Vapor-phase coating technology for abuse-deterrent pharmaceutical formulations

Abstract

A method for preparing an abuse-deterrent pharmaceutical composition having a drug-containing core encapsulated in one or more metal oxide materials is provided. The method includes the sequential steps of: (a) loading drug-containing particles into a reactor, (b) applying a vapor or gaseous metal precursor to the particles in the reactor, (c) pumping and purging the reactor one or more times using an inert gas, (d) applying a vapor or gaseous oxidizing agent to the particles in the reactor, and (e) pumping and purging the reactor one or more times using an inert gas. This produces an abuse-deterrent pharmaceutical composition comprising a drug-containing core encapsulated in one or more metal oxide materials.

Description

[Technical Field]

[0001] The present disclosure relates to pharmaceutical compositions and methods for preparing metal oxide encapsulated pharmaceuticals for abuse deterrence. [Background technology]

[0002] Existing abuse-deterrent formulations (ADFs) require many processing steps and the inclusion of large amounts of excipient materials that may negatively interact with the active pharmaceutical ingredient (API). ADF technologies primarily utilize wet phase coating or dry particle blending. The complexity of such processes significantly adds to manufacturing costs and is undesirable. More importantly, excipients used to deter drug abuse must not interfere with the actual pharmacological activity of the drug. This can be a significant challenge because excipients are specifically designed to prevent dissolution, for example. Summary of the Invention

[0003] This disclosure describes an ADF technique that uses a dry (vacuum / vapor) coating process to deposit existing materials for ADF. This technique can also enable the coating of new materials of interest for ADF that are not amenable to coating by existing techniques.

[0004] The methods described herein allow for the production of thin, uniform, conformal, and dense coatings regardless of particle size. These highly precise coatings can minimize the coating overload required to provide effective abuse deterrence, thereby minimizing the risk of the deterrent formulation affecting pharmacological performance. In addition, hybrid organic-inorganic coating structures can be prepared, enabling new modes of abuse deterrence that combine both physical and chemical barriers in a single process.

[0005] This technology is intended to create abuse-deterrent pharmaceutical formulations through advanced vapor-phase coating technology. The coating can be an organic polymer, an inorganic oxide, or some combination thereof. The ADF coating functions by providing a physical or chemical barrier to drug dissolution or fragmentation, preventing various dosage forms, such as dissolution in alcohol, syringe injection, crushing, or chewing. The physical barrier can have a pH-switching component to prevent dosage loading by the consumer without affecting the pharmacokinetics of the drug. The chemical barrier also functions as a pH solubility switch, which, when used in combination with pH-altering excipients, can prevent dissolution of the outside of the drug without affecting the pharmacokinetics of the drug. The ADF can also contain an aversive component, which alters the texture, taste, or odor of the compound to make dosage loading undesirable. For example, the aversive component can result in the formation of a highly viscous gel when the drug dissolves, preventing withdrawal into a syringe. Although other abuse-deterrent mechanisms (eg, agonist / antagonist pairs) are possible, the present disclosure is specifically directed to physical and chemical barriers, as well as aversive coatings.

[0006] Metal oxide materials are coated via one or more of the atomic layer deposition (ALD) or chemical vapor deposition (CVD) processes. Polymers are coated via one or more of the molecular layer deposition (MLD), initiated (hot filament) chemical vapor deposition (iCVD), or aerosol-assisted atomization deposition (AA-CVD) processes. These techniques share the unique benefits of high coating uniformity, good conformal coverage, and a relative lack of pinhole defects, regardless of particle size, and are easy to handle in the common reactor architectures described elsewhere herein. The particles being coated are agitated (by rotation, gas flow, or vibration) during deposition to ensure high throughput and good uniformity.

