Vapor deposition technology for the preparation of pharmaceutical compositions

Abstract

A process for the preparation of a pharmaceutical or veterinary composition in the form of a plurality of particles is provided, the process comprising: (a) loading a plurality of solid cores containing a biologically active agent into a fixed gas phase deposition reactor chamber; (b) applying a gas phase deposition technique to surround, enclose, and / or encapsulate the cores with one or more layers of a coating material, each layer containing one or more metal-containing compounds or metalloid-containing compounds; (c) optionally, repeating step (b) continuously to form a plurality of particles having a weight-, number-, and / or volume-based average diameter of from about 10 nm to about 100 μm, each particle comprising a respective solid core and a coating surrounding, enclosing, and / or encapsulating the core; wherein the gas phase deposition technique comprises: (1) introducing a pulse of a first reactive gas into the fixed gas phase deposition reactor chamber to allow the first reactive gas to contact the solid core for a predetermined immersion period; (2) after step (1), evacuating and / or purging the fixed gas phase deposition reactor chamber with an inert gas; (3) introducing a pulse of a second reactive gas into the fixed gas phase deposition reactor chamber to allow the second reactive gas to contact the solid core for a predetermined immersion period; (4) after step (3), evacuating and / or purging the fixed gas phase deposition reactor chamber with an inert gas; wherein either the first reactive gas or the second reactive gas contains a metal-containing compound or a metalloid-containing compound.

Description

Technical Field

[0001] The present invention relates to a novel process for manufacturing a composition useful in the field of drug delivery.

Background Art

[0002] The listing or discussion of documents clearly previously published herein should not necessarily be taken as an admission that the documents are part of the state of the art or common general knowledge.

[0003] In the field of drug delivery, the ability to control the drug release profile is of great importance. To ensure a more optimal pharmacokinetic profile, it is desirable to ensure that the active ingredient is released in vivo at a desired and predictable rate after administration.

[0004] In the case of sustained release compositions, it is also very important that the drug delivery composition provides a release profile that exhibits minimal initial rapid release of the active ingredient (high plasma concentration of the drug immediately after administration). For drugs with a narrow therapeutic window or drugs that are toxic at high plasma concentrations, such "burst" release can be dangerous.

[0005] In the case of an injectable suspension of the active ingredient, it is also important that the size of the suspended particles is controlled so that they can be injected through a needle. If large aggregated particles are present, not only will those particles clog the needle through which the suspension is injected, but they will not form a stable suspension in the injection solution (i.e., those particles will instead tend to sink to the bottom of the injection solution).

[0006] Thus, there is a general need in the art for effective and / or improved drug transport and delivery systems.

[0007] Atomic layer deposition (ALD) is a technique employed to deposit thin films containing various materials, including organic materials, biological materials, polymeric materials, and particularly inorganic materials such as metal oxides, onto a solid substrate. This is a technique that enables atomic and near-atomic scale manufacturing (ACSM) of materials, structures, devices, and systems for various applications (see, for example, Zhang et al. Nanomanuf. Metrol. 2022, https: / / doi.org / 10.1007 / s41871-022-00136-8). Based on its self-limiting nature, ALD can achieve atomic-level thicknesses that are controlled only by adjusting the number of growth cycles. Furthermore, multiple layers can be deposited, and the properties of each layer can be customized at the atomic level.

[0008] Due to its atomic-level control, ALD is used as an important technique, for example, in the manufacture of next-generation semiconductors, or in the atomic-level synthesis of advanced catalysts, as well as in the precise manufacture of nanostructures, nanoclusters, and single atoms (see, for example, Zhang et al. cited above).

[0009] This technique is typically carried out at low pressure and high temperature. The film coating is produced by alternately exposing a solid substrate within an ALD reactor chamber to reactants vaporized in the gas phase. The substrate can be a silicon wafer, granular material, or small particles (e.g., microparticles or nanoparticles).

[0010] The coated substrate is protected from chemical reactions (decomposition) and physical changes by the solid coating. ALD can potentially be used to control the release rate of substrate materials in a solvent, and thereby potentially be used in the formulation of pharmaceutical active ingredients.

[0011] In ALD, a first precursor, which can be a metal-containing substance, is supplied to the ALD reactor chamber (in a so-called "precursor pulse") to form an atomic or molecular monolayer adsorbed on the surface of the substrate. Next, the excess first precursor is purged from the reactor, and then a second precursor, such as water, is pulsed into the reactor. This reacts with the first precursor, resulting in the formation of, for example, a monolayer of metal oxide on the substrate surface. After subsequent purge pulses, a further pulse of the first precursor follows, and thus a new cycle of the same events (a so-called "ALD cycle") is initiated.

[0012] Alternatively, in "spatial ALD", separate reactor chambers contain each precursor, and the coated substrate is moved from one reactor chamber to another for the coating to be formed. In this method, or other methods of ALD, the introduction of the precursor to the coated substrate (or vice versa) can be regarded as equivalent to a "precursor pulse", and the separation of the precursor from the substrate to be coated (or vice versa) can be regarded as equivalent to a "purge pulse".

[0013] The thickness of the film coating is controlled, inter alia, by the number of ALD cycles performed.

[0014] In a normal ALD process, since only an atomic or molecular monolayer is generated during any one cycle, no distinguishable physical interface is formed between these monolayers and it is essentially a continuous band on the surface of the substrate.

[0015] International Patent Application No. 2014 / 187995 describes a process in which several ALD cycles are carried out, and subsequently the resulting coated substrate is periodically removed from the reactor and a redispersion / stirring step is performed to present a new surface available for the adsorption of the precursor.

[0016] The stirring step is performed to address problems mainly observed with nanoparticles and microparticles, namely, the problem that particle aggregation occurs during the ALD coating process and "pinholes" are formed by such contact points between particles. The redispersion / stirring step is carried out by placing the coated substrate in water and subjecting it to ultrasonic treatment, resulting in the deaggregation and the disruption of the contact points between the individual particles of the coated active material.

[0017] The particles were then reloaded into the reactor, and the steps of powder ALD coating and powder deaggregation were repeated 3 times up to a total of 4 cycles. This process has been found to enable the formation of coated particles with a substantial degree of pinhole-free coating (see also Hellrup et al, Int. J. Pharm., 529, 116 (2017)).

[0018] As described in International Patent Application No. 2014 / 187995, performing a "set" of ALD coating cycles followed by an intermittent dispersion process results in distinct separate layers of coating defined by a clear visible physical interface between such coating layers. Such an interface is clearer than the interfaces that can be seen between layers of different coating materials. The interface formed by such intermittent dispersion of the particles is clearly visible as regions of higher electron transmissivity by techniques such as transmission electron microscopy (TEM). As will be explained below, when a coating of the same material builds one atomic layer at a time from the surface of the substrate, a similar interface is not visible.

[0019] As described in International Patent Application No. 2021 / 111149, it has recently been found that it is advantageous to deaggregate aggregated particles into primary particles outside the reactor by a dry process involving a combination of mechanically advancing means and sieves (in particular acoustic sieve devices). This avoids the need to employ invasive deaggregation techniques such as sonication, and also the need to dry the particles before returning them to the reactor for further coating. It has been found that performing the deaggregation step in this way enables the presentation of essentially completely pinhole-free coated particles in a form that can be readily processed into pharmaceutical formulations.

[0020] As described in unpublished UK Patent Application No. 2108305.0, it has more recently been found that it is advantageous to use a vibrating sieve technique to deaggregate aggregated particles. In particular, the vibrating sieve technique results in deaggregated coated particles that are essentially free of cracks through which the active ingredient could be released in an uncontrolled manner.

[0021] In an attempt to further expand the processes described in International Patent Application No. 2021 / 111149 and UK Patent Application No. 2108305.0, it has been found that when a large-scale continuous flow reactor is used, the coating consistency between different particles coated together can become unsatisfactory. This problem has unexpectedly been solved by the process described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0022] According to a first aspect of the present invention, there is provided a process for the preparation of a composition in the form of a plurality of particles, the process comprising: (a) loading a plurality of solid cores containing a biologically active agent into a fixed gas phase deposition reactor chamber; and (b) applying a gas phase deposition technique to surround, enclose, and / or encapsulate the cores with one or more layers of one or more coating materials, each layer containing one or more metal-containing compounds or metalloid-containing compounds. (c) Optionally, step (b) above is continuously repeated to form a plurality of particles having a weight-, number-, and / or volume-based average diameter of from about 10 nm to about 100 μm, each comprising a respective solid core and a coating surrounding, encapsulating, and / or encapsulating the core. The vapor deposition technique is (1) introducing a pulse of a first reactive gas into a fixed vapor deposition reactor chamber to allow the first reactive gas to contact the solid core over a predetermined immersion period; (2) after step (1), evacuating and / or purging the fixed vapor deposition reactor chamber with an inert gas; (3) introducing a pulse of a second reactive gas into the fixed vapor deposition reactor chamber to allow the second reactive gas to contact the solid core over a predetermined immersion period; (4) after step (3), evacuating and / or purging the fixed vapor deposition reactor chamber with an inert gas, Either the first reactive gas or the second reactive gas contains a metal-containing compound or a metalloid-containing compound.

[0023] In the process of the present invention, both the first reactive gas and the second reactive gas are each brought into contact with the particles over a predetermined immersion period. The term "immersion" is used in this application only for clarity, i.e., so that the associated predetermined period can be readily distinguished from other predetermined periods that may be referred to in this application. It should be understood that the term "immersion" does not limit the associated predetermined period in any way.

[0024] A process having such an immersion time increases coating uniformity (also referred to as coating integrity or shell integrity, which can be measured as described below), since each gas is allowed to diffuse conformally over a high aspect ratio substrate, e.g., especially in powder. This is due to the fact that the substrate has an increased surface area and requires a longer period of time to stop using and react with all of the available surface sites.

[0025] The aforementioned advantage of including an immersion time is more pronounced when the process involves the use of reactants with low reactivity, since more time is provided for the reactants to react on the substrate surface. For example, this is evident for diethylzinc (DEZ) especially when depositing AlZnO, because its reaction probability towards the surface is lower than, for example, trimethylaluminum (TMA).

[0026] Known ALD processes are carried out in a continuous flow mode, meaning that the pump is actively pumping on the reactor throughout the process and the gas continuously passes over the powder substrate. In contrast, including an immersion time in the process prevents the continuous flow of gas over the powder substrate. For example, introducing an immersion time can involve closing a valve to prevent either inflow or outflow from the reactor chamber. When the valve is closed to prevent inflow (e.g., when the valve is arranged to close the inlet to the reactor chamber), the pressure within the reactor chamber can remain substantially constant during the immersion time. However, some change in pressure can occur due to the reactions taking place, and the pressure change will depend on the stoichiometry of those reactions. Alternatively, when the valve is closed to prevent outflow (e.g., when the valve is arranged to close the outlet of the reactor chamber), the pressure within the reactor chamber can steadily increase during the immersion time as more precursor enters the reactor chamber. This can beneficially push the precursor further into the powder bed, increasing the likelihood of reaction with the surface of the particles therein, thereby enhancing the effect of the immersion time.

[0027] An ALD process including such an immersion time is sometimes referred to as a "stop-flow" process.

[0028] Inclusion of the immersion time not only produces a coating with good shell integrity and a more controlled release profile, but also results in a coating composition closer to the ALD process settings. When using an ALD cycle scheme consisting of 3 DEZ cycles and 1 TMA cycle, an atomic ratio of 3:1 between Zn and Al is expected in the resulting shell. This does not apply when depositing in a continuous flow where the atomic ratio approaches 1:1 because the reaction probability is lower for DEZ than for TMA. When using a stop flow, the same ratio is very close to 3:1.

[0029] The process of the present invention also requires the use of a fixed gas phase deposition reactor chamber. It will be understood that a fixed reactor chamber in the context of the present invention is a reactor chamber that remains fixed while being used to carry out a gas phase deposition technique, except for negligible vibrations caused by the associated machinery. This is in contrast to a reactor chamber that rotates or vibrates during the gas phase deposition process, or otherwise moves actively.

[0030] It will be understood that the "predetermined period" of the immersion time can be any suitable period. This period depends greatly on the particle sample size (or batch size), with smaller sample sizes requiring less immersion time and larger sample sizes requiring longer immersion times. The immersion time can also depend on factors such as the properties of the solid core and / or the type of reactive gas. In addition, the immersion time can depend on the design of the ALD reactor, for example, the size of the reaction chamber, the distance to the inlet valve, and the valve to the pump. The immersion time can be in the range of about 2 seconds to about 30 minutes. For example, the immersion time can be about 30 seconds, 1 minute, 3 minutes, 10 minutes, or 15 minutes.

[0031] Those skilled in the art will understand that for any combination of the above variables, the beneficial effects provided by the immersion time are finite. For example, for a given process, the first 5-second period of the immersion time may provide significant benefits to coating uniformity and completeness, the second 5-second period of the immersion time may provide less but some additional benefits than those provided by the first period, and the third 5-second period may be an additional benefit that is almost negligible compared to the advantages already obtained (this is a simplified example for illustrative purposes only). In other words, the benefits provided by the immersion time as the immersion time increases can be modeled as a curve that initially increases with a high gradient, but the gradient decreases as the immersion time increases until a steady state is finally reached, at which point further immersion may no longer be advantageous.

[0032] The "benefits" of the immersion time are not limited to shell completeness, but it will be understood that the resulting shell completeness of the particles can be used as an indicator of the effectiveness of the immersion time. Thus, to select a suitable immersion time for a particular process, those skilled in the art may perform trials, including incrementally increasing the immersion time, to determine the desired compromise between the length of the immersion time and the benefits it provides to shell completeness. In the simplified example referred to above, those skilled in the art may determine that an immersion time close to 10 seconds is appropriate since minimal additional benefits are observed for any longer immersion time.

[0033] In some examples of the present invention, the predetermined immersion period can be selected to provide shell integrity as measured, for example, of at least about 70%, for example, at least about 80%, for example, at least about 90%, for example, at least about 95%, for example, about 98.5% as described below. It should be understood that the shell or coating integrity described herein can be considered the inverse of API dissolution in a solvent that dissolves the API but not the coating material. For example, about 5% API dissolution would indicate about 95% shell / coating integrity. Suitable methods for determining coating integrity via determination of API dissolution are provided in the examples described below.

[0034] During the process of the present invention, the valve to the pump inlet is closed so that the reactive gas is present in the reaction chamber without any active pumping action for a predetermined immersion time before the chamber is pumped. Depending on the reactor, the valve can be completely shut off so that no gas passes through, or if it is not possible to completely shut off the valve such that there is a minimal amount of pumping action present (e.g., nitrogen carrier gas can still flow within the chamber). In either scenario, it is understood that no active pumping action is occurring. That is, there is a substantial absence of pumping action.

[0035] Furthermore, the predetermined immersion period is preferably carried out in the substantial absence of mechanical agitation of the plurality of solid cores. Agitation or sieving of the solid cores can be carried out during other steps of the process as further described in the present application.

[0036] This process may optionally include performing multi-pulses of a reactive gas, i.e., short bursts of inflow, without purging / rinsing between each multi-pulse, and each multi-pulse pumps the reactor over a predetermined pump operation period. Such multi-pulsing is equivalent to performing a single long pulse of the reactive gas with respect to the amount of reactive substrate applied to the solid core. By applying the reactants in a multi-pulse fashion, a more consistent coating of the solid core is achieved. Each multi-pulse pump operation time can be about 0.1 to 1000 seconds, about 1 to 500 seconds, about 2 to 250 seconds, about 3 to 100 seconds, about 4 to 50 seconds, or about 5 to 10 seconds, for example, 9 seconds. The multi-pulses can be applied about 5 to 1000 times, about 10 to 250 times, or about 20 to 50 times in a single step.

[0037] The term "solid" is well understood by those skilled in the art to include any form of a substance that retains its shape and density when not confined and / or whose molecules are generally compressed as strongly as the repulsive forces between them allow. The solid core has at least a solid outer surface on which a layer of coating material can be deposited. The interior of the solid core can also be solid or, alternatively, can be hollow. For example, if the particles are spray dried before being placed in the reaction vessel, they can be hollow due to the spray drying technique. The core can alternatively include aggregates of smaller "primary" particles, i.e., secondary particles within the size range defined herein that are coated as described later in this specification.

[0038] The process of the present invention is preferably employed to produce a pharmaceutical composition. Accordingly, the composition, particularly the solid core, contains a pharmacologically effective amount of a biologically active agent.

[0039] In this regard, the solid core can consist essentially of, or contain, a biologically active agent (which agent may hereinafter be referred to interchangeably as "drug", as well as "active pharmaceutical ingredient (API)" and / or "active ingredient"). Biologically active agents also include biopharmaceuticals and / or biologics. The biologically active agent can also include a mixture of different APIs, as different API particles or particles containing more than one API.

[0040] "Consisting essentially of" a biologically active agent means that the solid core consists essentially of only the biologically active agent(s), i.e., does not contain non - biologically active substances (described hereinafter) such as excipients, carriers, and other active substances. This means that the core can contain less than about 5%, for example, less than about 2%, such as less than about 3%, for example, less than about 1% of such other excipients and / or active substances.

[0041] Alternatively, the core containing the biologically active agent can be mixed with one or more pharmaceutical ingredients that can include pharmaceutically acceptable excipients such as adjuvants, diluents, or carriers, and / or can include other biologically active ingredients, to contain such an agent.

[0042] The biologically active agent can be presented in crystalline, semi - crystalline, and / or amorphous states. The biologically active agent, regardless of its physical form, can further include any substance that is in a solid state, or can be converted to a solid state, at approximately room temperature (e.g., about 18 °C) and approximately atmospheric pressure. Such agents (and optionally, other pharmaceutical ingredients described herein) should also remain in solid form, for example, while being coated in an ALD reactor, and should not decompose physically or chemically to a significant extent (i.e., by about 10% w / w or less) while being coated or after being coated by at least one of the coating materials. The biologically active agent can be further presented in combination with another active substance (e.g., mixed or as a complex).

[0043] As used herein, the term "biologically active agent" or similar and / or related expressions generally refer to any agent or drug capable of producing a certain physiological effect (whether it has a therapeutic or prophylactic ability against a specific medical condition or state) in a living subject, including in particular mammalian and especially human subjects (patients).

[0044] Biologically active agents include, for example, analgesics, anesthetics, anti-ADHD agents, anorectics, anti-toxic agents, antibacterial agents, antimicrobials, antifungals, antivirals, antiparasitics, antiprotozoals, anthelmintics, ectoparasiticides, vaccines, anti-cancer agents, antimetabolites, alkylating agents, antitumor agents, topoisomerase inhibitors, immunomodulators, immunostimulants, immunosuppressants, anabolic steroids, anticoagulants, antiplatelet agents, antiepileptic agents, anti-dementia agents, antidepressants, antidotes, antihyperlipidemic agents, antigout agents, antimalarials, antimigraine agents, anti-Parkinson agents, anti-itch agents, antipsoriatic agents, antiemetics, anti-obesity agents, anti-asthma agents, antibiotics, antidiabetic agents, antiepileptic drugs, antifibrinolytics, antihemorrhagic agents, antitussives, antihypertensives, antimuscarinics, antimycobacterials, antioxidants, antipsychotics, antipyretics, antirheumatics, antiarrhythmics, anxiolytics, aphrodisiacs, cardiac glycosides, cardiotonics, enterogens, enteractogens, hypnotics, neuroleptics, astringents, bacteriostatics, beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, renin inhibitors, beta-adrenergic receptor blockers, blood products, blood substitutes, bronchodilators, inotropic agents, chemotherapeutic agents, coagulants, corticosteroids, antitussive suppressants, diuretics, deliriants, expectorants, pregnancy promoters, sex hormones, mood stabilizers, mucolytics, neuroprotective agents, nootropics, neurotoxins, dopamine agonists, anti-Parkinson's disease drugs, free radical scavengers, growth factors, fibrates, bile acid sequestrants, scar-forming agents, glucocorticoids, mineralocorticoids, hemostatic agents, hallucinogens, hypothalamic-pituitary hormones, immunizing agents, cathartics, antidiarrheals, lipid regulators, muscle relaxants, parasympathomimetics, parathyroid calcitonin, selenium, statins, stimulants, wakefulness promoters, decongestants, dietary minerals, bisphosphonates, cough suppressants, ophthalmic drugs, ontological drugs, H1 antagonists, H2 antagonists, proton pump inhibitors, prostaglandins, radiopharmaceuticals, hormones, sedatives, anti-allergy agents, appetite stimulants, steroids, sympathomimetics, thrombolytics, thyroid agents, vasodilators, xanthines, erectile dysfunction improvers, gastrointestinal drugs, histamine receptor antagonists, keratolytics, anti-angina agents, non-steroidal anti-inflammatory agents, COX-2 inhibitors, leukotriene inhibitors, macrolides, NSAIDs, nutrients, opioid analgesics, opioid antagonists, potassium channel activators,It may be selected from protease inhibitors, anti-osteoporosis agents, cognitive enhancers, anti-incontinence agents, nutritional oils, anti-benign prostatic hyperplasia agents, essential fatty acids, non-essential fatty acids, radiopharmaceuticals, anti-aging agents, vitamins, or mixtures of any of these.

