New injectable combination drug

Abstract

A pharmaceutical or veterinary formulation is provided, comprising: (a) a biologically active agent in admixture with a pharma- tically or veterinarily acceptable sustained release component; (b) an anti-inflammatory agent; and (c) a pharma-tically or veterinarily acceptable injectable carrier. The sustained release component may also be applied to the anti-inflammatory agent. The formulation may provide delayed or sustained release of the biologically active agent without causing an inflammatory response after injection, and is preferably provided in the form of a plurality of particles, (1) having an average diameter by weight, number, or volume of about 10 nm to about 700 μm, the particles comprising a solid core comprising the biologically active agent coated with a coating comprising at least one coating material applied by a vapor deposition technique, (2) the particles being suspended in a carrier system comprising a pharma-tically or veterinarily acceptable vehicle, and (3) the formulation is optionally in the form of particles coated with a coating comprising at least one coating material applied by a vapor deposition technique, further comprising an anti-inflammatory agent. The coated particles are preferably synthesised via atomic layer deposition.

Description

[Technical field]

[0001] The present invention relates to new formulations, for example for use in the field of drug delivery. [Background technology]

[0002] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.

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

[0004] For any sustained release composition, it is also very important that the release profile shows an initial minimal rapid release of the active ingredient, i.e., high drug concentrations in the plasma immediately after administration. Such a "burst" release would result in undesirable high concentrations of the active ingredient, which may be dangerous in the case of drugs with narrow therapeutic windows or agents that are toxic at high plasma concentrations, such as cytotoxic drugs.

[0005] For injectable suspensions of active ingredients, it is also important to ensure that the suspended particle size is controlled so that they can be injected through a needle: if large agglomerated particles are present, not only will they block the needle through which the suspension is injected, but they will not form a stable suspension in the injection fluid (i.e., they will instead tend to sink to the bottom of the injection fluid).

[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 used to deposit thin films on solid substrates, including a variety of materials, including organic, biological, polymeric, and especially inorganic materials such as metal oxides. It is a technique that enables atomic and near-atomic scale manufacturing (ACSM) of materials, structures, devices, and systems in versatile applications (see, for example, Zhang et al. Nanomanuf. Metrol. 2022, https: / / doi.org / 10.1007 / s41871-022-00136-8). Due to its self-limiting properties, 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] Because of its atomic level control, ALD is used as a key technique, for example, in the production of next generation semiconductors, or the atomic level synthesis of advanced catalysts, as well as for the precise fabrication of nanostructures, nanoclusters, and single atoms (see, e.g., Zhang et al., supra).

[0009] This technique is usually carried out at low pressure and high temperature. Film coatings are produced by alternately exposing a solid substrate in an ALD reactor chamber to reactants vaporized in the gas phase. The substrate can be a silicon wafer, a 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 also be used to control the release rate of substrate materials in a solvent. This could potentially allow ALD to be used in the formulation of active pharmaceutical ingredients.

[0011] In ALD, a first precursor, which may be metal-containing, is fed into the ALD reactor chamber (in a so-called "precursor pulse") and forms a monolayer of atoms or molecules adsorbed on the surface of the substrate. Excess first precursor is then purged from the reactor, and then a second precursor, such as water, is pulsed into the reactor. This reacts with the first precursor and forms a monolayer of, for example, a metal oxide on the substrate surface. A subsequent purge pulse is followed by a further pulse of the first precursor, thus initiating a new cycle of the same events (a so-called "ALD cycle").

[0012] The thickness of the film coating is controlled, among other things, by the number of ALD cycles performed.

[0013] In a typical ALD process, only monolayers of atoms or molecules are produced during any one cycle, so that no discernible physical interfaces form between these monolayers, resulting in essentially continuous bands at the surface of the substrate.

[0014] WO 2014 / 187995 describes a process in which several ALD cycles are performed, after which the resulting coated substrate is periodically removed from the reactor and a redispersion / agitation step is performed to present new surfaces available for adsorption of precursors.

[0015] The agitation step is performed to solve a problem observed primarily with nano- and microparticles, namely, particle agglomeration during the ALD coating process, which results in the formation of "pinholes" at the contact points between such particles. The redispersion / agitation step was performed by placing the coated substrate in water and sonicating, which resulted in deagglomeration and destruction of the contact points between individual particles of the coated active material.

[0016] The particles were then reloaded into the reactor and the steps of ALD coating the powder and deagglomerating the powder were repeated three times (for a total of four successive cycles). This process has been shown to enable the formation of coated particles that are, to a large extent, pinhole-free (see also Hellrup et al, Int. J. Pharm., 529, 116 (2017)).

[0017] When a novel injectable pharmaceutical product was tested in which ALD was used to coat drug microparticles with a metal oxide coating layer, as described below, and the coated particles were then suspended in an aqueous vehicle, an unexpected inflammatory response was observed in human patients. This problem can be reduced by using an anti-inflammatory agent in conjunction with the ALD-coated suspension of the injectable API. Summary of the Invention

[0018] Disclosure of the Invention According to a first aspect of the invention there is provided an injectable pharmaceutical or veterinary formulation comprising: (a) a biologically active agent in admixture with a pharma- ceutical or veterinarily acceptable sustained release component; (b) an anti-inflammatory agent; and (c) a pharma- ceutical or veterinary acceptable injectable carrier; This formulation is hereinafter referred to as the "formulation of the present invention." [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows the plasma concentration-time profiles of patients administered azacitidine. [Diagram 2] FIG. 2 shows the plasma concentration-time profiles of patients administered azacitidine. [Diagram 3] FIG. 3 shows the plasma concentration-time profile in minipigs following subcutaneous administration of a formulation of the invention. [Figure 4]FIG. 4 shows the positive effect of a subcutaneous co-administration formulation of the present invention with mixed oxide coated microparticles containing the anti-inflammatory agent indomethacin on the local inflammatory response. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] A "pharmaceutical or veterinarily acceptable sustained release component" includes a component that forms a so-called "depot" or "depot composition" following injection (e.g., intratumoral, or more preferably, subcutaneous or intramuscular), and thus provides controlled, sustained, and long-acting or prolonged release of the active ingredient(s). Such components include aqueous (or water-miscible) components (e.g., aqueous solutions of gelatin or polyvinylpyrrolidone), oil-based (or water-immiscible) components, polymer-based microsphere components, or polymer-based in situ gel-forming components.

[0021] Hydrophilic polymers can form gels in situ by a variety of mechanisms, for example, in the local environment driven by either temperature (such as poly(D,L-lactide-co-glycolide) (PLGA) / polyethylene glycol (PEG) triblock copolymers (PLGA-PEG-PLGA), polyethylene glycol-poly(L-alanine) (PEG-PLA), poly(N-isopropylacrylamide), or soluble extracellular matrix (ECM) / methylcellulose), pH (such as PEG-diacrylate (PEGDA), acrylic acid, or alginate), or ionic concentration (such as alginate / multiwalled carbon nanotubes, alginate / PEG / hyaluronic acid, or alginate / PEG). Hydrophilic polymers may alternatively form gels in situ by self-assembly of peptides such as, for example, RADA16 peptide (RADARADARADARADA) with a fibronectin binding motif (RADA16-GG-RGDS) or a collagen type 1 derived motif (RADA16-GGFPGERGVEGPGP), fluorenylmethoxycarbonyl (FMOC) dipeptide, Nap-GFFYGGGWRESAI / TIP-1 crosslinker, or leucine-α / β-dehydrophenylalanine. Hydrophilic polymers may alternatively form gels in situ, for example, by covalent bonding driven by a variety of mechanisms, for example, either photoinitiation (such as gelatin-methacrylate, or gelatin-methacrylate / hyaluronic acid (HA)-methacrylate), or reactive precursors (e.g., 8-arm PEG cysteine / N-hydroxysuccinimide, carboxymethyl chitosan / dextran, or konjac glucomannan-tyramine / heparin-tyramine).

[0022] Hydrophilic in situ gel-forming polymers can be derived, for example, from natural or synthetic sources. Examples of naturally occurring polymers include polysaccharides such as chitosan, alginate, hyaluronic acid (HA), dextran, starch, or proteins such as albumin, collagen, or gelatin. Examples of synthetic polymers for nanoparticle formulation include polyesters, polyanhydrides, or poly-alkyl-cyanoacrylates, such as poly(ethylene glycol) (PEG), polyacrylamide (PAM), poly(N-isopropylacrylamide) (PNIPAAM), poly(vinyl alcohol) (PVA), poly(vinyl ether) (PVE), poly(N,N diethylacrylamide) (PDEAM), poly(N-vinylcaprolactam) (PNVCa), poly(methyl methacrylate) (PMMA), or poly(oligo(ethylene glycol) methyl ether methacrylate) (PoEGMA). For example, more complex hydrogel systems can be used, such as either copolymers, e.g., poly(D,L-lactide-co-glycolide) (PLGA) / PEG triblock copolymers (PLGA-PEG-PLGA), in which multiple backbone groups can be crosslinked together, or interpenetrating networks (IPNs), in which a polymer mesh can be constructed from the linkage of oligomeric chains within an already assembled polymer scaffold.

[0023] The polymers may be combined with other materials, such as degradable polymer coatings on titanium dioxide (titania) nanotubes, to achieve controlled drug release, for example as orthopedic drug-eluting implants.

[0024] Hydrated ionic salts, such as calcium phosphate or calcium sulfate, may be used in medical drug depot applications because they may be injected as a suspension upon hydration and are considered to be both biocompatible and biodegradable.

[0025] The sustained release component may be applied to the aforementioned biologically active agent alone or may also be applied to the anti-inflammatory agent within the formulation of the present invention. When the sustained release component is applied to both active agents, these sustained release components may be the same or different in terms of their composition and / or function.

[0026] Whatever sustained release component is applied to each active agent, at least one depot composition is formed that provides sustained release of at least that biologically active agent following intratumoral or, preferably, subcutaneous or intramuscular injection of the formulation of the present invention into a subject.

[0027] When a sustained release component is applied to both a biologically active agent and an anti-inflammatory agent, it is preferred that a depot is formed that provides sustained release of the biologically active agent and the anti-inflammatory agent at essentially the same rate and / or for essentially the same period of time following intratumoral or, more preferably, subcutaneous or intramuscular injection of a formulation of the invention into a subject.

[0028] In other words, both the biologically active agent and the anti-inflammatory agent preferably form a depot (or together form a single depot composition) after administration, meaning that they have simultaneous release profiles, i.e., the release of both the biologically active agent and the anti-inflammatory agent is uniform and / or constant over an extended (and / or essentially the same) period of time.

[0029] "Essentially the same release rates of the biologically active agent and the anti-inflammatory agent and / or over essentially the same period of time" includes not only that the amount of active ingredient released from the depot composition(s) or their respective sustained release depot composition(s) per unit time (e.g., μg / hour or μg / day) is essentially the same, but also (in addition and / or instead) that the overall release may occur over essentially the same extended period of time after injection. "Essentially the same" in this context includes that the associated changes in the concentration of each active ingredient in the plasma (which may be measured at a particular time point after injection using techniques that are routine and / or standard to those skilled in the art) are within about ±50% of each other, including ±30%, such as ±20% of each other.

[0030] It is believed that the sustained release characteristics of the biologically active agent and the anti-inflammatory agent over time, at essentially the same rate, and for essentially the same period of time, may enable the administration of biologically active agents that may or are expected to cause local inflammation when injected into and exposed to, for example, tumor tissue, and more particularly muscle tissue and / or subcutaneous tissue. Although subcutaneous or intramuscular injections are often used for sustained release, one important limitation to such routes of administration is that such routes are often limited to non-irritating biologically active agents (see, for example, Muralidhar et al, Asian Journal of Biomaterial Research, 3, 6 (2017)). It is believed that the present invention may enable the use of biologically active agents that are irritating, may be irritating, and / or are expected to be irritating, for example, in that they may cause inflammation at a local level.

[0031] Furthermore, inflammation may provide both a key mutation and a suitable environment to promote tumor growth and thus may play a role in the establishment, progression, and / or aggressiveness of various malignancies. Many anti-inflammatory agents can alter the tumor itself or the tumor microenvironment, potentially decreasing migration, increasing apoptosis, and increasing susceptibility to other therapies (see, e.g., Rayburn et al, Molecular and Cell Pharmacology, 1(1), 29(2009)). It is believed that the present invention may enable the use of biologically active agents that, for example, when injected into and exposed to tumor tissue, cause, can cause, and / or are expected to cause local inflammation.

[0032] Thus, in an embodiment of the invention there is provided an injectable pharmaceutical or veterinary formulation comprising: (a) a biologically active agent that, when injected into and exposed to tumor tissue, e.g., muscle tissue and / or subcutaneous tissue, causes, is likely to cause, or is expected to cause, local inflammation; (b) an anti-inflammatory agent; and and (c) one or more sustained release components that form a depot composition that provides sustained release of the biologically active agent and optionally the anti-inflammatory agent over time following intratumoral, or more preferably subcutaneous or intramuscular, injection of the composition into a subject.

[0033] According to this aspect of the invention, the formulation preferably does not include anesthetics and / or analgesics.

[0034] Further, in accordance with this latter aspect of the invention, where one or more sustained release components provide sustained release of both the biologically active agent and the anti-inflammatory agent, such release is preferably at essentially the same rate and over essentially the same period of time, such that the anti-inflammatory agent reduces the degree of inflammation resulting from the biologically active agent during its release into the tissue (as discussed above).

[0035] "An agent that causes, may cause, or is expected to cause local irritation" includes agents (including those described below) that are known and / or expected to cause such local irritation based on information received post-experimentally (e.g., as described below) or from elsewhere (e.g., from the literature or product labeling).

[0036] In another embodiment, an injectable pharmaceutical or veterinary formulation comprises: (a) an injectable anticancer drug (e.g., azacitidine or lenalidomide, as defined below); (b) an anti-inflammatory agent; and (c) a sustained release component that forms a depot composition that provides sustained release of the anti-cancer drug and (optionally) the anti-inflammatory agent over time following intratumoral, or more preferably subcutaneous or intramuscular, injection of the composition into a subject.

[0037] In the context of the present invention, the terms "depot composition", "depot-forming composition" and "depot formulation" are used interchangeably to refer to a composition that releases drug slowly over time to allow less frequent administration.

[0038] Sustained release of a biologically active agent after injection is preferably obtained by encapsulating small injectable (e.g., micro) particles containing the biologically active agent in at least one coating material applied by vapor deposition techniques.

[0039] Thus, in a preferred aspect of the invention, there is provided a pharmaceutical or veterinary formulation comprising: (a) a plurality of particles having an average diameter by weight, number, or volume that is from about 10 nm to about 700 μm, the particles comprising a solid core containing a biologically active agent coated with a coating comprising at least one coating material applied by a vapor deposition technique; (b) the particles are suspended in a carrier system comprising a pharma- ceutically acceptable or veterinarily acceptable vehicle; and (c) there is provided a pharmaceutical or veterinary formulation comprising a plurality of particles, the formulation further comprising an anti-inflammatory agent; This formulation is also referred to hereinafter as the "formulation of the invention".

[0040] According to this aspect of the invention, at least the biologically active agent is preferably coated as described above. Also included in this aspect of the invention is an anti-inflammatory agent, which may or may not be provided in conjunction with a sustained release component as described herein. If so provided, such sustained release component may or may not be in the form of a similar coating on the core containing the anti-inflammatory agent, which coating comprises at least one coating material applied by vapor deposition techniques.

[0041] It will be well understood by those skilled in the art that the term "solid" includes any form of matter that retains its shape and density when unconfined and / or whose molecules are generally as tightly packed together as the repulsive forces between them allow. The solid core according to this aspect of the invention has at least a solid outer surface onto which a layer of coating material can be deposited. The interior of the solid core may also be solid or alternatively hollow. For example, if the particles are spray dried before being placed in a reaction vessel, they may be hollow due to the spray drying technique.

[0042] The formulation of the present invention comprises a pharmacologically effective amount of said biologically active agent. Preferably, the solid core of this embodiment of the formulation of the present invention comprises a pharmacologically effective amount of said biologically active agent.

[0043] Such solid cores may consist essentially of or may include a biologically active agent (which may hereinafter be referred to interchangeably as a "drug" and an "active pharmaceutical ingredient (API)" and / or an "active ingredient"). The term "biologically active agent" also includes biopharmaceuticals and / or biologics. The biologically active agent may also include a mixture of two or more different APIs, either as different API particles or as particles containing two or more APIs.

[0044] "Consisting essentially of" biologically active agent(s) includes that said solid core essentially only contains biologically active agent(s), i.e., does not contain non-biologically active substances (see below) such as excipients, carriers, etc. This means that the core may contain less than about 5%, such as less than about 3%, including less than about 2%, e.g., less than about 1% of such other excipients and / or active substances.