[0007] ALD deposition of metal oxides occurs at temperatures between about room temperature and 300°C by alternating the administration of precursors, such as TMA or TiCl4, and oxidizers, such as water vapor or ozone. The excellent chemical inertness and physical strength of metal oxides make them promising new candidates for ADF. They can also exhibit pH-dependent solubility characteristics. In the coating process, precursors are administered into the reactor in either static or flow mode. In static mode, the reactants are pulsed into the sealed reactor and allowed to remain there until consumed. The reaction byproducts are then pumped out, and the reactants are pulsed again until all reactive sites on the powder are occupied. The reactor is then purged of residual reactants with a stream of inert gas, which may or may not be heated or ionized to increase the efficiency of the purge. The cycle is then repeated with the second reactant. In flow mode, the reactant flow rate is set to ensure complete or near-complete consumption in the reactor without closing the reactor exhaust. Organic polymer layers can be deposited in this reactor via either molecular layer deposition or initiated (hot filament) chemical vapor deposition (iCVD). MLD is an alternative process similar to the process described for ALD above and can be used to deposit condensation polymers, such as branched or crosslinked polyamides and polyesters. pH-responsive polyesters or polyamides are commonly used in pharmaceutical enteric coatings and are also of interest for ADF-based chemical and physical barriers. Depending on the chemical formulation, gels can also form for aversive formulations. In the MLD process, particles are coated by alternating physisorbed or chemisorbed monolayers composed of one or more complimentary pairs of multifunctional Lewis acids and bases. The Lewis bases can be composed of multifunctional alcohols, such as diethylene glycol, or amines, such as ethylenediamine. The Lewis acids can be composed of multifunctional acid chlorides, such as succinyl chloride, glutaryl chloride, or adipoyl chloride.Trifunctional Lewis acids or bases, such as trimesoyl chloride, can be used to induce branching or crosslinking. Hybrid organic-inorganic materials can also be prepared using metal-organic precursors (e.g., TMA) as the Lewis acid. These alternating layers can be applied in either static or flow mode, as specified in ALD above.

[0008] The iCVD process can be used to deposit chain-growth polymers, such as poly(acrylates), poly(methacrylates), and poly(styrenes), as well as their copolymers. Among these materials, amino esters of acrylic and methacrylic acid (e.g., pDMAEMA and pEMAEMA) are commonly used for ADF due to their pH-dependent swelling behavior. Additionally, hydrogel materials (e.g., crosslinked acrylamides) can exhibit high swelling properties and are therefore prime candidates for aversive coatings. In the iCVD process, one or more monomer precursors selected from a subset of vinyl, acrylate, methacrylate, acrylamide, methacrylamide, or styrene chemicals flow into the reactor via a vapor delivery system (i.e., bubbler or direct liquid injection) capable of delivering 1–100 g / min of monomer vapor. A second injector provides delivery of a thermal initiator, e.g., an organic peroxide, from which copolymers can also be prepared. The initiator flows over a heated element before entering the reactor. The heated element decomposes the initiator to form two peroxy radicals without interacting with the monomer vapor, which then induce chain-growth polymerization of the monomer species physically adsorbed on the surface of the particle being coated.

[0009] These processes result in dense, conformal, and highly uniform films that cannot be produced by current top-layer pharmaceutical coating processes. These precision coatings can achieve good abuse deterrence while minimizing the coating's effect on pharmacological behavior. Furthermore, by enabling the same performance with thinner coatings, excipient loading can be minimized, allowing for increased drug doses in smaller dosage form elements. In addition, the dense, continuous metal oxide coatings made possible by this technology represent a new class of physical barrier that has not been previously explored. Finally, these processes can be used in combination to create layered structures with multiple physical and chemical barriers, resulting in a unique combination of abuse-deterrent properties that cannot be achieved using a single material alone.

[0010] In one aspect, a method for preparing a pharmaceutical composition having a drug-containing core encapsulated in one or more metal oxide materials and having abuse-deterrent properties is provided. The method includes the sequential steps of: (a) loading drug-containing particles into a reactor; (b) applying a vapor or gaseous metal precursor to the particles in the reactor; (c) pumping and purging the reactor one or more times using an inert gas; (d) applying a vapor or gaseous oxidizing agent to the particles in the reactor; and (e) pumping and purging the reactor one or more times using an inert gas. This produces a pharmaceutical composition comprising a drug-containing core encapsulated in one or more metal oxide materials.

[0011] A practice may include one or more of the following characteristics:

[0012] The sequence of steps (b) to (e) can be repeated one or more times to increase the overall thickness of the one or more metal oxide materials encapsulating the core.

[0013] The reactor pressure may be allowed to stabilize after step (a), step (b) and / or step (d).

[0014] The contents of the reactor may be agitated before and / or during step (b), step (c) and / or step (e).

[0015] A subset of the vapor or gaseous contents may be pumped out prior to step (c) and / or step (e).

[0016] The metal oxide layer can have a thickness in the range of 0.1 nm to 100 nm.

[0017] The particles can include a drug and one or more pharmaceutically acceptable excipients.