[0045] The biologically active agent can also be a cytokine, a peptide mimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, or a mixture thereof. Non-limiting examples of therapeutic peptides / proteins are as follows: Repirin, Cetuximab, Dornase alfa, Denileukin diftitox, Etanercept, Vivaglazin, Leuprolide, Alteplase, Interferon alpha-n1, Darbepoetin alfa, Reteplease, Epoetin alfa, Salmon calcitonin, Interferon alpha-n3, Pegfilgrastim, Sargramostim, Secretin, Peginterferon alpha-2b, Asparaginase, Thyrotropin alpha, Antihemophilic factor, Anakinra, Gramicidin D, Intravenous immunoglobulin, Anistreplase, Insulin (usually), Tenecteplase, Menotropin, Interferon gamma-1b, Interferon alpha-2a (recombinant), Coagulation factor VIIa, Oprelvekin, Parathyroid hormone, Glucagon (recombinant), Aldesleukin, Botulinum toxin type B, Omalizumab, Lutropin alpha, Insulin lispro, Insulin glargine, Collagenase, Rasburicase, Adalimumab, Imiglucerase, Abciximab, Alpha-1-proteinase inhibitor, Pegaspargase, Interferon beta-1a, Pegademase bovine, Human serum albumin, Eptifibatide, Iodinated serum albumin, Infliximab, Follitropin beta, Vasopressin, Interferon beta-1b, Hyaluronidase, Rituximab, Basiliximab, Muromonab, Digoxin immune Fab (sheep), Ibritumomab, Daptomycin, Tositumomab, Pegvisomant, Botulinum toxin type A, Pancreatic lipase, Streptokinase, Alemtuzumab, Arglucerase, Capromab, Laronidase, Urofollitropin, Efalizumab, Serum albumin, Chorionic gonadotropin alpha, Anti-thymocyte globulin, Filgrastim, Coagulation factor IX, Becaplermin, Agalsidase beta, Interferon alpha-2b, Oxytocin, Enfuvirtide, Palivizumab, Daclizumab, Bevacizumab, Alcitumomab, Eculizumab, Panitumumab, Ranibizumab,Idursulfase, alglucosidase alfa, exenatide, mecasermin, pramlintide, galactosidase alfa, abatacept, cosyntropin, corticotropin, insulin aspart, insulin detemir, insulin glulisine, pegaptanib, nesiritide, timafacine, defibrotide, natural alpha interferon / multiferon, glatiramer acetate, perocto, teicoplanin, canakinumab, ipilimumab, slodexide, tocilizumab, teriparatide, pertuzumab, rilonacept, denosumab, liraglutide, semaglutide, exenatide, lixisenatide, albiglutide, dulaglutide, tildrakizumab, golimumab, belatacept, buserelin, velaglucerase alfa, tesamorelin, brentuximab vedotin, taliglucerase alfa, belimumab, aflibercept, asparaginase Erwinia chrysanthemi, ocriplasmin, glucarpidase, teduglutide, lirilumab, certolizumab pegol, insulin isophane, epoetin zeta, obinutuzumab, fibrinolysin, also known as plasmin, follitropin alpha, romiplostim, lucinactant, natalizumab, aliskiren, ragweed pollen extract, secukinumab, somatropin (recombinant), drotrecogin alpha, alefacept, OspA lipoprotein, urokinase, abarelix, sermorelin, aprotinin, gemtuzumab ozogamicin, satsuma-mab pentetide, albiglutide, antithrombin alpha, antithrombin III (human), asfotase alfa, atezolizumab, autologous cultured chondrocytes, beractant, blinatumomab, C1 esterase inhibitor (human), coagulation factor XIII A subunit (recombinant), corn starch alpha, daratumumab, desirudin, dulaglutide, erosulfase alfa, evolocumab, fibrinogen concentrate (human), filgrastim-sndz, intrinsic factor, hepatitis B immune globulin, human calcitonin, human Clostridium tetani toxoid immune globulin, human rabies virus immune globulin, human Rho(D) immune globulin, human Rho(D) immune globulin, hyaluronidase (human, recombinant), idarucizumab, immunoglobulin (human)Berdilizumab, ustekinumab, turuktogualfa, tuberculin purified protein derivative, simoctogualfa, siltuximab, severipase alpha, sacrosidase, ramucirumab, prothrombin complex concentrate, poractant alpha, pembrolizumab, peginterferon beta-1a, ofatumumab, obinutuzumab, nivolumab, necitumumab, metreleptin, methoxypolyethylene glycol-epoetin beta, mopolizumab, ixekizumab, insulin degludec, insulin (porcine), insulin (bovine), thyroglobulin, anthrax immune globulin (human), anti-inhibitor coagulant complex, brodalumab, C1 esterase inhibitor (recombinant), chorionic gonadotropin (human), chorionic gonadotropin (recombinant), coagulation factor X (human), dinutuximab, emoctocog alfa, factor IX complex (human), hepatitis A vaccine, human varicella zoster immune globulin, ibritumomab tiuxetan, lenograstim, pegloticase, protamine sulfate, protein S (human), sipuleucel-T, somatropin (recombinant), susoctogualfa, and thrombomodulin alpha. And sarcomere and synthetic forms of antisense RNA, RNA interference agents, messenger RNA, transfer RNA, ribosomal RNA containing RNA aptamers.,

[0046] Non-limiting examples of drugs that can be used in accordance with the present invention are all-trans retinoic acid (tretinoin), alprazolam, allopurinol, amiodarone, amlodipine, asparaginase, astemizole, atenolol, azathioprine, azelaic acid, beclomethasone, bendamustine, bleomycin, budesonide, buprenorphine, butalbital, capecitabine, carbamazepine, carbidopa, carboplatin, cefotaxime, cephalexin, chlorambucil, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clonazepam, clozapine, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin, diazepam, diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine, docetaxel, doxorubicin, doxazosin, enalapril, epirubicin, erlotinib, estradiol, etodolac, etoposide, everolimus, famotidine, felodipine, fentanyl citrate, phenoxyphenazine, filgrastim, finasteride, fluconazole, flunisolide, fluorouracil, flurbiprofen, fluranaer, fluvoxamine, furosemide, gemcitabine, glipizide, glibride, ibuprofen, ifosfamide, imatinib, indomethacin, irinotecan, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen, lamotrigine, lansoprazole, loperamide, loratadine, lorazepam, lovastatin, medroxyprogesterone, mefenamic acid, mercaptopurine, mesna, methotrexate, methylprednisolone, midazolam, mitomycin, mitoxantrone, moxidectin, mometasone, nabumetone, naproxen, nicergoline, nifedipine, norfloxacin, omeprazole, oxaliplatin, paclitaxel, phenytoin, piroxicam, procarbazine, quinapril, ramipril, risperidone, rituximab, sertraline, simvastatin, sulindac, sunitinib, temsirolimus, terbinafine, terfenadine, thioguanine, trastuzumab, triamcinolone, valproic acid, vinblastine, vincristine, vinorelbine, zolpidem,or a pharmaceutically acceptable salt of any of these.

[0047] The compositions produced by the process of the present invention may contain benzodiazepines such as alprazolam, chlordiazepoxide, clobazam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, quazepam, temazepam, triazolam, and pharmaceutically acceptable salts of any of these.

[0048] An anesthetic that may also be employed in the compositions produced by the process of the present invention may be local or systemic. Local anesthetics that may be mentioned include amylocaine, ambucaine, articaine, benzocaine, benzonatate, bupivacaine, butacaine, butanilicaine, chloroprocaine, cinchocaine, cocaine, cyclomethycaine, dibucaine, diperodon, dimethocaine, eutocaine, etidocaine, hexylcaine, fomocaine, photocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine, mepivacaine, meprilocaine, metabutoxycaine, nitracaine, orthocaine, oxethacaine, oxybuprocaine, paraethoxycaine, phenacaine, piperocaine, pyridocaine, pramocaine,prilocaine, procaine, procaine amide, propalacaine, propoxycaine, pyrocaine, quiniso-caine, ropivacaine, trimecaine, tricaine, tropacocaine, or a pharmaceutically acceptable salt of any of these.

[0049] Psychiatric drugs can also be employed in the compositions produced by the process of the present invention. Psychiatric drugs that may be mentioned include 5-HTP, acamprosate, agomelatine, alimemazine, amphetamine, dextroamphetamine, amisulpride, amitriptyline, amobarbital, amobarbital / secobarbital, amoxapine, amphetamine(s), aripiprazole, asenapine, atomoxetine, baclofen, benperidol, bromperidol, bupropion, buspirone, butabarbital, carbamazepine, chloral hydrate, chlorpromazine, chlorprothixene, citalopram, chlormethiazole, clomipramine, clonidine, clozapine, cyclobarbital / diazepam, cyproheptadine, cytisine, desipramine, desvenlafaxine, dextroamphetamine, dextromethylphenidate, diphenhydramine, disulfiram, divalproex sodium, doxepin, doxylamine, duloxetine, enanthic acid, escitalopram, eszopiclone, fluoxetine, flupenthixol, fluphenazine, fluspirilene, fluvoxamine, gabapentin, glutethimide, guanfacine, haloperidol, hydroxyzine, iloperidone, imipramine, lamotrigine, levetiracetam, levomepromazine, levomilnacipran, lisdexamfetamine, lithium salts, lurasidone, melatonin, melperone, meprobamate, methamphetamine, netamidone, methylphenidate, mianserin, mirtazapine, moclobemide, nalmefene, naltrexone, niaprazine, nortriptyline, olanzapine, ondansetron, oxcarbazepine, paliperidone, paroxetine, penfluridol, pentobarbital, perazine, periciazine, perphenazine, phenelzine, phenobarbital, pimozide, pregabalin, promethazine, prothipendyl, protriptyline, quetiapine, ramelteon, reboxetine, reboxetine, reserpine, risperidone, rubidium chloride, secobarbital, selegiline, sertindole, sertraline, sodium oxybate, sodium valproate, sodium valproate, sulpiride, thioridazine, thiothixene, tianeptine, tizanidine, topiramate, tranylcypromine, trazodone,It contains trifluoperazine, trimipramine, tryptophan, valerian, valproic acid (in a ratio of 2.3:1), varenicline, venlafaxine, vilazodone, vortioxetine, zaleplon, diprasidone, zolpidem, zopiclone, zotepine, zuclopenthixol, and pharmaceutically acceptable salts of any of these.

[0050] Antiparkinson drugs that may be mentioned include levodopa and apomorphine, and pharmaceutically acceptable salts of these.

[0051] Opioid analgesics that may be employed in the composition produced by the process of the present invention include buprenorphine, butorphanol, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, nor-methadone, opium, oxycodone, oxymorphone, pentazocine, tapentadol, tramadol, and pharmaceutically acceptable salts of any of these.

[0052] Opioid antagonists that may be employed in the composition produced by the process of the present invention include naloxone, nalorphine, nicomorphine, diprenorphine, levallorphan, samidorphan, nalorphine, alvimopan, methylnaltrexone, naloxegol, 6β-naltrexone, axelopran, bebenopran, methylsamidorphan, naldemedine, preferably nalmefene, and especially naltrexone, and pharmaceutically acceptable salts of any of these.

[0053] Anticancer agents that may be included in the composition produced by the process of the present invention include the following: actinomycin, afatinib, all-trans retinoic acid, amsacrine, anagrelide, arsenic trioxide, axitinib, azacitidine, azathioprine, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, chlorambucil, cladribine, clofarabine, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, erlotinib, estramustine, etoposide, everolimus, fludarabine, fluorouracil, gefitinib, guadecitabine, gemcitabine, hydroxycarbamide, hydroxyurea, idarubicin, idelalisib, ifosfamide, imatinib, irinotecan, ixazomib, cabozantinib, carfilzomib, crizotinib, lapatinib, lomustine, mechlorethamine, melphalan, mercaptopurine, mesna, methotrexate, mitotane, mitoxantrone, nelarabine, nilotinib, niraparib, olaparib, oxaliplatin, paclitaxel, panobinostat, pazopanib, pemetrexed, pixantrone, ponatinib, procarbazine, regorafenib, luxolitinib, sonidegib, sorafenib, sunitinib, tegafur, temozolomide, teniposide, thioguanine, thiotepa, topotecan, trabectedin, valrubicin, vandetanib, vemurafenib, venetoclax, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, visimodegib, and pharmaceutically acceptable salts of any of these.

[0054] Such compounds can be used in any one of the following cancers: adenocystic carcinoma, adrenal cancer, amyloidosis, anal cancer, ataxia-telangiectasia, dysplastic nevus syndrome, basal cell carcinoma, bile duct cancer, Birt-Hogg-Dubé syndrome, canal syndrome, bladder cancer, bone cancer, brain tumor, breast cancer (including male breast cancer), canceroid tumor, cervical cancer, colorectal cancer, ductal carcinoma in situ of breast, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, HER2-positive breast cancer, islet cell tumor, juvenile polyposis syndrome, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, all types of acute lymphoblastic leukemia, acute myeloid leukemia, adult leukemia, pediatric leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lobular carcinoma, lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, malignant glioma, melanoma, meningioma, multiple myeloma, myelodysplastic syndrome, nasopharyngeal cancer, neuroendocrine tumor, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor, parathyroid cancer, penile cancer, peritoneal cancer, Peutz-Jeghers syndrome, pituitary tumor, polycythemia vera, prostate cancer, renal cell carcinoma, retinoblastoma, salivary gland cancer, sarcoma, Kaposi sarcoma, skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymoma, thyroid cancer, uterine (endometrial) cancer, vaginal cancer, Wilms tumor.

[0055] Cancers that may be mentioned include myelodysplastic syndrome and subtypes, such as acute myeloid leukemia, refractory anemia or refractory anemia with ring sideroblasts (with neutropenia or thrombocytopenia or if transfusion is required), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myeloid leukemia (myelomonocytic leukemia).

[0056] Osteoporosis drugs that may be mentioned include bisphosphonates such as clodronic acid, ibandronic acid, pamidronic acid, zoledronic acid, etidronic acid, alendronic acid, risedronic acid, tiludronic acid, bonedronate and derivatives (e.g., acid derivatives of these compounds).

[0057] Other drugs that may be mentioned for use in the compositions produced by the process of the present invention include immunomodulatory imide drugs such as thalidomide, and their analogs such as pomalidomide, lenalidomide, and apremilast, and pharmaceutically acceptable salts of any of these. Other drugs that may be mentioned include angiotensin II receptor type 2 agonists such as compound 21 (C21, 3-[4-(1H-imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophene-2-[(N-butyloxylcarbamate)-sulfonamide]) and pharmaceutically acceptable (e.g., sodium) salts thereof.

[0058] Preferred anticancer agents include lenalidomide, which is useful for the treatment of multiple myeloma and anemia in low to intermediate risk myelodysplastic syndromes, and azacitidine, which is particularly useful for the treatment of certain subtypes of myelodysplastic syndromes. Another specific anticancer drug that may be mentioned is cisplatin, a chemotherapeutic agent useful for a number of cancers including testicular cancer, cervical cancer, ovarian cancer, bladder cancer, lung cancer, esophageal cancer, and head and neck cancer, as well as brain tumors, neuroblastomas, and mesotheliomas.

[0059] Other preferred biologically active agents that may be mentioned include liraglutide, which is useful for the treatment of type 2 diabetes and the prevention of diabetes-related cardiovascular complications. Specific drugs that may be mentioned in this regard include exenatide, lixisenatide, albiglutide, dulaglutide, more preferably tirzepatide and semaglutide, and particularly glucagon-like peptide-1 receptor agonists such as liraglutide.

[0060] Alternatively, the compositions produced by the process of the present invention may also include, instead of (or in addition to) the biologically active agent, a diagnostic agent (i.e., an agent that does not have direct therapeutic activity per se but can be used for the diagnosis of conditions such as contrast agents for bioimaging or contrast media).

[0061] The composition produced by the process of the present invention can cause an inflammatory response, for example, subcutaneously after injection. This response can be generated by any component, or combination of components, of such a formulation (including coatings or delivery systems).

[0062] Biological active agents that may be particularly mentioned in this regard include those that can cause, or are expected to cause, an inflammatory response when administered to a patient, either alone or in the form of a composition produced by the process of the present invention.

[0063] Biological active agents that may be particularly mentioned for use in a composition produced by the process of the present invention in this regard include, for example, anti-tumor agents, topoisomerase inhibitors, immunomodulators (such as thalidomide, pomalidomide, lenalidomide, and apremilast), immunostimulants, immunosuppressants, chemotherapeutic agents, growth factors, vasodilators, and radiopharmaceuticals.

[0064] Specific biological agents that may be mentioned in this regard include the specific anticancer agents listed above, in particular, actinomycin, azacitidine, azathioprine, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, chlorambucil, cladribine, clofarabine, cytarabine, dabrafenib, dacarbazine, dactinomycin, daunorubicin, decitabine, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, estramustine, etoposide, everolimus, fludarabine, fluorouracil, guadecitabine, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, ixazomib, carfilzomib, lomustine, mechlorethamine, melphalan, mercaptopurine, mesna, methotrexate, mitotane, mitoxantrone, nelarabine, oxaliplatin, paclitaxel, panobinostat, pemetrexed, pixantrone, procarbazine, tegafur, temozolomide, teniposide, thioguanine, thiotepa, topotecan, trabectedin, valrubicin, venetoclax, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine, and any one or more of the pharmaceutically acceptable salts of any of these are included.

[0065] Further biological agents that may be mentioned in this regard include certain cytokines, proteins, and vaccines, as well as therapeutic peptides / proteins such as daratumumab, isatuximab, and complement C1 esterase inhibitor.

[0066] Other drugs that may be mentioned in this regard include bendamustine, bleomycin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, everolimus, fluorouracil, gemcitabine, ifosfamide, irinotecan, mercaptopurine, mesna, methotrexate, midazolam, mitomycin, oxaliplatin, paclitaxel, procarbazine, temsirolimus, thioguanine, vinblastine, vincristine, vinorelbine, or pharmaceutically acceptable salts of any of these.

[0067] Such mild inflammatory responses can be alleviated by co - administration with an anti - inflammatory agent suitable for injection.

[0068] Suitable anti-inflammatory agents that can be employed in this regard include butylpyrazolidine (e.g., phenylbutazone, mofebutazone, oxyphenbutazone, clofezone, kebufone, and suxibuzone), acetic acid derivatives and related substances (indomethacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpyramide, oxametacin, progulmetacin, ketorolac, aceclofenac, and bufexamac), oxicams (e.g., piroxicam, tenoxicam, droxicam, lornoxicam, and meloxicam), propionic acid derivatives (e.g., ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen, benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen, alminoprofen, dexketoprofen, vedaprofen, carprofen, and tepoxalin), fenamates (e.g., mefenamic acid, tolfenamic acid, flufenamic acid, meclofenamic acid, and flunixin), coxibs (e.g., celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, firocoxib, robenacoxib, mabacoxib, and simicoxib), other non-steroidal anti-inflammatory agents (e.g., nabumetone, niflumic acid, azapropazone, glucosamine, benzydamine, glucosaminoglycan polysulfate, proquazone, orgotein, nimesulide, phenyramidol, diacerhein, moriniflumate, tenidap, oxaceprol, chondroitin sulfate, pentosan polysulfate, and aminopropionitrile), corticosteroids (e.g., 11-dehydrocorticosterone, 11-deoxycorticosterone, 11-deoxycortisol, 11-ketoprogesterone, 11β-hydroxy pregnenolone, 11β-hydroxyprogesterone, 11β,17α,21-trihydroxy pregnenolone, 17α,21-dihydroxy pregnenolone, 17α-hydroxy pregnenolone, 17α-hydroxyprogesterone, 18-hydroxy-11-deoxycorticosterone,18-Hydroxycorticosterone, 18-hydroxyprogesterone, 21-deoxycortisol, 21-deoxycortisone, 21-hydroxypregnenolone (prevedionolone), aldosterone, corticosterone (17-deoxycortisol), cortisol (hydrocortisone), cortisone, pregnenolone, progesterone, flugestone (flurogestone), flumetholone, medrysone (hydroxymethylprogesterone), prevedionolone acetate (21-acetoxypregnenolone), chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluparolone, fluprednisolone, loteprednol, methylprednisolone, prednicarbate, prednisolone, prednisone, tixocortol, triamcinolone, alclometasone, beclometasone, betamethasone, clobetasol, clobetasone, clocortolone, desoxymethasone, dexamethasone, diflorasone, diflucortolone, flucortolone, flumethasone, fluocortine, fluocortolone, fluprednide, fluticasone, fluticasone furoate, halometasone, meprednisone, mometasone, mometasone furoate, paramethasone, prednylidene, rimexolone, ubrocortazole (halobetasol), amcinonide, budesonide, ciclesonide, deflazacort, desonide, hormonacorteflucortolone acetonide (flucronide), fludroxycortide (flurandrenolone, flurandrenolide), flunisolide, fluocinolone acetonide, fluocinonide, halcinonide and triamcinolone acetonide), quinoline (e.g., oxyquinoline), gold preparations (e.g., sodium aurothiomalate, sodium aurothiosulfate, auranofin, aurothioglucose and aurothiophol), penicillamine and similar agents (e.g., bucillamine, etc.), and antihistamines (acrivastine, alimemazine, antazoline, astemizole, azatadine, azelastine, bamipine, bilastine, bromodiphenhydramine, brompheniramine, bucrizine, cetirizine, cinnarizine, cyclizine, cyproheptadine, deptropine, desloratadine, dexbrompheniramine, dexchlorpheniramine,It includes dienylpyraline, dimenhydrinate, dimethindene, doxylamine, ebastine, epinastine, phenindamine, pheniramine, fexofenadine, histapyrrodine, hydroxyethylpromethazine, isothipendyl, carbinoxamine, ketotifen, kifenadine, clemastine, chlorcyclizine, chlorphenamine, chlorphenoxamine, chloropyramine, levocetirizine, loratadine, mebhydrolin, mequitazine, meclozine, mepyramine, metapyrylene, methdilazine, mizolastine, oxatomide, oxomemazine, pimexene, promethazine, pyrrobutamine, rupatadine, secifenadine, talastine, tenalidine, terfenadine, thiazinamium, tiethylperazine, tonzylamine, trimethobenzamide, tripelennamine, triprolidine, and tritocbarine). Any one or more combinations of the aforementioned anti-inflammatory agents can be used.