[0045] In the alternative, the core comprising the biologically active agent may comprise such agent in admixture with one or more pharmaceutical ingredients, such as one or more pharma- ceutically acceptable excipients, such as adjuvants, diluents, or carriers, and / or may comprise other biologically active ingredients, including one or more of the essential anti-inflammatory agents included in the formulations of the invention. Thus, the biologically active agent may be provided in combination (e.g., as a mixture or as a complex) with another active agent, such as one or more of the essential anti-inflammatory agents included in the formulations of the invention.

[0046] The biologically active agent may be provided in a crystalline, partially crystalline, and / or amorphous state. The biologically active agent may further include any material that is in or can be converted to a solid state at about room temperature (e.g., about 18° C.) and about atmospheric pressure, regardless of physical form. Such agents must also remain in solid form while being coated in a vapor deposition (e.g., ALD) reactor, and must not significantly physically or chemically degrade (i.e., about 10% w / w or less) while being coated or after being covered by at least one layer of the aforementioned coating material.

[0047] As used herein, the term "biologically active agent" or similar and / or related expressions generally refers to any agent or drug capable of producing some kind of physiological effect (whether therapeutic or prophylactic for a particular disease state or condition) in a living subject, including, inter alia, mammalian, and particularly human subjects (patients).

[0048] Biologically active agents include, for example, analgesics, anesthetics, anti-ADHD agents, anorexics, anti-addictive agents, antibacterial agents, antimicrobial agents, antifungal agents, antiviral agents, antiparasitic agents, antiprotozoal agents, anthelmintics, ectoparasiticides, vaccines, anticancer agents, antimetabolites, alkylating agents, antitumor agents, topoisomerase inhibitors, immunomodulators, immunostimulants, immunosuppressants, anabolic steroids, anticoagulants, antiplatelet agents, anticonvulsants, antidementia agents, antidepressants, antidotes, antihyperlipidemic agents, antigout agents, antimalarials, antimigraine agents, antiparkinsonian agents, antipruritic agents, antipsoriatic agents, antiemetics, antiobesity agents, antiasthmatic agents, antibiotics, quality, antidiabetic, antiepileptic, antifibrinolytic, antihemorrhagic, antitussive, antihypertensive, antimuscarinic, antimycobacterial, antioxidant, antipsychotic, antipyretic, antirheumatic, antiarrhythmic, anxiolytic, aphrodisiac, cardiac glycoside, cardiotonic, entheogen, entactogen, euphoric, orexigenic, antithyroid, anxiolytic, hypnotic, neuroleptic, astringent, bacteriostatic, beta-blocker, calcium channel blocker, ACE inhibitor, angiotensin II receptor antagonist, renin inhibitor, beta-adrenergic receptor blocker, blood products, blood substitutes, bronchodilator, cardiac inotropicagent), chemotherapy drugs, coagulants, corticosteroids, cough suppressants, diuretics, deliriants, expectorants, fertility drugs, sex hormones, mood stabilizers, mucolytics, neuroprotectants, nootropics, neurotoxins, dopamine agonists, antiparkinsonian drugs, free radical scavengers, growth factors, fibrates, bile acid sequestrants, scar forming drugs, glucocorticoids, mineralocorticoids, hemostatic drugs, hallucinogens, hypothalamic-pituitary hormones, immune agents, laxatives, antidiarrheals, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, selenics, statins, stimulants, wake promoting drugs, decongestants, dietary minerals, biphosphonates, cough suppressants, ophthalmic drugs, ontology drugs, H1 antagonists, H2 antagonists, proton pumps The therapeutic agent may be selected from a prostate cancer treatment agent, a prostaglandin, a radiopharmaceutical, a hormone, a sedative, an anti-allergic agent, an appetite stimulant, a steroid, a sympathomimetic, a thrombolytic agent, a thyroid agent, a vasodilator, a xanthine, an erectile dysfunction improving agent, a gastrointestinal agent, a histamine receptor antagonist, a keratolytic agent, an anti-anginal agent, a non-steroidal anti-inflammatory agent, a COX-2 inhibitor, a leukotriene inhibitor, a macrolide, an NSAID, a nutritional agent, an opioid analgesic, an opioid antagonist, a potassium channel activator, a protease inhibitor, an anti-osteoporosis agent, a cognitive enhancer, an anti-urinary incontinence agent, a nutritional oil, an anti-benign prostatic hyperplasia agent, an essential fatty acid, a non-essential fatty acid, a radiopharmaceutical, an anti-aging agent, a vitamin, or a mixture of any of these.

[0049] The biologically active agent may also be a cytokine, a peptidomimetic, 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: lepirudin, cetuximab, dornase alfa, denileukin diftitox, etanercept, bivalirudin, leuprolide, alteplase, interferon alfa-n1, darbepoetin alfa, reteplase, epoetin alfa, salmon calcitonin, interferon alfa-n3, pegfilgrastim, sargramostim, secretin, peginterferon alfa-2b, asparaginase. , thyrotropin alfa, antihemophilic factor, anakinra, gramicidin D, intravenous immunoglobulin, anistreplase, insulin (regular), tenecteplase, menotropins, interferon gamma-1b, interferon alfa-2a (recombinant), coagulation factor VIIa, oprelvekin, palifermin, glucagon (recombinant), aldesleukin, botulinum toxin type B, omalizumab, lutropin alfa, insulin lispro, insulin glargine, collagenase, rasburicase, a Darimumab, Imiglucerase, Abciximab, Alpha-1-proteinase inhibitor, Pegaspargase, Interferon beta-1a, Pegademase bovine, Human serum albumin, Eptifibatide, Iodized serum albumin, Infliximab, Follitropin beta, Vasopressin, Interferon beta-1b, Hyaluronidase, Rituximab, Basiliximab, Muromonab, Digoxin immune Fab (ovine), Ibritumomab, Daptomycin, Tositumomab, Pegvisomant, Vogt Turinum toxin type A, pancrelipase, streptokinase, alemtuzumab, alglucerase, capromab, laronidase, urofollitropin, efalizumab, serum albumin, choriogonadotropin alpha, antithymocyte globulin, filgrastim, coagulation factor IX, becapremin, agalsidase beta, interferon alpha-2b, oxytocin, enfuvirtide, palivizumab, daclizumab, bevacizumab, arcitumomab, eculizumab, panitumumab, ranibizumab,Idursulfase, alglucosidase alfa, exenatide, mecasermin, pramlintide, galsulfase, abatacept, cosyntropin, corticotropin, insulin aspart, insulin detemir, insulin glulisine, pegaptanib, nesiritide, thymalfasin, defibrotide, natural alpha interferon / multiferon, glatiramer acetate, perotact , teicoplanin, canakinumab, ipilimumab, sulodexide, tocilizumab, teriparatide, pertuzumab, rilonacept, denosumab, liraglutide, semaglutide, golimumab, belatacept, buserelin, velaglucerase alfa, tesamorelin, brentuximab vedotin, taliglucerase alfa, belimumab, aflibercept, asparaginase Erwinia chrysanthemis, octagonist Liplasmin, Glucarpidase, Teduglutide, Raxibacumab, Certolizumab Astimlimab Pegol, Insulin Isophane, Epoetin Zeta, Obinutuzumab, Fibrinolysin, Aliasplasmin, Follitropin Alfa, Romiplostim, Lucinactant, Natalizumab, Aliskiren, Ragweed Pollen Extract, Secukinumab, Somatotropin (Recombinant), Drotrecogin Alfa, Alefacept, OspA Lipoprotein, Urokinase, Abarelix, Sermorelin, Aprotinin, Gemtuzumab Ozogamicin, Satumomab Pendetide, Albiglutide, Antithrombin Alfa, Antithrombin III (Human), Asfotase Alfa, Atezolizumab, Autologous Cultured Chondrocytes, Veractant, Blinatumomab, C1 Esterase Inhibitor (Human), Coagulation Factor XIII A subunit (recombinant), cornstat alfa, daratumumab, desirudin, dulaglutide, elosulfase alfa, evolocumab, fibrinogen concentrate (human), filgrastim-sndz, gastric intrinsic factor, hepatitis B immunoglobulin, human calcitonin, human clostridial tetanytoxoid immunoglobulin, human rabies virus immunoglobulin, human Rho(D) immunoglobulin, human Rho(D) immunoglobulin, hyaluronidase (human, recombinant), idarucizumab, immunoglobulin (human), vedolizumab, ustekinumab, turoctocog alfa,Tuberculin purified protein derivative, simoctocog alfa, siltuximab, sebelipase alfa, saclosidase, ramucirumab, prothrombin complex concentrate, poractant alfa, pembrolizumab, peginterferon beta-1a, ofatumumab, obiltoxaximab, nivolumab, necitumumab, metreleptin, methoxypolyethylene glycol-epoetin beta, mepolizumab, ixekizumab, insulin degludec, insulin (porcine), insulin (bovine), thyroglobulin, anthrax immunoglobulin thrombomodulin (human), anti-inhibitor coagulation complex, brodalumab, C1 esterase inhibitor (recombinant), chorionic gonadotropin (human), chorionic gonadotropin (recombinant), coagulation factor X (human), dinutuximab, efmoloctocog alfa, factor IX complex (human), hepatitis A vaccine, human varicella-zoster immunoglobulin, ibritumomab tiuxetan, lenograstim, pegloticase, protamine sulfate, protein S (human), sipuleucel-T, somatropin (recombinant), susoctocog alfa, and thrombomodulin alpha.

[0050] Non-limiting examples of drugs that may be used in accordance with the present invention include all-trans retinoic acid (tretinoin), alprazolam, allopurinol, amiodarone, amlodipine, asparaginase, astemizole, atenolol, azathioprine, azelatin, beclomethasone, bendamustine, bleomycin, budesonide, buprenorphine, butalbital, capecitabine, carbamazepine, carbidopa, carboplatin, cefotaxime, cephalexin, chlorambucil, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, cyclosporine ... thromycin, 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, fexofenadine, filgrastim, finasteride, fluconazole, flunisulfamethox ... Solid, fluorouracil, flurbiprofen, fluralaner, fluvoxamine, furosemide, gemcitabine, glipizide, glyburide, 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, phenyloin, piroxicam, procarbazine, quinapril, ramipril, risperidone, rituximab, sertraline, simvastatin, sulindac, sunitinib, temsirolimus, terbinafine, terfenadine, thioguanine, trastuzumab, triamcinolone, valproic acid, vinblastine, vincristine, vinorelbine, zolpidem,or a pharma- ceutically acceptable salt thereof.

[0051] Formulations of the invention may include benzodiazipines such as alprazolam, chlordiazepoxide, clobazam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, quazepam, temazepam, triazolam, and pharma- ceutically acceptable salts of any of these.

[0052] Anesthetics that may also be used in the formulations 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, eucaine, etidocaine, hexylcaine, fomocaine, photocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine, cyclomethy ... In some embodiments, the medicament may be an agonist, an anti-inflammatory, or a medicament. In particular, the medicament may be an anti-inflammatory, or a medicament. Examples of medicament may include, but are not limited to, acetaminocaine, metabutoxycaine, nitracaine, orthocaine, oxetacaine, oxybuprocaine, paraethoxycaine, phenacaine, piperocaine, pyridocaine, pramocaine, prilocaine, procaine, procainamide, proparacaine, propoxycaine, pyrrocaine, quinisocaine, ropivacaine, trimecaine, tricaine, tropacocaine, or a pharmaceutically acceptable salt of any of these.

[0053] Psychiatric drugs may also be used in the formulations of the present invention. Psychiatric drugs that may be mentioned include 5-HTP, acamprosate, agomelatine, alimemazine, amphetamine, dexamphetamine, amisulpride, amitriptyline, amobarbital, amobarbital / secobarbital, amoxapine, amphetamine(s), aripiprazole, asenapine, atomoxetine, baclofen, benperidol, bromperidol, bupropion, buspirone, butobarbital, carbamazepine, chloral hydrate, chlorpromazine, chlorprothixene, citalopram, clomethiazole. , clomipramine, clonidine, clozapine, cyclobarbital / diazepam, cyproheptadine, cytisine, desipramine, desvenlafaxine, dexamphetamine, dextromethylphenidate, diphenhydramine, disulfiram, divalproex sodium, doxepin, doxylamine, duloxetine, enanthate, escitalopram, ezopiclone, fluoxetine, flupentixol, fluphenazine, fluspirilene, fluvoxamine, gabapentin, glutethimide, guanfacine, haloperidol, hidramine, Droxizine, iloperidone, imipramine, lamotrigine, levetiracetam, levomepromazine, levomilnacipran, lisdexamfetamine, lithium salts, lurasidone, melatonin, melperone, meprobamate, methamphetamine, netadon, methylphenidate, mianserin, mirtazapine, moclobemide, nalmefene, naltrexone, niaprazine, nortriptyline, olanzapine, ondansetron, oxcarbazepine, paliperidone, paroxetine, penfluridol, pentobarbital, perazine, pelisin Azine, 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, trifluoperazine,Trimipramine, tryptophan, valerian, valproic acid (2.3:1 ratio), varenicline, venlafaxine, vilazodone, vortioxetine, zaleplon, ziprasidone, zolpidem, zopiclone, zotepine, zuclopenthixol, and pharma- ceutically acceptable salts of any of these.

[0054] Opioid analgesics that may be used in the formulations of the present invention include buprenorphine, butorphanol, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, nomethadone, opium, oxycodone, oxymorphone, pentazocine, tapentadol, tramadol, and pharma- ceutically acceptable salts of any of these.

[0055] Opioid antagonists that may be used in the formulations of the invention include naloxone, nalorphine, niconalorphine, diprenorphine, levallorphan, samidorphan, nalodein, alvimopan, methylnaltrexone, naloxegol, 6β-naltrexone, axeroplan, bebenoplan, methylsamidorphan, naldemedine, preferably nalmefene, especially naltrexone, and pharmaceutically acceptable salts of any of these.

[0056] Anticancer drugs that may be included in the formulations of the present invention include 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, cytarabinose, and cyclosporine. bin, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, erlotinib, estramustine, etoposide, everolimus, fludarabine, fluorouracil, gefitinib, guadecitabine, gemcitabine, hydroxycarbamide, hydroxyurea, idarubicin, idelalisib, ifosfa , 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, progesterone, rifapril ... These include rocarbazine, regorafenib, ruxolitinib, sonidegib, sorafenib, sunitinib, tegafur, temozolomide, teniposide, thioguanine, thiotepa, topotecan, trabectedin, valrubicin, vandetanib, vemurafenib, venetoclax, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, and pharmaceutically acceptable salts of any of these.

[0057] Such compounds may be used in any one of the following cancers: adenocystic carcinoma, adrenal adenocarcinoma, amyloidosis, anal cancer, ataxia-telangiectasia, atypical mole syndrome, basal cell carcinoma, cholangiocarcinoma, Birt-Hogg Dube, duct syndrome, bladder cancer, bone cancer, brain tumors, breast cancer (including male breast cancer), carcinomatous tumors, cervical cancer, colon cancer, ductal carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, HER2 positive, breast cancer, islet cell tumors, juvenile polyposis syndrome, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, all types of acute lymphocytic leukemia, acute myeloid leukemia, adult leukemia, childhood leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lobular carcinoma, lung cancer, small cell lung cancer, Hodgkin's Lymphoma, non-Hodgkin's 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, multiple erythrocytoma, prostate cancer, renal cell carcinoma, retinoblastoma, salivary gland cancer, sarcoma, Kaposi's sarcoma, skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymoma, thyroid cancer, uterine (endometrial) cancer, vaginal cancer, Wilms' tumor.

[0058] Cancers that may be mentioned include myelodysplastic syndromes and subtypes, such as acute myeloid leukemia, refractory anemia or refractory anemia with ringed sideroblasts (with neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transition, and chronic myelogenous (myelomonocytic) leukemia.

[0059] Other drugs that may be mentioned for use in the formulations 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.

[0060] Preferred anti-cancer agents include lenalidomide, which is useful in the treatment of multiple myeloma and anemia in low- to intermediate-risk myelodysplastic syndromes, and azacitidine, which is particularly useful in the treatment of certain subtypes of myelodysplastic syndromes.

[0061] Other preferred biologically active agents that may be mentioned include liraglutide, which is useful in the treatment of type 2 diabetes and in the prevention of cardiovascular complications associated with diabetes.

[0062] Alternatively, the formulations described herein may also include, instead of (or in addition to) a biologically active agent, a diagnostic agent (i.e., an agent that has no direct therapeutic activity itself but can be used in the diagnosis of a disease state, such as contrast agents or contrast media for bioimaging).

[0063] The formulations of the invention may include one or more of any of the aforementioned biologically active agents, particularly taking into account the fact that any component or combination of components of the formulations of the invention (including coatings or carrier systems) may cause an inflammatory response, for example after subcutaneous injection.

[0064] However, biologically active agents which may be mentioned in particular include those which, when administered to a patient, either on their own or in the form of a formulation of the invention, may produce an inflammatory response or may be expected to produce such a response.