[0018] The particles can have a median particle size of 0.1 μm to 1000 μm on a volume average basis.

[0019] The pharmaceutical composition can be removed from the reactor and mixed with a pharmaceutically acceptable diluent or carrier.

[0020] The particles can consist essentially of an active pharmaceutical ingredient (API).

[0021] The API can be any drug subject to abuse, for example, an opioid (oxycodone, naloxone, morphine, naltrexone, hydrocodone, sufuntanil, oxymorphone, codeine, fentanyl, hydromorphone, codeine, fentanyl, and tapentadol).

[0022] The one or more metal oxide materials may include aluminum oxide, titanium oxide, iron oxide, gallium oxide, magnesium oxide, zinc oxide, niobium oxide, hafnium oxide, tantalum oxide, lanthanum oxide, and / or zirconium dioxide.

[0023] The one or more metal oxide materials may be comprised of aluminum oxide and / or titanium oxide.

[0024] The oxidizing agent may be selected from the group of water, ozone and organic peroxides.

[0025] In another embodiment, pharmaceutical compositions having a drug-containing core encapsulated in one or more metal oxide materials may be prepared by any of the methods described above.

[0026] 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 disclosure belongs. Methods and materials are described herein for use in this disclosure; other suitable methods and materials known in the art can also be used. Materials, methods, and examples are for illustrative purposes only and are 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.

[0027] Other features and advantages of the present disclosure will be apparent from the following detailed description, the drawings, and the claims. [Brief explanation of the drawings]

[0028] [Figure 1] FIG. 1 is a schematic diagram of a rotary reactor for ALD and / or CVD coating of particles, e.g., drugs. [Figure 2] 1 is a table showing typical process conditions for the present method. [Figure 3] 1 is a graph depicting representative residual gas analysis traces measured during steps (d), (h), (i) and (m) of one cycle of the method. DETAILED DESCRIPTION OF THE INVENTION

[0029] The present disclosure provides methods for preparing pharmaceutical compositions containing a drug encapsulated by one or more layers of metal oxide. Such pharmaceutical compositions have abuse-deterrent properties, such as reduced friability and / or reduced solubility. Overall, the provided methods for preparing pharmaceutical compositions can safely, reliably, and predictably produce pharmaceutical compositions having the above-described properties. As a result, the provided pharmaceutical compositions and methods for preparing metal oxide-encapsulated drugs have increased therapeutic value, increased commercial value, and lower production costs per therapeutic dose.

[0030] The production of beneficial pharmaceutical compositions has been made possible by the discovery that a vaporous or gaseous metal precursor and a vaporous or gaseous oxidant are applied sequentially, with each application of the metal or oxidant being followed by one or more pump-purge cycles using an inert gas, with the entire reaction preferably occurring at or below 35°C.

[0031] Provided herein are methods utilizing mechanical systems and chemical engineering processes. The disclosure also provides exemplary components and operating conditions for the systems and processes, as well as exemplary drug substrates, vaporous and gaseous metal precursors, and vaporous and gaseous oxidants.

[0032] Metal Oxide Materials The term "metal oxide material" in its broadest sense includes all materials formed by the reaction of an element considered a metal with an oxygen-based oxidizer. Exemplary metal oxide materials include, but are not limited to, aluminum oxide, titanium dioxide, iron oxide, gallium oxide, magnesium oxide, zinc oxide, niobium oxide, hafnium oxide, tantalum oxide, lanthanum oxide, and zirconium dioxide. Exemplary oxidizers include, but are not limited to, water, ozone, and inorganic peroxides.

[0033] Atomic Layer Deposition (ALD) Atomic layer deposition is a thin film deposition technique in which the sequential addition of self-limiting monolayers of elements or compounds allows the deposition of films with thickness and uniformity controlled to the atomic or molecular monolayer level. Self-limiting means that only a single atomic layer is formed at a time; subsequent process steps are required to regenerate the surface to allow further deposition.

[0034] Chemical Vapor Deposition (CVD) Chemical vapor deposition is a thin film deposition technique whereby elements or chemical compounds are deposited on a surface by chemical reactions in a gas layer or on the surface. It is distinguished from atomic layer deposition in that the deposition is not self-limiting, i.e., the film continues to grow as long as chemicals are supplied. It is distinguished from physical vapor deposition in that the chemical reaction results in a deposited film that is chemically different from the precursor species.