[0069] Preferred anti-inflammatory agents include non-steroidal anti-inflammatory drugs such as diclofenac, ketoprofen, meloxicam, aceclofenac, flurbiprofen, parecoxib, ketorolac, indomethacin, or pharmaceutically acceptable salts thereof.

[0070] The subject may receive (or may already be receiving) one or more of the aforementioned co-therapeutic agents and / or anti-inflammatory agents, separate from the composition produced by the process of the present invention, which means receiving a predetermined dose of one or more of these other therapeutic agents before, in addition to, and / or subsequent to treatment with the composition produced by the process of the present invention.

[0071] When a biologically active agent is "administered in combination" with such an anti-inflammatory agent, the active ingredients can be administered together in the same formulation or separately (simultaneously or sequentially) in different formulations (hereinafter referred to as "combination products").

[0072] Such combination products provide for the administration of a biologically active agent in combination with an anti-inflammatory agent and can thus be presented as separate formulations, at least one of which is a composition made by the process of the invention and at least one of which can contain the anti-inflammatory agent in a separate formulation or be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation containing the biologically active agent and the anti-inflammatory agent).

[0073] In this regard, the anti-inflammatory agent can be co-presented with the biologically active agent in appropriate doses in one or more of the cores forming part of the composition made by the process of the invention previously described herein, or can be formulated using a process for a coating the same or similar to that previously described herein for biologically active agents that includes the process of the invention and that allows for the release of other anti-inflammatory agents over the same or different timescales.

[0074] Pharmaceutically acceptable salts of the biologically active agent include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting the free acid or free base form of the compound of the invention with one equivalent or more of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., in vacuo, by lyophilization or by filtration). The salts can also be prepared using techniques known to those skilled in the art, such as by exchanging the counterion of the compound of the invention in salt form with another counterion, for example, using a suitable ion exchange resin.

[0075] Specific salts that may be mentioned include, for example, acid addition salts such as hydrochloric acid, L-lactic acid, acetic acid, phosphoric acid, (+)-L-tartaric acid, citric acid, propionic acid, butyric acid, hexanoic acid, L-aspartic acid, L-glutamic acid, succinic acid, ethylenediaminetetraacetic acid (EDTA), maleic acid, methanesulfonic acid, and the like.

[0076] The composition produced by the process of the present invention may contain a pharmacologically effective amount of a biologically active agent. The term "pharmacologically effective amount" refers to the amount of such an active ingredient that, whether administered alone or in combination with another active ingredient, is capable of producing the desired physiological change (such as a therapeutic effect) in a treated patient. Such a biological or medical response, or such an effect, in a patient can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs of, or feels, the effect), and includes at least partial alleviation of the symptoms of the disease or disorder being treated, or cure or prevention of the disease or disorder.

[0077] Accordingly, the dosage of the active ingredient that can be administered to a patient must be sufficient to affect a therapeutic response over a reasonable and / or relevant time frame. Those skilled in the art will recognize that the selection of the precise dosage and composition and the most appropriate delivery regimen depends not only on the nature of the active ingredient, but also, inter alia, on the pharmacological properties of the formulation, the route of administration, the nature and severity of the condition being treated, the physical and mental state of the recipient, and the age, condition, weight, sex, and response of the patient being treated, the stage / severity of the disease, and genetic differences between patients.

[0078] Administration of the composition produced by the process of the present invention can be continuous or intermittent (e.g., by bolus injection). The dosage of the active ingredient can also be determined by the timing and frequency of administration.

[0079] In any case, a physician or other person skilled in the art will be able to routinely determine the actual dosage of any particular active ingredient that is most suitable for an individual patient.

[0080] Non-biological active adjuvants, diluents, and carriers that can be employed in the core to be coated according to the present invention include pharmaceutically acceptable substances that are water-soluble, such as carbohydrates, for example sugars like lactose and / or trehalose, and sugar alcohols such as mannitol, sorbitol, and xylitol, or pharmaceutically acceptable inorganic salts such as sodium chloride. Preferred carrier / excipient materials include sugars and sugar alcohols. Such carrier / excipient materials are particularly useful when the biologically active agent is, for example, a macromolecular complex such as a peptide, protein, or a part of a genetic material as generally described, and / or a specific peptide / protein previously described herein including a vaccine. Thus, when embedding the macromolecular complex in the excipient, the core for coating becomes larger, and accordingly, the coated particles often become larger.

[0081] In addition to containing one or more biological active agents, the core can include one or more non-biological active adjuvants, diluents, and carriers, including a skin softener, and / or other excipients having functional properties such as a buffer and / or a pH adjuster (for example, citric acid).

[0082] When injected, the formulation produced by the process of the present invention provides a depot formulation in which the biologically active agent is released over a long period. That period can be at least about 3 days, for example, about 5 days, or about 7 days, and up to about 1 year, for example, about 3 weeks (for example, about 2 weeks or about 4 weeks), or about 12 weeks (for example, about 10 weeks or about 14 weeks).

[0083] The solid core is provided in the form of nanoparticles or, more preferably, microparticles. Preferred weight-, number-, or volume-based average diameters are from about 50 nm (for example, about 100 nm, for example, about 250 nm) to about 30 μm, for example, from about 500 nm to about 100 μm, more specifically, from about 1 μm to about 50 μm, for example, about 25 μm, for example, about 20 μm.

[0084] As used herein, the term "weight-based average diameter" is understood by those skilled in the art to include that the average particle size is characterized and defined from a particle size distribution by weight, i.e., the existing fraction (relative amount) in each size class is defined as a weight fraction obtained, for example, by sieving (e.g., wet sieving). As used herein, the term "number-based average diameter" is understood by those skilled in the art to include that the average particle size is characterized and defined from a particle size distribution by number, i.e., the existing fraction (relative amount) in each size class is defined as a number fraction measured, for example, by microscopy. As used herein, the term "volume-based average diameter" is understood by those skilled in the art to include that the average particle size is characterized and defined from a particle size distribution by volume, i.e., the existing fraction (relative amount) in each size class is defined as a volume fraction measured, for example, by laser diffraction. Those skilled in the art will also understand that there are other suitable ways of expressing the average diameter, such as the area-based average diameter, and that these other expressions of the average diameter are interchangeable with those used herein. For example, other devices well known in the art, such as those sold by Malvern Instruments, Ltd (Worcestershire, UK) and Shimadzu (Kyoto, Japan), may be employed to measure the particle size.

[0085] The solid core can have a preferred weight, number, or volume-based average diameter of from about 50 nm (e.g., about 100 nm, e.g., about 250 nm) to about 30 μm, e.g., from about 500 nm to about 100 μm, more specifically from about 1 μm to about 50 μm, e.g., about 25 μm, e.g., about 20 μm.

[0086] In the process of the present invention, at least 200 mg of the solid core can be optionally loaded into a fixed gas-phase deposition reactor chamber with at least 1 g or at least 10 g, in order for the gas-phase deposition technique to be applied.

[0087] The particles can be spherical, i.e., they have an aspect ratio of less than about 20, more preferably less than about 10, e.g., less than about 4, especially less than about 2, and / or can have a variation in radius (measured from the center of gravity to the particle surface) of at most about 50% of the average value, e.g., at most about 30% of that value, e.g., at most about 20% of that value, for at least about 90% of the particles.

[0088] Nevertheless, according to the present invention, it is also possible to coat the particles into any shape. For example, particles of irregular shape (e.g., “raisin” shape), needle shape, flake shape, or cubic shape can be coated. For non-spherical particles, the size can be indicated, for example, as the size of the corresponding spherical particles of the same weight, volume, or surface area. Hollow particles, as well as particles having pores, gaps, etc., such as fibrous or “entangled” particles, can also be coated according to the present invention.

[0089] The particles can be obtained in a suitable form for being coated, or for being obtained in that form, by, for example, wet grinding, dry grinding, air jet grinding (including cryogenic micronization), ball milling such as planetary ball milling, and by using an end runner mill, roller mill, vibration mill, hammer mill, roller mill, fluid energy mill, pin mill, etc., by means of a particle size reduction process (e.g., crushing, cutting, milling, or grinding) to, for example, an average diameter on a specified weight basis (previously defined herein). Alternatively, the particles can be prepared directly in a suitable size and shape by, for example, spray drying, freeze drying, spray freeze drying, vacuum drying, precipitation including the use of supercritical fluids, or other top-down methods (i.e., reducing the size of large particles, e.g., by grinding, etc.) or bottom-up methods (i.e., increasing the size of small particles, e.g., by sol-gel technology, crystallization, etc.). Alternatively, the nanoparticles can be produced by well-known techniques such as gas condensation, attrition, chemical precipitation, ion implantation, pyrolysis, hydrothermal synthesis.

[0090] In order to remove impurities that may be derived from the generation of particles, it may be necessary (depending on the method by which the particles including the core are initially provided) to wash and / or purify the particles and then dry them. Drying can be carried out by a number of techniques known to those skilled in the art, including evaporation, spray drying, vacuum drying, freeze drying, fluid bed drying, microwave drying, IR radiation, drum drying, etc. When dried, the core can then be deagglomerated by grinding, screening, milling, and / or dry ultrasonic treatment. Alternatively, the core can be treated to remove any volatile substances that may be adsorbed on its surface, for example, by exposing the particles to vacuum and / or high temperature.

[0091] The surface of the core can be chemically activated, for example, by treatment with hydrogen peroxide, ozone, free radical-containing reactants, or by applying plasma treatment to generate free oxygen radicals on the surface of the core, prior to applying the first layer of the coating material. This, in turn, can create favorable adsorption / nucleation sites on the core for the reactants (the reactants can be referred to interchangeably as "precursors" hereinafter) used to deposit the coating material by vapor deposition techniques.

[0092] More than one layer of the coating material is applied continuously to the core. Preferred vapor deposition techniques include ALD or related techniques, such as atomic layer epitaxy (ALE), molecular layer deposition (MLD, which is a similar technique to ALD but differs in that molecules (usually organic molecules) are deposited in each pulse instead of atoms), molecular layer epitaxy (MLE), chemical vapor deposition (CVD), atomic layer CVD, molecular layer CVD, physical vapor deposition (PVD), sputtering PVD, reactive sputtering PVD, evaporation PVD, and binary reaction sequence chemistry. ALD is the preferred coating method according to the present invention.

[0093] When ALD is employed, the coating material can be prepared by supplying a precursor or reactant into the ALD reactor chamber (in a so-called "precursor pulse") to form an atomic or molecular monolayer adsorbed on the surface of the particles. After a subsequent purge pulse, a second precursor pulse that reacts with the first precursor follows in the reactor, resulting in the formation of a monolayer of a compound on the substrate surface. Following another purge pulse, a further pulse of the first precursor follows, and thus the start of a new cycle of the same events, which is an ALD cycle, continues.

[0094] In most cases, the first of the successive reactions involves several functional groups or lone pairs or radicals such as hydroxy groups (-OH) or primary or secondary amino groups (-NH2 or -NHR, where R is an aliphatic group such as an alkyl group, for example) on the surface to be coated. The individual reactions are preferably carried out separately under conditions such that all excess reagents and reaction products are essentially removed before subsequent reactions are carried out.

[0095] Two or more separate layers or coating materials (also referred to herein as "coatings" or "shells", and all of these terms are used interchangeably herein) are applied (i.e., "separately applied") to a solid core containing a biologically active agent. Such "separate application" of a "separate layer, coating, or shell" means that the solid core is coated with a first layer of the coating material, this layer being formed by more than one cycle (e.g., a plurality of cycles or a set of cycles) as described herein, each cycle producing a monolayer of the coating material, and then the resulting coated core can be subjected to some form of sieving step such as the sieving techniques, steps, or processes described herein.

[0096] In other words, a "vapor deposition (e.g., ALD) cycle" can be repeated several times to provide a "set of vapor deposition (e.g., ALD) cycles" which can consist of, for example, 10, 25, or 100 cycles. However, after this set of cycles, the coated core can undergo some form of sieving step such as the sieving techniques, steps, or processes described herein, followed by a further set of cycles.

[0097] This process can be repeated as many times as necessary, and in this regard, the number of individual layers of the coating material(s) as defined herein corresponds to the number of these intermittent sieving steps. Optionally, at least one of those sieving steps includes a vibrating sieving step. In some examples, at least the final sieving step includes a vibrating sieving step that is performed before the application of the final layer (set of cycles) of the coating material. In further examples, more than one (each including) of the sieving steps includes the vibrating sieving techniques, steps, or processes described herein.

[0098] Such vibrating sieving techniques can include a vibrating motor coupled to a sieve, providing means for vibratingly advancing a solid product mass formed by coating the core through a sieve that can be located inside or (preferably) outside (i.e., on the outer side) of the reactor, and configured to de-aggregate any particle aggregates during the vibrating advancement of the coated core before receiving a second layer and / or further layers of the coating material. This process can be repeated the necessary and / or appropriate number of times before applying the final layer of the coating material.

[0099] The means for vibrating and pushing forward may include a vibration motor coupled to the sieve. The vibration motor is configured to vibrate and / or rotate when power is supplied thereto. For example, the vibration motor may be a piezoelectric vibration motor including a piezoelectric material that changes shape when an electric field is applied as a result of the inverse piezoelectric effect. The change in the shape of the piezoelectric material causes acoustic or ultrasonic vibrations of the piezoelectric vibration motor.

[0100] Alternatively, the vibration motor may be an eccentric rotating mass (ERM) vibration motor including a mass that is rotated when power is supplied to the motor. The mass is eccentric from the axis of rotation, and the rotation of the mass causes the motor to become unbalanced and vibrate and / or rotate. Further, the ERM vibration motor may include a plurality of masses disposed at different positions with respect to the motor. For example, the ERM vibration motor may include an upper mass and a lower mass each disposed at opposite ends of the motor. By changing the angle of each mass with respect to the other masses, the vibration and / or rotation of the ERM vibration motor can be changed.

[0101] The vibration motor may be coupled to the sieve in such a manner that the vibration and / or rotation of the motor is transmitted to the sieve when power is supplied thereto.

[0102] The sieve and the vibration motor can be suspended from a mount (e.g., a frame that can be placed on the floor) via suspension means such that the vibrations are not substantially transmitted to the mount or attenuated by the mount, and the sieve and the motor vibrate freely with respect to the mount. Thereby, the vibration motor and the sieve can vibrate and / or rotate without obstacles and also reduce the noise generated during the vibrating sieving process. The suspension means can include one or more springs or bellows (i.e., air cushions or equivalent cushioning means) that couple the sieve and / or the motor to the mount. Manufacturers of vibrating sieves or shifters suitable for performing such processes include, for example, Russell Finex, SWECO, Filtra Vibracion, VibraScreener, Gough Engineering, and Farley Greene.

[0103] Preferably, the vibrating sieving technique further includes controlling a vibration probe coupled to the sieve. The vibration probe can be controlled to vibrate the sieve at a frequency different from the frequency of the vibration caused by the vibration motor. Preferably, the vibration probe vibrates the sieve at a frequency higher than the vibration caused by the vibration motor, and more preferably, the frequency is within the ultrasonic range.

[0104] Providing additional vibration to the sieve by the vibration probe reduces the occurrence of sieve clogging, reduces the possibility of the sieve being overloaded, and decreases the time required to clean the sieve mesh.

[0105] Any and all screening steps, if not including such steps in a vibration screening technique, can nonetheless be performed by one or more other means of pushing the coated mass through the sieve manually, mechanically, and / or automatically. Thus, mechanical forces can take the form of tapping, vibration, application of a pressure gradient (e.g., jet), horizontal rotation, mechanical periodic displacement of the sieve, centrifugal force, screening, or combinations thereof such as vibration and tapping, rotation and tapping.

[0106] Such alternative means of pushing are preferably mechanical and can also be vibration, and suitable alternative means of applying a vibration force (i.e., not including a vibration motor coupled to the sieve) push a mass of powder coated through a mesh or sieve. Alternative mechanical means of generating vibrations around an equilibrium point can include acoustic waves (including sound waves and ultrasonic waves) or can be other methods including mechanical (e.g., tapping) or combinations thereof such as ultrasonic and sound waves, sound waves and tapping, ultrasonic and tapping.

[0107] In such cases, at least one of these alternative mechanical screening steps is preferably performed by an acoustic wave shifter as described below. Preferred manufacturers of acoustic wave shifters include Advantech Manufacturing, Endecott, and Tsutsui.

[0108] Preferably, the vibration screening technique includes screening particles coated at a throughput of at least 1 g / min. More preferably, the vibration screening technique includes screening particles coated at a throughput of 4 g / min or more.

[0109] The throughput depends on the area of the sieve mesh, the sieve mesh size, the particle size, the adhesiveness of the particles, and the static properties of the particles. By combining some of these functions, much higher throughput is possible. Thus, the vibrating sieving technique may preferably include sieving coated particles at a throughput of up to 1 kg / min or more.

[0110] Any one of the above throughputs represents a significant improvement over known mechanical sieving or the use of sieving techniques. For example, sonic sieving has been found to involve sieving over a period of 15 minutes with a 15-minute cooling time required to store the device. To sieve 20 g of coated particles, 9 sets of 15 minutes of active sieving time, i.e., a total time of 255 minutes (including cooling), were required. In comparison, by using the vibrating sieving technique essential to the process of the present invention, 20 g of coated particles can be continuously sieved for up to 20 minutes, or more preferably in just 5 minutes or less.

[0111] The sieve mesh size can be determined such that the ratio of the size of the sieved or sonicated particles to the sieve mesh size is about 1:>1, preferably about 1:2, and optionally about 1:4. The sieve mesh size can range from about 20 μm to about 100 μm, preferably from about 20 μm to about 60 μm.

[0112] Suitable sieve meshes can include perforated plates, microplates, grids, diamonds, threads, polymers, or wires (woven wire sieves), but are preferably formed from a metal such as stainless steel.

[0113] Surprisingly, using a stainless steel mesh within such vibrating sieving techniques is particle coating-friendly, similar to using a softer polymer sieving as part of mechanical sieving techniques such as sonic sieving.

[0114] Also, a known problem with sieving powders is the generation of potentially dangerous static electricity. Steel mesh has the advantage of removing static electricity from powders, but this does not apply to the polymer mesh that needs to be used in a sonic shifter.

[0115] Furthermore, since the sound wave moves through the mesh rather than vibrating the mesh, the mesh size of known sonic shifters is limited to about 100 μm. That limitation does not exist for use in a vibrating sieve technique because it does not rely on sound waves to generate vibrations for sieving. Thus, the vibrating sieve technique described herein allows larger particles to be sieved than would be possible if alternative mechanical sieving techniques were used.