[0065] In this regard, biologically active agents that may be particularly mentioned for use in the formulations of the invention include, for example, anti-tumor agents, topoisomerase inhibitors, immunomodulatory agents (such as thalidomide, pomalidomide, lenalidomide, and apremilast), immunostimulants, immunosuppressants, chemotherapeutic agents, growth factors, vasodilators, and radiopharmaceuticals.

[0066] Particular biologically active agents which may be mentioned in this respect include the particular 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, epothilones, estramustine, etoposide, everolimus, fludarabine, fluorouracil, guadecitabine, gemcitabine, hydroxylase, hydroxylase inhibitors ... and any one or more of: cyclohexyl urea, 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 pharmaceutically acceptable salts of any of these.

[0067] Further biologically active agents that may be mentioned in this respect include certain cytokines, proteins and vaccines, as well as therapeutic peptides / proteins such as daratumumab and isatuximab.

[0068] 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 a pharma- ceutically acceptable salt of any of these. A particular drug that may be mentioned is cisplatin.

[0069] Non-biologically active adjuvants, diluents and carriers that may be used in the cores coated according to the relevant aspects of the invention may include pharma- ceutically acceptable substances that are soluble in water, such as carbohydrates, e.g., sugars such as lactose and / or trehalose, and sugar alcohols such as mannitol, sorbitol and xylitol, or pharma- ceutically 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 a complex macromolecule, e.g., a peptide, protein or part of genetic material as generally described, and / or the aforementioned specific peptides / proteins, including vaccines. Embedding the macromolecule complex in an excipient in this way often results in a larger core for coating, and therefore a larger coated particle.

[0070] In a preferred embodiment of this aspect of the invention, the core is provided in the form of nanoparticles, or more preferably microparticles, preferably having an average diameter by weight, number, or volume of about 50 nm (e.g., about 100 nm, e.g., about 250 nm) to about 30 μm, e.g., about 500 nm to about 100 μm, more particularly about 1 μm to about 50 μm (e.g., about 25 μm, e.g., about 20 μm).

[0071] As used herein, the term "weight-based mean diameter" will be understood by those skilled in the art to include the mean particle size being characterized and defined from a particle size distribution by weight, i.e., a distribution in which 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 mean diameter" will be understood by those skilled in the art to include the mean particle size being characterized and defined from a particle size distribution by number, i.e., a distribution in which 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 mean diameter" will be understood by those skilled in the art to include the mean particle size being characterized and defined from a particle size distribution by volume, i.e., a distribution in which 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 mean diameter, such as area-based mean diameter, and these other expressions of mean diameter are interchangeable with those used herein. Other instruments well known in the art may be used to measure particle size, for example those sold by Malvern Instruments, Ltd (Worcestershire, UK) and Shimadzu (Kyoto, Japan).

[0072] The particles may be spherical, i.e., they have an aspect ratio of less than about 20, more preferably less than about 10, such as less than about 4, especially less than about 2, and / or may have a variation in radius (measured from the center of gravity to the particle surface) of at least about 90% of the particles of not more than about 50% of the average value, such as not more than about 30% of that value, for example not more than about 20% of that value.

[0073] Nevertheless, according to this aspect of the invention, coating of particles to any shape is also possible. For example, irregularly shaped (e.g., "raisin" shaped), needle-shaped, flaky or rectangular shaped particles can be coated. For non-spherical particles, the size can be indicated as the corresponding spherical particle size of, for example, the same weight, volume or surface area. Hollow particles, as well as particles with pores, interstices, etc., such as fibrous or "entangled" particles, can also be coated according to the invention.

[0074] The particles may be obtained in a form suitable for them to be coated, or in that form, for example, by a particle size reduction process (e.g., milling, cutting, milling, or grinding) to a specified weight-based average diameter (as defined herein), for example, by utilizing wet grinding, dry grinding, air jet milling (including cryogenic micronization), ball milling such as planetary ball milling, as well as end runner mills, roller mills, vibratory mills, hammer mills, roller mills, fluid energy mills, pin mills, and the like. Alternatively, the particles may be directly prepared to a suitable size and shape, for example, by spray drying, freeze drying, spray freeze drying, vacuum drying, precipitation including the use of supercritical fluids, or other top-down methods (i.e., reducing large particle sizes, for example, by grinding), or bottom-up methods (i.e., increasing small particle sizes, for example, by sol-gel techniques, crystallization, and the like). Alternatively, nanoparticles may be made by well-known techniques such as gas condensation, attrition, chemical precipitation, ion implantation, pyrolysis, hydrothermal synthesis, and the like.

[0075] The particles may need to be washed and / or cleaned to remove impurities that may result from their production (depending on the method by which the particles containing the cores are initially provided) and then dried. Drying may be carried out by many techniques known to those skilled in the art, including evaporation, spray drying, vacuum drying, freeze drying, fluidized bed drying, microwave drying, IR radiation, drum drying, etc. If dried, the cores may then be deagglomerated by grinding, screening, milling, and / or dry sonication. Alternatively, the cores may be treated to remove any volatile materials that may be absorbed on their surface, for example by exposing the particles to vacuum and / or elevated temperatures.

[0076] The surface of the core may be chemically activated prior to application of the first layer of coating material, for example, by treatment with hydrogen peroxide, ozone, a free radical-containing reactant, or by applying a plasma treatment to create free oxygen radicals on the surface of the core, which may, for example, generate favorable adsorption / nucleation sites on the core for the ALD precursors.

[0077] Preferred methods for applying the coating(s) to the cores containing biologically active agents according to the aforementioned preferred aspects of the invention include gas phase techniques such as ALD or related techniques such as atomic layer epitaxy (ALE), molecular layer deposition (MLD, a technique similar to ALD except 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 invention.

[0078] The coating materials that may be applied to the core are pharma- ceutically acceptable, in that they should be essentially non-toxic.

[0079] The coating material may comprise an organic or polymeric material, such as a polyamide, a polyimide, a polyurea, a polyurethane, a polythiourea, a polyester, or a polyimine. The coating material may also comprise a hybrid material (such as between an organic material and an inorganic material), including a material that is a combination between a metal or another element and an alcohol, a carboxylic acid, an amine, or a nitrile. However, it is preferred that the coating material comprises an inorganic material.

[0080] Inorganic coating materials may include one or more metals or metalloids, or may include one or more metal-containing or metalloid-containing compounds, such as metals or metalloids, oxides, nitrides, sulfides, selenides, carbonates, and / or other ternary compounds, etc. Metals and metalloids, hydroxides, especially oxides, especially metal oxides are preferred.

[0081] Metals that may be mentioned include alkali metals, alkaline earth metals, noble metals, transition metals, post-transition metals, lanthanides, etc. 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, in particular aluminum, silicon, titanium and / or zinc.

[0082] As noted above, the formulations of the present invention may comprise two or more separate layers of (eg, inorganic) coating materials, such that the nature and chemical composition(s) of those layers may vary from layer to layer.

[0083] Individual layers may also include mixtures of two or more inorganic materials, such as metal oxides or metalloid oxides, and / or may include multiple layers or composites of different inorganic or organic materials to modify the properties of the layer.

[0084] Coating materials that may be mentioned include aluminum oxide (Al2O3), titanium dioxide (TiO2), iron oxide (Fex O y , for example 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.

[0085] The layers of coating material (individually or collectively) in the coated cores of the relevant formulations may consist essentially of (e.g., greater than about 80%, such as greater than about 90%, e.g., about 95%, such as about 98%) iron oxide, titanium dioxide, or more preferably zinc oxide, silicon oxide, and / or aluminum oxide.

[0086] The processes described herein are particularly useful when the coating material(s) applied to the core include zinc oxide, silicon dioxide, and / or aluminum oxide.

[0087] More preferably, the inorganic coating material is zinc oxide, more particularly (i) zinc oxide (ZnO); (ii) in admixture with one or more other metal and / or metalloid oxides, The atomic ratio ((i):(ii)) is between at least about 1:10 (eg, about 1:6) and at most about 10:1 (eg, about 6:1).

[0088] Preferably, the atomic ratio ((i):(ii)) is between at least about 1:1 and at most about 6:1.

[0089] Coatings comprising a mixture of zinc oxide and one or more other metal and / or metalloid oxides are hereinafter referred to as "mixed oxide" coatings or coating material(s).

[0090] Thus, the core containing the biologically active agent may be coated with a coating material comprising a mixture of zinc oxide and one or more other metal and / or metalloid oxides, with an atomic ratio of zinc oxide to other oxide(s) that is at least about 1:10 (e.g., at least about 1:6, including at least about 1:4, such as at least 1:2), including at least about 2.25:1 (e.g., at least about 2.5:1, such as at least about 3.25:1 or at least about 2.75:1, including 3:1), preferably at least about 1:1 (e.g., at least about 1.5:1, such as at least about 2:1), and up to (i.e., less than) about 10:1, such as up to about 5.5:1, such as up to about 4.5:1, or up to about 6:1, including up to about 5:1, including up to about 4:1 (e.g., up to about 3.75:1).

[0091] In ALD, in most cases, the first of a sequence of reactions involves some functional group or free electron pair or radical on the surface to be coated, such as a hydroxy group (-OH) or a primary or secondary amino group (-NH2 or -NHR, where R is an aliphatic group, e.g., an alkyl group). Each reaction is advantageously carried out separately under conditions such that essentially all excess reagents and reaction products are removed before carrying out the next reaction.

[0092] Thus, when ALD is used, the above mixed oxide coatings can be prepared by supplying a first zinc-, other metal-, or metalloid-containing precursor to an ALD reactor chamber (in a so-called "precursor pulse") to form a zinc-, other metal-, or metalloid-containing monolayer of atoms or molecules adsorbed on the surface of the particle. A second precursor (e.g., water) is then pulsed into the reactor and reacts with the first precursor to form a monolayer of zinc, metal, or metalloid oxide, respectively, on the substrate surface. A subsequent purge pulse is followed by a further pulse of the first precursor, thus initiating a new cycle of the same events (a so-called "ALD cycle").

[0093] To create a mixed oxide coating in which the atomic ratio of zinc oxide to one or more other metal and / or metalloid oxides is between (for example) about 1:1 and up to about 6:1, one skilled in the art will understand that for every one ALD cycle (i.e., monolayer) of the other oxide(s), about 1 to about 6 ALD cycles of zinc oxide must also be deposited. For example, if a mixed oxide coating with a 3:1 atomic ratio (zinc:other oxide) is to be formed, three zinc-containing precursor pulses are followed by a second precursor pulse each to form three monolayers of zinc oxide, then one pulse of the other metal and / or metalloid-containing precursor, followed by a second precursor pulse to form one monolayer of the oxide of the other metal and / or metalloid. Alternatively, six monolayers of zinc oxide may be followed by two monolayers of the other oxide, or any other combination, to provide an overall atomic ratio of about 3:1. In this regard, the order of pulses to generate the relevant oxides is not important, so long as the resulting atomic ratios are ultimately within the relevant range.

[0094] If such mixed oxide coatings are used, the other metal or metalloid oxide materials preferably include one or the other, or both, of aluminum oxide (Al2O3) and / or silicon dioxide (SiO2).

[0095] There is further provided a method of preparing a plurality of coated particles according to the invention, the coated particles being made by applying, by vapor deposition techniques, precursors of at least two metal and / or metalloid oxides forming a mixed oxide onto a solid core and / or a previously coated solid core. Precursors for forming metal or metalloid oxides often include water, oxygen, ozone, and / or oxygen precursors such as hydrogen peroxide, and metal and / or metalloid compounds, typically organometallic or organometalloid compounds.

[0096] Non-limiting examples of precursors are as follows: Precursors of zinc oxide can be water and di-C1-C5 alkyl zinc, such as diethyl zinc; Precursors of aluminum oxide can be water and tri-C1-C5 alkyl aluminum, such as trimethyl aluminum; Precursors of silicon oxide (silica) can be water as oxygen precursor, and silane, alkyl silane, amino silane, and orthosilicate tetraethyl ester; Precursors of iron oxide include oxygen, ozone and water as oxygen precursor, and di-C1-C5 alkyl iron, dicyclopropyl iron, and FeCl3. It will be understood that a person skilled in the art will recognize which precursors are suitable for the purposes disclosed herein.

[0097] In ALD, the layer of coating material may be applied at a process temperature of about 20°C to about 800°C, or about 40°C to about 200°C, such as about 40°C to about 150°C, such as about 50°C to about 100°C. The optimal process temperature depends on the reactivity of the precursors and / or materials (including biologically active agents) used in the core and / or the melting point of the core material(s). Lower temperatures, such as about 30°C to about 100°C, are preferably used. In particular, in one embodiment of the above method, a temperature of about 20°C to about 80°C, such as about 30°C to about 70°C, such as about 40°C to about 60°C, such as about 50°C, is employed.

[0098] When coatings containing zinc oxide are applied using ALD at low temperatures, such as from about 50° C. to about 100° C., they have found that the coating material is largely crystalline in nature, unlike other coating materials, such as aluminum oxide and titanium oxide, which form amorphous layers.

[0099] Without being limited by theory, it is understood that because zinc oxide is crystalline, when zinc oxide alone is employed as a coating material, interfaces may form between adjacent crystals of zinc oxide deposited by ALD, which may allow penetration of the carrier system, medium, or solvent in which the zinc oxide is partially soluble (e.g., an aqueous solvent system) after suspension therein. It is believed that this may cause dissolution that is too rapid for the depot-forming composition that is intended to be made.

[0100] Furthermore, previous studies have shown that the relative bioavailability of formulations containing zinc oxide coated active ingredients is lower than that of uncoated active ingredients when suspended in aqueous media. It is believed that this decrease in relative bioavailability is due to the degradation of the active ingredient before it can be released into the systemic circulation. It is believed that the penetration of water through the crystal interfaces in such zinc oxide coatings results in hydrolysis of the active ingredient within the interior of the coated particles.

[0101] These problems may be alleviated by making the mixed oxide coatings described herein. In particular, by forming the mixed oxide coatings described herein that are primarily, but not entirely, composed of zinc oxide, it was possible to coat the active ingredient with a coating that appears to be essentially amorphous, or a composite between crystalline and amorphous materials, and / or that may reduce the penetration of injection vehicles such as water. In this regard, it appears that the presence of the aforementioned perceived interfaces may be reduced or avoided entirely by employing the mixed oxide aspects of the present invention in either a heterogeneous manner (where other oxides "fill" the gaps formed by the interfaces) or a homogeneous manner (where a true composite of mixed oxide materials is formed during deposition in a manner in which interfaces are potentially avoided in the first place).

[0102] The vapor deposition reactor chamber used may optionally and / or preferably be a stationary vapor deposition reactor chamber. The term "stationary" in the context of a vapor deposition reactor chamber will be understood to mean that the reactor chamber remains fixed during use to carry out a vapor deposition technique, excluding negligible movement and / or vibration, such as caused by associated machinery, for example.

[0103] Furthermore, a so-called "stop-flow" process may be employed. Using the stop-flow process, once the first precursor is fed into the reactor chamber, it may be allowed to contact the core within the reactor chamber for a predetermined period of time (which may be considered as a soak time) before the first precursor is purged from the reactor chamber. During the predetermined period of time, there is preferably a substantial absence of pumps that may provide gas flow and / or a substantial absence of mechanical agitation of the core.

[0104] The employment of a stop-flow process can enhance the uniformity of the coating by allowing each gas to conform and diffuse into a high aspect ratio substrate such as a powder. The advantage can be even more pronounced when using a slower reacting precursor, since the precursor is given more time to react on the surface. This can be particularly evident when depositing a mixed oxide coating according to the present invention. For example, when depositing a mixed zinc oxide / aluminum oxide coating as described herein, we have found that a zinc-containing precursor, such as diethylzinc (DEZ), has a lower reaction probability toward the surface of the substrate than an aluminum-containing precursor, such as trimethylaluminum (TMA).

[0105] In addition to producing coatings with good shell integrity and more controlled release profiles, the employment of such a stopped-flow process may improve the ability to achieve specific coating compositions.

[0106] For example, as noted above, when attempting to employ gas phase techniques to produce a coating in which the atomic ratio between zinc and aluminum in the resulting shell is 3:1, it was found that a ratio much closer to 3:1 could be achieved using a stopped-flow process than when depositing the material using a continuous flow of precursor.

[0107] Preferably and / or optionally, a "multi-pulse" technique may be employed to deliver the first precursor, the second precursor, or both precursors to the reactor chamber.

[0108] Using such multi-pulse techniques, each precursor may be delivered to the reactor chamber as multiple "sub-pulses," each lasting for a short period of time, such as, for example, 1 second to about 1 minute (depending on the size and nature of the vapor deposition reactor), rather than as one continuous pulse. The precursor may be allowed to contact the core in the reactor chamber for a predetermined period of time, such as, for example, about 1-500 seconds, about 2-250 seconds, about 3-100 seconds, about 4-50 seconds, or about 5-10 seconds, such as 9 seconds, after each sub-pulse. Again, depending on the size and nature of the vapor deposition reactor, this time may extend up to several minutes (e.g., up to about 30 minutes). The introduction of the sub-pulses, followed by a period of soak time, may be repeated a predetermined number of times, such as, for example, about 5-1000 times, about 10-250 times, or about 20-50 times, in a single step.