[0035] Reactor System The term "reactor system" in its broadest sense includes all systems that can be used to conduct ALD or mixed ALD / CVD or CVD. An exemplary reactor system is illustrated in FIG. 1 and described further below.

[0036] FIG. 1 illustrates a reactor system 10 for coating particles, e.g., heat-sensitive particles, with a thin film coating. The reactor system 10 can perform the coating using ALD and / or CVD coating conditions. The relative contributions of the ALD and CVD processes to the thin film coating can be controlled by appropriate selection of process conditions. In particular, the reactor system 10 allows a primarily ALD process, e.g., substantially the entire ALD process, to be performed at a low processing temperature, e.g., below 50°C, e.g., 35°C or below. For example, the reactor system 10 can form a thin film metal oxide on particles primarily by ALD at a temperature between 22 and 35°C, e.g., between 25 and 35°C, between 25 and 30°C, or between 30 and 35°C. Generally, the particles can remain at or be maintained at such a temperature. This can be achieved by having the reactant gases and / or the interior surfaces of the reactor chamber (e.g., chamber 20 and drum 40, discussed below) remain at or be maintained at such a temperature.

[0037] Performing the ALD reaction at low temperature conditions allows the coating to be formed on the particles without degrading the biological component, e.g., vaccine or biopharmaceutical component. For example, amorphous forms of biological components can be coated without destroying the biological component or covering the biological component with crystalline forms.

[0038] Reactor system 10 includes a stationary vacuum chamber 20 connected by vacuum piping 22 to a vacuum pump 24. Vacuum pump 24 can be an industrial vacuum pump sufficient to establish a pressure of less than 1 Torr, e.g., 1-100 mTorr, e.g., 50 mTorr. Vacuum pump 24 allows chamber 20 to be maintained at a desired pressure and allows for the removal of reaction by-products and unreacted process gases.

[0039] In operation, reactor 10 performs an ALD thin film coating process by bringing gaseous precursors of the coating into 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, which can provide angstrom-level control of deposition. Additionally, the ALD reaction can be performed at low temperature conditions, e.g., below 50°C, e.g., below 35°C.

[0040] Chamber 20 is also connected to a chemical delivery system 30. Chemical delivery system 20 includes three or more gas sources 32a, 32b, and 32c connected to vacuum chamber 20 by corresponding delivery lines 34a, 34b, and 34c and control valves 36a, 36b, and 36c. Chemical delivery system 30 can include a combination of restrictors, gas flow controllers, pressure transducers, and ultrasonic flow meters to provide controllable flow rates of various gases into chamber 20. Chemical delivery system 30 can also include one or more temperature control components, such as heat exchangers, resistance heaters, heat lamps, etc., to heat or cool the various gases before they enter chamber 20. While FIG. 1 illustrates separate gas lines running in parallel from each gas source to the chamber, two or more gas lines can be joined, for example, by one or more three-way valves, before the combined line reaches chamber 20. Additionally, although FIG. 1 illustrates three gas sources, the use of four gas sources can enable the in situ formation of laminated structures having alternating layers of two different metal oxides.

[0041] Two of the gas sources provide two chemically distinct gaseous reactants for the coating process to chamber 20. Suitable reactants include any one or combination of the following: monomer vapor, metal organics, metal halides, oxidizers such as ozone or water vapor, and polymer or nanoparticle aerosols (dry or wet). For example, first gas source 32a can provide gaseous trimethylaluminum (TMA) or titanium tetrachloride (TiCl4), while second gas source 32b can provide water vapor.

[0042] 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, coating, and particles being processed. For example, the purge gas can be N2 or a noble gas, such as argon.

[0043] A rotating coating drum 40 is held inside the chamber 20. The drum 40 may be connected to a motor 44 by a driver shaft 42 that extends through a sealed port in the sidewall of the chamber 20. The 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.

[0044] The particles to be coated are shown as particle bed 50 and are located within the interior volume 46 of drum 40. Drum 40 and chamber 20 may include sealable ports (not shown) to allow particles to be placed into and removed from drum 40.

[0045] The body of the drum 40 comprises one or more of porous material, solid metal, and porous metal. The pores through the cylindrical side wall of the drum 40 can have dimensions of 10 μm.