[0116] When the (vibrating) sieve is located outside the reactor (i.e., on the outside), step (2) of the process of the present invention includes discharging the coated particles from the vapor deposition reactor before subjecting the coated particles to agitation, and step (3) includes reintroducing the deagglomerated coated particles from step (2) into the vapor deposition reactor before applying a further layer of at least one coating material to the reintroduced particles.

[0117] Alternatively, the coated core can undergo the aforementioned vibrating sieving step(s) internally without being removed from the apparatus by a continuous process. Such a process involves means for vibratingly advancing the solid product mass formed by coating the core through a sieve located within the reactor, and is configured to deagglomerate any particle aggregates during such vibrating sieving of the coated core by the advancing means applied within the reactor before the core receives a second coating and / or further coatings. This process is continued the necessary and / or appropriate number of times before applying the final coating, as described herein.

[0118] Having a sieve located within the reaction vessel means that the coating can be applied by a continuous process that does not require removing the particles from the reactor. Thus, there is no need to manually handle the particles, nor is an external machine needed to de-aggregate the agglomerated particles. This not only significantly shortens the time during which the coating process is carried out, but also makes it more convenient and reduces the risk of harmful (e.g., toxic) materials being handled by personnel. Also, by limiting manual work, the reproducibility of the process is enhanced and the risk of contamination is reduced.

[0119] After external de-aggregation, by applying a separate layer of the coating material, a visible and distinguishable interface can be observed by analyzing the coated particles according to the present invention, for example, observed as a highly electron-transmissive region by TEM. In this regard, the thickness of the layer between the interfaces directly corresponds to the number of cycles in each series carried out within the ALD reactor and between individual external stirring steps.

[0120] In an ALD coating process, since the coating occurs at the atomic level, such a distinct physical interface is typically more difficult to observe.

[0121] Without being limited by theory, it is believed that removing the coated particles from the vacuum conditions of the ALD reactor and exposing the newly coated surface to the atmosphere results in a restructuring of the structure due to relaxation and re-organization of the outermost atomic layer. Such a process is believed to involve re-organization of the atoms at the surface (and near the surface), driven by the thermodynamic tendency to reduce the free energy of the surface.

[0122] Furthermore, the surface adsorption of species, such as hydrocarbons that are always present in the air, can contribute to this phenomenon, similar to the surface modification resulting from the reaction of the formed coating with hydrocarbons and oxygen in the atmosphere, etc. Therefore, when such an interface is chemically analyzed, the interface may contain trace contaminants or core materials such as APIs that form part of the core, which do not originate from coating processes such as ALD.

[0123] Therefore, regardless of whether it is carried out inside or outside the reactor, the particle aggregates are broken down by means of vibratingly pushing them through a sieve, and thus the aggregates are separated into individual particles or aggregates of a desired and predetermined size (thereby achieving deaggregation). Regarding the latter, in some cases, since the individual primary particle sizes are very small (i.e., <1 μm), it is impossible to achieve "complete" deaggregation (i.e., the aggregates are broken down into individual particles). Instead, deaggregation is achieved by breaking down larger aggregates into smaller aggregates of secondary particles of the desired size, as determined by the size of the sieve mesh. The smaller aggregates are then coated by a vapor-phase technique to form "particles" that are completely coated in the form of small aggregate particles. Thus, the term "particle", when referring to deaggregated and coated particles in the context of the present invention, refers to both individual (primary) particles and aggregated (secondary) particles of the desired size.

[0124] In any case, the desired particle size (regardless of whether it is individual particles or aggregates of the desired size) is maintained. Furthermore, the continuous application of the vapor-phase coating mechanism to the particles after such deaggregation via the vibrating sieving means means that a complete coating is formed on the particles, thus forming completely coated particles (individual or aggregates of the desired size).

[0125] Regardless of whether it is carried out inside or outside the reactor, the process of the present invention involves performing the iterative coating and deaggregation / stirring process described above at least once, preferably 2 times, more preferably 3 times, for example, 4 times including 5 times, more specifically 6 times, for example, 7 times, and about 40 times or less including about 100 times or less, for example, about 50 times or less, for example, about 30 times or less, for example, 2 to 20 times, for example, 3 to 15 times, for example, 10 times, for example, 9 or 8 times, more preferably 6 or 7 times, particularly, 4 or 5 times, in a manner that involves execution.

[0126] Regardless of whether it is carried out inside or outside the reactor, at least one sieving step is carried out, and further, it is preferable that the step preferably includes the vibrating sieving step described above. The final sieving step more preferably includes the vibrating sieving step carried out before the application of the final layer (set of cycles) of the coating material. However, it is more preferable that more than one (including each) of the sieving steps includes the vibrating sieving technique, step, or process described herein.

[0127] The preferred repetition of these steps further benefits the improved throughput of any vibrating sieving technique.

[0128] The total thickness of the coating (meaning all separate layers / coatings / shells) is in the range of about 0.5 nm to about 2 μm on average.

[0129] The minimum thickness of each individual layer / coating / shell is in the range of about 0.1 nm on average (for example, about 0.5 nm, or about 0.75 nm, for example, 1 nm).

[0130] The maximum thickness of each individual layer / coating / shell will depend on the size of the core (initially), and then the size of the core with the previously applied coating, and on average can be about one-hundredth of the average diameter of that core or the core with the previously applied coating (i.e., the average diameter based on weight, number, or volume).

[0131] Preferably, for particles with an average diameter of about 100 nm to about 1 μm, the total thickness of the coating should be about 1 nm to about 5 nm on average, and for particles with an average diameter of about 1 μm to about 20 μm, the thickness of the coating should be about 1 nm to about 10 nm on average, and for particles with an average diameter of about 20 μm to about 700 μm, the thickness of the coating should be about 1 nm to about 100 nm on average.

[0132] After applying the coating / shell, by performing one or more deaggregation steps such as sonication, the coated particles are essentially more tightly "bonded" or "adhered" immediately after applying a thicker coating, and it has been found that wear, pinholes, breaks, gaps, cracks, and / or voids (hereinafter "cracks") occur in the layer / coating. As a result, when deaggregation occurs, the core containing the biologically active ingredient can be exposed to the elements.

[0133] As described in International Patent Application No. PCT / GB2020 / 053129, surprisingly, by performing a mechanical sieving process (as opposed to the ultrasonic treatment described in International Patent Application No. 2014 / 187995, manually or by pushing the particles through the sieve manually by means of the mechanical sieving process described in International Patent Application No. PCT / GB2020 / 053129), it has been found that significantly fewer pinholes, gaps, or cracks occur in the coating material. In turn, this results in particles being coated in such a way that they are not only completely covered by the layer / coating, but also in a manner that does not break the layer of coating material formed before and / or during pharmaceutical formulation, and enables the particles to be easily (e.g., using non-invasive techniques such as vortexing) de-aggregated.

[0134] Very surprisingly, it has also been found that when using the vibratory sieving technique, the above-mentioned low-frequency pinholes, gaps, or cracks in the coating material can be maintained. This is surprising considering that the techniques described herein preferably employ a stainless steel sieve (as opposed to the softer polymer sieves used in the mechanical sieving process described in International Patent Application No. PCT / GB2020 / 053129), which may be preferred for such vibratory sieving techniques. Previous attempts to manually push particles through a metal sieve resulted in significant formation of pinholes, gaps, or cracks in the coating material.

[0135] For example, if it is intended to provide a sample in suspension before administration to a patient, it is necessary to provide de-aggregated primary particles with no pinholes or cracks in the coating. Such cracks result in an unwanted initial peak (burst) in the plasma concentration of the active ingredient immediately after administration.

[0136] The processes described herein result in deaggregated coated particles in which the cracks are essentially absent such that the active ingredient can be released in an uncontrolled manner. By "essentially free of such cracks" in the coating(s) is meant that less than about 1% of the surface of the coated particle contains abrasions, pinholes, breaks, gaps, cracks and / or voids through which the active ingredient could potentially be exposed (e.g., to an element).

[0137] In this regard, an (inorganic, e.g., mixed oxide) coating typically completely surrounds, envelops, and / or encapsulates the solid core. In this way, the risk of an initial drug concentration burst due to direct contact of the drug with a solvent in which the relevant active ingredient is soluble is minimized. This can include not only body fluids but also any medium in which such coated particles can be suspended prior to injection.

[0138] Accordingly, in one embodiment of the invention, there are provided the particles previously disclosed herein, and the coating that surrounds, envelops, and / or encapsulates the core covers at least about 65%, e.g., at least about 80%, more specifically at least about 90%, e.g., at least about 91%, e.g., at least about 92%, e.g., at least about 93%, e.g., at least about 94%, e.g., at least about 95%, e.g., at least about 96%, e.g., at least about 97%, e.g., at least about 98%, e.g., at least about 99%, e.g., approximately or about 100% of the surface of the solid core such that the coating essentially completely surrounds, envelops, and / or encapsulates the core.

[0139] As used herein, the term "essentially completely coating so as to completely surround, envelop, and / or encapsulate the core" means a coating of at least about 98% or at least about 99% of the surface of the solid core.

[0140] Some minor cracks may appear in the coating without affecting its essential function in terms of controlling release. However, in a further embodiment, there are provided particles as previously disclosed herein, wherein at least about 90% of the particles do not show cracks in the coating that surrounds, envelops, and / or encapsulates the core. In one embodiment, at least about 91%, such as at least about 92%, such as at least about 93%, such as at least about 94%, such as at least about 95%, such as at least about 96%, such as at least about 97%, such as at least about 98%, such as at least about 99%, such as approximately 100% of the particles do not show the cracks.

[0141] The layers of coating material can together be of essentially uniform thickness over the surface area of the particles. "Essentially uniform" thickness means that for at least about 10%, such as about 25%, such as about 50% of the coated particles present in a composition made by the process of the invention, as measured by TEM, the degree of variation in the thickness of the coating is about ±20% or less, including ±50% or less of the average thickness.

[0142] Coating materials that can be applied to the core can be pharmaceutically acceptable in that they must be essentially non-toxic.

[0143] Coating materials can include organic or polymeric materials such as polyamides, polyimides, polyureas, polyurethanes, polythioureas, polyesters, or polyimines. Coating materials can also include hybrid materials (such as between organic and inorganic materials) that include materials that are combinations between a metal or another element and an alcohol, carboxylic acid, amine, or nitrile. However, it is preferred that the coating materials include inorganic materials.

[0144] The inorganic coating material may contain one or more metals or metalloids, or may contain one or more metal-containing compounds or metalloid-containing compounds such as metals, or metalloids, oxides, nitrides, sulfides, selenides, carbonates, and / or other ternary compounds. Metals, and metalloids, hydroxides, particularly oxides, particularly metal oxides are preferred.

[0145] The metals that may be mentioned include alkali metals, alkaline earth metals, noble metals, transition metals, post-transition metals, lanthanides, etc. The metals and metalloids that may be mentioned include aluminum, titanium, magnesium, iron, gallium, zinc, zirconium, niobium, hafnium, tantalum, lanthanum, and / or silicon, more preferably aluminum, titanium, magnesium, iron, gallium, zinc, zirconium, and / or silicon, particularly aluminum, silicon, titanium and / or zinc.

[0146] The metal-containing precursor or metalloid-containing precursor can be applied as either the first or second reactive gas during the vapor deposition technique. In some processes, it may be advantageous to start with a metal-containing precursor or metalloid-containing precursor, while in other processes, it may be advantageous to start with an oxygen precursor such as water. This may depend, for example, on the part of the surface of the compound to be coated.

[0147] In embodiments of the present invention, each iteration of applying the vapor deposition technique can be performed using the same or different first and second reactive gases as in the iteration before step (b). For example, the metal-containing precursor or metalloid-containing precursor used in one iteration can be different from the metal-containing precursor or metalloid-containing precursor used in subsequent iterations. Further, in embodiments of the present invention involving particle deaggregation between iterations of the vapor deposition technique, the metal-containing precursor or metalloid-containing precursor can alternately be the first reactive gas to the second reactive gas, or vice versa.

[0148] As described above, since the composition produced by the process of the present invention comprises two or more individual layers of an inorganic coating material, the properties and chemical composition(s) of those layers can differ from layer to layer.

[0149] Individual layers can also comprise a mixture of two or more inorganic materials such as metal oxides or metalloid oxides, and / or can comprise multiple layers or composites of different inorganic or organic materials in order to modify the properties of the layer.

[0150] Coating materials that may be mentioned include those containing aluminum oxide (Al2O3), titanium dioxide (TiO2), iron oxide (FexOy, e.g., FeO and / or Fe2O3 and / or Fe3O4), gallium oxide (Ga2O3), magnesium oxide (MgO), zinc oxide (ZnO), niobium oxide (Nb2O5), hafnium oxide (HfO2), tantalum oxide (Ta2O5), lanthanum oxide (La2O3), zirconium dioxide (ZrO2), and / or silicon dioxide (SiO2). Preferred coating materials include aluminum oxide, titanium dioxide, iron oxide, gallium oxide, magnesium oxide, zinc oxide, zirconium dioxide, and silicon dioxide. More preferred coating materials include iron oxide, titanium dioxide, zinc sulfide, more preferably zinc oxide, silicon dioxide, and / or aluminum oxide.

[0151] The layers of coating material (on an individual or collective basis) in the composition produced by the process of the present invention can consist essentially of (e.g., greater than about 80%, e.g., greater than about 90%, e.g., about 95%, e.g., about 98%) iron oxide, titanium dioxide, or more preferably zinc oxide, silicon dioxide, and / or aluminum oxide.

[0152] The process of the present invention is particularly useful when the coating material(s) applied to the core comprises zinc oxide, silicon dioxide, and / or aluminum oxide.

[0153] The inorganic coating material is (i) zinc oxide (ZnO), and (ii) more preferably further comprises a mixture of one or more other metal oxides and / or metalloid oxides, The atomic ratio ((i):(ii)) is at least about 1:6 to a maximum of about 6:1.

[0154] A coating comprising zinc oxide and a mixture of one or more other metal oxides and / or metalloid oxides is hereinafter referred to as a "mixed oxide" coating or coating material(s).

[0155] Thus, the biologically active agent-containing core can be coated with a coating material comprising zinc oxide and a mixture of one or more other metal oxides and / or metalloid oxides in an atomic ratio of zinc oxide to the other oxide(s) (if any) or vice versa of at least about 2.25:1, including at least about 1:1 (e.g., at least about 1.5:1, e.g., at least about 2:1), e.g., at least about 2.5:1 (e.g., at least about 3.25:1 or at least about 2.75:1 (including 3:1)) up to a maximum of about 5.5:1, up to a maximum of 6:1 (i.e., less than or equal to that), or up to a maximum of about 5:1, e.g., up to a maximum of 4:1 (e.g., up to a maximum of about 3.75:1), up to a maximum of 4.5:1.

[0156] To create a mixed oxide coating having an atomic ratio of zinc oxide to one or more other metal oxides and / or metalloid oxides of from about 1:1 to a maximum of about 6:1, one of ordinary skill in the art will understand that for each ALD cycle (i.e., monolayer) of the other oxide(s), from about 1 to about 6 ALD cycles of zinc oxide must also be deposited. For example, for a mixed oxide coating with an atomic ratio of 3:1 (zinc: other oxide) to be formed, after three zinc-containing precursor pulses, each followed by a second precursor pulse, three monolayers of zinc oxide are formed, then followed by one pulse of the other metal-containing precursor and / or metalloid-containing precursor, followed by a second precursor pulse, and one monolayer of the oxide of the other metal and / or metalloid is formed. Alternatively, after six monolayers of zinc oxide, two monolayers of the other oxide, or any other combination, may follow to provide an overall atomic ratio of about 3:1. In this regard, the order of the pulses to produce the relevant oxides is not important as long as the resulting atomic ratio is ultimately within the relevant range.

[0157] Between the separate coatings described herein (e.g., between separate deaggregation steps), and / or at any time while the coating is being applied, different coating materials such as pharmaceutically acceptable and essentially non-toxic coating materials may also be applied in addition. Such materials may include multiple layers or composites of the mixed oxide and one or more different inorganic or organic materials to modify the properties of the layer(s).

[0158] In ALD, the layer of coating material can be applied at a process temperature of about 20°C to about 800°C, or about 40°C to about 200°C, for example, about 40°C to about 150°C, for example, about 50°C to about 100°C. The optimal process temperature depends on the reactivity of the precursor and / or substance (including biologically active agents) employed in the core, and / or the melting point of the core substance(s). When the core to be coated contains a biologically active ingredient, it is preferable to employ a lower temperature such as about 20°C to about 100°C. In particular, in one embodiment of the present method, a temperature of about 20°C to about 80°C, for example, about 30°C to about 70°C, for example, about 40°C to about 60°C, for example, about 50°C is employed.

[0159] When a coating containing zinc oxide is applied using ALD at a low temperature such as about 50°C to about 100°C (unlike other coating materials such as aluminum oxide and titanium oxide that form amorphous layers), the coating material has been found to be mostly crystalline in nature.

[0160] Without being limited by theory, since zinc oxide is crystalline, when only zinc oxide is employed as the coating material, an interface can be formed between adjacent crystals of zinc oxide deposited by ALD, through which a support system, medium, or solvent (e.g., an aqueous solvent system) in which zinc oxide is partially soluble can penetrate after suspension therein. This is considered to result in too rapid dissolution in the depot-forming composition intended to be produced.

[0161] Now, as described herein, it has been found that these problems can be alleviated by fabricating a mixed oxide coating. In particular, it has been found that these problems can be alleviated by fabricating a mixture of two or more metal oxides and / or metalloid oxides (mixed oxides) coating, as described herein. In particular, by forming a mixed oxide coating as described herein, which can be composed primarily of zinc oxide, although not completely, a coating that appears to be a composite material between an essentially amorphous or crystalline material and an amorphous material, and / or a coating that can reduce the ingress of an injection vehicle such as water can coat the active ingredient. In this regard, the presence of the aforementioned perceived interface can be reduced or completely avoided by employing the mixed oxide according to this aspect of the invention in either a non-uniform manner (where other oxides "fill" the gaps formed by the interface) or a uniform manner (wherein a true composite material of the mixed oxide material is formed during deposition in a manner that potentially avoids the interface initially).

[0162] Accordingly, a method for preparing a plurality of coated particles according to the present invention is provided, the coated particles being produced by applying, by a vapor deposition technique, precursors of at least two metal oxides and / or metalloid oxides that form a mixed oxide onto a solid core and / or a previously coated solid core. Precursors for forming the metal oxide or metalloid oxide often include oxygen precursors such as water, oxygen, ozone, and / or hydrogen peroxide, as well as metal compounds and / or metalloid compounds, typically organometallic compounds or organometalloid compounds.

[0163] Non-limiting examples of precursors are as follows: The precursor of zinc oxide can be zinc di(C1-C5)alkyl such as water and diethylzinc. The precursor of aluminum oxide can be tri(C1-C5)alkylaluminum such as water and trimethylaluminum. The precursor of silicon oxide (silica) can be water as an oxygen precursor, as well as silane, alkylsilane, aminosilane, and tetraethyl orthosilicate. The precursors of iron oxide include oxygen, ozone, and water as oxygen precursors, as well as di(C1-C5)alkyl-iron, dicyclopropyl-iron, and FeCl3. It will be understood that those skilled in the art recognize which precursors are suitable for the purposes disclosed herein.

[0164] The plurality of coated particles produced according to the process of the present invention essentially do not contain the aforementioned cracks in the applied coating, through which the active ingredient is potentially (e.g., to the element) exposed, but before subjecting it to further pharmaceutical formulation processing, two further optional steps can be applied to the plurality of coated particles.

[0165] The first optional step can include the application of a final overcoating layer after the final deaggregation step previously described herein, and the thickness of the outer "overcoating" layer / coating, or "sealing shell" (these terms are used interchangeably herein) must be less than that of the previously applied separate layer / coating / shell (or "subshell").

[0166] Thus, the thickness can be about 0.7 times or less (e.g., about 0.6 times) the average thickness of the widest previously applied subshell. Alternatively, the thickness can be about 0.7 times or less (e.g., about 0.6 times) the average thickness of the last subshell applied, and / or about 0.7 times or less (e.g., about 0.6 times) the average of the average thicknesses of all previously applied subshells. For particles up to about 20 μm in size, the thickness can be in the range of about 0.3 nm to about 10 nm on average. For larger particles, the thickness can be about 1 / 1000 or less of the average of the weight, number, or volume-based average diameter of the coated particles.

[0167] The role of the sealing shell is to provide a "sealing" overcoating layer on the particles and cover their cracks, so that particles are produced that are coated in such a way that they are not only completely covered by the sealing shell, but also can be easily (e.g., using non-invasive techniques such as vortexing) deaggregated in a manner that does not break the subshells formed below before and / or during pharmaceutical formulation.

[0168] For the reasons described herein, the sealing shell preferably does not contain zinc oxide. On the other hand, the sealing shell can contain silicon dioxide, or more preferably aluminum oxide.