[0109] Preferably, two or more separate layers or coating materials (also referred to herein as "coatings" or "shells", all of which terms are used interchangeably herein) are applied sequentially (i.e., "separately applied") to the solid core containing the biologically active agent.

[0110] "Separate application" of "separate layer, coating, or shell" means that a solid core is coated with a first layer of coating material and then the resulting coated core is subjected to some form of deagglomeration process. In this regard, the number of separate layers of coating material(s) defined herein corresponds to the number of these intermittent deagglomeration steps, with a final mechanical deagglomeration occurring prior to application of a final layer of coating material.

[0111] In other words, a "vapor deposition (e.g., ALD) cycle" can be repeated several times to provide a "vapor deposition (e.g., ALD) set" of cycles, which can consist of, for example, 10, 25, or 100 cycles. However, after this series of cycles, the coated cores are subjected to some form of deagglomeration step, which is then followed by a further series of cycles.

[0112] This process may be repeated as many times as necessary, in that the number of separate layers of coating material(s) defined herein corresponds to the number of these intermittent deagglomeration steps, with a final mechanical deagglomeration being performed prior to application of a final layer (series of cycles) of coating material.

[0113] The terms "deagglomeration" and "disaggregation" are used interchangeably when referring to coated particles, and deagglomeration of coated particle agglomerates is preferably accomplished by mechanical sieving techniques.

[0114] The coated cores may be removed from the coating apparatus, such as an ALD reactor, and then subjected to an external deagglomeration step, for example as described in International Patent Application No. WO 2014 / 187995. Such an external deagglomeration step may include agitation, such as wet or dry sonication, or, preferably, sieving the resulting solid product mass discharged from the reactor, for example by passing through a sieve or mesh, to deagglomerate the particles, for example as described below, before returning the particles to the coating apparatus for the next coating step. Again, this process may be continued as many times as necessary and / or appropriate before applying the final coating.

[0115] In the external deagglomeration process, deagglomeration can alternatively be performed by subjecting the wet or dry coated particles to one or more of nozzle aerosol generation, milling, grinding, stirring, high shear mixing and / or homogenization. If the deagglomeration step(s) is performed on wet particles, the deagglomerated particles should be dried (as described above for the cores) prior to the next coating step.

[0116] However, in such external processes, the deagglomeration step(s) may include one or more sieving steps, which may include jet sieving, hand sieving, vibratory sieve shaking, horizontal sieve shaking, tap sieving, or (preferably) sonic sieving as described below, or a similar process involving any combination of these sieving steps. Manufacturers of suitable sonic sifters include Advantech Manufacturing, Endecott, and Tsutsui.

[0117] It is further preferred that at least one of the mechanical screening steps comprises a vibratory screening technique.

[0118] Such vibratory screening techniques may include a vibratory motor coupled to a sieve to provide a means for vibratory passing of the solid product mass formed by coating the cores through a sieve which may be located internal or (preferably) external (i.e., outside) of the reactor, and configured to deagglomerate any particle agglomerates during the vibratory passing of the coated cores prior to subjecting them to a second and / or further layer(s) of coating material. This process may be repeated as many times as necessary and / or appropriate prior to applying a final layer of coating material.

[0119] The vibrationally passing means comprises a vibration motor coupled to the sieve. The vibration motor is configured to vibrate and / or rotate when powered. 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 shape of the piezoelectric material induces acoustic or ultrasonic vibration of the piezoelectric vibration motor.

[0120] Alternatively, the vibration motor may be an eccentric rotating mass (ERM) vibration motor that includes a mass that is rotated when power is provided to the motor. The mass is eccentric from the axis of rotation, and rotation of the mass causes the motor to become unbalanced and vibrate and / or rotate. Additionally, an ERM vibration motor may include multiple masses located at different positions relative to the motor. For example, an ERM vibration motor may include an upper mass and a lower mass, each located at opposite ends of the motor. By varying each mass and its angle relative to the other mass, the vibration and / or rotation of the ERM vibration motor can be varied.

[0121] The vibration motor is coupled to the sieve in a manner such that when power is supplied, vibration and / or rotation of the motor is transmitted to the sieve.

[0122] The sieve and vibrating motor may be suspended from a mount (e.g., a frame that may be placed on the floor) via a suspension means such that the sieve and motor are free to vibrate relative to the mount without vibrations being substantially transmitted to or damped by the mount. This allows the vibrating motor and sieve to vibrate and / or rotate without obstruction and also reduces noise generated during the vibratory sieving process. The suspension means may include one or more springs or bellows (i.e., air cushions or equivalent cushioning means) that couple the sieve and / or motor to the mount. Manufacturers of vibrating sieves or sifters suitable for carrying out such processes include, for example, Russell Finex, SWECO, Filtra Vibracion, VibraScreener, Gough Engineering, and Farley Greene.

[0123] Preferably, the vibrating sieving technique further comprises controlling a vibrating probe coupled to the sieve. The vibrating probe may be controlled to vibrate the sieve at a frequency other than the frequency of the vibrations caused by the vibration motor. Preferably, the vibrating probe vibrates the sieve at a higher frequency than the vibrations caused by the vibration motor, more preferably the frequency is in the ultrasonic range.

[0124] Providing additional vibration to the sieve by the vibrating probe reduces the occurrence of sieve clogging, reduces the likelihood of the sieve being overloaded, and reduces the time required to clean the sieve mesh.

[0125] Preferably, the vibratory sieving technique involves sieving the coated particles at a throughput of at least 1 g / min. More preferably, the vibratory sieving technique involves sieving the coated particles at a throughput of 4 g / min or more.

[0126] The throughput depends on the sieve mesh area, sieve mesh size, particle size, particle cohesion, and particle static properties. Combining several of these features allows for much higher throughput. Thus, the vibratory sieving technique may more preferably include sieving coated particles at throughputs of up to 1 kg / min or more.

[0127] Any of the above throughputs represent a significant improvement over the use of known mechanical sieving or screening techniques. For example, we have found that sonic sieving involves 15 minutes of sieving, with a 15 minute cooling time required to store the equipment. To sieve 20 g of coated particles, 9 sets of 15 minutes of active sieving time were required, i.e., a total time (including cooling) of 255 minutes. By comparison, by using the aforementioned vibration sieving technique, 20 g of coated particles can be continuously sieved in a maximum of 20 minutes, or more preferably in only 5 minutes or less.

[0128] The mesh size of the sieve may be determined such that the ratio of the size of the sieved or sonic sieved particles to the mesh size of the sieve is greater than about 1:1, preferably about 1:2, and optionally about 1:4. The mesh size of the size may range from about 20 μm to about 100 μm, preferably about 20 μm to about 60 μm.

[0129] Suitable sieve meshes may include perforated plates, microplates, grids, diamonds, threads, polymers or wires (woven wire sieves), but are preferably formed from a metal such as stainless steel.

[0130] Surprisingly, the use of stainless steel mesh within a vibratory sieving technique is as gentle on particle coatings as the use of softer polymeric sieving mesh as part of a mechanical sieving technique such as sonic sieving.

[0131] Also, a known problem with sifting powders is the generation of potentially dangerous static electricity. Steel mesh has the advantage of removing static electricity from the powder, whereas polymer mesh does not. Polymer mesh must be used with a sonic sifter.

[0132] Furthermore, the mesh size of known sonic sifters is limited to about 100 μm because the sound waves move through the mesh rather than vibrating it. That limitation does not exist for use with vibratory sifting techniques because they do not rely on sound waves to create vibrations in the sieve. Thus, the vibratory sifting techniques described herein allow for sifting of larger particles than would be possible if alternative mechanical sifting techniques were used.

[0133] When the (e.g., vibrating) screen is located external to the reactor (i.e., outside the reactor), the process of making the coated cores of the formulation of the present invention includes discharging the coated particles from the vapor deposition reactor before subjecting the coated particles to agitation, and reintroducing the deagglomerated coated particles into the vapor deposition reactor before applying at least one additional layer of coating material to the reintroduced particles.

[0134] The inventors have found that applying separate layers of coating material after external deagglomeration results in visible and discernible interfaces that can be observed by analyzing the coated particles according to the invention, e.g., by TEM, as regions of high electron transparency. In this regard, the thickness of the layer between the interfaces directly corresponds to the number of cycles performed in each series within the ALD reactor and between the individual external agitation steps.

[0135] In ALD coating processes, such distinct physical interfaces are typically more difficult to observe because the coating occurs at the atomic level.

[0136] 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 air leads to structural reorganization due to relaxation and restructuring of the outermost atomic layers. Such a process is believed to involve a reorganization of the atoms at (and near) the surface, driven by a thermodynamic tendency to reduce the free energy of the surface.

[0137] Furthermore, surface adsorption of species (e.g., hydrocarbons, which are always present in air) may contribute to this phenomenon, as well as reactions of coatings formed with hydrocarbons, as well as surface modification by atmospheric oxygen, etc. Thus, chemical analysis of such interfaces may contain traces of contaminants not originating from the coating process, such as ALD, or core materials, such as APIs, that form part of the core.

[0138] Alternatively, the coated cores may be subjected to the aforementioned deagglomeration process internally, without being removed from the apparatus, by a continuous process. Such a process preferably comprises forcing the solid product mass formed by coating the cores through a sieve disposed within the reactor, the sieve being configured to deagglomerate particle agglomerates upon forcing the coated cores by forcing means applied within the reactor, before being subjected to a second and / or further coating. This process may be continued as many times as necessary and / or appropriate, before applying a final coating, as described herein.

[0139] Locating a deagglomeration step (e.g. sieving) within the reaction vessel means that the coating can be applied by a continuous process without the need to remove the particles from the reactor. There is therefore no need for manual handling of the particles, and no external machinery is required to deagglomerate the agglomerated particles. This not only significantly reduces the time over 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. It also makes the process more repeatable by limiting manual handling, reducing the risk of contamination.

[0140] Whether performed inside or outside the reactor, the particle agglomerates are preferably broken down by forcing them through a sieve, thus separating the agglomerates into individual particles or agglomerates of a desired and predetermined size (thereby achieving deagglomeration). With regard to the latter, in some cases, the individual primary particle sizes are so small (i.e., less than 1 μm) that it is not possible to achieve "complete" deagglomeration (i.e., the agglomerates are broken down into individual particles). Instead, deagglomeration is achieved by breaking down the larger agglomerates into smaller agglomerates of secondary particles of the desired size, as determined by the size of the sieve mesh. The smaller agglomerates are then coated by gas-phase techniques to form fully coated "particles" in the form of small agglomerate particles. Thus, the term "particles", when referring to deagglomerated and coated particles in the context of the present invention, refers to both individual (primary) particles and agglomerated (secondary) particles of the desired size.

[0141] In either case, the desired particle size (whether it be individual particles or agglomerates of the desired size) is maintained, and furthermore, continued application of the gas phase coating mechanism to the particles after such deagglomeration by sieving will form a complete coating on the particles, thus meaning that fully coated particles (individual or agglomerates of the desired size) are formed.

[0142] The repeated coating and deagglomeration process as described above, whether carried out inside or outside the reactor, may be carried out at least 1 time, preferably 2 times, more preferably 3 times, such as 4 times including 5 times, more particularly 6 times, for example 7 times, and up to about 100 times, for example up to about 50 times, such as up to about 40 times, including up to about 30 times, such as 2 to 20 times, for example 3 to 15 times, such as 10 times, for example 9 or 8 times, more preferably 6 or 7 times, especially 4 or 5 times.

[0143] Whether performed inside or outside the reactor, it is preferred that at least one screening step is performed, which further preferably comprises a vibratory screening step as described above. It is further preferred that a final screening step comprises a vibratory screening step performed prior to application of a final layer (series of cycles) of coating material. However, it is further preferred that two or more (including each) of the screening steps comprise a vibratory screening technique, step or process as described herein.

[0144] The preferred repetition of these steps further benefits the improved throughput of any vibratory screening technique.

[0145] 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.

[0146] The minimum thickness of each individual layer / coating / shell is in the range of about 0.1 nm on average (including about 0.5 nm, such as about 0.75 nm, eg 1 nm).

[0147] 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 any previously applied coatings, and can be, on average, about 1 / 100 of the average diameter (i.e., average diameter based on weight, number, or volume) of the core, or of the cores to which the previously applied coatings have been applied.

[0148] Preferably, for particles having an average diameter of about 100 nm to about 1 μm, the total coating thickness should be, on average, about 1 nm to about 5 nm, for particles having an average diameter of about 1 μm to about 20 μm, the coating thickness should be, on average, about 1 nm to about 10 nm, and for particles having an average diameter of about 20 μm to about 700 μm, the coating thickness should be, on average, about 1 nm to about 100 nm.

[0149] It has been found that applying a coating / shell followed by one or more disaggregation steps, such as sonication, can result in wear, pinholes, breaks, gaps, cracks, and / or voids (hereinafter "cracks") in the layer / coating because the coated particles are essentially "bonded" or "glued" more tightly upon application of a thicker coating, which can expose the core containing the biologically active component to the external environment upon disaggregation.

[0150] Since it is intended to provide the particles in suspension prior to administration to a patient, it is necessary to provide deagglomerated primary particles without pinholes or cracks in the coating, which would result in an undesirable initial peak (burst) in the plasma concentration of the active ingredient immediately after administration.

[0151] We have discovered that performing one or more of the deagglomeration steps described herein results in significantly fewer pinholes, gaps, or cracks in the final layer of coating material, resulting in particles that are not only completely covered with that layer / coating, but are also coated in a manner that allows the particles to be readily deagglomerated (e.g., using non-invasive techniques such as vortexing) in a manner that does not disrupt the layer of coating material formed prior to and / or during pharmaceutical formulation.

[0152] In this regard, the (e.g. inorganic, such as mixed oxide) coating typically completely surrounds, encloses, and / or encapsulates the solid core containing the active ingredient(s), thus minimizing the risk of an initial drug concentration burst resulting from direct drug contact with a solvent in which the relevant active ingredient is soluble, which may include not only bodily fluids but also any medium in which such coated particles may be suspended prior to injection.

[0153] Thus, in a further embodiment of this aspect of the invention, there is provided a particle as disclosed herein, wherein the coating surrounding, surrounding and / or encapsulating the core covers at least about 50%, such as at least about 65%, for example at least about 75%, such as at least about 80%, more particularly at least about 90%, such as at least about 91%, for example at least about 92%, such as at least about 93%, for example at least about 94%, such as at least about 95%, for example at least about 96%, such as at least about 97%, for example at least about 98%, for example at least about 99%, such as about or about 100% of the surface of the core, such that the coating essentially completely surrounds, surrounds and / or encapsulates the core.

[0154] As used herein, the term "essentially completely coating, completely surrounding, enclosing, and / or encapsulating the core" refers to coverage of at least about 98%, or at least about 99%, of the surface of the solid core.

[0155] Alternatively, the processes described herein may result in deagglomerated coated particles that are essentially free of such cracks through which the active ingredient may be released in an uncontrolled manner.

[0156] Although some minor cracks may appear in the coating without affecting the essential function in terms of controlling release, in further embodiments, particles as disclosed herein are provided in which at least about 90% of the particles do not exhibit cracks in the coating surrounding, surrounding and / or encapsulating 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 exhibit such cracks.

[0157] Alternatively, the coating(s) being "essentially free of such cracks" means that less than about 1% of the surface of the coated particle contains wear, pinholes, breaks, gaps, cracks and / or voids (through which the active ingredient is potentially exposed (e.g., to the elements)).

[0158] The layers of coating material can be of essentially uniform thickness across the surface area of ​​the particle collectively. By "essentially uniform" thickness is meant that the degree of variation in coating thickness of at least about 10%, such as about 25%, for example about 50% of the coated particles present in the compositions of the invention is about ±20% or less (including ±50% or less) of the average thickness as measured by TEM.

[0159] Different coating materials, such as pharma- ceutically acceptable and essentially non-toxic coating materials, may also be additionally applied between the separate coatings described herein (e.g., during a separate deagglomeration step) and / or while the coatings are being applied. Such materials may include multiple layers or composites of the mixed oxides and one or more different inorganic or organic materials to modify the properties of the layer(s).

[0160] Although the coated particles according to the present invention are essentially free of the aforementioned cracks in the applied coating through which the active ingredient could potentially be exposed (e.g., to the external environment), two further optional steps may be applied to the coated particles before subjecting them to further processing of the pharmaceutical formulation.

[0161] The first optional step, after the final deagglomeration step described above, may involve the application of a final overcoating layer, where the thickness of that outer "overcoating" layer / coating, or "sealing shell" (these terms are used interchangeably herein) should be thinner than any previously applied separate layer / coating / shell (or "subshell").