[0046] In operation, as the drum 40 rotates, one of the gases flows from the chemical delivery system 30 into the chamber 20. The combination of fine pores (1-100 μm), holes (0.1-10 mm), or larger openings in the coating drum helps confine the particles within the coating drum, while simultaneously allowing for rapid delivery of precursor chemicals and pumping away by-products or unreacted species. The pores in the drum 40 allow gas to flow between the outside of the drum 40, i.e., the reactor chamber 40, and the interior of the drum 40. Additionally, the rotation of the drum 40 agitates and separates the particles, ensuring that a large surface area of ​​the particles remains exposed. This allows for rapid, uniform interaction of the particle surfaces with the process gas.

[0047] In some implementations, one or more temperature control components are integrated 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 in or on the sidewalls of the drum 40.

[0048] Reactor system 10 also includes a controller 60 coupled to various controllable components, such as vacuum chamber 24, gas distribution system 30, motor 44, temperature control system, etc., to control the operation of reactor system 10. Controller 60 may also be coupled to various sensors, such as pressure sensors, flow meters, etc., to provide closed-loop control of gas pressure within chamber 20.

[0049] In general, the controller 60 can operate the reactor system 10 according to a "recipe." The recipe specifies the operating values ​​of each controllable element as a function of time. For example, the recipe can specify the time for which the vacuum pump 24 operates, the time and flow rate 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).

[0050] The controller 60 and other computing device portions of the systems described herein can be implemented with digital electronic circuitry, or with computer software, firmware, or hardware. For example, the controller can include a processor to execute a computer program product, e.g., a computer program stored on a non-transitory machine-readable storage medium. Such computer programs (also known as programs, software, software applications, or code) can be written in any form of programming language, including compiled or interpreted languages, and can be arranged in any form, including stand-alone programs, or as modules, components, subroutines, or other units 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, e.g., an FPGA (field-programmable gate array) or an ASIC (application-specific integrated circuit).

[0051] Operation First, particles are loaded into drum 40 of reactor system 10. The particles may have a solid core containing a drug, such as one of the drugs discussed above. Once any access ports are sealed, controller 60 operates reactor system 10 according to a recipe to form a thin film metal oxide layer on the particles.

[0052] In particular, two reactant gases are alternately supplied to the chamber 20, with each supply step of reactant gases being followed by a purge cycle, in which an inert gas is supplied to the chamber 20 to push 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, in which the chamber 20 is filled with gas to a particular pressure, a delay time is allowed to elapse, and the chamber 20 is evacuated by the vacuum pump 24 before the next pulse begins.

[0053] In particular, the controller 60 can operate the reactor system 10 as follows.

[0054] In the first reactant half-cycle, drum 40 agitates particles 50 while motor 44 rotates. i) The gas delivery system 30 is activated to flow a first reactant gas, e.g., TMA, from source 32a into the chamber 20 until a first specific pressure is achieved, which can be from 0.1 Torr to half the saturation pressure of the reactant gas. ii) Stopping the flow of the first reactant and allowing a specified delay time, e.g., measured by a timer in the controller, to pass, allowing the first reactant to flow through the particle bed in the drum 40 and react with the surfaces of the particles 50 inside the drum 40. iii) The vacuum pump 50 evacuates the chamber 20, for example, to a pressure below 1 Torr, for example, 1 to 100 mTorr, for example, 50 mTorr.

[0055] These steps (i) to (iii) can be repeated a number of times set by the strategy, for example, 2 to 10 times, for example, 6 times.

[0056] Next, in the first purge cycle, the drum agitates the particles 50 while the motor 44 rotates. iv) The gas delivery system 30 is activated to flow an inert gas, such as N2, from the source 32c into the chamber 20 until a second specified pressure is achieved, which can be between 1 and 100 Torr. v) Stopping the flow of inert gas and allowing a specified delay time to pass, e.g., as measured by a timer in the controller, allows the inert gas to flow through the pores of the drum 40 and diffuse into the particles 50, replacing the reactant gas and any vaporous by-products. vi) The vacuum pump 50 evacuates the chamber 20, for example, to a pressure below 1 Torr, for example, 1 to 500 mTorr, for example, 50 mTorr.

[0057] These steps (iv) to (vi) can be repeated a number of times set by the strategy, for example, 6 to 20 times, for example, 16 times.