[0169] This optional step can include subjecting the few remaining particles with broken and / or cracked shells / coatings to a process where all the particles are suspended in a solvent (the active ingredient is soluble, for example, at a solubility of at least about 1 mg / mL, but the least soluble material of the coating is insoluble, for example, at a solubility of about 0.1 μg / mL or less), followed by separating the solid particles from the solvent, for example, by centrifugation, sedimentation, aggregation, and / or filtration, so as to ensure that mainly intact particles remain.

[0170] As previously discussed herein, the above optional step provides a means for further potentially reducing the possibility of an (possibly) undesirable initial peak (burst) in the plasma concentration of the active ingredient.

[0171] At the end of the process, the coated particles can be dried using one or more of the techniques previously described herein for drying the core. The drying can occur in the absence or presence of one or more pharmaceutically acceptable excipients (e.g., sugars or sugar alcohols).

[0172] Alternatively, at the end of the process, the separated particles can be resuspended in a solvent (e.g., water, with or without the presence of one or more pharmaceutically acceptable excipients as defined herein) for subsequent storage and / or administration to a patient.

[0173] Before applying the first layer of the coating material or between successive coatings, the core and / or the partially coated particles can be subjected to one or more alternative and / or preliminary surface treatments. In this regard, one or more intermediate layers containing different materials (i.e., other than inorganic material(s)) can be applied to the relevant surface to protect the core or the partially coated particles from an undesirable reaction with the precursor(s) during the coating step(s) / deposition process, to enhance the coating efficiency, or to reduce aggregation.

[0174] The intermediate layer can include one or more surfactants, for example, for the purpose of reducing the aggregation of the particles to be coated and providing a hydrophilic surface suitable for subsequent coating. Suitable surfactants in this regard include well-known nonionic, anionic, cationic, or zwitterionic surfactants of the Tween series, such as Tween 80. Alternatively, if the active ingredient employed as part of the core (or as the core) is prone to reacting with one or more precursor compounds that can be present in the gas phase during the coating (e.g., ALD) process, the core can be subjected to a preliminary surface treatment.

[0175] The application of an "intermediate" layer / surface treatment of this nature can alternatively be achieved by liquid phase non-coating techniques followed by lyophilization, spray drying, or other drying methods to provide particles having a surface layer to which a coating material can later be applied.

[0176] The outer surface of the particles of the composition produced by the process of the present invention can also be derivatized or functionalized, for example, by attaching one or more chemical compounds or moieties to the outer surface of the final layer of the coating material, using, for example, chemical compounds or moieties that enhance the targeted delivery of the particles within the patient to whom the nanoparticles are administered. Such compounds can be organic molecules (e.g., PEG) polymers, antibodies or antibody fragments, or receptor-binding proteins or peptides, etc.

[0177] Alternatively, the moiety can be an anchoring group such as a moiety containing silane functionality (see, for example, Herrera et al, J. Mater. Chem., 18, 3650 (2008) and US8,097,742). Another compound, for example, a desired targeting compound, can be attached to such an anchoring group by covalent bonds, or non-covalent bonds including hydrogen bonds or van der Waals bonds, or combinations thereof.

[0178] The presence of such an anchoring group can provide a versatile tool for targeted delivery to a specific site within the body. Alternatively, the use of compounds such as PEG can cause the particles to circulate in the bloodstream for a longer period of time, ensuring that they do not accumulate in the liver or spleen (the natural mechanism by which the body eliminates particles, which can prevent delivery to diseased tissue).

[0179] The composition produced by the process of the present invention is suitable for administration to a patient as prepared (i.e., as a plurality of particles), or preferably, is formulated with one or more pharmaceutically acceptable excipients including adjuvants, diluents, or carriers for use in the medical or veterinary fields (including therapy and / or diagnosis if the core includes diagnostic materials).

[0180] Also provided are compositions produced by the process of the present invention for use in medicine, diagnosis, and / or veterinary practice, and pharmaceutical (or veterinary) formulations comprising a composition produced by the process of the present invention and a pharmaceutically (or veterinarily) acceptable adjuvant, diluent, or carrier.

[0181] The compositions produced by the process of the present invention can be administered, optionally, in the form of a pharmaceutical (or veterinary) formulation comprising a compound in a pharmaceutically (or veterinarily) acceptable dosage form, locally, topically, or systemically, e.g., orally (enterally), by injection or infusion, intravenously or intraarterially (including intravascular or other perivascular devices / formulations such as stents), intramuscularly, intraosseously, intracranially, intraventricularly, intrasynovially, intrasternal, intramedullary, intralesionally, intracranial, intratumorally, dermally, intradermally, subcutaneously, transmucosally (e.g., sublingually or buccally), rectally, transdermally, nasally, pulmonary (e.g., by inhalation, tracheally or bronchially), topically, or by any other parenteral route (e.g., subcutaneously or intramuscularly).

[0182] The incorporation of the compositions produced by the process of the present invention into pharmaceutical formulations can be achieved by taking fully into account the intended route of administration and standard pharmaceutical practice. Pharmaceutically acceptable excipients such as carriers can be chemically inert to the biologically active agent and may not have adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers can also impart immediate or modified release of the active agent from the particles in the compositions produced by the process of the present invention.

[0183] A pharmaceutical (or veterinary) formulation comprising a composition produced by the process of the present invention may contain different types of particles, for example, particles containing different active ingredients, which may have different functionalizations (previously described herein), different sizes of particles, and / or different thicknesses of layers of coating material, or combinations thereof. In a single pharmaceutical formulation, by combining particles having different coating thicknesses and / or different core sizes, drug release after administration to a patient can be controlled (e.g., varied or extended) over a specific period.

[0184] For oral administration (i.e., oral administration to the gastrointestinal tract with swallowing), the composition produced by the process of the present invention can be formulated into various dosage forms. The pharmaceutically acceptable carrier or diluent can be solid or liquid. Solid preparations include granules (the granules can contain some or all of the plurality of particles of the composition produced by the process of the present invention in the presence of, for example, a carrier and other excipients such as a binder or a pH adjuster), compressed tablets, pills, troches, capsules, cachets, etc. Carriers include those previously disclosed herein with respect to the formulation of the biologically active agent in the core, as well as materials well known to those skilled in the art, including magnesium carbonate, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, lactose, microcrystalline cellulose, low crystalline cellulose, etc.

[0185] The solid dosage form may contain additional excipients such as flavoring agents, lubricants, binders, preservatives, disintegrants, and / or encapsulating materials. For example, the composition produced by the process of the present invention can be encapsulated, for example, in soft or hard shell capsules, such as gelatin capsules.

[0186] Compositions produced by the process of the present invention formulated for rectal administration may include suppositories containing suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters, or polyethylene glycols, which are solid at room temperature but liquefy and / or dissolve within the rectal cavity to release the particles of the composition produced by the process of the present invention.

[0187] For parenteral administration such as subcutaneous injection and / or intramuscular injection, the composition produced by the process of the present invention may be in a sterile injectable and / or infusible dosage form, for example, in the form of a sterile aqueous or oily suspension of the composition produced by the process of the present invention.

[0188] The sterile aqueous suspension of the particles of the composition produced by the process of the present invention can be formulated according to techniques known in the art. The aqueous medium should contain at least about 50% water, but may contain other aqueous excipients such as Ringer's solution, and may also contain polar co-solvents (e.g., ethanol, glycerol, propylene glycol, 1,3-butanediol, polyethylene glycols of various molecular weights, and tetraethylene glycol), viscosity increasing agents, or thickening agents (e.g., carboxymethyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, sodium glycolate starch, poloxamer, e.g., poloxamer 407, polyvinyl pyrrolidone, cyclodextrin, e.g., hydroxypropyl-β-cyclodextrin, polyvinyl pyrrolidone, and polyethylene glycols of various molecular weights), surfactants / wetting agents (e.g., sorbitan esters, sodium lauryl sulfate, monoglycerides, polyoxyethylene esters, polyoxyethylene alkyl ethers, polyoxyl glycerides, and preferably Tweens (polysorbates) such as Tween 80 and Tween 20) to achieve a homogeneous suspension. Preferred components include isotonicity regulators (e.g., sodium lactate, dextrose, especially sodium chloride), pH regulators and / or buffers (e.g., citric acid, sodium citrate, especially phosphate buffers, e.g., disodium hydrogen phosphate hydrate, sodium phosphate, monosodium dihydrogen phosphate monohydrate, and combinations thereof, which can be employed in combination with standard inorganic acids and bases such as hydrochloric acid and sodium hydroxide), and other components such as mannitol, croscarmellose sodium, and hyaluronic acid.

[0189] An oily or oil-based carrier system may contain one or more pharmaceutically or veterinarily acceptable liquid lipids, including fixed oils such as monoglycerides, diglycerides, or triglycerides, including Miglyol (e.g., 812N), propylene glycol dicaprylocaprate (Miglyol 840, C8 / C10 ester), tricaprylin (Miglyol oil), Gelucire 43 / 01, kollisolv GTA, Labrafil. The carrier system may also contain polysorbates such as polysorbate 20, polysorbate 60, polysorbate 80, glycols such as propylene glycol, polyethylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and / or natural and / or purified pharmaceutically acceptable oils such as olive oil, peanut oil, soybean oil, corn oil, cottonseed oil, sesame oil, castor oil, oleic acid, and their polyoxyethylated versions (e.g., sorbitan trioleate, Lauroglycol 90, Capryol PGMC, PEG-60 hydrogenated castor oil, polyoxyl 35 castor oil). More preferred carrier systems contain monoglycerides, diglycerides, and / or triglycerides, and most preferred are medium-chain triglycerides such as alkyl chain triglycerides (e.g., C6-C12 alkyl chain triglycerides).

[0190] Such injectable suspensions can be formulated according to techniques well known to those skilled in the art by employing suitable dispersing or wetting agents (e.g., Tweens such as Tween 80) and suspending agents.

[0191] Compositions produced by the process of the present invention suitable for injection may also be in the form of a liquid, sol, paste, or gel that can be administered via a surgical administration device, such as a syringe equipped with a needle for injection, a catheter, etc., to form a depot formulation.

[0192] The use of the composition produced by the process of the present invention can control the dissolution rate and pharmacokinetic profile by reducing any burst effect previously defined herein and / or by reducing the Cmax in the plasma concentration-time profile, and thus increasing the length of release of the biologically active ingredient from the formulation.

[0193] These factors not only reduce the frequency with which a formulation by the process of the present invention needs to be administered to a subject, but also allow more time for the subject as an outpatient, enabling the subject to have a better quality of life.

[0194] The composition produced by the process of the present invention also has the advantage that by controlling the release of the active ingredient at a stable rate over a long period of time, it provides a lower daily exposure to potentially toxic drugs, which is expected to reduce undesirable side effects.

[0195] The composition produced by the process of the present invention can be contained within a reservoir and injection or infusion means, the coated particles and carrier system are housed separately, and mixing occurs before and / or during injection or infusion.

[0196] The composition produced by the process of the present invention can also be formulated as an inhalation powder for use with, for example, a dry powder inhaler for inhalation (see, for example, Kumaresan et al, Pharma Times, 44, 14 (2012) and Mack et al., Inhalation, 6, 16 (2012). The relevant disclosures are incorporated herein by reference). The preferred particle size of the plurality of particles in the composition produced by the process of the present invention for use in inhalation into the lungs is in the range of about 2 to about 10 μm.

[0197] The compositions produced by the process of the present invention can also be formulated for topical administration to the skin or mucosa. For topical application, pharmaceutical formulations can be provided, for example, in the form of lotions, gels, pastes, tinctures, transdermal patches, gels for transmucosal delivery, all of which can contain the compositions produced by the process of the present invention. The compositions can also be formulated in suitable ointments containing the compositions produced by the process of the present invention suspended in carriers such as mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, or water. Suitable carriers for lotions or creams include mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0198] The pharmaceutical formulation can contain from about 1% to about 99% by weight, such as from about 10% to about 90% by weight (such as about 20% by weight, for example, about 50% by weight) of the coated particles, the remainder being constituted by the carrier system and / or other pharmaceutically acceptable excipients.

[0199] The pharmaceutical formulation can be in the form of a liquid, sol, or gel that can be administered via a surgical administration device, such as a needle, catheter, etc., to form a depot formulation.

[0200] In any case, the compositions produced by the process of the present invention are formulated with conventional pharmaceutical additives and / or excipients used in the art for the preparation of pharmaceutical formulations and can then be incorporated into various types of pharmaceutical preparations and / or dosage forms using standard techniques (e.g., see Lachman et al., ‘The Theory and Practice of Industrial Pharmacy’, Lea & Febiger, 3rd edition (1986), ‘Remington: The Science and Practice of Pharmacy’, Troy (ed.), University of the Sciences in Philadelphia, 21st edition (2006), and / or ‘Aulton’s Pharmaceutics: The Design and Manufacture of Medicines’, Aulton and Taylor (eds.), Elsevier, 4th edition, 2013, and the documents referred to therein. The relevant disclosures in all of those documents are incorporated herein by reference). Otherwise, the preparation of suitable formulations can be achieved non-inventively by a person skilled in the art using routine techniques.

[0201] According to a further aspect of the invention, there is provided a process for the preparation of a pharmaceutical or veterinary formulation comprising mixing the coated particles prepared as described herein together with a pharmaceutically or veterinarily acceptable adjuvant, diluent, or carrier.

[0202] Such formulations are injectable and / or infusable and thus preferably comprise one or more compositions produced by the process of the invention suspended in a pharmaceutically or veterinarily acceptable aqueous and / or oily carrier.

[0203] Furthermore, there is provided an injectable and / or infusible dosage form comprising a composition produced by the process of the present invention, said composition being contained within a reservoir connected to and / or associated with injection or infusion means (e.g., a syringe equipped with a hypodermic needle, a catheter, etc.). In this regard, the composition produced by the process of the present invention can be stored prior to being loaded into a suitable injectable and / or infusible dosage means (e.g., a syringe equipped with a hypodermic needle), or alternatively can be prepared immediately prior to being loaded into such dosage means.

[0204] Accordingly, (a) a composition produced by the process of the present invention, and (b) a pharmaceutically or veterinarily acceptable carrier system, a kit of parts is provided. There is further provided a kit of parts comprising a composition produced by the process of the present invention, together with instructions for the end user for mixing these particles with a pharmaceutically or veterinarily acceptable aqueous and / or oily carrier system.

[0205] As described above herein, there is further provided an injectable and / or infusible dosage form modified by including at least two chambers, within one of which is located a composition produced by the process of the present invention and within the other of which is located a pharmaceutically or veterinarily acceptable carrier system, such that mixing to produce a suspension or otherwise occurs before and / or during injection or infusion.

[0206] When the term "about" is employed herein in relation to, for example, a quantity (such as concentration, dimension (size and / or weight), period), relative quantity (percentage, weight ratio, atomic ratio, size ratio, aspect ratio, proportion, multiple, or fraction), relative humidity, lux, temperature, or pressure, it is always understood that such a variable is an approximate value and thus can vary by ±15%, for example, ±10%, for example, ±5%, preferably ±2% (for example, ±1%) from the number specified herein. This also applies even if such a number is presented as a percentage (for example, "about 15%" can mean any value between 8.5% and 11.5%, meaning ±15% of the number 10).

[0207] The compositions produced by the process of the present invention enable the formulation of a variety of pharmaceutically active compounds. The compositions produced by the process of the present invention can be used to effectively treat a wide variety of disorders depending on the biologically active agent contained therein.

[0208] The compositions produced by the process of the present invention can form a uniform and stable suspension in an injection solution (i.e., without sedimentation) and can be further formulated in the form of an injection suspension of coated particles having a size distribution that can be injected through a needle. In this regard, the compositions produced by the process of the present invention can contain an inert ingredient that can prevent the early gelation of the compositions produced by the process of the present invention and / or can contain an aqueous medium that is viscous enough to prevent sedimentation that would lead to a risk of under - or over - dosing of the active ingredient as the suspension becomes "non - homogeneous".

[0209] Furthermore, the compositions produced by the process of the present invention can be stored under normal storage conditions and maintain their physical and / or chemical integrity.

[0210] The phrase "maintain their physical and chemical integrity" essentially means chemical stability and physical stability.

[0211] "Chemical stability" means that any composition produced by the process of the present invention can be stored under normal storage conditions with a slight degree of chemical degradation or decomposition (regardless of the presence or absence of appropriate pharmaceutical packaging).

[0212] "Physical stability" means that any composition produced by the process of the present invention can be stored under normal storage conditions with a slight degree of physical transformation such as sedimentation described above, or a change in the properties and / or integrity of the coated particles, for example, a change in the coating itself or the active ingredient (including dissolution, solvation, solid phase transition, etc.) (regardless of the presence or absence of appropriate pharmaceutical packaging).

[0213] Examples of "normal storage conditions" for the compositions produced by the process of the present invention include temperatures of about -50°C to about +80°C (preferably about -25°C to about +75°C, for example, about 50°C), and / or pressures of about 0.1 to about 2 bar (preferably atmospheric pressure), and / or exposure to ultraviolet / visible light of about 460 lux, and / or relative humidity of about 5 to about 95% (preferably about 10 to about 40%) over a long period (i.e., about 12 months or more, for example, about 6 months).

[0214] Under such conditions, it may be found that less than about 15%, more preferably less than about 10%, particularly less than about 5% of the composition produced by the process of the present invention is chemically and / or physically degraded. Those skilled in the art will understand that the above upper and lower limits of temperature and pressure represent the extreme values of normal storage conditions and that certain combinations of these extreme values are not experienced during normal storage (for example, a temperature of 50°C and a pressure of 0.1 bar).

[0215] Furthermore, the compositions produced by the process of the present invention can provide a release and / or pharmacokinetic profile that minimizes any burst effect, characterized by the maximum concentration immediately after administration, and / or minimizes Cmax.

[0216] The compositions and processes described herein may have the advantage that, in the treatment of related conditions using certain biological agents, they are more convenient, effective, less toxic, have a broad range of activity, are potent, may produce fewer side effects, or may have other useful pharmacological properties for physicians and / or patients than any similar treatments that may be described in the prior art for the same active ingredient.

[0217] The present invention is illustrated by, but not in any way limited to, the following examples, with reference to the accompanying figures, wherein FIGS. 1-4 show dose-adjusted plasma concentration versus time curves after administration of samples prepared according to each example.

Brief Description of the Drawings

[0218]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Example

[0219] Comparative Example 1 Coated lenalidomide microparticles I using continuous flow ALD Microparticles of lenalidomide 99.9% (APIChem, China) were used as received. The average diameter of the lenalidomide particles was 10 μm as determined by laser diffraction (Shimadzu, SALD-7500nano, Kyoto, Japan). The particle size distribution determined by laser diffraction was as follows: D 10 2.7 μm, D 50 10.4 μm, and D 90 24.9 μm.

[0220] The microparticles or solid cores were coated as described in Steps 1-4.

[0221] 1. The microparticles were loaded into an ALD reactor (Picosun, SUNALE™ R-series, Espoo, Finland) and subjected to 3 ALD cycles using diethylzinc and water as precursors, followed by 1 ALD cycle of trimethylaluminum and water as precursors at a reactor temperature of 50 °C. This was repeated 6 times, i.e., 6×(3 cycles of Zn + 1 cycle of Al), resulting in a total of 24 cycles. This process formed a first layer of mixed oxide with an atomic ratio of zinc:aluminum of approximately 3:1.

[0222] The ALD reactor comprises a reaction chamber filled with fine particles. The ALD reactor further comprises precursor bottles each containing a separate precursor, and each precursor bottle is connected to the reaction chamber via a valve. The ALD reactor also comprises a pump and associated piping for pumping an inert gas such as nitrogen through the reaction chamber, and this pump is also connected to the reaction chamber via a valve.

[0223] The ALD cycle is carried out as follows. Steps a - e represent the first cycle, subsequent cycles start from step d as specified in step l, and the last cycle ends at step k. a. Reagent pulse: Water is evaporated and carried into the reaction chamber by inert nitrogen gas by opening the valve to the precursor bottle for 0.1 seconds. The water adsorbs on the surface of the drug particles and presents hydroxyl groups externally or on the particles. b. Then, the reactor is pumped for 3 seconds. c. Steps a - b above are repeated 100 times. d. Purge pulse: The chamber is purged with nitrogen. When this is not the first cycle, gaseous water and organic gases are removed. e. Reagent pulse: Diethylzinc or trimethylaluminum is evaporated and carried into the reaction chamber by inert nitrogen gas by opening the valve to the precursor bottle for 0.1 seconds. Diethylzinc or trimethylaluminum adsorbs on the surface of the drug particles and reacts with the hydroxyl groups. This releases ethane from diethylzinc or methane from trimethylaluminum. f. Then, the reactor is pumped for 3 seconds. g. Steps e - f above are repeated 100 times. h. Purge pulse: The chamber is purged with nitrogen. Unreacted reagents and organic gases are removed. i. Reagent pulse: Evaporate water and open the valve to the precursor bottle for 0.1 seconds, and transport it into the reaction chamber by inert nitrogen gas. The water adsorbs on the surface of the drug particles and reacts with the organometallic surface. The remaining ethyl or methyl groups are each converted to ethane and methane, respectively. Thereby, the surface is coated with a metal oxide layer and presents hydroxyl groups on the outside of the particles. j. Then, the reactor was pumped for 3 seconds. k. The above steps i - j were repeated 100 times. l. The cycle was repeated from step d.

