to increase the total thickness of the metal oxide layer before step (b) is performed.

18. 12. The pharmaceutical composition of claim 11, wherein the contents of the reactor are stirred before and / or during step (a) and / or step (b).

19. 13. The pharmaceutical composition of claim 12, wherein the reactor pressure stabilizes the following steps (a1), (a2), and / or (a4).

20. 12. The pharmaceutical composition of claim 11, wherein the contents of the reactor are stirred before and / or during step (a1), step (a3), and / or step (a5).

21. 13. The pharmaceutical composition of claim 12, wherein a subset of the vapor or gaseous content is pumped out prior to step (a3) ​​and / or step (a5).

22. 12. The pharmaceutical composition of claim 11, wherein the metal oxide layer has a thickness in the range of 0.1 nm to 30 nm.

23. 12. The pharmaceutical composition of claim 11, wherein the polymer layer has a thickness in the range of 0.1 nm to 100 nm.

24. 22. The pharmaceutical composition of claim 21, wherein steps (a2)-(a5) are repeated two or more times, and between each repetition, the particles are not removed from the reactor.

25. 12. The pharmaceutical composition of claim 11, wherein steps (a2)-(a5) are repeated two or more times, and during step (a), the particles are not removed from the reactor.

26. 12. The pharmaceutical composition of claim 11, wherein steps (b1)-(b4) are repeated two or more times, and between each repetition, the particles are not removed from the reactor.

27. 12. The pharmaceutical composition of claim 11, wherein steps (b1)-(b4) are repeated two or more times, and during step (b), the particles are not removed from the reactor.

28. 12. The pharmaceutical composition of claim 11, wherein the particles comprising an API further comprise one or more pharma- ceutically acceptable excipients.

29. 12. The pharmaceutical composition of claim 11, wherein the particles comprising the API have a median particle size, on a volume-average basis, of between 0.1 μm and 20 μm prior to step (a).

30. 12. The pharmaceutical composition of claim 11, wherein the particles subjected to step (a) comprise a first API and a second API.

31. 12. The pharmaceutical composition of claim 11, wherein the particles subjected to step (a) consist of an API.

32. 12. The pharmaceutical composition of claim 11, wherein the particles subjected to step (a) consist of a first API and a second API.

33. 12. The pharmaceutical composition of claim 11, wherein the particles subjected to step (a) comprise an API and one or more pharma- ceutically acceptable excipients.

34. 12. The pharmaceutical composition of claim 11, wherein the particles subjected to step (a) comprise a first API, a second API, and one or more pharma- ceutically acceptable excipients.

35. 12. The pharmaceutical composition of claim 11, wherein the particles subjected to step (a) consist of an API and one or more pharma- ceutically acceptable excipients.

36. 12. The pharmaceutical composition of claim 11, wherein the particles subjected to step (a) consist of a first API, a second API, and one or more pharma- ceutically acceptable excipients.

37. 37. The pharmaceutical composition of any one of claims 1 to 36, wherein the metal oxide layer comprises aluminum oxide, titanium oxide, iron oxide, silicon dioxide, magnesium oxide, or zinc oxide.

38. 38. The pharmaceutical composition of any one of claims 1 to 37, wherein the polymer layer comprises a polyamide, a polyimide, a polyurea, a polyurethane, a polythiourea, a polyester, or a polyimine.

39. 39. The pharmaceutical composition of any one of claims 1 to 38, wherein the polymer layer is biodegradable.

40. 40. The pharmaceutical composition of any one of claims 1 to 39, comprising an inner metal oxide layer, an intermediate polymer layer, and an outer metal oxide layer.

41. 1. A method for preparing coated particles comprising an active pharmaceutical ingredient (API)-containing core surrounded by one or more metal oxide layers and one or more polymer layers, comprising the following sequence of steps: (a) performing atomic layer deposition to apply a metal oxide layer to particles comprising an API, thereby preparing particles comprising an API surrounded by a metal oxide layer; and thereafter (b) performing molecular layer deposition to apply a polymer layer to said particle comprising a drug surrounded by a metal oxide layer, thereby preparing a coated particle comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers. A method comprising:

42. performing atomic layer deposition, (a1) loading the particles comprising the API into a reactor; (a2) applying a vapor or gaseous metal precursor to the particles in the reactor; (a3) performing one or more pump-purge cycles of the reactor using an inert gas; (a4) applying a vapor or gaseous oxidant to the particles in the reactor; and (a5) performing one or more pump-purge cycles of the reactor using an inert gas; 42. The method of claim 41 , comprising:

43. 43. The method of claim 42, wherein steps (a2) through (a5) are performed two or more times to increase the total thickness of the metal oxide layer before step (b) is performed.

44. 44. The method of claim 43, wherein steps (a2)-(a5) are performed 5-50 times to increase the total thickness of the metal oxide layer before step (b) is performed.