[0162] Thus, the thickness can be about 0.7 times (e.g., about 0.6 times) or less on average the thickness of the widest previously applied subshell. Alternatively, the thickness can be about 0.7 times (e.g., about 0.6 times) or less on average the thickness of the last subshell applied and / or about 0.7 times (e.g., about 0.6 times) or less on average the average thickness of all previously applied subshells. The thickness can range from about 0.3 nm to about 10 nm on average for particles up to about 20 μm. For larger particles, the thickness can be about 1 / 1000 or less on average the average diameter based on weight, number, or volume of the coated particles.

[0163] The role of such a sealing shell is to provide a "sealing" overcoating layer to the particles, covering their cracks, resulting in particles that are not only completely covered with the sealing shell, but also covered in a manner that allows the particles to be easily deagglomerated (e.g., using non-invasive techniques such as vortexing) in a manner that does not disrupt the underlying subshell formed prior to and / or during pharmaceutical formulation.

[0164] For reasons described herein, the sealing shell preferably does not include zinc oxide, although it may include silicon dioxide or, more preferably, aluminum oxide.

[0165] A second optional step may involve subjecting the few remaining particles having broken and / or cracked shells / coatings to a treatment in which all particles are suspended in a solvent in which the active ingredient is soluble (e.g., with a solubility of at least about 0.1 mg / mL) but the least soluble material in the coating is insoluble (e.g., with a solubility of about 0.1 μg / mL or less), followed by separation of the solid particles from the solvent, for example by centrifugation, sedimentation, flocculation, and / or filtration, thereby ensuring that primarily intact particles remain.

[0166] The above optional steps provide a means of further potentially reducing the possibility of a (possibly) undesirable initial peak (burst) in plasma concentration of the active ingredient, as previously discussed.

[0167] At the end of the process, the coated particles can be dried using one or more of the techniques previously described for drying the cores. Drying can occur in the absence or presence of one or more pharma- ceutically acceptable excipients (e.g., sugars or sugar alcohols).

[0168] Alternatively, at the end of the process, the separated particles may be resuspended in a solvent (e.g., water, with or without one or more pharma- ceutically acceptable excipients as defined herein) for subsequent storage and / or administration to a patient.

[0169] Prior to applying the first layer of coating material or between successive coatings, the cores and / or partially coated particles may be subjected to one or more alternative and / or preliminary surface treatments. In this regard, one or more intermediate layers comprising a different material (i.e. other than the inorganic material(s)) may be applied to the relevant surface, for example to protect the cores or partially coated particles from undesired reactions with precursors during the coating step(s) / deposition process, to enhance coating efficiency, or to reduce agglomeration.

[0170] The intermediate layer may contain one or more surfactants, for example, to reduce the agglomeration of the particles to be coated and provide a hydrophilic surface suitable for subsequent coating. In this regard, suitable surfactants include well-known nonionic, anionic, cationic, or zwitterionic surfactants, such as the Tween series (e.g., Tween 80). Alternatively, the core may be subjected to a preliminary surface treatment if the active ingredient used as part of (or as) the core is susceptible to react with one or more precursor compounds that may be present in the gas phase during the coating (e.g., ALD) process.

[0171] Application of an "intermediate" layer / surface treatment of this nature may alternatively be accomplished by liquid phase non-coating techniques followed by freeze drying, spray drying, or other drying methods to provide the particles with a surface layer onto which a coating material can then be applied.

[0172] The outer surface of the particles of the formulations of the invention may also be derivatized or functionalized with chemical compounds or moieties that enhance, for example, targeted delivery of the particles within a patient to which the nanoparticles are administered, for example, by attaching one or more chemical compounds or moieties to the outer surface of the final layer of coating material. Such compounds may be organic molecules (e.g., PEG) polymers, antibodies or antibody fragments, or receptor binding proteins or peptides, etc.

[0173] Alternatively, the moiety can be an anchor group, such as a moiety containing a silane functional group (see, e.g., Herrera et al, J. Mater. Chem., 18, 3650 (2008) and US 8,097,742). Another compound (e.g., a desired targeting compound) can be attached to such an anchor group by covalent or non-covalent bonds (including hydrogen bonds or van der Waals bonds), or a combination thereof.

[0174] The presence of such anchoring groups can provide a versatile tool for targeted delivery to specific sites in the body. Alternatively, compounds such as PEG can be used to allow particles to circulate longer in the bloodstream and avoid accumulation in the liver or spleen (the body's natural mechanisms for eliminating particles, potentially preventing delivery to diseased tissues).

[0175] The formulations of the invention may be used, for example, in medical, diagnostic, and / or veterinary practice.

[0176] The pharmaceutical (or veterinary) formulations of the invention may contain different types of particles, e.g., particles containing different active ingredients with different functionalization (as described above), particles of different sizes and / or different thicknesses of coating, or combinations thereof. By combining particles with different coating thicknesses and / or different core sizes in a single pharmaceutical formulation, drug release after administration to a patient may be controlled (e.g., varied or extended) over a particular period of time.

[0177] The formulations of the invention may be administered systemically, for example, by injection or infusion, intravenously or intra-arterially (including by intravascular or other perivascular devices / formulations (e.g., stents)), intramuscularly, intraosseously, intracerebrally, intraventricularly, intrasynovially, intrasternally, intrathecally, intralesional, intracranial, intratumoral, cutaneous, intradermal, subcutaneously, transdermally, intraperitoneally, in the form of a pharma- ceutically (or veterinarily) acceptable dosage form. As noted above, preferred routes of administration include intratumoral, more preferably subcutaneously and / or intramuscularly.

[0178] Preparation of the formulations of the present invention can be accomplished by incorporating the active ingredients (including coated particles) described herein into a suitable pharma- ceutically or veterinarily acceptable carrier system, taking into account the intended route of administration and standard pharmaceutical practice. A suitable carrier system must therefore be chemically inert to the biologically active agent(s) used and have no adverse side effects or toxicity under the conditions of use. Such pharma-ceutically acceptable carriers can also impart immediate or modified release of the biologically active agent from the particles of the formulations of the present invention.

[0179] To form a depot composition after subcutaneous, intratumoral and / or intramuscular injection, more preferably subcutaneous and / or intramuscular injection, the formulations of the present invention may be in the form of a sterile injectable and / or injectable dosage form, for example a sterile aqueous or oleaginous suspension of the formulations of the present invention.

[0180] Formulations of the invention that include an aqueous carrier system may be formulated as a sterile aqueous suspension of particles (coated or not) according to techniques known in the art. The aqueous medium should contain at least about 50% water, but may include other aqueous excipients such as Ringer's solution, and may also include polar co-solvents (e.g., ethanol, glycerol, propylene glycol, 1,3-butanediol, polyethylene glycols of various molecular weights, and tetraglycols), viscosity increasing or thickening agents (e.g., carboxymethylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, sodium starch glycolate, poloxamers such as poloxamer 407, polyvinylpyrrolidone, cyclodextrins such as hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, and polyethylene glycols of various molecular weights), surfactants / wetting agents to achieve homogeneous suspension (e.g., sorbitan esters, sodium lauryl sulfate, monoglycerides, polyoxyethylene esters, polyoxyethylene alkyl ethers, polyoxylglycerides, and preferably Tweens (polysorbates), e.g., Tween 80 and Tween 20). Preferred ingredients include isotonicity modifiers (e.g., sodium lactate, dextrose, especially sodium chloride), pH adjusters and / or buffers (e.g., citric acid, sodium citrate, especially phosphate buffers such as disodium hydrogen phosphate hydrate, sodium phosphate, sodium dihydrogen phosphate monohydrate, and combinations thereof, which may be employed in combination with standard inorganic acids and bases such as hydrochloric acid and sodium hydroxide), and other ingredients such as mannitol, croscarmellose sodium, and hyaluronic acid.

[0181] In the alternative, the oily or oil-based carrier system may comprise one or more pharma- ceutically or veterinarily acceptable liquid lipids, which may include fixed oils such as mono-, di-, or triglycerides, including Miglyol (e.g., 812N), propylene glycol dicaprylocaprate (Miglyol 840, C8 / C10 ester), tricaprylin (Miglyol oil), Gelcire 43 / 01, Corisolv GTA, Labrafil. The carrier system may also include 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 refined pharma- ceutically acceptable oils, such as olive oil, peanut oil, soybean oil, corn oil, cottonseed oil, sesame oil, castor oil, oleic acid, and polyoxyethylated versions thereof (e.g., sorbitan trioleate, lauroglycol 90, capryol PGMC, PEG-60 hydrogenated castor oil, polyoxyl 35 castor oil).More preferred carrier systems include mono-, di-, and / or triglycerides, including alkyl chain triglycerides (e.g., C6-C 12 Medium chain triglycerides, such as alkyl chain triglycerides, are most preferred.

[0182] Such injection suspensions may be formulated according to techniques well known to those skilled in the art by employing suitable dispersing or wetting agents (eg, Tween, such as Tween 80) and suspending agents.

[0183] The formulations of the present invention may further be formulated in the form of an injectable suspension of (e.g., coated) particles having a size distribution that is capable of forming a homogenous and stable (i.e., non-settling) suspension in an injection fluid and that can be injected through a needle.

[0184] In this regard, the formulations of the present invention may include a vehicle that is sufficiently viscous to prevent settling that would result in a suspension that is not "homogeneous" and therefore the risk of under- or overdosing of the active ingredient. For any given multi-coated particle, this may be achieved by the addition of known viscosity modifiers (as discussed above) or, more preferably, by providing a more viscous carrier system itself.

[0185] The formulations of the present invention may be stored under normal storage conditions and may maintain their physical and / or chemical integrity.

[0186] The phrase "maintaining physical and chemical integrity" essentially means chemical stability and physical stability.

[0187] "Chemical stability" includes the ability of the formulations of the present invention to be stored (with or without appropriate pharmaceutical packaging) under normal storage conditions with only minor amounts of chemical degradation or decomposition. The term "chemical stability" also includes "stereochemical" and / or "conformational" stability, which refers to resistance to stereochemical transformations, such as racemization, at one or more chiral centers within the molecule of the active ingredient.

[0188] "Physical stability" includes that the formulations of the present invention may be stored (with or without appropriate pharmaceutical packaging) under normal storage conditions with only a small degree of physical transformation (e.g., precipitation as described above) or change in the properties and / or integrity of the coated particles, e.g., the coating itself or the active ingredient (including dissolution, solvation, solid-state phase transitions, etc.).

[0189] Examples of "normal storage conditions" for the formulations of the present invention include temperatures of about -50°C to about +80°C (preferably about -25°C to about +75°C, such as about 50°C) for an extended period of time (i.e., about 12 months or more, e.g., about 6 months), and / or pressures of about 0.1 to about 2 bar (preferably atmospheric pressure), and / or exposure to about 460 lux of ultraviolet / visible light, and / or relative humidity of about 5 to about 95% (preferably about 10 to about 40%).

[0190] Under such conditions, the formulations of the invention may be found to be chemically and / or physically degraded / decomposed, optionally to less than about 15%, more preferably less than about 10%, especially less than about 5%.Those skilled in the art will appreciate that the above upper and lower limits of temperature and pressure represent the extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g., a temperature of 50°C and a pressure of 0.1 bar).

[0191] The formulations of the present invention may be in the form of a liquid, sol, or gel that can be administered through a surgical administration device, such as a needle, catheter, etc., to form a depot formulation.

[0192] In any case, the preparation of suitable formulations can be achieved by those skilled in the art using routine techniques without inventive methods. Thus, the formulations of the present invention and dosage forms containing same can be formulated with conventional pharmaceutical additives and / or excipients used in the art for the preparation of pharmaceutical formulations, and then incorporated into various types of pharmaceutical formulations and / or dosage forms using standard techniques (see, for example, Lachman et al., 'The Theory and Practice of Industrial Pharmacy', Lea & Febiger, 30, 2002). rd edition (1986), 'Remington: The Science and Practice of Pharmacy', Troy (ed.), University of the Sciences in Philadelphia, 21 stedition (2006), and / or 'Aulton's Pharmaceutics: The Design and Manufacture of Medicines', Aulton and Taylor (eds.), Elsevier, 4 th edition, 2013), and the documents cited therein, the relevant disclosures of all of which are incorporated herein by reference.

[0193] Anti-inflammatory agents that may be used in the formulations of the present invention include butylpyrazolidines (such as phenylbutazone, mofebutazone, oxyphenbutazone, clofezone, kebuzone, and suxibuzone), acetic acid derivatives and related substances (such as indomethacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpyramide, oxametacin, proglumetacin, ketorolac, aceclofenac, and bufexamac), propionic acid derivatives (such as piroxicam, tenoxicam, , droxicam, lornoxicam, meloxicam, ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen, benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen, aluminoprofen, dexketoprofen, vedaprofen, carprofen, and tepoxalin), fenamates (mefenamic acid, tolfenamic acid, flufenamic acid, meclofenamic acid, and flunixin), coxib (celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, firocoxib, robenacoxib, mavacoxib, and cimicoxib), other nonsteroidal anti-inflammatory agents (nabumetone, niflumic acid, azapropazone, glucosamine, benzydamine, glucosaminoglycan polysulfate, proquazone, orgotein, nimesulide, feprazone, diacerein, morniflumate, tenidap, oxaceprol, chondroitin sulfate, pentosan polysulfate, and aminopropionite lysine, etc.), corticosteroids (11-dehydrocorticosterone, 11-deoxycorticosterone, 11-deoxycortisol, 11-ketoprogesterone, 11β-hydroxypregnenolone, 11β-hydroxyprogesterone, 11β,17α,21-trihydroxypregnenolone, 17α,21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 17α-hydroxyprogesterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxycorticosterone, 18-hydroxyprogesterone,21-deoxycortisol, 21-deoxycortisone, 21-hydroxypregnenolone (prevedilone), aldosterone, corticosterone (17-deoxycortisol), cortisol (hydrocortisone), cortisone, pregnenolone, progesterone, flugestone (flurogestone), fluorometholone, medrysone (hydroxymethylprogesterone), prevedilone acetate (21-acetoxypregnenolone), chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluoxetine Perolone, fluprednisolone, loteprednol, methylprednisolone, prednicarbate, prednisolone, prednisone, tixocortol, triamcinolone, alclometasone, beclomethasone, betamethasone, clobetasol, clobetasone, clocortolone, desoximetasone, dexamethasone, diflorasone, difluocortolone, fluclorolone, flumethasone, fluocortin, fluocortolone, fluprednidene, fluticasone, fluticasone furoate, halometasone, meprednisone, mometasone, mometasone furoate , paramethasone, prednylidene, rimexolone, urobetasol (halobetasol), amcinonide, budesonide, ciclesonide, deflazacort, desonide, formocortal flucloronone acetonide (flucloronide), fludroxycortide (flurandrenolon, flurandrenolide), flunisolide, fluocinolone acetonide, fluocinonide, halcinonide, and triamcinolone acetonide, etc.), quinolines (oxycinchophen, etc.), gold preparations (gold sodium thiomalate, gold sodium thiosulfate, auranofin, aurothioglucose, etc.), penicillamine and similar drugs (such as bucillamine), antihistamines (acrivastine, alimemazine, antazoline, astemizole, azatadine, azelastine, bamipine, bilastine, bromdiphenhydramine, brompheniramine, buclizine, cetirizine, cinnarizine, cyclizine, cyproheptadine, deptropine, desloratadine, dexbrompheniramine, dexchlorpheniramine, diphenylpyraline, dimenhydrinate, dimethindene, doxylamine, ebastine, epinastine,phenindamine, pheniramine, fexofenadine, histapirrodine, hydroxyethylpromethazin, isothipendyl, carbinoxamine, ketotifen, quifenadine, clemastine, chlorcyclizine, chlorphenamine, chlorphenoxamine, chloropyramine, levocetirizine, loratadine, mebhydroline, mequitazine, meclozine, mepyramine, methapyrilene, methdilazine, mizolastine, oxatomide, oxomemazine, pimethixene, promethazine, pyrobutamine, rupatadine, sequifenadine, talastine, thenarizine, terfenadine, thiazinam, thiethylperazine, thonzylamine, trimethobenzamide, tripelennamine, triprolidine, and tritocubarine. Combinations of any one or more of the aforementioned anti-inflammatory agents may be used.

[0194] Preferred anti-inflammatory agents include corticosteroids and nonsteroidal anti-inflammatory drugs, such as diclofenac, ketoprofen, meloxicam, aceclofenac, flurbiprofen, parecoxib, ketollac tromethamine, indomethacin, or any pharmaceutically acceptable salt of these compounds.Preferred corticosteroids that can be used according to the present invention include hydrocortisone, triamcinolone, more preferably methylprednisolone, prednisolone, dexamethasone, betamethasone, or any pharmaceutically acceptable salt of these compounds.Combinations of one or more of the above corticosteroids and nonsteroidal anti-inflammatory drugs can be used.