[0224] 2. Next, the powder was taken out of the reactor and deagglomerated by a sonic sifter (Tsutsui Sonic Agitated Sifting Machine SW - 20AT) with a mesh size of 32 μm.

[0225] 3. The resulting deagglomerated powder was reloaded into the ALD reactor, and steps 1 - 2 were repeated twice to form the second and third layers of mixed oxide with an atomic ratio of zinc:aluminum of approximately 3:1.

[0226] 4. The resulting deagglomerated powder was reloaded into the ALD reactor, and step 1 was repeated once.

[0227] Comparative Example 2 Coated lenalidomide microparticles II using continuous - flow ALD This was the same as Comparative Example 1 except that two additional layers were formed. In other words, before performing step 4, step 3 was repeated once.

[0228] Example 3 Coated lenalidomide microparticles I using stop - flow ALD Particles of lenalidomide 99.9% (Kyongbo, South Korea) were used as received. The average diameter of the lenalidomide particles was 4 μm as determined as described in Comparative Example 1 above. The particle size distribution determined by laser diffraction was as follows: D 10 0.6 μm, D 50 3.9 μm, and D 90 15.6 μm.

[0229] The particles were coated essentially as described in Steps 1 - 4 of Comparative Example 1, except that the ALD cycle was carried out as follows (Steps a - d represent the first cycle and subsequent cycles start from Step a as specified in Step e). a. Reagent Pulse 1: i. The valve on the pipe between the pump and the ALD reactor was closed. ii. The valve on the water precursor bottle was opened for 1 second to fill the reaction chamber with the evaporated moisture. iii. The valve to the water precursor bottle was closed and the chamber was allowed to rest for 30 seconds (soak time) before reopening the pump valve to ensure that the water vapor was adsorbed on the surface of the drug particles and presented hydroxyl groups either externally or on the particles. iv. Subsequently, the reactor was pumped for 9 seconds. v. Steps i - iv above were repeated 20 times. b. Purge Pulse: The chamber was purged with nitrogen in continuous flow. When this was not the first cycle, gaseous water and organic gas were removed. c. Reagent Pulse: i. The valve on the pipe between the pump and the ALD reactor was closed. ii. The valve on the diethylzinc or trimethylaluminum precursor bottle was opened for 1 second to fill the reaction chamber with the evaporated metal - containing precursor. iii. The valve to the precursor bottle was closed and the chamber was allowed to rest for 30 seconds (soak time) before reopening to the pump to ensure that the metal - containing precursor vapor reacted with the hydroxyl groups on the surface of the drug particles. iv. Subsequently, the reactor was pumped for 9 seconds. v. Steps i - iv above were repeated 20 times. d. Purge pulse: The chamber was purged with nitrogen in continuous flow. Unreacted reagents and organic gases were removed. e. The cycle was repeated from step a.

[0230] Example 4 Coated Lenalidomide Fine Particles II Using Stop - Flow ALD This was the same as Comparative Example 3, except that two additional layers were formed. In other words, before performing step 4, step 3 was repeated once.

[0231] Example 5 Determination of Drug Loading This example describes the analysis of the drug loading of lenalidomide in the particles obtained in Comparative Examples 1 and 2 and Examples 3 and 4.

[0232] Materials and Methods To determine the drug loading (i.e., w / w% of lenalidomide in the powder), UPLC (4.6×100 mm, 2.6 μm particles, C18WP column (SunShell, ChromaNik Technologies Inc, Osaka, Japan)) equipped with a diode array detector (Shimadzu, Japan) set at 223 nm was employed using Prominence - i (Shimadzu, Japan). The materials were dissolved in 2M phosphoric acid in acetonitrile / water (1:1), diluted with methanol / 12.5 mM phosphate buffer at pH 3.4 (4:1) before filtration (0.2 μm RC, Lab Logistics Group, Germany), and further analyzed by UPLC (n = 2).

[0233] The UPLC assay was set according to Table 1.

Table 1

[0234] The concentration of the injected sample was automatically calculated by the software supplied by the manufacturer. The drug loading was calculated according to the following equation, where C LEN is the analyzed concentration of lenalidomide, and m sample is the sample mass.

Number

[0235] Results The drug loading of lenalidomide in the particles according to Comparative Example 1 was determined to be 94.8%.

[0236] The drug loading of lenalidomide in the particles according to Comparative Example 2 was determined to be 92.6%.

[0237] The drug loading of lenalidomide in the particles according to Example 3 was determined to be 76.0%.

[0238] The drug loading of lenalidomide in the particles according to Example 4 was determined to be 67.7%.

[0239] Example 6 Coating integrity This example describes the analysis of the coating integrity of the particles obtained in Comparative Examples 1 and 2 and Examples 3 and 4.

[0240] The coating integrity of the coated lenalidomide was determined by preparing a suspension of the coated material in DMSO, a solvent that dissolves the API but not the coating material. Thus, the release of lenalidomide from the product can occur only due to "defects" in the coating. The integrity of the coating can be evaluated by measuring the released lenalidomide using an HPLC method. The lower the percentage of released lenalidomide, the better the coating integrity.

[0241] Materials and methods To determine the coating integrity (i.e., w / w% of lenalidomide released in the powder), UPLC (4.6 × 100 mm, 2.6 μm particles, C18WP column (SunShell, ChromaNik Technologies Inc, Osaka, Japan)) equipped with a diode array detector (Shimadzu, Japan) set at 223 nm, Prominence-i (Shimadzu, Japan) was used. 25 mg of the material was dispersed in 25 mL of DMSO and placed on a rotating table for 3 hours. 1 mL of the sample was taken out for further analysis using filtration (0.2 μm RC, Lab Logistics Group, Germany) and UPLC (n = 1) according to the settings in Table 1 above.

[0242] The concentration of the injected sample was automatically calculated by the software supplied by the manufacturer. The amount of API dissolved in the coating integrity assay was calculated according to the following equation, where c a is the concentration of API from the analysis (mg / ml), V t is the total sample volume (ml), m API is the mass of API weighed in (mg), and the drug load is the API content (fraction) of the coated API.

Number

[0243] Results The amount of API dissolved in the coating integrity assay of the particles according to Comparative Example 1 was determined to be 74%.

[0244] The amount of API dissolved in the coating integrity assay of the particles according to Comparative Example 2 was determined to be 51%.

[0245] The amount of API dissolved in the coating integrity assay of the particles according to Example 3 was determined to be 15%.

[0246] In the particle coating integrity assay according to Example 4, the amount of API dissolved was determined to be 7%.

[0247] Example 7 Preparation of Formulations This example describes the preparation of formulations of the coated lenalidomide particles disclosed herein.

[0248] Materials and Methods Suspensions of the coated microparticles of lenalidomide according to Comparative Examples 1 and 2 and Examples 3 and 4 were prepared.

[0249] The powders of the coated microparticles of lenalidomide according to Comparative Examples 1 and 2 and Examples 3 and 4 were mixed with veterinary Hyonate® (Boehringer Ingelheim Animal Health, France) as a vehicle. Veterinary Hyonate® is a veterinary pharmaceutical used for animal injection containing a sterile isotonic phosphate buffer of 10 mg / mL sodium hyaluronate (pH 7.4). The composition of veterinary Hyonate® is presented in Table 2 below.

Table 2

[0250] The microparticles were reconstituted by adding the vehicle to the vial having the powder of the microparticles to obtain the following lenalidomide concentrations. - 50 mg / ml of lenalidomide for the particles according to Comparative Example 1, - 5 mg / ml and 50 mg / ml of lenalidomide for the particles according to Comparative Example 2, - 20 mg / ml of lenalidomide for the particles according to Example 3, and - 20 mg / ml of lenalidomide for the particles according to Example 4.

[0251] Results Suspensions of the coated lenalidomide particles according to Comparative Examples 1 and 2 and Examples 3 and 4 were obtained, respectively.

[0252] Comparative Example 8 In Vivo Pharmacokinetics Study I This example describes the preclinical pharmacokinetics study of lenalidomide after administration of the coated lenalidomide formulations according to Comparative Examples 1 and 2 in male and female Sprague Dawley rats.

[0253] Materials and Methods Male and female Sprague Dawley rats weighing 231 - 285 g on the dosing day were supplied by Charles River (UK). The duration of the study was 14 days. 36 rats were used in this study.

[0254] The hair in the dosing area was shaved before injection and the injection site was marked. A suspension prepared as described in Example 7 using the coated lenalidomide particles according to Comparative Examples 1 and 2 was drawn into a 1 mL BD syringe and a single subcutaneous injection (about 0.12 mL) was administered to the flanks of each rat through a 23G needle (BD microlance).

[0255] Blood samples (about 0.2 mL) were collected from the tail vein into K2EDTA tubes at the following time points: 0.25, 0.5, 1, 2, 3, 6, 12, 24, 48, 72, 120, 168, 264, and 336 hours after dosing. Plasma was separated by centrifugation (1500 g, 10 minutes at 4°C) as soon as practically possible following blood collection. The animals were sacrificed on the last day of the study. Plasma samples were stored in a -80°C freezer and analysis was deferred.

[0256] UPLC-MS / MS was used to determine the plasma concentration.

[0257] 35 μL of rat plasma was pipetted into a 96-well plate and the samples were prepared by adding 35 μL of 5% DMF in acetonitrile and 70 μL of internal standard working solution using a TECAN Genesis liquid handling robot. The 96-well plate was shaken for 15 minutes and centrifuged. Then, all samples were injected onto a UPLC-MS / MS system (Xevo TQ-s micro coupled to an Acquity I-Class UPLC system, Waters, Milford, MA, USA) with the settings specified in Table 3 below.

Table 3

[0258] Pharmacokinetic analysis of lenalidomide in plasma was performed according to a standard non-compartmental approach using PKanalix (2021, Lixoft, Antony, France). The dose-normalized plasma concentration of lenalidomide after a single subcutaneous administration of the formulation was evaluated and the following plasma pharmacokinetic parameters were evaluated. · The dose is expressed as mg / kg body weight of the rat. · “C max ”: The maximum concentration found in the analysis expressed as ng / mL. · “AUC ∞ ”: The area under the concentration-time curve to infinite time expressed as ng*h / mL. · “C max / D”: The maximum concentration normalized to 1 mg / kg expressed as ng / mL / mg / kg body weight of the rat. · “AUC ∞ / D”: The area under the concentration-time curve to infinite time normalized to 1 mg / kg expressed as ng*h / mL / mg / kg body weight of the rat. · “Fr.Rel. 0-12h ”: The fraction released during the first 12 hours of the area under the concentration-time curve to infinite time expressed as a percentage.

[0259] Results Figures 1 and 2 respectively show the plasma concentration-time curves (plasma concentration of lenalidomide in ng / mL vs. sampling time in time units) for the samples obtained by Comparative Examples 1 and 2, respectively.

Table 4

[0260] Example 9 In Vivo Pharmacokinetics Study II This example describes the preclinical pharmacokinetics study of lenalidomide after administration of the coated lenalidomide formulations according to Examples 3 and 4 in male and female Sprague Dawley rats.

[0261] Materials and Methods Male Sprague Dawley rats weighing 260 - 343 g on the dosing day were supplied by Charles River (UK). The duration of the study was 14 days. 44 rats were used in this study.

[0262] The hair in the dosing area was shaved before injection and the injection site was marked. A suspension prepared as described in Example 7 using the coated lenalidomide particles according to Comparative Examples 3 and 4 was drawn into a 1 mL BD syringe and a single subcutaneous injection (about 0.15 mL) was administered to the flanks of each rat through a 23G needle (BD microlance).

[0263] Blood samples (about 0.2 mL) were collected from the tail vein into K2EDTA tubes at the following time points: 0.25, 0.5, 1, 2, 3, 6, 12, 24, 48, 72, 120, 168, 216, 264, and 336 hours after dosing. Plasma was separated by centrifugation (1500 g, 10 minutes at 4°C) as soon as practically possible following blood collection. The animals were sacrificed on the last day of the study. Plasma samples were stored in a -80°C freezer and analysis was deferred.

[0264] UPLC-MS / MS was used to determine the plasma concentration.

[0265] 35 μL of rat plasma was pipetted into a 96-well plate and samples were prepared by adding 35 μL of 5% DMF in acetonitrile and 70 μL of internal standard working solution using a TECAN Genesis liquid handling robot. The 96-well plate was shaken for 15 minutes and centrifuged. Then, all samples were injected onto a UPLC-MS / MS system (Xevo TQ-s micro coupled to an Acquity I-Class UPLC system, Waters, Milford, MA, USA) with the settings specified in Table 2 above.

[0266] Pharmacokinetic analysis of lenalidomide in plasma was performed according to a standard non-compartmental approach using Phoenix WinNonlin version 8.3 (Certara, USA). The dose-normalized plasma concentration of lenalidomide after a single subcutaneous administration of the formulation was evaluated and the following plasma pharmacokinetic parameters were evaluated. · Dose is expressed as mg / kg body weight of the rat. · “C max ”: The maximum concentration found in the analysis expressed as ng / mL. · “AUC ∞ ”: The area under the concentration-time curve up to infinite time expressed as ng*h / mL. · “C max / D”: The maximum concentration normalized to 1 mg / kg expressed as ng / mL / mg / kg body weight of the rat. · “AUC ∞ / D”: The area under the concentration-time curve up to infinite time normalized to 1 mg / kg expressed as ng*h / mL / mg / kg body weight of the rat. · “Fr.Rel. 0-12h ”: The fraction released during the first 12 hours of the area under the concentration-time curve up to infinite time expressed as a percentage.

[0267] Results Figures 3 and 4 show the respective plasma concentration-time curves (plasma concentration of lenalidomide in ng / mL vs. sampling time in units of time) for the samples obtained by Examples 3 and 4, respectively.

Table 5

[0268] The maximum concentration normalized by dosage was lower for Example 3 compared to Comparative Example 1, as indicated by both the lower maximum concentration and the lower fraction released during the first 12 hours.

[0269] The maximum concentration normalized by dosage was lower for Example 4 compared to Comparative Example 2, as indicated by both the lower maximum concentration and the lower fraction released during the first 12 hours.

[0270] Overall, Comparative Example 8 and Example 9 demonstrated that coated lenalidomide particles produced by stop-flow ALD exhibit a release profile with lower initial release than coated lenalidomide particles produced using continuous-flow ALD.

[0271] Comparative Example 10 Coated indomethacin microparticles I using continuous-flow ALD Microparticles of indomethacin 99.9% (ReechPharma, CA, USA) were used as received. The average diameter of the indomethacin particles was 10.5 μm as determined by laser diffraction (Shimadzu, SALD-7500nano, Kyoto, Japan). The particle size distribution determined by laser diffraction was as follows: D 10 4.2 μm, D 50 10.5 μm, and D 90 23.8 μm.

[0272] The microparticles or solid cores were coated as described in Steps 1 - 4.

[0273] 1. The microparticles were loaded into an ALD reactor (Picosun, SUNALE™ R-series, Espoo, Finland) and subjected to three ALD cycles using diethylzinc and water as precursors, followed by one ALD cycle of trimethylaluminum and water as precursors at a reactor temperature of 50 °C. This was repeated six times, i.e., 6 × (3 cycles of Zn + 1 cycle of Al), resulting in a total of 24 cycles. This process formed a first layer of mixed oxide with an atomic ratio of zinc:aluminum of approximately 3:1.

[0274] The ALD reactor comprises a reaction chamber loaded with microparticles. The ALD reactor further comprises precursor bottles each containing a separate precursor, and each precursor bottle is connected to the reaction chamber via a valve. The ALD reactor also comprises a pump and associated piping for pumping an inert gas such as nitrogen through the reaction chamber, and this pump is also connected to the reaction chamber via a valve.

[0275] The ALD cycles were performed as follows. Steps a - e represent the first cycle, subsequent cycles start from step d as specified in step l, and the last cycle ends at step k. a. Reagent pulse: Water was evaporated and carried into the reaction chamber by inert nitrogen gas by opening the valve to the precursor bottle for 0.1 s. The water adsorbed on the surface of the drug particles and presented hydroxyl groups either externally or on the particles. b. Subsequently, the reactor was pumped for 3 s. c. Steps a - b above were repeated 100 times. d. Purge pulse: The chamber was purged with nitrogen. If this was not the first cycle, gaseous water and organic gases were removed. e. Reagent Pulse: Diethylzinc or trimethylaluminum was evaporated and transported into the reaction chamber with inert nitrogen gas by opening the valve to the precursor bottle for 0.1 seconds. Diethylzinc or trimethylaluminum adsorbed on the surface of the drug particles and reacted with the hydroxyl groups. This releases ethane from diethylzinc or methane from trimethylaluminum. f. Subsequently, the reactor was pumped for 3 seconds. g. The above steps e - f were repeated 100 times. h. Purge Pulse: The chamber was purged with nitrogen. Unreacted reagents and organic gases were removed. i. Reagent Pulse: Water was evaporated and transported into the reaction chamber with inert nitrogen gas by opening the valve to the precursor bottle for 0.1 seconds. Water adsorbed on the surface of the drug particles and reacted with the organometallic surface. The remaining ethyl or methyl groups were each converted to ethane and methane respectively. Thereby, the surface was coated with a metal oxide layer and presented hydroxyl groups on the outside of the particles. j. Subsequently, the reactor was pumped for 3 seconds. k. The above steps i - j were repeated 100 times. l. The cycle was repeated from step d.

[0276] 2. Next, the powder was taken out of the reactor and de - aggregated by a sonic sifter (Tsutsui Sonic Agitated Sifting Machine SW - 20AT) equipped with a 20μm mesh size sieve.

[0277] 3. The resulting de - aggregated powder was re - loaded into the ALD reactor, and steps 1 - 2 were repeated 2 times to form the second and third layers of mixed oxides with an atomic ratio of zinc:aluminum of approximately 3:1.

[0278] 4. The resulting de - aggregated powder was re - loaded into the ALD reactor, and step 1 was repeated 1 time.

[0279] Example 11 Coated indomethacin microparticles I using a stop flow Microparticles of indomethacin 99.9% (ReechPharma, CA, USA) were used as received. The average diameter and particle size distribution were as described in Comparative Example 10.

[0280] The microparticles were coated essentially as described in Steps 1-4 of Comparative Example 10, except that the ALD cycle was carried out as follows (Steps a-d represent the first cycle, and subsequent cycles start from Step a as specified in Step e). a. Reagent pulse 1: i. The valve on the pipe between the pump and the ALD reactor was closed. ii. The valve on the water precursor bottle was opened for 1 second to fill the reaction chamber with the evaporated moisture. iii. The valve to the water precursor bottle was closed, and the chamber was allowed to rest for 15 seconds (soaking time) before reopening the pump valve to ensure that water vapor was adsorbed on the surface of the drug particles and presented hydroxyl groups externally or on the particles. iv. Thereafter, the reactor was pumped for 9 seconds. v. Steps i-iv above were repeated 20 times. b. Purge pulse: The chamber was purged with nitrogen in a continuous flow. If this was not the first cycle, gaseous water and organic gases were removed. c. Reagent pulse: i. The valve on the pipe between the pump and the ALD reactor was closed. ii. The valve on the diethylzinc or trimethylaluminum precursor bottle was opened for 1 second to fill the reaction chamber with the evaporated metal-containing precursor. iii. The valve to the precursor bottle was closed, and the chamber was allowed to rest for 15 seconds (soaking time) before reopening to the pump to ensure that the metal-containing precursor vapor reacted with the hydroxyl groups on the surface of the drug particles. iv. Thereafter, the reactor was pumped for 9 seconds. v. Steps i-iv above were repeated 20 times. d. Purge Pulse: The chamber was purged with nitrogen in continuous flow. Unreacted reagents and organic gases were removed. e. The cycle was repeated from step a.

[0281] Example 12 Determination of Drug Loading This example describes the analysis of the drug loading of indomethacin in the particles obtained in Example 11.