[0058] In the second reactant half-cycle, drum 40 agitates particles 50 while motor 44 rotates. vii) The gas delivery system 30 is activated to flow a second reactant gas, e.g., HO, from the source 32a into the chamber 20 until a third specified pressure is achieved, which may be from 0.1 Torr to half the saturation pressure of the reactant gas. viii) Stopping the flow of the second reactant and allowing a specified delay time, e.g., measured by a timer in the controller, to pass, allowing the second reactant to flow through the pores of the drum 40 and react with the surfaces of the particles 50 inside the drum 40. ix) The vacuum pump 50 evacuates the chamber 20, for example, to a pressure below 1 Torr, for example, 1 to 500 mTorr, for example, 50 mTorr.

[0059] These steps (vii) to (ix) can be repeated a number of times set by the strategy, for example, 2 to 10 times, for example, 6 times.

[0060] 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.

[0061] 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 strategy, for example, 1 to 10 times.

[0062] As noted above, the coating process can be carried out at low processing temperatures, e.g., below 50°C, e.g., 35°C or lower. In particular, the particles can remain at or be maintained at such temperatures during all of steps (i)-(ix) described 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 the corresponding cycles. Additionally, the physical components of the chamber can remain at or be maintained at such temperatures, e.g., using a cooling system, e.g., a thermoelectric cooler, if necessary.

[0063] Method for preparing a pharmaceutical composition containing a drug encapsulated by one or more layers of a metal oxide Two exemplary methods are provided for producing pharmaceutical compositions comprising a drug-containing core encapsulated in one or more metal oxide materials. The first exemplary method includes the following sequential steps: (a) loading drug-containing particles into a reactor; (b) applying a vapor or gaseous metal precursor to the substrate in the reactor; (c) pumping and purging the reactor one or more times using an inert gas; (d) applying a vapor or gaseous oxidant to the substrate in the reactor; and (e) pumping and purging the reactor one or more times using an inert gas. During the method, the temperature of the particles does not exceed 35°C.

[0064] 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 encapsulating the solid core of the coated particle. In some embodiments, the pressure of the reactor is stabilized after step (a), step (b), and / or step (d). In some embodiments, the contents of the reactor are agitated before and / or during step (b), step (c), and / or step (e). In some embodiments, a subset of the vapor or gaseous contents are pumped out before step (c) and / or step (e).

[0065] A second exemplary method includes the steps of: (a) loading drug-containing particles into a reactor; (b) reducing the reactor pressure to less than 1 Torr; (c) stirring the reactor contents until the reactor contents have a desired water content; (d) adding vaporous or gaseous metal precursor to pressurize the reactor to at least 10 Torr; (e) stabilizing the reactor pressure; (f) stirring the reactor contents; (g) pumping a subset of the vaporous or gaseous contents and determining when to stop pumping based on an analysis of the contents in the reactor, including the metal precursor and metal precursor by-products that react with exposed hydroxyl residues on the substrate or on the surface of the particles; and (h) removing any undesired metal precursors. (i) adding vaporous or gaseous oxidant to pressurize the reactor to at least 10 Torr; (j) stabilizing the pressure in the reactor; (k) stirring the contents of the reactor; (l) pumping out a subset of the vaporous or gaseous contents and determining when to stop pumping based on an analysis of the contents in the reactor, including the metal precursor, metal precursor by-products that react with hydroxyl residues exposed on the substrate or on the surface of the particles, and unreacted oxidant; and (m) performing a series of pump-purge cycles of the reactor using an inert gas.

[0066] 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 encapsulating the solid core of the coated particle.

[0067] 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 copolymer, cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylethylcellulose, 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; (3) fillers, such as lactose monohydrate, lactose anhydrous, microcrystalline cellulose, and various starches; (4) Lubricants, agents that act on the flowability of powders being compressed, including, for example, colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel; (5) Sweeteners, e.g., any natural or artificial sweetener, including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acisulfame 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 chemicals, such as phenol, or quaternary compounds, such as benzalkonium chloride; (8) Buffer; (9) Diluents, e.g., pharmaceutically acceptable inert fillers, e.g., microcrystalline cellulose, lactose, dicalcium 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, such as croscarmellose sodium, crospovidone, sodium starch glycolate; and (12) Effervescent agents, e.g., effervescent couples, such as organic acids (e.g., citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid, and anhydrides and acid salts), or 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). [Example]

[0068] The following materials and methods were used in the examples described herein. [Example]

[0069] Nanometer-level precision is used to prepare particles containing drugs encapsulated in a uniformly thin layer of aluminum oxide coating. In this example, one of the disclosed methods for preparing metal oxide-encapsulated drugs is performed and data is presented. In this example, the vaporous or gaseous metal precursor is trimethylaluminum (TMA), the by-product gaseous methane is formed after TMA reacts with hydroxyl groups exposed on the particle or on the surface of the coated particle, and the oxidant is water vapor.