[0195] However, in the formulations of the present invention, the biologically active agent is "combined" with the anti-inflammatory agent, meaning that each active ingredient is presented (i.e., formulated) as a combined preparation containing both active agents that are then administered together.

[0196] In the formulation of the present invention, the anti-inflammatory agent is (1) formulating it with a biologically active agent and a sustained release component (e.g., in the form of a solid core within a coated particle) and then suspending the resulting composition within the carrier system of a formulation of the invention (which formulation is hereinafter referred to as a "combination preparation"); or (2) dissolving and / or suspending it in the carrier system of the formulation of the present invention (which formulation is hereinafter referred to as the "combination preparation"); It may be present in the presence of other biologically active agents at appropriate dosages.

[0197] In embodiment (2) above, the anti-inflammatory agent may be provided in the formulation of the invention in any form separate from the other components (e.g. the core) containing said (other) biologically active agent. This may be achieved, for example, by dissolving or suspending the anti-inflammatory agent directly in a carrier system / vehicle that also forms part of the formulation of the invention, or by providing it in a form whose release, like the (other) biologically active agent, may be controlled after injection.

[0198] The latter option may be achieved, for example, by providing the anti-inflammatory agent in combination with one or more sustained release components as described above, more preferably in the form of (e.g., additional) particles suspended in the carrier system of the formulation of the invention, the additional particles having an average diameter by weight, number, or volume that is from about 10 nm to about 700 μm, and comprising a core containing the anti-inflammatory agent, the core being coated, at least in part, with one or more coating materials as described above, which may enable release of the anti-inflammatory agent over the same or different time scales (such formulations are hereinafter referred to as "combined suspensions").

[0199] In such combination suspensions, the coated cores containing the anti-inflammatory agents may differ in terms of their chemical composition(s) and / or physical form(s), although for the reasons mentioned above, it is preferred that the coatings used are the same or similar to those used in the formulations of the present invention.

[0200] This may mean that the anti-inflammatory agent is coated with one or more inorganic coatings as described above, e.g., one or more inorganic coating materials including one or more metal-containing or metalloid-containing compounds such as metal or metalloid oxides, e.g., iron oxide, titanium dioxide, zinc sulfide, more preferably zinc oxide, silicon dioxide, and / or aluminum oxide, which coating material consists essentially (e.g., greater than about 80%, such as greater than about 90%, e.g., about 95%, such as about 98%) of such oxides (individually or collectively), and more particularly, the inorganic coating is (i) zinc oxide; (ii) in admixture with one or more other metal and / or metalloid oxides, The atomic ratio ((i):(ii)) is at least about 1:10, such as at least about 1:6, and up to about 10:1, such as about 6:1.

[0201] Preferably, the atomic ratio ((i):(ii)) is at least about 1:1 and at most about 6:1.

[0202] According to this aspect of the invention, the formulation may comprise from about 1% to about 99% by weight, such as about 10% (such as about 20% by weight, e.g., about 50% to about 90% by weight) of the coated particles, with the remainder being made up of the carrier system and / or other excipients.

[0203] According to a further aspect of the invention, there is provided a process for preparing the formulations of the invention, which process comprises mixing the biologically active ingredient together with one or more sustained release components (e.g., to make coated particles containing the biologically active ingredient as described herein) with an anti-inflammatory agent and a carrier system as described herein.

[0204] The above process is (A) making a combination preparation as defined above, comprising a biologically active ingredient, an anti-inflammatory agent, and one or more sustained release ingredients (e.g., in the form of a coated core as described herein, containing both active ingredients); and / or (B) separately providing a component comprising the biologically active ingredient together with one or more sustained release components (e.g. in the form of a coated core as described above) and mixing this with the anti-inflammatory agent (optionally in association with one or more (different or the same) sustained release components, which may therefore be uncoated or in the form of particles coated as described above), and then It may further comprise mixing components (A) and / or (B) above, together with a carrier system as described herein, where necessary and / or appropriate, (e.g., further) with an anti-inflammatory agent.

[0205] In a further embodiment of the present invention there is provided a method of treating a medical condition in a patient comprising: (1) A first injectable pharmaceutical or veterinary formulation, (a) a biologically active agent, the agent being useful for treating a medical condition; and (b) a sustained release component that forms a depot composition (e.g., a plurality of coated cores as defined herein) that provides sustained release of the biologically active agent in a subject following intratumoral or, more preferably, subcutaneous and / or intramuscular injection of the first formulation into the subject; and (c) making a first injectable pharmaceutical or veterinary formulation comprising a carrier system as defined herein; (2) injecting the subject intratumorally, or more preferably subcutaneously and / or intramuscularly (as appropriate), with the first formulation; (3) if a local inflammatory response is observed, administering an anti-inflammatory agent to the patient according to one or more of the principles set forth above or below.

[0206] In two further aspects of the invention there are provided the following: A biologically active agent for use in a method of treating a medical condition for which the agent is useful, and Use of a biologically active agent in the manufacture of a medicament for use in a method of treating a medical condition for which the agent is useful. This use / method is (1) A first injectable pharmaceutical or veterinary formulation, (a) a biologically active agent, the agent being useful for treating a medical condition; and (b) a sustained release component that forms a depot composition (e.g., a plurality of coated cores as defined herein) that provides sustained release of the biologically active agent in a subject following intratumoral or, more preferably, subcutaneous and / or intramuscular injection of the first formulation into the subject; and (c) making a first injectable pharmaceutical or veterinary formulation comprising a carrier system as defined herein; (2) injecting the subject intratumorally, or more preferably subcutaneously and / or intramuscularly (as appropriate), with the first formulation; (3) if a local inflammatory response is observed, administering an anti-inflammatory agent to the patient according to one or more of the principles set forth above or below.

[0207] In a preferred aspect of this embodiment of the invention, the administration of the anti-inflammatory agent may further comprise the production of a second injectable pharmaceutical or veterinary formulation comprising said anti-inflammatory agent, and a sustained release component (e.g., a plurality of coated cores comprising said anti-inflammatory agent as defined herein), and a carrier system forming a depot composition that provides sustained release of said anti-inflammatory agent within the subject to provide an anti-inflammatory effect following intratumoral, or preferably subcutaneous or intramuscular, injection of the formulation into the subject.

[0208] In this regard, the administration of an anti-inflammatory agent may include intratumoral or, more preferably, subcutaneous and / or intramuscular injection of the second formulation into a subject as part of a treatment for a condition that may be treated by the biologically active agent in the absence of the anti-inflammatory agent. Such administration of the anti-inflammatory agent may occur essentially simultaneously (e.g., within about 1 minute or simultaneously) with administration of the biologically active agent, or may occur on multiple occasions prior to (e.g., up to about 10 minutes before) or at any time after the injection, in accordance with standard safety practices.

[0209] Alternatively, the anti-inflammatory agent may be applied in the form of a topical preparation on the surface of the skin around the injection point. Such topical preparations containing the anti-inflammatory agent may be commercially available and / or made using routine techniques, for example, in the form of creams, lotions, gels, mousses, ointments, tapes, and bandages, solutions, etc., and may be applied on multiple occasions, before the injection (e.g., up to about 10 minutes before), during the injection (i.e., for example, during about 1 minute or at the same time), or at any time after the injection, in accordance with standard safety standards. Preferred topical nonsteroidal anti-inflammatory compositions may include diclofenac, ibuprofen, diclofenac, eltenac, etoricoxib, felbinac, flufenamate, flurbiprofen, indomethacin, ibuprofen, ketoprofen, nimesulide, piketoprofen, and piroxicam. Preferred corticosteroid-based topical compositions may include clobetasone, hydrocortisone, beclomethasone, clobetasol, fluticasone, and mometasone.

[0210] When the biologically active agent and the anti-inflammatory agent are administered simultaneously, in a further embodiment there is provided a method of treating a medical condition in a patient, the method comprising: (1) An injectable pharmaceutical or veterinary preparation, (a) a biologically active agent that, when injected into and exposed to tumor tissue, or more preferably muscle tissue and / or subcutaneous tissue, causes, is likely to cause, or is expected to cause, local inflammation; (b) an anti-inflammatory agent; and (c) one or more sustained release components that form a depot composition that provides sustained release of the biologically active agent and (optionally) the anti-inflammatory agent in a subject following intratumoral, or more preferably subcutaneous or intramuscular, injection (where appropriate) of the formulation into the subject; (d) a carrier system as defined herein; and making an injectable pharmaceutical or veterinary formulation comprising: (2) injecting the formulation intratumorally, or more preferably subcutaneously or intramuscularly, into a subject to treat a condition that can be treated by the biologically active agent in the absence of the anti-inflammatory agent; Includes.

[0211] In two further aspects of the invention there are provided the following: A biologically active agent for use in a method of treating a medical condition for which the agent is useful, and Use of a biologically active agent in the manufacture of a medicament for use in a method of treating a medical condition for which the agent is useful; This use / method is (1) An injectable pharmaceutical or veterinary preparation, (a) a biologically active agent that, when injected into and exposed to tumor tissue, or more preferably muscle tissue and / or subcutaneous tissue, causes, is likely to cause, or is expected to cause, local inflammation; (b) an anti-inflammatory agent; and (c) one or more sustained release components that form a depot composition that provides sustained release of the biologically active agent and (optionally) the anti-inflammatory agent in a subject following intratumoral, or more preferably subcutaneous or intramuscular, injection (where appropriate) of the formulation into the subject; (d) a carrier system as defined herein; and making an injectable pharmaceutical or veterinary formulation comprising: (2) injecting the formulation intratumorally, or more preferably subcutaneously or intramuscularly, into a subject to treat a condition that can be treated by the biologically active agent in the absence of the anti-inflammatory agent.

[0212] The term "agent that causes, has the potential to cause, or is expected to cause localized inflammation" is as defined herein.

[0213] For the avoidance of doubt with respect to this latter aspect of the invention, the anti-inflammatory agent is administered in an amount of: The inflammatory active agent may be combined with one or more sustained release components, may be combined separately from the inflammatory active agent with one or more sustained release components; and / or May not be combined with one or more sustained release ingredients.

[0214] The formulations of the present invention may be provided in the form of sterile injectable and / or infusible dosage forms that can be administered via a surgical administration device (e.g., a syringe with an injection needle, catheter, etc.) to form a depot formulation.

[0215] Additionally, injectable and / or injectable dosage forms are provided that include the formulations of the invention, the formulations being contained within a reservoir that is connected to and / or associated with an injection or infusion means (e.g., a syringe with a needle, catheter, etc. for injection).

[0216] Alternatively, the formulations of the invention may be stored prior to loading into a suitable injectable and / or injectable administration means (e.g. a syringe with a needle for injection) or may be prepared immediately prior to loading into such an administration means.

[0217] Thus, a sterile injectable and / or infusible dosage form may comprise a receptacle or reservoir in communication with the injection or infusion means which may be preloaded with the formulation of the invention, which may be loaded prior to use, or may comprise one or more reservoirs in which the formulation of the invention and the coated particles of the carrier system are contained separately and mixing occurs prior to and / or during injection or infusion.

[0218] therefore, (1) a biologically active ingredient in combination with one or more sustained release components as described above, and optionally an anti-inflammatory agent in combination with one or more sustained release components as described above; (2) a carrier system for the formulation of the present invention; Further provided is a kit of parts comprising components (1) together with instructions for the end user to mix with (2) (and optionally an additional anti-inflammatory agent formulated as described herein with respect to any aspect of the invention) prior to injection.

[0219] In addition, (1) a biologically active ingredient in combination with one or more sustained release components as described above; (2) a carrier system for the formulation of the present invention; To end users (i) mixing component (1) with (2) prior to injection; (ii) If a local inflammatory reaction is observed following injection, a kit of parts is provided, comprising, together with instructions for administering an anti-inflammatory agent to the patient according to one or more of the principles set out above or below.

[0220] (a) coated particles of the formulation of the invention (whether those particles contain a biologically active ingredient, an anti-inflammatory agent, or both such active ingredients, e.g., in a combination preparation as described above), and (b) a carrier system for the formulation of the invention, and (c) a kit of parts, including, where necessary and / or appropriate, an anti-inflammatory agent, which may be in the form of uncoated or coated particles as described above; As well as the coated particles of the formulation of the invention (as described in (a) above), together with instructions for the end user to mix the particles with the carrier system (b) according to the invention (and optionally the anti-inflammatory agent (c)).

[0221] There is further provided a pre-loaded injectable and / or injectable dosage form as described above but modified by including at least two chambers, in one of which are disposed the coated particles of the formulation of the invention (as described in (1) or (a) in the immediately preceding paragraph) and in the other of which is disposed the carrier system of the formulation of the invention of (2) or (b) in the immediately preceding paragraph, with mixing occurring before and / or during injection or infusion. In such dosage forms, an anti-inflammatory agent may optionally be included in either or both of the chambers.

[0222] In addition to the above, the subject may receive (or may already be receiving) one or more of the aforementioned anti-inflammatory agents separate from the formulation of the invention, meaning receiving one or more of these anti-inflammatory agents in prescribed doses prior to, in addition to, and / or following treatment with any of the following: a formulation according to the invention, or A formulation which in all other respects is a formulation of the invention, provided that it does not contain an anti-inflammatory agent.

[0223] In the latter case, the formulations containing the biologically active agent and the anti-inflammatory agent are administered separately (simultaneously or sequentially) in different formulations.

[0224] Thus, there is further provided a method of treating a patient, comprising: (A) a pharmaceutical formulation of the invention, or a formulation which is in all other respects a formulation of the invention, provided that it does not contain an anti-inflammatory agent; and (B) administering a pharmaceutical formulation comprising an anti-inflammatory agent as defined above or in admixture with one or more pharma- ceutical or veterinarily acceptable excipients, such as a carrier system according to the present invention; In that method, components (A) and (B) are each provided in a form that is suitable for administration in conjunction with one another (hereinafter referred to as the "combination method").

[0225] In two further aspects of the invention there is provided: A biologically active agent for use in a method of treating a medical condition for which the agent is useful, and Use of a biologically active agent in the manufacture of a medicament for use in a method of treating a medical condition for which the agent is useful; This use / method includes the combination method defined above.

[0226] Component (B) of the above combination method may differ from component (A) in its chemical composition and / or physical form, for example, it may be prepared by directly dissolving or suspending the anti-inflammatory agent in a carrier system / vehicle which may be the same or different from that used in the formulation of the present invention, or by providing it in a form whose release, like the (other) biologically active agent, can also be controlled after injection.

[0227] In this respect, said component (B) may also be in a form essentially identical to or at least similar to the formulation of the invention, or may be a formulation which does not contain an anti-inflammatory agent but is instead in all other respects a formulation of the invention, provided that it is in the form of a plurality of particles suspended in, for example, a carrier system, the particles being (a) have an average diameter based on weight, number, or volume that is from about 10 nm to about 700 μm; (b) comprising a solid core comprising the anti-inflammatory agent, the core being at least partially coated with one or more coatings as described above (e.g., an inorganic coating), e.g., one or more inorganic coating materials comprising one or more metal-containing or metalloid-containing compounds such as metal or metalloid oxides, e.g., iron oxide, titanium dioxide, zinc sulfide, more preferably zinc oxide, silicon dioxide, and / or aluminum oxide, which coating materials consist essentially (e.g., greater than about 80%, such as greater than about 90%, e.g., about 95%, such as about 98%) of such oxides (individually or collectively); more particularly, the inorganic coating is (i) zinc oxide; (ii) in admixture with one or more other metal and / or metalloid oxides, The atomic ratio ((i):(ii)) is at least about 1:10 (such as about 1:6) and at most about 10:1 (such as about 6:1).

[0228] Preferably, the atomic ratio ((i):(ii)) is at least about 1:1 and at most about 6:1.

[0229] In any event, for the avoidance of doubt, all aspects, including preferred aspects, for the formulations of the invention disclosed and / or claimed herein are generally equally applicable as aspects and / or preferences of the coated cores comprising one or more anti-inflammatory agents as described above, whether provided as a combined preparation, combination preparation, or combination suspension, or as part of a combination method or combination pack, and for the avoidance of doubt, such aspects, preferences and features, singly or in combination, are hereby incorporated by reference to these aspects of the invention.

[0230] According to a further aspect of the present invention there is provided a combination method as defined above, which method comprises bringing component (A) as defined above into association with component (B) as defined above, thus rendering the two components suitable for administration in combination with one another.

[0231] By "associating" the two components with each other, components (A) and (B) of the combination method are (i) may be provided as separate formulations (i.e., independent of each other) and then combined for use in conjunction with each other in a combination therapy; or (ii) They may be packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

[0232] A kit of parts comprising the components (A) and (B) of the combination method defined above, packaged and presented together as separate components of a combination pack for use in conjunction with one another in a combination treatment; and (I) one of components (A) and (B) described herein, (II) A kit of parts is further provided that includes the component together with instructions for use in conjunction with the other of the two components.

[0233] As mentioned above, the combination methods described herein may include two or more formulations containing appropriate amounts / doses of biologically active agents and / or two or more formulations containing appropriate amounts / doses of anti-inflammatory agents to provide for the repeated administration as described above.