[0282] Materials and Methods To determine the drug loading (i.e., w / w% of indomethacin in the powder), UPLC (Nexera, Shimadzu, Japan) equipped with a diode array detector (Shimadzu, Japan) set at 254 nm was used, employing a 3×100 mm, 2.6 μm particle, phenylhexyl column (Thermo Fisher Scientific Inc., MA, USA). The material was dissolved in 2 M phosphoric acid in acetonitrile / water (1:1), diluted with acetonitrile / water (3:1) before filtration (0.2 μm RC, Lab Logistics Group, Germany), and further analyzed by UPLC (n = 3).

[0283] The UPLC assay was set according to Table 6. [Table 6]

[0284] The concentration of the injected sample was automatically calculated by the software supplied by the manufacturer. The drug loading was calculated according to the following equation, where C sample is the analyzed concentration of indomethacin, V t is the total sample volume, and m sample is the sample mass. [Equation]

[0285] Results The drug loading of indomethacin in the particles according to Example 11 was determined to be 83.2%.

[0286] Example 13 Determination of coating integrity This example describes the analysis of the coating integrity of the particles obtained in Example 11.

[0287] The coating integrity of the coated indomethacin was determined by preparing a suspension of the coated material in DMSO, a solvent that dissolves the API but not the coating material. Thus, the release of indomethacin from the product can occur only due to "defects" in the coating. The integrity of the coating can be evaluated by measuring the released indomethacin using an HPLC method. The lower the percentage of released indomethacin, the better the coating integrity.

[0288] Materials and methods To determine the coating integrity (i.e., the w / w% of indomethacin released in the powder), UPLC (Nexera, Shimadzu, Japan) equipped with a diode array detector (Shimadzu, Japan) set at 254 nm using a 3×100 mm, 2.6 μm particle, phenylhexyl column (Thermo Fisher Scientific Inc., MA, USA) was used. 25 mg of the material was dispersed in 25 mL of DMSO and placed on a rotating table for 3 hours. 1 mL of the sample was removed for further analysis using filtration (0.2 μm RC, Lab Logistics Group, Germany) and UPLC (n = 1) according to the settings in Table 6 above.

[0289] The concentration of the injected sample was automatically calculated by the software supplied by the manufacturer. The amount of API dissolved in the coating integrity assay was calculated according to the following equation, where c a is the concentration of the API from the analysis (mg / ml), and V tis the total sample volume (ml), and m API is the mass of the API weighed in (mg), and the drug loading is the API content (fraction) of the coated API.

Number

[0290] Results In the coating integrity assay of the particles according to Example 11, the amount of API dissolved was determined to be 13.0%.

[0291] Example 14 Coated indomethacin microparticles II using stop flow Microparticles of indomethacin 99.9% (ReechPharma, CA, USA) were used as received. The average diameter and particle size distribution were as described in Comparative Example 10.

[0292] The particles were coated essentially as described in Steps 1-4 of Example 11, except that the immersion time was 30 seconds instead of 15 seconds in both Steps a and c.

[0293] Example 15 Determination of drug loading This example describes the analysis of the drug loading of indomethacin in the particles obtained in Example 14.

[0294] Materials and methods The materials and methods were as described in Example 12, except that the particles analyzed were those obtained in Example 14 instead of those obtained in Example 11.

[0295] Results The drug loading of indomethacin in the particles according to Example 14 was determined to be 82.3%.

[0296] Example 16 Determination of coating integrity This example describes the analysis of the coating integrity of the particles obtained in Example 14.

[0297] The coating integrity of the coated indomethacin was determined as described in Example 13.

[0298] Materials and Methods The materials and methods were as described in Example 13, except that the particles analyzed were those obtained in Example 14, not those obtained in Example 11.

[0299] Results The amount of API dissolved in the coating integrity assay of the particles according to Example 14 was determined to be 10.6%.

[0300] Comparative Example 17 Coated lenalidomide microparticles using continuous flow ALD This was the same as Comparative Example 10, except that microparticles of 99.9% lenalidomide (Kyongbo, South Korea) were used instead of 99.9% indomethacin. The average diameter of the lenalidomide particles was determined to be 4.3 μm by laser diffraction (Shimadzu, SALD-7500nano, Kyoto, Japan). The particle size distribution determined by laser diffraction was as follows: D10 0.9 μm, D50 4.3 μm, and D90 15.6 μm.

[0301] All other aspects of the process used in Comparative Example 17 were identical to those of Comparative Example 10, except for the microparticles used.

[0302] Example 18 Coated lenalidomide microparticles I using stop flow Particles of lenalidomide 99.9% (Kyongbo, South Korea) were used as received. The average diameter of the lenalidomide particles was 4.3 μm as determined as described in Comparative Example 17 above. The particle size distribution determined by laser diffraction was as follows. D10 0.9 μm, D50 4.3 μm, and D90 15.6 μm.

[0303] The particles were coated essentially as described in Steps 1 - 4 of Example 17, except as follows. - In Step 3, Steps 1 - 2 were repeated 4 times to form the second, third, fourth, and fifth layers of the mixed oxide having an atomic ratio of zinc:aluminum of about 3:1. - The ALD cycles were carried out as follows (Steps a - d represent the first cycle and subsequent cycles start from Step a as specified in Step e). a. Reagent Pulse 1: i. The valve on the pipe between the pump and the ALD reactor was closed. ii. The valve on the water precursor bottle was opened for 1 second to fill the reaction chamber with the evaporated moisture. iii. The valve to the water precursor bottle was closed and the chamber was allowed to rest for 30 seconds (soak time) before opening the pump valve again to ensure that the water vapor was adsorbed on the surface of the drug particles and presented hydroxyl groups either externally or on the particles. iv. Subsequently, the reactor was pumped for 9 seconds. v. Steps i - iv above were repeated 20 times. b. Purge Pulse: The chamber was purged with nitrogen in a continuous flow. If this was not the first cycle, gaseous water and organic gas were removed. c. Reagent Pulse: i. The valve on the pipe between the pump and the ALD reactor was closed. ii. The valve on the diethylzinc or trimethylaluminum precursor bottle was opened for 1 second to fill the reaction chamber with the evaporated metal - containing precursor. iii. Close the valve to the precursor bottle and, before reopening it to the pump, allow the chamber to rest for 30 seconds (soaking time) to ensure that the metal-containing precursor vapor reacts with the hydroxyl groups on the surface of the drug particles. iv. Subsequently, the reactor was pumped for 9 seconds. v. Steps i - iv above were repeated 20 times. d. Purge pulse: The chamber was purged with nitrogen in a continuous flow to remove unreacted reagents and organic gases. e. The cycle was repeated from step a.

[0304] Example 19 Determination of drug loading This example describes the analysis of the drug loading of lenalidomide in the particles obtained in Example 18.

[0305] Materials and methods The materials and methods were as described in Example 12, except that the particles analyzed were those obtained in Example 18, not those obtained in Example 11.

[0306] Results The drug loading of lenalidomide in the particles according to Example 18 was determined to be 69.2%.

[0307] Example 20 Determination of coating integrity This example describes the analysis of the coating integrity of the particles obtained in Example 18.

[0308] The coating integrity of the coated lenalidomide was determined as described in Example 13.

[0309] Materials and methods The materials and methods were as described in Example 13, except that the particles analyzed were those obtained in Example 18, not those obtained in Example 11.

[0310] Results In the particle coating integrity assay according to Example 18, the amount of API dissolved was determined to be 6.8%.

[0311] Example 21 Preparation of the formulation This example describes the preparation of a formulation of the coated lenalidomide particles disclosed herein.

[0312] The powder of the coated microparticles of lenalidomide according to the example was mixed with veterinary Hyonate® (Boehringer Ingelheim Animal Health, France) as a vehicle. Veterinary Hyonate® is a veterinary pharmaceutical used for the injection of animals, which contains a sterile isotonic phosphate buffer of sodium hyaluronate (pH 7.4) at 10 mg / mL. The composition of veterinary Hyonate® is presented in Table 9 below.

Table 7

[0313] The microparticles were reconstituted by adding the vehicle to a vial having the powder of the microparticles to obtain the following lenalidomide concentrations: - 20 mg / mL of lenalidomide of the particles according to Example 18.

[0314] Example 22 In vivo pharmacokinetic study This example describes the preclinical pharmacokinetic study of lenalidomide after administration of the coated lenalidomide formulation according to Example 21 in male and female Sprague Dawley rats.

[0315] Materials and methods Male and female Sprague Dawley rats weighing 260 - 343 g on the administration date were supplied by Charles River (UK). The duration of the study was 14 days. In each study group of the study, 3 rats of each sex were used. The study group was the coated particulate formulation according to Example 21, and as a control, uncoated particulates of lenalidomide were used.

[0316] The hair in the administration area was shaved before injection, and the injection site was marked. A suspension prepared as described in Example 21 using the coated lenalidomide particles according to Example 18 was drawn into a 1 mL BD syringe, and a single subcutaneous injection (about 0.12 mL) was administered to the flanks of each rat through a 23G needle (BD microlance).

[0317] Blood samples (about 0.2 mL) were collected from the tail vein into K2EDTA tubes at the following time points: 0.25, 0.5, 1, 2, 3, 6, 12, 24, 48, 72, 120, 168, 264, and 336 hours after administration. Plasma was separated by centrifugation (1500 g, 10 minutes at 4°C) as soon as practically possible following blood collection. The animals were sacrificed on the last day of the study. Plasma samples were stored in a -80°C freezer and analysis was deferred.

[0318] UPLC-MS / MS was used to determine the plasma concentration.

[0319] 35 μL of rat plasma was pipetted into a 384-well plate, and the samples were prepared by adding 35 μL of 5% DMSO in acetonitrile and 70 μL of internal standard working solution using a TECAN EVO Ware liquid handling robot. The 384-well plate was shaken for 15 minutes and centrifuged. Then, all samples were injected onto a UPLC-MS / MS system (Xevo TQ-s micro coupled to an Acquity I-Class UPLC system, Waters, Milford, MA, USA) having the settings specified in Table 10 below.

Table 8

[0320] Pharmacokinetic analysis of lenalidomide in plasma was performed according to the use of non-compartmental analysis (NCA) using the software Phoenix WinNonlin version 8.3 (Certara, USA). The dose-normalized plasma concentration of lenalidomide after single subcutaneous administration of the formulation was evaluated, and the following plasma pharmacokinetic parameters were evaluated. ·C max - Maximum observed plasma concentration (ng / mL) ·T max - Time to reach C max (hours) ·AUC 0-24h - AUC from time 0 to 24 hours (h·ng / mL). ·AUC last - AUC from time 0 to the time of the last detectable or last (at 336 hours) measured plasma concentration (h·ng / mL).

[0321] Nominal plasma sampling times and nominal doses were used for non-compartmental PK analysis. Animal PK was calculated with the extravascular dosing option within WinNonlin. Reported plasma concentrations below the LLOQ but above 3 ng / mL were included in the PK analysis, while reported plasma concentrations below the LLOQ were omitted from the analysis.

[0322] C max and T max were derived from the observed plasma concentration data. AUC was evaluated by integration of the plasma concentration-time curve using linear interpolation to increase plasma levels and logarithmic interpolation to decrease plasma levels (linear up-down method).

[0323] Results Figure 5 shows the plasma concentration-time curves (plasma concentration of lenalidomide in ng / mL vs. sampling time in time units) for the samples obtained according to Example 21 and for the samples obtained using uncoated microparticles of lenalidomide as a control.

[0324] More specifically, the plasma concentration (ng / mL) of lenalidomide over time (time) is shown in a semi-log plot (where y is on a logarithmic scale). The squares represent the results from female rats (n = 3), and the circles represent the results from male rats (n = 3). The un-filled symbols represent the results from the control (uncoated microparticles of lenalidomide), and the filled symbols represent the results from the lenalidomide-coated microparticles according to Example 21.

Table 9

[0325] The maximum concentration was lower and reached more slowly for Example 21 compared to the control.

[0326] AUC 0-24h and AUC last represent the amount of lenalidomide released at 24 hours and 336 hours, respectively. For the control, more than 96% of the total amount of lenalidomide released was released in the first 24 hours. In contrast, for Example 21, the amount of lenalidomide released after 24 hours was about 12% of the amount released after 336 hours, and as can be seen from Figure 5, drug release was not yet complete.

[0327] Thus, Example 21 demonstrated that the coated lenalidomide particles produced by stop-flow ALD exhibit a release profile with lower initial release than the uncoated lenalidomide particles.

[0328] Example 23 Coated Lenalidomide Microparticles II Using Stop-Flow Particles of lenalidomide 99.9% (Kyongbo, South Korea) were used as received. The average diameter of the lenalidomide particles was 4 μm as determined by the method described in Comparative Example 17 above. The particle size distribution determined by laser diffraction was as follows. D 10 0.6 μm, D 50 3.9 μm, and D 90 15.6 μm.

[0329] The particles were coated essentially as described in Example 18, except that the layers were formed with alternating 4:1 (Zn:Al) and 3:1 (Zn:Al) sets instead of a consistent 3:1 (Zn:Al) set. Thus, Sets 1, 3, and 5 each included a total of 25 cycles and had a ratio of 4 cycles of Zn: 1 cycle of Al. On the other hand, Sets 2, 4, and 6 each included a total of 24 cycles and had a ratio of 3 cycles of Zn: 1 cycle of Al.

[0330] Example 24 Determination of Drug Loading This example describes the analysis of the drug loading of lenalidomide in the particles obtained in Example 23.

[0331] Materials and Methods The materials and methods were as described in Example 12, except that the particles analyzed were those obtained in Example 23, not those obtained in Example 11.

[0332] Results The drug loading of lenalidomide in the particles according to Example 23 was determined to be 75.2%.

[0333] Example 25 Determination of Coating Integrity This example describes the analysis of the coating integrity of the particles obtained in Example 23.

[0334] The coating integrity of the coated lenalidomide was determined as described in Example 13.

[0335] Materials and Methods The materials and methods were as described in Example 13, except that the particles analyzed were obtained in Example 23 instead of Example 11.

[0336] Results The amount of API dissolved in the particle coating integrity assay according to the example was determined to be 16.2%.

[0337] Example 26 Preparation of Formulation For this example, a formulation of the coated lenalidomide particles disclosed herein was prepared as described in Example 21, except that the particles obtained in Example 23 were used instead of the particles obtained in Example 18.

[0338] Example 27 In Vivo Pharmacokinetic Study This example describes the preclinical pharmacokinetic study of lenalidomide after administration of the coated lenalidomide formulation according to Example 26 in male and female Sprague Dawley rats.

[0339] Materials and Methods Male and female Sprague Dawley rats weighing 260 - 343 g on the day of dosing were supplied by Charles River (UK). The duration of the study was 14 days. In each study group of the study, 3 rats of each sex were used. The study group was the microparticle formulation coated according to the example, and as a control, uncoated microparticles of lenalidomide were used.

[0340] The hair in the administration area was shaved before injection and the injection site was marked. A suspension prepared as described in Example 26 using the lenalidomide particles coated according to Example 23 was drawn into a 1 mL BD syringe, and a single subcutaneous injection (about 0.12 mL) was administered to the flanks of each rat through a 23G needle (BD microlance).

[0341] Blood samples (about 0.2 mL) were collected from the tail vein into K2EDTA tubes at the following time points: 0.25, 0.5, 1, 2, 3, 6, 12, 24, 48, 72, 120, 168, 264, and 336 hours post-administration. Plasma was separated by centrifugation (1500 g, 10 minutes at 4 °C) as soon as practically possible following blood collection. Animals were sacrificed on the last day of the study. Plasma samples were stored in a freezer at -80 °C and analysis was deferred.

[0342] UPLC-MS / MS was used to determine the plasma concentration.

[0343] 35 μL of rat plasma was pipetted into a 384-well plate and samples were prepared by adding 35 μL of 5% DMSO in acetonitrile and 70 μL of internal standard working solution using a TECAN EVO Ware liquid handling robot. The 384-well plate was shaken for 15 minutes and centrifuged. All samples were then injected onto a UPLC-MS / MS system (Xevo TQ-s micro coupled to an Acquity I-Class UPLC system, Waters, Milford, MA, USA) with the settings specified in Table 12 below.

Table 10

[0344] Pharmacokinetic analysis of lenalidomide in plasma was performed according to the use of non-compartmental analysis (NCA) using version 8.3 of the software Phoenix WinNonlin (Certara, USA). The dose-normalized plasma concentration of lenalidomide following a single subcutaneous administration of the formulation was evaluated and the following plasma pharmacokinetic parameters were evaluated. ·C max - Maximum observed plasma concentration (ng / mL) ·T max - C max - Time to reach (hours) ·AUC 0-24h- AUC (h·ng / mL) from time 0 to the time up to 24 hours. · AUC last - AUC (h·ng / mL) from time 0 to the time up to the last detectable or the last (at 336 hours) measured plasma concentration.

[0345] The nominal plasma sampling time points and the nominal doses were used for non-compartmental PK analysis. The PK of the animals was calculated with the extravascular dosing option in WinNonlin. Reported plasma concentrations below the LLOQ but above 3 ng / mL were included in the PK analysis, while unreported plasma concentrations below the LLOQ were omitted from the analysis.

[0346] C max and T max were derived from the observed plasma concentration data. The AUC was evaluated by integration of the plasma concentration-time curve using linear interpolation to increase plasma levels and logarithmic interpolation to decrease plasma levels (linear up-down method).

[0347] Results Figure 6 shows the plasma concentration-time curves (plasma concentration of lenalidomide in ng / mL vs. sampling time in units of time) for the samples obtained according to Example 26 and for the samples obtained using uncoated microparticles of lenalidomide as a control.

[0348] More specifically, the plasma concentration (ng / mL) of lenalidomide over time (time) is shown in a semi-logarithmic plot (where y is on a logarithmic scale). The squares show the results from female rats (n = 3), and the circles show the results from male rats (n = 3). The unshaded symbols show the results from the control (uncoated microparticles of lenalidomide), and the filled symbols show the results from the coated microparticles of lenalidomide according to Example 26. [Table 11]

[0349] The maximum concentration was lower for Example 21 compared to the control.

[0350] For the control, more than 96% of the total amount of lenalidomide released was released in the first 24 hours. In contrast, for Example 26, the amount of lenalidomide released after 24 hours was about 25% of the amount released after 336 hours, and as can be seen from Figure 6, drug release had not been completed yet.

[0351] Therefore, Example 26 demonstrated that the coated lenalidomide particles produced by stop-flow ALD exhibited a release profile with lower initial release than the uncoated lenalidomide particles.

[0352] Example 28 Coated liraglutide microparticles using stop-flow R&D grade liraglutide (MedChemExpress, New Jersey, US) with 98.5% purity and 90.8% peptide content was suspended in a solution of 0.1% Span 85 (Sigma-Aldrich, MO, USA) in cyclohexane (Merck, Germany). The particle size distribution was determined by laser diffraction (SALD-7500nano (Shimadzu, Japan), 405 nm laser) as follows: %D(10): 2.0 μm, %D(50): 7.3 μm, %D(90): 23.8 μm.

[0353] The raw material was dispersed in purified water (0.8 - 2 MΩ / cm2) to form a milky white liquid with a liraglutide concentration of 15% by weight, and the raw material was spray-dried in a Mini Spray Drier (B-290, med Dehumidifier B-296 equipped with a two-fluid nozzle, BUECHI Labortechnik GmbH, Germany). The dispersion was at an inlet temperature of 115°C and a suction rate of 100% (about 35 m 3 / time), pump speed 8% (3.8 mL / min), nozzle clean 2, volumetric flow 35 mm (N2, approximately 600 L / hour) for spray drying, which resulted in an outlet temperature of 73 °C. The total mass yield approximated 77.5%. The spray-dried material was assayed using a Nexera UPLC-UV-DAD (Shimadzu, Japan) equipped with a SunShell nC18-WP, 4.6×100 mm, 2.6 μm particle size column (Chromanik Technologies Inc., Japan), and it was found to have a liraglutide content of 100.1 ± 0.2% (relative) in the spray-dried material. The particle size of the spray-dried material as determined as above was as follows: %D(10): 1.7 μm, %D(50): 8.2 μm, %D(90): 21.2 μm.