[0070] method Briefly, the method comprises: (a) loading drug-containing particles into a reactor; (b) reducing the reactor pressure to less than 1 Torr; (c) performing a residual gas analysis (RGA) to monitor the water vapor level within the reactor and stirring the contents of the reactor until the contents of the reactor have a desired moisture content; (d) adding vaporous or gaseous TMA and pressurizing the reactor to at least 1 Torr; (e) stabilizing the reactor pressure; (f) agitating the contents of the reactor; (g) pumping a vapor or a subset of the gaseous contents, including gaseous methane and unreacted TMA, and performing an RGA to monitor the levels of gaseous methane and unreacted TMA in the reactor to determine when to stop pumping; (h) performing a series of pump-purge cycles of the reactor using nitrogen gas; (i) adding water vapor to pressurize the reactor to at least 1 Torr; (j) stabilizing the reactor pressure; (k) agitating the contents of the reactor; (l) pumping a subset of the vapor or gaseous contents, including water vapor, and performing an RGA to monitor the level of water vapor in the reactor to determine when to stop pumping; (m) performing a series of pump-purge cycles of the reactor using nitrogen gas; The following successive steps were included:

[0071] While carrying out the method, the internal temperature of the reactor does not exceed 35°C. Additionally, steps (b) through (m) are repeated two or more times to increase the total thickness of the aluminum oxide encapsulating the solid core. Figure 2 includes representative process conditions for carrying out the method.

[0072] result Figure 3 shows representative residual gas analysis traces measured during steps (d), (h), (i), and (m) of one cycle of this method. This method reproducibly demonstrates growth rates of metal oxide coatings of 2-4 Å per cycle. In contrast, a different method, where ALD growth is limited, demonstrated an average cycle-by-cycle growth of only 1 Å per cycle. Without being bound by any particular theory, given the growth rates observed with this method, growth may be mediated by a combination of ALD and CVD.

Claims

1. A method for preparing an abuse-deterrent pharmaceutical composition comprising opioid-containing particles encapsulated in a coating layer comprising titanium oxide, comprising: (a) loading opioid-containing particles into a reactor; (b) applying a vapor or gaseous metal precursor to the opioid-containing particles in the reactor; (c) performing one or more pump-purge cycles of the reactor using an inert gas; (d) applying a vaporous or gaseous oxidant to the opioid-containing particles in the reactor; and (e) performing one or more pump-purge cycles of the reactor using an inert gas; and the coating layer reduces the solubility and friability of the opioid-containing particles, and the coating layer has a thickness in the range of 0.1 nm to 100 nm; method.

2. 10. The method of claim 1, wherein the sequential steps (b) through (e) are repeated one or more times to increase the total thickness of the coating layer.

3. 10. The method of claim 1, wherein the reactor pressure is stabilized at less than 1 Torr after step (a), at least 1 Torr after step (b), and / or at least 1 Torr after step (d).

4. 10. The method of claim 1, wherein the reactor contents are agitated before and / or during step (b), step (c), and / or step (e).

5. 10. The method of claim 1, wherein a subset of the vapor or gaseous content is pumped prior to step (c) and / or step (e).

6. 10. The method of claim 1, wherein the opioid-containing particles comprise one or more pharmaceutically acceptable excipients.

7. 10. The method of claim 1, wherein the opioid-containing particles have a volume-averaged median particle size of 0.1 μm to 1000 μm.

8. 10. The method of claim 1, wherein the pharmaceutical composition is removed from the reactor and mixed with a pharmaceutically acceptable diluent or carrier.

9. 10. The method of claim 1, wherein the opioid-containing particles consist essentially of an opioid.

10. The method of claim 1 , wherein the coating layer is less than 50 nanometers thick.

11. The method of claim 1 , wherein the coating layer is less than 10 nanometers thick.

12. 10. The method of claim 1, wherein the opioid-containing particles have a median particle size of less than 10 microns on a volume average basis.

13. 10. The method of claim 1, wherein the opioid-containing particles have a median particle size of less than 1 micron on a volume average basis.

14. 10. The method of claim 1, wherein the opioid-containing particles have a median particle size of less than 100 nanometers on a volume average basis.

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