[0234] In this regard, with respect to the combination methods described herein, "administration in conjunction with" includes that components (A) and (B) of the combination method are administered sequentially, separately, and / or simultaneously over the course of treatment of the relevant condition.

[0235] Thus, the term "in conjunction with" includes that one or the other of the two formulations may be administered (optionally repeatedly) before, after, and / or simultaneously with the administration of the other component. As used in this context, the terms "co-administered" and "administered simultaneously with" include individual doses of a biologically active agent and an anti-inflammatory agent administered within 48 hours (e.g., 24 hours) of each other.

[0236] For any of the combination methods or products according to the invention, the respective formulations are administered in conjunction with one another, optionally repeatedly, in a manner that may enable a greater beneficial effect for the subject over the course of treatment of the relevant condition than if a formulation containing only the relevant biologically active agent were administered in the absence of the anti-inflammatory agent (e.g., repeatedly as described herein) over the same course of treatment.

[0237] The determination of whether a combination method or product provides a greater beneficial effect with respect to treatment and over the course of treatment depends on the condition being treated and / or its severity, but can be routinely accomplished by one of ordinary skill in the art.

[0238] For example, a physician may first administer a formulation of the invention, or a formulation which in all other respects is a formulation of the invention, with the proviso that it does not contain an anti-inflammatory agent, to treat a patient with a relevant condition and then find that the person exhibits an inflammatory response (which may be caused by the active ingredient itself and / or any other components of the formulation).

[0239] The physician then administers the following, as described above: The above combination method or combination pack ingredients (B), combination preparations, Combination preparations, and / or Combined suspension may be administered, any of which includes an anti-inflammatory agent as described above.

[0240] All formulations of the present invention, including the combination preparations, combination preparations, combination suspensions, and / or combination methods and combination packs according to the present invention, can be used in human medicine. In particular, they can be used in any indication for which the subject-related biologically active agent is either approved for use or otherwise known to be useful.

[0241] Biologically active agents and anti-inflammatory agents that may be used in the formulations of the invention, including the combination preparations, combination preparations, combination suspensions, and / or combination methods and combination packs according to the invention, may be provided in the form of (e.g., pharma- ceutically acceptable) salts, including those described in the art and described in Martindale-The Complete Drug Reference, 38 th Edition, Pharmaceutical Press, London (2014) and documents cited therein, the relevant disclosures of all of which documents are incorporated herein by reference.

[0242] Otherwise, pharma- ceutically acceptable salts of biologically active agents include acid addition salts and base addition salts.Such salts may be formed by conventional means, for example, by reacting the free acid or free base form of the biologically active compound with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (for example, by vacuum, lyophilization or filtration).Salts may also be prepared using techniques known to those skilled in the art, for example, by exchanging the counterion of the biologically active compound in the form of a salt with another counterion using a suitable ion exchange resin.

[0243] The formulations of the present invention may contain a pharmacologically effective amount of the relevant biologically active agent. The term "pharmacologically effective amount" refers to the amount of such active ingredient, whether administered alone or in combination with another active ingredient, that is capable of producing a desired physiological change (such as a therapeutic effect) in a treated patient. Such biological or medical response in a patient, or such effect, may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels an effect), and includes at least partial alleviation of the symptoms of the disease or disorder being treated, or a cure or prevention of said disease or disorder.

[0244] The amount of any active agent that may be used in the formulations of the present invention, including the combination preparations, combination preparations, combination suspensions, and / or combination methods and combination packs according to the present invention, should be sufficient to exert its pharmacological effect in the relevant pathology.

[0245] Therefore, the dose of 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 recognize that the selection of the exact dose and composition and the most suitable delivery regimen is influenced not only by the nature of the active ingredient, but also by, among others, the pharmacological properties of the formulation, the route of administration, the nature and severity of the pathology 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 the genetic differences between patients.

[0246] Because administration of the formulations of the present invention can be continuous or intermittent (eg, by bolus injection), the dosage of such other active ingredients will also be determined by the timing and frequency of administration.

[0247] In any event, a physician or other skilled artisan can routinely determine the actual dosage of any particular active ingredient which will be most suitable for an individual patient, and dosages of the relevant active ingredients as described above are known in the art and are set forth in the medical literature (Martindale-The Complete Drug Reference, 38 U.S.C. 5,311,133; 5,311,133; and 5,311,133). th Edition, Pharmaceutical Press, London (2014) and documents cited therein, the relevant disclosures of all of which are incorporated herein by reference.

[0248] In this regard, the formulations of the present invention, and the uses and methods described herein, allow for the formulation of a wide variety of pharma- ceutical active compounds, which, depending on the biologically active agent contained therein, can be used to effectively treat a wide variety of disorders.

[0249] Use of the formulations of the invention may control the dissolution rate and / or pharmacokinetic profile of the biologically active ingredient contained in the formulation by reducing any burst effect (characterized by a concentration maximum shortly after administration) and / or by reducing the Cmax in the plasma concentration-time profile (thus increasing the length of release of the biologically active ingredient from the formulation).

[0250] The formulations and processes described herein may have advantages in treating the relevant condition with a particular biologically active agent that may be more convenient for the physician and / or patient, may be more effective, may be less toxic, may have a broader spectrum of activity, may be more potent, may cause fewer side effects, or may have other useful pharmacological properties, than any similar treatment that may be described in the prior art for the same active ingredient.

[0251] Whenever the word "about" is used herein, for example in the context of an amount (e.g., number, concentration, dimension (size and / or weight), dose, duration, pharmacokinetic parameter, etc.), relative amount (percentage, weight ratio, size ratio, atomic ratio, aspect ratio, proportion, multiple, fraction, etc.), relative humidity, lux, temperature or pressure, it will be understood that such variables are approximate and thus may vary from the numerical values ​​specified herein by ±15%, such as ±10%, for example ±5%, preferably ±2% (e.g. ±1%). This is true even when such numerical values ​​are expressed as percentages in the first place (e.g., "about 15%" may mean ±15% of the numerical value 10, which may be anywhere from 8.5% to 11.5%).

[0252] The present invention is illustrated by the following examples, but is in no way limited thereto, with reference to Figures 1 and 2, which show the plasma concentration-time profiles of two patients administered azacitidine according to the treatment protocol in the clinical trial described in Comparative Example 2 below. Figure 3 shows the plasma concentration-time profile in a miniature pig following subcutaneous administration of a formulation of the present invention, and Figure 4 shows the positive impact on the local inflammatory response of a subcutaneous co-administration formulation of the present invention with mixed oxide coated microparticles containing the anti-inflammatory agent indomethacin. EXAMPLES

[0253] Comparative Example 1 Coated Azacitidine Microparticles A sample of microparticles of Azacitidine (MSN Labs, India) was prepared by jet milling. The particle size distribution, as determined by laser diffraction, was as follows: D 10 1.2μm, D 50 3.8μm, D 90 11.3 μm.

[0254] The powder was loaded into an ALD reactor (Picosun, SUNALE™ R-series, Espoo, Finland) and 24 ALD cycles were performed at a reactor temperature of 50 °C. The coating sequence consisted of three ALD cycles with diethylzinc and water as precursors for three ALD cycles, followed by one cycle of trimethylaluminum and water, repeated six times to form a mixed oxide layer with an atomic ratio of zinc:aluminum of 3:1. The thickness of the first layer was about 4 to about 8 nm (estimated from the number of ALD cycles).

[0255] The powder was removed from the reactor and deagglomerated by forcing it through a polymeric sieve with a mesh size of 20 μm using a sonic sifter.

[0256] The resulting deagglomerated powder was reloaded into the ALD reactor and 24 additional ALD cycles were performed as before to form a second layer of mixed oxides in the ratios described above, followed by extraction from the reactor and deagglomeration by sonic sieving means as described above, followed by reloading to form a third layer, deagglomeration, and then reloading to form a final, fourth layer.

[0257] To determine the drug loading (i.e., w / w% of azacitidine in the powder), a HPLC (Prominence-i (Shimadzu, Japan)) with a diode array detector (Shimadzu, Japan) set at 223 nm was used, using a 4.6 x 250 mm, 3 μm particles, C18 column (Luna, Phenomenex, USA). The nanoshell coating was dissolved in 5 M phosphoric acid in DMSO, and the slurry was then diluted with DMSO before filtering (0.2 μm RC, Lab Logistics Group, Germany) and further analyzing by HPLC (n=2). The drug loading was determined to be 81.3%.

[0258] Comparative Example 2 Phase Ia Clinical Trials: An open pilot Phase Ia clinical trial was conducted to evaluate the pharmacokinetics, tolerability, and safety of the coated azacitidine microparticles of Comparative Example 1 above suspended in Hyonate vet (Boehringer Ingelheim Animal Health, aqueous solution containing sodium hyaluronate (10 mg / mL), sodium chloride (8.5 mg / mL), disodium phosphate (0.223 mg / mL), disodium monohydrogen phosphate (40 μg / mL), HCl, and NaOH for pH adjustment) and administered as a subcutaneous injection for the treatment of intermediate 2 or higher risk MDS, CMML, or AML in patients already receiving treatment with azacitidine.

[0259] AUC 0-24h , AUC 0-last , AUC 0-∞) , C max , C las t, terminal t1 / 2 , volume of distribution V d Pharmacokinetic parameters including concentration and clearance were measured.

[0260] Local tolerance was measured by examination of the injection site for pain, tender erythema / redness, and induration / swelling, which were rated on a 4-point scale, with 1 being considered mild and 4 being considered potentially life-threatening.

[0261] The study was intended to include 6 patients, consisting of a screening phase, a treatment phase, an interim analysis, and a follow-up phase.

[0262] Inclusion criteria included: · Written informed consent prior to any study-specific procedures. Patients aged 18 or older Body mass index (BMI) > 19 and < 32 kg / m at screening 2 BSA At least 6 cycles of treatment for patients diagnosed with: 2 Current treatment with azacitidine corresponding to BSA ×5 or ×4: a.Intermediate 2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS) b. Chronic myelomonocytic leukemia (CMML) with 10-29% myeloblasts c. Acute myeloid leukemia (AML) according to the World Health Organization (WHO) classification Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Hematology recovery and clinical chemistry evaluation by clinical practice at the start of the last azacitidine treatment cycle prior to the screening visit Female subjects of non-childbearing potential (defined as premenopausal women with documented tubal ligation or hysterectomy or bilateral oophorectomy, or postmenopausal women defined as 12 months of amenorrhea) Male patients agreed to use appropriate contraception Willingness and ability to comply with study procedures, visit schedules, study limitations, and requirements

[0263] Exclusion criteria included: The patient must have participated in another study / intervention involving the investigational drug within 30 days (or 5 half-lives of the investigational drug prior to screening, whichever is longer) prior to screening. Diagnosis of malignancy within the past 5 years (excluding uncomplicated basal cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other localized malignancies that have been excised or irradiated with a high probability of cure) Any significant medical condition, laboratory abnormality, or psychiatric disorder that would prevent the patient from participating in the study. · History of alcohol or drug abuse within the past 12 months Any condition that would place the patient at unacceptable risk if he or she were to participate in the study, including the presence of a laboratory abnormality Any other reason for ineligibility to participate as determined by the investigator.

[0264] The duration of patients in the study was intended to be approximately 2-3 months. This time frame consisted of a 3-4 week screening period followed by days 1-4 of uncoated azacitidine (Vidaza® or generic azacitidine (Mylan), lyophilized powder for injection suspended in water for injection), both at 100 mg / m 2 The treatment phase consisted of approximately 4 weeks, including daily injections of BSA, 25 mg / mL.

[0265] Samples were taken for pharmacokinetic analysis on day 4 (before study drug initiation). Mean maximum plasma concentration (C max ) is 562ng / mL, with a t of 0.433 hours max The mean half-life was 6.82 hours. Mean AUC inf was 1120 ng / mL.

[0266] On day 5, a single dose of the test drug suspension (100 mg / m2 BSA, 100 mg / mL) was administered. Samples were to be collected for pharmacokinetic analysis on days 5-8, then on days 10, 12, 15, 17, and 19.

[0267] Also, after the study phase, it was intended that the last azacitidine dose would be replaced with a single dose of azacitidine comparator (as above) and a follow-up visit would be scheduled on the same day.

[0268] However, after two enrolled patients had been admitted to the study, the study was put on hold following a meeting of the internal safety committee responsible for reviewing the safety data.

[0269] It was noted that both patients exhibited induration and inflammation (redness and mild pain) classified as moderate at the injection site. It was decided not to enroll any further patients in the study and to request additional expert review / analysis of the biopsy results from the two patients.

[0270] Nevertheless, the plasma concentration time curves of two patients after administration of the test drug are shown in Figures 1 and 2, respectively, and show a clear steady-state sustained release of azacitidine from the injected test drug formulation. The plasma concentration time curves are graphed on a semi-logarithmic scale (squares). The mean maximum plasma concentration (C max ) is 94.8ng / mL, (T max ) occurred 1.02 hours later. The mean half-life was 15.2 hours. Mean AUC inf was 495 ng / mL.

[0271] Example 1 Combination preparation of the present invention Various formulations of the present invention containing a combination of azacitidine and indomethacin are prepared as follows.

[0272] (A) A mixture of microparticles of azacytidine and indomethacin in a weight ratio of 100:1 to 1:10 is prepared by jet milling. The particle size distribution determined by laser diffraction is 0.1-100 μm mean particle size.

[0273] The resulting powder is coated with ALD as described above in Comparative Example 1, formulated in a vehicle, and used to treat patients suffering from MDS as described above in Comparative Example 2.

[0274] (B) Prepare microparticles containing, for example, a co-precipitated mixture of azacytidine and indomethacin in a weight ratio of 100:1 to 1:10. The particle size distribution, determined by laser diffraction, is between 0.1 and 100 µm in mean particle size.

[0275] The microparticles are coated with ALD as described above in Comparative Example 1, formulated in a vehicle, and used to treat patients suffering from MDS as described above in Comparative Example 2.

[0276] (C) Two sets of microparticle samples are prepared separately by jet milling. The first set contains azacytidine and the second set contains indomethacin. The particle size distribution in both sets of samples, as determined by laser diffraction, is between 0.1 and 100 μm.

[0277] Both sets of samples are coated separately by ALD, as described in Comparative Example 1 above, and mixed in a formulation where the weight ratio between the first and second set of powders is between 100:1 and 1:10.

[0278] The mixed powder is formulated in a vehicle and used to treat patients suffering from MDS as described in Comparative Example 2 above.

[0279] (D) A sample of azacitidine is prepared as described above in Comparative Example 1 and formulated in a vehicle as described above in Comparative Example 2. Additional formulations containing indomethacin particles are similarly prepared.

[0280] Both formulations are used for essentially simultaneous injections at different sites for the treatment of patients suffering from MDS, as described above in Comparative Example 2. The dose ratio by weight of azacitidine and indomethacin in the two different injections is 100:1 to 1:10.

[0281] (E) Coated particles of azacitidine are prepared essentially as described in Comparative Example 1 above and formulated in a vehicle described in Comparative Example 2 above, further comprising dissolved and / or suspended indomethacin.

[0282] This formulation is used to treat patients suffering from MDS, as described in Comparative Example 2 above.

[0283] In all of the above cases (A) to (E), the inflammatory response at the subcutaneous administration site (and the formed depot) is suppressed by the anti-inflammatory properties of indomethacin.

[0284] Comparative Example 3 Mixed oxide coated azacitidine microparticles II The same procedure as described in Example 1 was carried out to produce coated azacitidine microparticles with a drug loading determined to be 80.1%.

[0285] Comparative Example 4 Mixed oxide coated azacitidine microparticles III Essentially the same procedure described in Example 1 was carried out, except that 30 ALD cycles were performed at a reactor temperature of 50° C. and a coating sequence of two ALD cycles using diethylzinc and water as precursors, followed by one cycle of trimethylaluminum and water, repeated 10 times, was used to form a mixed oxide layer with an atomic ratio of zinc:aluminum of 2:1. The thickness of the first layer was estimated to be about 5 to about 10 nm.

[0286] The powder was removed from the reactor and deagglomerated by passing it through a polymeric sieve with a mesh size of 20 μm using a sonic shifter, then the deagglomerated powder was reloaded into the ALD reactor and 30 more ALD cycles were performed as above to form a second layer of mixed oxides in the same ratios, extracted from the reactor and deagglomerated using a sonic shifter as above, and the process was repeated to form a total of eight layers.

[0287] Drug loading was determined to be 69.1%.

[0288] Comparative Example 5 Mixed oxide coated indomethacin microparticles A microparticle sample of indomethacin (Recce Pharmaceuticals, Australia) was prepared by jet milling. The particle size distribution, determined by laser diffraction, was as follows: D 10 1.2μm, D 50 3.8μm, D 90 11.3 μm.