45. 4. The method of claim 3, wherein the step of performing molecular layer deposition further comprises: (b1) applying a vaporous polymer precursor A to said particles comprising API inclusions surrounded by a metal oxide layer in said reactor; (b2) performing one or more pump-purge cycles of the reactor using an inert gas; (b3) applying a vaporous polymer precursor B to the particles in the reactor; and (b4) performing one or more pump-purge cycles of the reactor using an inert gas.

45. The method of any one of claims 41 to 44, comprising:

46. 45. The method of claim 44, wherein steps (b1)-(b4) are performed two or more times to increase the total thickness of the polymer layer.

47. 47. The method of claim 46, wherein steps (a2)-(a5) are performed 5-50 times to increase the total thickness of the metal oxide layer before step (b) is performed.

48. 42. The method of claim 41 , wherein the contents of the reactor are stirred before and / or during step (a) and / or step (b).

49. 43. The method of claim 42, wherein the reactor pressure is stabilized during the next steps (a1), (a2), and / or (a4).

50. 42. The method of claim 41 , wherein the reactor contents are stirred before and / or during step (a1), step (a3), and / or step (a5).

51. 43. The method of claim 42, wherein a subset of the vapor or gaseous contents is pumped out prior to step (a3) ​​and / or step (a5).

52. 42. The method of claim 41 , wherein the metal oxide layer has a thickness in the range of 0.1 nm to 20 nm.

53. 42. The method of claim 41, wherein the polymer layer has a thickness in the range of 0.1 nm to 400 nm.

54. 42. The method of claim 41, wherein steps (a2) through (a5) are repeated two or more times, and between each repetition, the particles are not removed from the reactor.

55. 42. The method of claim 41, wherein steps (a2) through (a5) are repeated two or more times, and during step (a), the particles are not removed from the reactor.

56. 42. The method of claim 41, wherein steps (b1)-(b4) are repeated two or more times, and between each repetition, the particles are not removed from the reactor.

57. 42. The method of claim 41, wherein steps (b1)-(b4) are repeated two or more times, and during step (b), the particles are not removed from the reactor.

58. 42. The method of claim 41, wherein the particles comprising an API further comprise one or more pharma- ceutically acceptable excipients.

59. 42. The method of claim 41 , wherein the particles comprising the API have a median particle size, on a volume average basis, of between 0.1 μm and 20 μm prior to step (a).

60. 42. The method of claim 41, wherein the particles have a median particle size, on a volume average basis, of between 0.1 μm and 5 μm prior to step (a).

61. 42. The method of claim 41, wherein the particles have a median particle size, on a volume average basis, of between 0.1 μm and 1000 μm prior to step (a).

62. 42. The method of claim 41 , wherein the particles subjected to step (a) comprise a first API and a second API.

63. 42. The method of claim 41 , wherein the particles subjected to step (a) consist of an API.

64. 42. The method of claim 41 , wherein the particles subjected to step (a) consist of a first API and a second API.

65. 42. The method of claim 41 , wherein the particles subjected to step (a) comprise an API and one or more pharma- ceutically acceptable excipients.

66. 42. The method of claim 41 , wherein the particles subjected to step (a) comprise a first API, a second API, and one or more pharma- ceutically acceptable excipients.

67. 42. The method of claim 41 , wherein the particles subjected to step (a) consist of an API and one or more pharma- ceutically acceptable excipients.

68. 42. The method of claim 41 , wherein the particles subjected to step (a) consist of a first API, a second API, and one or more pharma- ceutically acceptable excipients.

69. 42. The method of claim 41, further comprising mixing the coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers with a pharma- ceutically acceptable diluent or carrier.

70. 42. The method of claim 41, further comprising processing the coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers to form a tablet or capsule.

71. 42. The method of claim 41, further comprising mixing the coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers with a pharma- ceutically acceptable diluent or carrier to form a mixture and processing the mixture to form a tablet or capsule.

72. 42. The method of claim 41, further comprising performing atomic layer deposition to apply a metal oxide layer to said particle comprising an API-containing core surrounded by a metal oxide layer and a polymer layer, thereby preparing a particle comprising an API surrounded by an inner metal oxide layer, an intermediate polymer layer, and an outer metal oxide layer.

73. performing molecular layer deposition to apply a polymer layer to said particle comprising an API surrounded by an inner metal oxide layer, an intermediate polymer layer, and an outer metal oxide layer, thereby preparing a particle comprising an API surrounded by an inner metal oxide layer, an inner intermediate polymer layer, and an outer intermediate metal oxide layer, and an outer polymer layer.

43. The method of claim 42, further comprising:

74. 74. The method of any one of claims 41 to 73, further comprising mixing the coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers with a pharma- ceutically acceptable diluent or carrier.

75. 74. The method of any one of claims 41-73, further comprising processing the coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers to form a tablet or capsule.

76. 74. The method of any one of claims 41 to 73, further comprising mixing the coated particles comprising an API-containing core surrounded by one or more metal oxide layers and one or more polymer layers with a pharma- ceutically acceptable diluent or carrier to form a mixture and processing the mixture to form a tablet or capsule.

Images