[0354] The microparticles were coated essentially as described in steps 1 to 4 of Example 10, except for the following: - Before step 1, 3 cycles of Al were performed, - In step 1, 3 cycles of Zn + 1 cycle of Al were repeated 10 times per set (resulting in a total of 40 cycles per set), - In step 3, steps 1 to 2 were repeated 4 times to form the second, third, fourth, and fifth layers of a mixed oxide having an atomic ratio of zinc:aluminum of approximately 3:1, - In step 4, an additional 3 cycles of Al were performed to complete the process, - The ALD cycles were performed as follows (steps a to d represent the first cycle, and subsequent cycles start from step a as specified in step e). a. Reagent pulse 1: i. The valve on the pipe between the pump and the ALD reactor was closed. ii. The valve on the diethylzinc or trimethylaluminum precursor bottle was opened for 1 second to fill the reaction chamber with the evaporated metal-containing precursor. iii. Close the valve to the precursor bottle and allow the chamber to rest for 30 seconds (soaking time) before reopening it to the pump, ensuring that the metal-containing precursor vapor reacts with the hydroxyl groups on the surface of the drug particles. iv. Subsequently, the reactor was pumped for 9 seconds. v. The above steps a - d were repeated 20 times. b. Purge pulse: The chamber was purged with nitrogen in a continuous flow to remove unreacted reagents and organic gases. c. Reagent pulse: i. Close the valve on the pipe between the pump and the ALD reactor. ii. Open the valve on the water precursor bottle for 1 second to fill the reaction chamber with the evaporated moisture. iii. Close the valve to the water precursor bottle and allow the chamber to rest for 30 seconds (soaking time) before reopening the pump valve, ensuring that the water vapor adsorbs onto the surface of the drug particles and presents hydroxyl groups either externally or on the particles. iv. Subsequently, the reactor was pumped for 9 seconds. v. The above steps i - iv were repeated 20 times. d. Purge pulse: The chamber was purged with nitrogen in a continuous flow. If this was not the first cycle, gaseous water and organic gases were removed. e. The cycle was repeated starting from step a.

[0355] Example 29 Determination of drug loading This example describes the analysis of the drug loading of liraglutide in the particles obtained in Example 28.

[0356] Materials and methods To determine the drug loading (i.e., w / w% of liraglutide in the powder), HPLC (Prominence-i, Shimadzu, Japan) equipped with a diode array detector (Shimadzu, Japan) set at 220 nm was used with a 4.6×150 mm, 2.6 μm particle, PS C18 column (Kinetex, Phenomenex Inc., CA, USA). The material was dissolved in 2 M phosphoric acid in acetonitrile / water (1:1) and diluted with 0.1% trifluoroacetic acid acetonitrile / water (1:9), and further analyzed by HPLC (n = 3).

[0357] The HPLC assay was set according to Table 14.

Table 12

[0358] The concentration of the injected sample was automatically calculated by the software supplied by the manufacturer. The drug loading was calculated according to the following equation, where C sample is the analyzed concentration of liraglutide, V t is the total volume of the sample, and m sample is the sample mass.

Equation

[0359] Results The drug loading of liraglutide in the particles according to Example 28 was determined to be 53.1%.

[0360] Example 30 Determination of coating integrity (DMSO) This example describes the analysis of the coating integrity of the particles obtained in Example 28.

[0361] To determine coating completeness, a sample of the particles obtained in Example 28 was suspended in dimethyl sulfoxide (Rathburn, UK) at a concentration of 0.4 mg of liraglutide per 1 mL of solvent and rotated on an overhead stirrer for up to 72 hours. Intermittent samples were taken, centrifuged at 2697 rcf for 10 minutes, and the supernatant was diluted with the above mobile phase A before injection into the above HPLC system for quantification.

[0362] The concentration of the injected sample was automatically calculated by the software supplied by the manufacturer. The amount of API dissolved in the coating completeness assay was calculated according to the following equation, where c a is the concentration of API from the analysis (mg / ml), V t is the total sample volume (ml), m API is the mass of API weighed in (mg), and the drug load is the API content (fraction) of the coated API.

Number

[0363] Results The amount of API dissolved in the coating completeness assay of the particles according to Example 28 was determined to be 3.0% after 3 hours and 5.2% after 72 hours.

[0364] Example 31 Preparation of Formulation This example describes the preparation of a formulation of the coated liraglutide particles disclosed herein.

[0365] The powder of coated microparticles of liraglutide according to the examples was mixed with veterinary Hyonate® (Boehringer Ingelheim Animal Health, France) as a vehicle. Veterinary Hyonate® is a veterinary pharmaceutical used for animal injection, containing a sterile isotonic phosphate buffer of sodium hyaluronate at 10 mg / mL (pH 7.4). The composition of veterinary Hyonate® is presented in Table 15 below.

Table 13

[0366] The microparticles were reconstituted by adding the vehicle to a vial having the powder of the microparticles to obtain the following liraglutide concentrations: - 10 mg / ml of liraglutide of the particles according to Example 28.

[0367] Example 32 In vivo pharmacokinetic study This example describes the preclinical pharmacokinetic study of liraglutide after administration of the coated liraglutide formulation according to Example 31 in male Sprague Dawley rats.

[0368] Materials and methods Male Sprague Dawley rats weighing approximately 300 g on the dosing day were supplied by Charles River (UK). The duration of the study was 28 days. Four rats were used in each study group of the study. The study group was the coated microparticle formulation according to Example 31, and as a control, a liraglutide solution (Victoza®, Novo Nordisk, Denmark) diluted 10-fold with injectable saline.

[0369] Shave the hair in the administration area before injection and mark the injection site. Using the coated liraglutide particles according to Example 28, draw the suspension prepared as described in Example 32 into a 1 mL BD syringe and administer a single subcutaneous injection (about 0.08 mL and 0.17 mL) to the flanks of each rat through a 23G needle (BD Microlance). In the control group, the control preparation (about 0.10 mL) was intravenously injected into the tail vein and, after a 7-day washout period, subcutaneously injected into the flanks of each rat.

[0370] Blood samples (about 0.2 mL) were collected from the jugular vein into K2EDTA tubes at the following time points: from the animals administered the microparticles coated according to the examples, 1, 3, 6, 12, 24, 48, 72, 120, 168, 251, 384, 480, 576, and 672 hours after administration. Blood samples were collected at the following time points: 0.25, 1, 3, 6, 9, 12, and 24 hours after administration following the intravenous injection of the control preparation, and at the following time points: 1, 2, 3, 6, 9, 12, 24, and 48 hours after administration following the subcutaneous injection of the control preparation.

[0371] As soon as substantially possible following blood collection, plasma was separated by centrifugation (1500 g, 10 minutes at 4 °C). The animals were sacrificed on the last day of the study. The plasma samples were stored in a freezer at -80 °C and analysis was postponed.

[0372] UPLC-MS / MS was used to determine the plasma concentration.

[0373] 35 μL of rat plasma was pipetted into a 384-well plate and the samples were prepared by adding 35 μL of 5% DMSO in acetonitrile and 70 μL of the internal standard working solution using a TECAN EVO-2 liquid handling robot. The 384-well plate was shaken for 15 minutes and centrifuged. Then, all samples were injected onto a UPLC-MS / MS system (Xevo TQ-s micro coupled to an Acquity I-Class UPLC system, Waters, MA, USA) with the settings specified in Table 16 below.

Table 14

[0374] The pharmacokinetic analysis of lenalidomide in plasma was performed according to the use of non-compartmental analysis (NCA) using the software Phoenix WinNonlin version 8.3 (Certara, USA). The dose-normalized plasma concentration of lenalidomide after single subcutaneous administration of the formulation was evaluated, and the following plasma pharmacokinetic parameters were evaluated. ·C max - Maximum observed plasma concentration (ng / mL) ·t max - C max Time to reach (hours) ·t last - Time of the last detectable or last (at 672 hours) measured plasma concentration (hours). ·AUC 0-24h - Area under the curve (AUC) from time 0 to 24 hours (h·ng / mL). ·AUC last - AUC from time 0 to t last (h·ng / mL). ·t 1 / 2,z - Terminal phase half-life (hours) ·AUC inf - Infinitely extrapolated AUC (h·ng / mL). ·F abs - Absolute bioavailability. ·F rel - Relative bioavailability. ·R 0-24h - Fraction released 24 hours after injection.

[0375] The nominal plasma sampling times and nominal doses were used for non-compartmental PK analysis. The PK of the animals was calculated with the extravascular dosing option in WinNonlin. Reported plasma concentrations that were below the LLOQ but above 1 ng / mL were included in the PK analysis, while reported plasma concentrations that were below the LLOQ were omitted from the analysis.

[0376] Cmax and t max was derived from the observed plasma concentration data. The AUC was evaluated by integration of the plasma concentration versus time curve using linear interpolation to increase the plasma level and logarithmic interpolation to decrease the plasma level (linear up-down method). The AUC inf for the concentration in the last quantifiable sample and the primary rate constant λ z associated with the terminal portion of the curve were used to extrapolate the area to infinity from the AUC last . t 1 / 2,z was calculated by ln2 / λ z . F abs was calculated as the fraction of the AUC inf from intravenous and subcutaneous injections normalized by the dose. F rel was calculated as the fraction of the AUC inf from subcutaneous administration of the control formulation and particulate administration coded according to Example 31 normalized by the dose.

[0377] Results Figure 7 shows the plasma concentration-time curves (plasma concentration of liraglutide in ng / mL vs. sampling time in days) for the samples obtained according to Example 31 and the samples obtained using a known liraglutide solution as a control.

[0378] More specifically, the plasma concentration (ng / mL) over time (days) is shown in a semi-logarithmic plot (y is on a logarithmic scale). The filled squares show the results from rats (n = 4) administered coated microparticles of lenalidomide according to the example at 5.6 mg / kg. The filled circles show the results from rats (n = 4) administered coated microparticles of lenalidomide according to the example at 2.8 mg / kg. The unfilled squares show the results from rats intravenously administered the control (liraglutide solution) at 0.2 mg / kg. The unfilled circles show the results from rats subcutaneously administered the control (liraglutide solution) at 0.2 mg / kg. [Table 15]

[0379] Example 33 Injectability at 100 mg / mL in Hyonate Preparation of the formulation The powder of the coated microparticles of liraglutide according to Example 28 was mixed together with veterinary Hyonate® (Boehringer Ingelheim Animal Health, France) as vehicle.

[0380] The microparticles were reconstituted by adding the vehicle to a vial having the powder of the microparticles to obtain the following liraglutide concentrations: - 100 mg / ml of liraglutide of the particles according to Example 28.

[0381] Materials and methods The suspension prepared as described above using the coated liraglutide particles according to Example 28 was drawn into a 1 mL HSW HENKE-JECT® 3-part syringe (Henke-Sass, Wolf GmbH, Germany). A 27G × 19 mm injection needle (Microlance 3, BD, USA) was attached to the syringe and mounted in a custom syringe holder inside a TA.XTplus Texture Analyser instrument equipped with Exponent Connect software (Stable Microsystems Ltd., UK). Using the texture analyser, the force required to extend the piston while pushing down the syringe piston to dispense the contents was measured. In this method, the instrument was operated in compression test mode and the piston was moved at a test speed of 10 mm / second until a threshold force of 50 N, corresponding to completely dispensing the contents of the syringe into the air, was measured. A threshold of 15 N was considered the upper threshold of the acceptable force during injection.

[0382] Results The maximum injection force of the suspension described above was determined to be 10.3 N.

Claims

1. A process for the preparation of a pharmaceutical or veterinary composition in the form of a plurality of particles, said process comprising: (a) loading a plurality of solid cores containing a biologically active agent into a fixed gas-phase deposition reactor chamber; (b) applying a gas-phase deposition technique to surround, enclose, and / or encapsulate said cores with one or more layers of one or more coating materials, each layer containing one or more metal-containing compounds or metalloid-containing compounds; (c) optionally, continuously repeating step (b) to form a plurality of particles having an average diameter on a weight, number, and / or volume basis of from about 10 nm to about 100 μm, each particle comprising a respective solid core and a coating surrounding, enclosing, and / or encapsulating said core; wherein said gas-phase deposition technique comprises: (1) introducing a pulse of a first reactive gas into said fixed gas-phase deposition reactor chamber, allowing said first reactive gas to contact said solid cores for a predetermined immersion period; (2) after step (1), evacuating and / or purging said fixed gas-phase deposition reactor chamber with an inert gas; (3) introducing a pulse of a second reactive gas into said fixed gas-phase deposition reactor chamber, allowing said second reactive gas to contact said solid cores for a predetermined immersion period; (4) after step (3), evacuating and / or purging said fixed gas-phase deposition reactor chamber with an inert gas; wherein either said first reactive gas or said second reactive gas comprises a metal-containing compound or a metalloid-containing compound.

2. The process according to claim 1, wherein step (1), step (3), or both step (1) and (3) comprise allowing each respective reactive gas to contact the respective solid cores for the respective predetermined immersion period in the substantial absence of a pumping action that could cause gas flow.

3. The process according to claim 1 or 2, wherein step (1), step (3), or both step (1) and (3) comprise allowing each respective reactive gas to contact the respective solid cores for the respective predetermined immersion period in the substantial absence of mechanical agitation of the plurality of solid cores.

4. The process according to any one of the preceding claims, wherein the predetermined immersion period is from about 2 seconds to about 30 minutes. **Claim 5** where step (1), step (3), or both step (1) and (3) are 〇 after the predetermined immersion period, operating the reactor by pumping for a predetermined pumping operation period; 〇 repeating a step of introducing a pulse of each of the reactive gases, a step of enabling each of the reactive gases to contact the solid core for a predetermined immersion period, and a step of operating the reactor by pumping for a predetermined pumping operation period, a predetermined number of times; the process according to any one of the preceding claims. **Claim 6** The process according to any one of the preceding claims, wherein each iteration of step (b) is performed using first and second reactive gases that are the same as or different from the iteration of step (b) immediately preceding it. **Claim 7** The process according to any one of the preceding claims, wherein between one or more consecutive pairs of iterations of step (b), the process includes de-aggregating the coated solid core. **Claim 8** One or more instances of de-aggregating the coated solid core include removing the coated solid core from the fixed gas phase deposition reactor chamber, sieving or sonicating the coated solid core, and reloading the coated solid core into the fixed gas phase deposition reactor chamber to repeat step (b); the process according to claim 7. **Claim 9** The sieving or sonicating of the coated solid core is performed using a sieve having a mesh size determined such that the ratio of the size of the sieved or sonicated particles to the mesh size of the sieve is about 1:>1, preferably about 1:2, and optionally about 1:4; the process according to claim 8. **Claim 10** The process according to any one of the preceding claims, wherein at least 200 mg of the solid core is loaded into the fixed gas phase deposition reactor chamber, optionally at least 1 g or at least 10 g, for the gas phase deposition technique to be applied. **Claim 11** The process according to any one of the preceding claims, wherein 3 to 10 individual layers of coating material are continuously applied to the core. **Claim 12** The process according to any one of the preceding claims, wherein the total thickness of the individual layers of the coating material is from about 0.5 nm to about 2 μm.

13. The process according to any one of the preceding claims, wherein the maximum thickness of the individual layers of the coating material is about one-hundredth of the average diameter of the core, based on the weight, number, or volume of the core, including any other previously applied individual layers of the coating material located between the individual layers and the outer surface of the core.

14. The process according to any one of the preceding claims, wherein the coating material of one or more of the individual layers comprises one or more inorganic coating materials.

15. The process according to claim 14, wherein the one or more metal-containing compounds or metalloid-containing compounds comprise hydroxides and / or oxides.

16. The process according to claim 14 or 15, wherein the one or more coating materials comprise silicon oxide, aluminum oxide, titanium dioxide, zinc sulfide, and / or zinc oxide.

17. The process according to claim 16, wherein the one or more coating materials comprise a mixture of zinc oxide with one or the other or both of silicon dioxide and aluminum oxide.

18. The process according to any one of the preceding claims, comprising applying separate layers of the coating material to the core and / or the previously coated core by atomic layer deposition.

19. The process according to any one of the preceding claims, wherein the core comprises a pharmaceutically acceptable excipient.

20. The process according to any one of the preceding claims, wherein the carrier / excipient material is a sugar or sugar alcohol and / or a pH adjuster.

21. The process according to any one of claims 1 to 18, wherein the core consists essentially of a biologically active agent.

22. The biological active agent is an analgesic, anesthetic, anti-ADHD agent, anorectic agent, anti-toxic agent, antibacterial agent, antimicrobial agent, antifungal agent, antiviral agent, antiparasitic agent, antiprotozoal agent, anthelmintic, ectoparasiticide, vaccine, anti-cancer agent, antimetabolite, alkylating agent, anti-tumor agent, topoisomerase, immunomodulator, immunostimulant, immunosuppressant, anabolic steroid, anticoagulant, antiplatelet agent, antiepileptic agent, anti-dementia agent, antidepressant, antidote, antihyperlipidemic agent, antigout agent, antimalarial agent, antimigraine agent, anti-inflammatory agent, anti-Parkinson agent, anti-itch agent, anti-psoriasis agent, antiemetic, anti-obesity agent, anthelmintic, anti-asthmatic agent, antibiotic, antidiabetic agent, antiepileptic drug, antifibrinolytic agent, antihemorrhagic agent, antihistamine drug, antitussive, antihypertensive drug, antimuscarinic agent, antimycobacterial agent, antioxidant, antipsychotic agent, antipyretic agent, antirheumatic agent, antiarrhythmic agent, anxiolytic agent, aphrodisiac, cardiac glycoside, cardiotonic agent, entheogen, entactogen, hallucinogen, appetizer, antithyroid agent, anxiolytic sedative, hypnotic, neuroleptic, astringent, bacteriostatic agent, beta blocker, calcium channel blocker, ACE inhibitor, angiotensin II receptor antagonist, renin inhibitor, beta adrenergic receptor blocker, blood product, substitute blood, bronchodilator, cardiotonic inotropic agent, chemotherapeutic agent, coagulant, corticosteroid, antitussive agent, diuretic, deliriant, expectorant, pregnancy promoter, sex hormone, mood stabilizer, mucolytic agent, neuroprotective agent, nootropic agent, neurotoxin, dopamine agonist, free radical scavenger, growth factor, fibrate, bile acid sequestrant, scar-forming agent, glucocorticoid, mineralocorticoid, hemostatic agent, hallucinogenic agent, hypothalamic-pituitary hormone, immunizing agent, cathartic, antidiarrheal agent, lipid regulator, muscle relaxant, parasympathomimetic agent, parathyroid calcitonin, selenium, statin, stimulant, wakefulness promoter, decongestant, dietary mineral, bisphosphonate, cough suppressant, ophthalmic drug, ontogenic drug, H1 antagonist, H2 antagonist, proton pump inhibitor, prostaglandin, radiopharmaceutical, hormone, sedative, anti-allergy agent, appetite stimulant, steroid, sympathomimetic agent, thrombolytic agent, thyroid agent, vasodilator, xanthine, erectile dysfunction improvement agent, gastrointestinal drug, histamine receptor antagonist, keratolytic agent, antianginal agent, non-steroidal anti-inflammatory agent, COX-2 inhibitor, leukotriene inhibitor, macrolide, NSAID, nutrient, opioid analgesic, opioid antagonist,The process according to any one of the preceding claims, selected from a potassium channel activator, a protease inhibitor, an anti-osteoporosis agent, a cognitive enhancer, an anti-incontinence agent, a nutritional oil, an anti-benign prostatic hyperplasia agent, an essential fatty acid, a non-essential fatty acid, a cytokine, a peptidomimetic, a peptide, a protein, a radiopharmaceutical, an anti-aging agent, a toxoid, a serum, an antibody, a nucleoside, a nucleotide, a vitamin, a part of a genetic material, a nucleic acid, or a mixture of any of these.

23. The process according to any one of claims 1 to 21, wherein the biologically active agent is an anticancer agent.

24. The process according to claim 23, wherein the biologically active agent is azacitidine.

25. A composition obtainable by the process according to any one of the preceding claims.

26. A pharmaceutical or veterinary formulation comprising the composition according to claim 25 and a pharmaceutically acceptable or veterinarily acceptable adjuvant, diluent, or carrier.

27. The pharmaceutical or veterinary pharmaceutical preparation according to claim 26, in the form of a sterile injectable and / or infusible dosage form.

28. The pharmaceutical or veterinary pharmaceutical preparation according to claim 26 or 27, in the form of a liquid, sol, or gel that can be administered via a surgical administration device for forming a depot preparation.

29. A process for the preparation of a pharmaceutical or veterinary pharmaceutical preparation according to any one of claims 26 to 28, comprising mixing the composition according to claim 25 with a relevant pharmaceutically acceptable or veterinarily acceptable adjuvant, diluent, or carrier.

30. The composition according to claim 25 or the preparation according to any one of claims 26 to 28 for use in the treatment of cancer, wherein the biologically active agent is as defined in claim 23 or 24.

31. Use of the composition according to claim 25 or the preparation according to any one of claims 26 to 28 for the manufacture of a medicament for the treatment of cancer, wherein the biologically active agent is as defined in claim 23 or 24.

32. A method for the treatment of cancer, comprising administering to a patient in need of such treatment the composition according to claim 25 or the preparation according to any one of claims 26 to 28, wherein the biologically active agent is as defined in claim 22.

33. The composition or preparation for use according to claim 30, the use according to claim 31, or the method according to claim 32, wherein the biologically active agent is as defined in claim 24 and the cancer is one or more of myelodysplastic syndromes or subtypes thereof.

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