[0289] The same ALD coating and intermittent deagglomeration process as described in Example 1 was carried out to form coated indomethacin microparticles having four distinct mixed oxide layers with an atomic ratio of zinc:aluminum of 3:1.

[0290] The drug loading was determined to be 80.1%.

[0291] Comparative Example 6 Mixed oxide coated lactose microparticles A fine particle sample of lactose (InhaLac® 400, Meggle, Germany) was used. The nominal particle size distribution was as follows: 10 0.8~1.6μm, D 50 4.0~11.0μm, D 90 15~35.0μm.

[0292] The powder was loaded into an ALD reactor (Picosun, SUNALE™ R-series, Espoo, Finland) and 48 ALD cycles were performed at a reactor temperature of 50 °C. The coating sequence consisted of three ALD cycles with diethylzinc and water as precursors for three ALD cycles, followed by one cycle of trimethylaluminum and water, repeated 12 times to form a mixed oxide layer with a zinc:aluminum atomic ratio of 3:1. The thickness of the first layer was about 8-16 nm (estimated from the number of ALD cycles).

[0293] The powder was removed from the reactor and deagglomerated by forcing it through a polymeric sieve with a mesh size of 20 μm using a sonic sifter.

[0294] The resulting deagglomerated powder was reloaded into the ALD reactor and subjected to 48 additional ALD cycles as before to form a second layer of the mixed oxides in the aforementioned ratios, and subsequently extracted from the reactor.

[0295] The particle size distribution of the coated lactose microparticles, as determined by laser diffraction, was as follows: D 10 2.1μm, D 50 7.6μm, D 90 23.4μm.

[0296] Example 2 Combination Preparation II of the Present Invention The coated microparticles from Comparative Example 3 above were co-suspended in Hyonate vet in glass vials along with the coated indomethacin microparticles from Comparative Example 5 above to obtain final concentrations of each coated active ingredient as shown in Table 1 below, where the formulations are also identified by the methods mentioned below. [Table 1]

[0297] Comparative Example 7 Formulations Comprising Mixed Oxide Coated Azacitidine, Indomethacin, and Lactose Microparticles Following the procedures described in Example 2 above, suspensions of azacytidine coated microparticles at final concentrations of 100 mg / mL and 200 mg / mL (hereinafter referred to as "Formulation B" and "Formulation E", respectively), indomethacin (from Comparative Example 5 above), and lactose coated microparticles (from Comparative Example 6 above), labeled "Formulation C" (indomethacin) and "Formulation A" (lactose), respectively, at a final concentration of 100 mg / mL in 2.2 mL of Hyanoate vet were produced.

[0298] Example 3 Mini Pig Study I The objective of this study, carried out at Scantox A / S, Denmark, was to evaluate the local tolerance and pharmacokinetics of azacitidine formulated according to the present invention administered by subcutaneous injection to minipigs, as well as the local tolerance following administration of azacitidine formulated according to the present invention and indomethacin formulated as described herein.

[0299] Minipigs were chosen as the test model due to their well-accepted suitability in this type of study and the similarity of skin physiology between humans and minipigs. To reduce the risk of severe local reactions, a staggered dose scheme was chosen, starting with two doses corresponding to ¼ and ½ of the equivalent human clinical dose before reaching the full dose.

[0300] The animals weighed 24.9 kg when allocated to the study and were housed in accordance with EU Directive 2010 / 63 / EU of 22 September 2010 on the protection of animals used for scientific purposes. In brief, standard minipig chow, in an amount of approximately 350 g per chow, was offered twice a day (morning and afternoon). The amount of chow could be adjusted during the course of the study to allow for a reasonable growth of the animals. A supply of dehydrated grass (Compact Gras, Hartog BV, Netherands) was also given daily and the animals had free access to household quality drinking water.

[0301] One week prior to the start of treatment, animals were anesthetized by intramuscular injection in the neck (1.0 mL / 10 kg body weight) and a total of six injection sites (approximately 2×2 cm) were tattooed on the back of the neck.

[0302] The animals were then anesthetized again 3 days before treatment and an ear vein catheter was implanted to collect blood samples during the study. For pain treatment during the study, the animals were given an intramuscular injection of meloxicam 5 mg / mL (0.08 mL / kg) into the hind limb immediately prior to implantation and administered once daily for the next 2 days.

[0303] Animals received an intravenous injection of 200 mg ampicillin / mL (0.05 mL / kg). Catheters were flushed with 10 mL of sterile saline and locked using 0.5 mL of TauroLock Hep500 (taurolidine citrate with 500 IE / mL heparin). A stopper, e.g., BioNectar IV Access System, was applied to the luer.

[0304] Between blood samples, TauroLockTM Hep500 creates a heparin lock on the catheter.

[0305] A single dose of the test formulation was given by subcutaneous injection at each of the six marked injection sites as shown in Table 2 below. [Table 2]

[0306] Local tolerance On day 1 of the study, animals were anesthetized and administered Formulations A and B subcutaneously at injection sites 1, 2, and 3 with the relevant dose volumes as shown in Table 2 above. On day 41 of the study, animals were anesthetized and administered Formulations D and C subcutaneously at injection sites 5 and 6 with the relevant dose volumes as shown in Table 2 above.

[0307] These injections were assessed for local tolerance.

[0308] In each case, prior to injection, the relevant sample vial was inverted three times immediately before withdrawing the sample for each injection in order to avoid settling of the test material and resulting deviation from the correct dose.

[0309] All clinical signs of ill-health and behavioral changes were recorded daily. In addition, dose-related observations were performed pre-dose / related and within 30 minutes post-dose and any deviations from normal were noted.

[0310] Injection sites were photographed, scored, and recorded 30 minutes, 2 hours, and 6 hours after dosing, and then recorded daily until no more scores were indicated. From day 10 onwards, no photographs were taken and injection sites were only scored every 2 days until no more scores were indicated or the study was terminated.

[0311] Injection sites 5 and 6 were photographed, scored, and recorded 30 minutes, and 2 and 6 hours after dosing, and daily through day 48. Thereafter, no photographs of the injection sites were taken and the injection sites were only scored twice weekly until scoring was not indicated or the study was terminated.

[0312] Particular attention was paid to bleeding, erythema, swelling (adaptation / measurement of size), hardness / induration and necrosis, as well as any other signs of inflammatory or allergic reaction. Parameters were scored according to the following grading system: 0 (absent), 1 (minimal), 2 (slight), 3 (moderate), and 4 (marked).

[0313] Blood samples were taken from the animals and clinical pathology parameters were assessed on day 2. An additional sample was taken on day 5. Animals were fasted overnight but had access to water before blood samples were taken.

[0314] For hematology, at least 2.5 mL of K3 EDTA stabilized blood was collected. From this sample, a backup smear was prepared and stained with May-Grunwald and Giemsa to allow later manual determination of the white blood cell percentage. The smear was not analyzed and was discarded at the end of the study. For coagulation studies, 1.8 mL of citrate stabilized blood was collected. The parameters, methods and units for the laboratory investigations are presented in Table 3 below. [Table 3]

[0315] Approximately 3 mL of blood was collected for clinical chemistry in tubes with a coagulation activator for serum. The parameters, methods and units for the laboratory investigations are presented in Table 4 below. [Table 4]

[0316] Full thickness biopsies were taken from injection sites 1 on days 3 and 7, and from injection sites 2 and 3 on days 2 and 6. A single control biopsy was taken outside the injection site for comparison with histopathological evaluation. Full thickness biopsies were taken from injection sites 5 and 6 on days 43 and 47.

[0317] Animals were anesthetized prior to biopsy collection and were given an intramuscular injection of 10 mg / mL (0.02 mL / kg) methadone to prevent pain responses approximately 30 min prior to the first sampling of the biopsy.

[0318] Biopsies were collected using an 8 mm punch and fixed in phosphate-buffered neutral 4% formaldehyde. After fixation, specimens were trimmed and processed. Specimens were embedded in paraffin, sectioned at a nominal thickness of approximately 5 μm, stained with hematoxylin and eosin, and examined by light microscopy. All pathological findings were entered directly into Instem Provantis® (version 9.3.0.0). Histological changes were graded on a 5-point scale (minimal, mild, moderate, marked, and severe).

[0319] Pharmacokinetics (PK) On study day 22, animals were anesthetized and administered Formulation B subcutaneously at injection site 4 at the relevant dose volume as shown above in Table 4. This injection was evaluated for PK parameters.

[0320] Prior to injection, the relevant sample vial was inverted three times immediately prior to withdrawing the sample as described above for each injection to avoid settling of the test material and resulting deviation from the correct dose.

[0321] On the day of dosing, blood samples were taken at the following time points: pre-treatment and 30 min, 2 h, 6 h, 10 h, 24 h, 48 h, 72 h, 120 h, and 168 h after treatment.

[0322] Approximately 3 mL of blood samples were collected from the jugular / bijugular trunk. Blood was sampled into vacutainers containing K2-EDTA as an anticoagulant. The vacutainers were placed in ice water until centrifugation (10 min, 1270G, +4°C). Each plasma sample was divided into two aliquots of approximately 0.5 mL, transferred to cryotubes, and frozen at or below -18°C within 90 min of collection. The first set of samples was sent on dry ice (approximately -70°C) for analysis (shipment was sent without a thermologger). The second set of samples was stored at or below -18°C as backup samples. The backup samples were shipped a few days after receipt of the primary samples.

[0323] Azacitidine in plasma was determined by UPLC-MS / MS. Azacitidine was extracted from plasma by protein precipitation using DMF:acetonitrile (5:95). After injection into a linear phase chromatography column, the material was eluted with an acetonitrile and aqueous gradient and detected by MS / MS.

[0324] Individual plasma concentration profiles were subjected to non-compartmental pharmacokinetic analysis using the software PKanalix (version 2020).

[0325] If the plasma concentration obtained in the pre-dose sample was below the LLOQ, the data point was entered as zero. All other concentrations below the LLOQ were entered as half the value of the LLOQ (1 / 2*LLOQ). Consecutive data points below the LLOQ after Tmax were excluded from modeling and analysis.

[0326] The maximum plasma concentration (Cmax) and the time at which it occurred (Tmax) were estimated by visual inspection of the data.

[0327] The area under the curve from time 0 to the time of the last quantifiable concentration (AUC(0-t)) and the area under the curve from time 0 to infinity (AUCinf) were calculated according to the linear / logarithmic trapezoidal method. If the extrapolated area (AUC(extrapolated%)) was greater than 20%, the AUCinf was considered unreliable.

[0328] Half-lives T1 / 2 were calculated as ln2 / 1z, where 1z was the elimination rate constant. Half-lives were calculated only if at least three data points could be included. If the regression line yielded an Rsq of less than 0.80, the results were not considered reliable.

[0329] After collection of the last blood sample / treatment, the animals were no longer part of the study and were terminated.

[0330] result No reaction was initially observed after administration of Formulation A (lactose) at injection site 1. However, on day 14, a soft swelling was observed (maximum 10×15 mm, barely perceptible).

[0331] The day after administration of Formulation B at injection site 2 (azacitidine, 50 mg), a hard swelling (maximum 40 x 20 mm) was observed that persisted for at least 28 days. Minimal to slight erythema was observed on days 2 and 3, and again from day 7 onwards. The day after administration of Formulation B at injection site 4 (also azacitidine, 50 mg), a soft swelling (maximum 10 x 10 mm, barely perceptible) persisted for up to 11 days after administration (days 23-33). From days 23 to 28, minimal erythema was observed.

[0332] However, the day after administration of Formulation B at injection site 3 (azacitidine, 100 mg), a firm, well-circumscribed swelling (up to 55×30 mm) at the injection site occurred, which persisted for at least 28 days. Mild erythema was observed on days 2 and 3, and again from day 7 onwards.

[0333] Conversely, the day after administration of Formulation D (azacitidine 50 mg + indomethacin 50 mg) at injection site 5, no injection site reactions were observed.

[0334] With regard to PK parameters, a single subcutaneous dose of 50 mg coated azacitidine (injection site 4) demonstrated systemic exposure with a sustained release profile, as shown in Figure 3. The duration was 120 hours, with 47% of exposure observed within the first 12 hours after dosing.

[0335] The histopathological results showed the following: Injection site 2: moderate inflammation and moderate necrosis on day 3, mild inflammation and moderate necrosis on day 7. Injection Site 5 Moderate inflammation and mild necrosis on day 45 (3 days after injection) and minimal inflammation and minimal necrosis on day 49 (7 days after injection).

[0336] It was concluded that subcutaneous administration of Formulation D (combination of mixed oxide coated azacitidine and mixed oxide coated indomethacin) caused fewer skin reactions than subcutaneous administration of Formulation B (mixed oxide coated azacitidine alone).

[0337] Example 4 Mini Pig Study II A study similar to that described in Example 3 above was carried out in five minipigs. On the day of arrival, animals were assigned a final number using a randomization scheme. Animals received a chip with a unique numeric code.

[0338] Approximately one week prior to the start of treatment, two injection sites were marked on the neck of the minipigs in the same manner as described in Example 3 above.

[0339] The animal treatment schedule is as shown in Table 5 below, with reference to the specific formulations prepared according to the relevant Examples and Comparisons above. Vidaza® (Mylan), a commercially available injectable formulation of azacitidine having a concentration of 25 mg / mL, can be considered to provide an equivalent dose of "uncoated" azacitidine. [Table 5]

[0340] Essentially the same treatment protocol was followed as described above in Example 3. For each animal, a subcutaneous injection of the appropriate formulation was administered at the dose volume indicated above on day 1 (injection site 1 for each animal) and day 8 (injection site 2 for each animal).

[0341] Observations were performed at necropsy on day 29 essentially in the same manner as described in Example 3 above.

[0342] mm 3 The size of the inflammatory swelling at is shown in Figure 4 as follows: Animal 1 / injection site 1 (50 mg azacitidine, lower concentration particles, diamonds), Animal 3 / injection site 1 (50 mg azacitidine, higher concentration particles, triangles), Animal 2 / injection site 2 (50 mg azacitidine + 50 mg indomethacin with lower concentration particles, crossed), and Animal 5 / injection site 2 (50 mg azacytidine + 25 mg indomethacin, squares).

[0343] FIG. 4 clearly shows the profound effect of administration of azacitidine with indomethacin.

Claims

1. 1. An injectable pharmaceutical or veterinary formulation suitable for subcutaneous or intramuscular injection, comprising: (a) a plurality of particles having an average diameter by weight, number, or volume that is from about 500 nm to about 100 μm, the particles comprising a solid core that includes a biologically active agent coated with a coating that includes at least one coating material applied by a vapor deposition technique; (b) the particles are suspended in a carrier system comprising a pharmaceutically or veterinarily acceptable vehicle; and (c) the formulation further comprises an anti-inflammatory agent, and the sustained release component is also applied to the anti-inflammatory agent; (d) the formulation forms a depot after subcutaneous or intramuscular injection; Injectable pharmaceutical or veterinary preparations.

2. 10. The formulation of claim 1, wherein the sustained release component provides sustained release of the biologically active agent and the anti-inflammatory agent at essentially the same rate and / or over essentially the same period of time.

3. 3. The formulation of claim 1 or claim 2, wherein the coating material comprises one or more metal oxides.

4. 4. The formulation of claim 3, wherein the coating material comprises zinc oxide.

5. 10. The formulation of claim 1, wherein the coating material comprises at least one separate mixture of zinc oxide and one or more other metal and / or metalloid oxides in an atomic ratio that is between about 1:10 (e.g., about 1:6 or about 1:1) and up to about 10:1 (e.g., about 6:1) atomic ratio.

6. 6. The formulation of claim 5, wherein the one or more other metal and / or metalloid oxides are selected from aluminum oxide and / or silicon dioxide.

7. 10. The formulation of claim 1, wherein the core is coated with one or more discrete layers surrounding the core, wherein if two or more discrete layers of coating material are applied, they are applied sequentially to the core.

8. 8. The formulation of claim 7, wherein 2 to 10 separate layers of said coating material are applied.

9. 10. The formulation of claim 1, wherein the particles have an average diameter based on weight, number, or volume of about 1 μm to about 50 μm.

10. 10. The formulation of claim 1, wherein the total thickness of the coating is from about 0.5 nm to about 2 μm.

11. 10. The formulation of claim 1, wherein the vapor deposition technique is atomic layer deposition.

12. 10. The formulation according to claim 1 in the form of a sterile injectable and / or infusible dosage form.

13. 13. The formulation of claim 12 in a form that is administrable via a surgical administration device to form a depot formulation.

14. 10. The formulation of claim 1, wherein the biologically active agent produces or can be expected to produce an inflammatory response when administered to a patient.

15. 15. The formulation of claim 14, wherein the biologically active agent is selected from the group consisting of anti-tumor agents, topoisomerase inhibitors, immunomodulators, immunostimulators, immunosuppressants, chemotherapeutic agents, growth factors, vasodilators, radiopharmaceuticals, and combinations thereof.

16. 16. The formulation of claim 14 or 15, wherein the biologically active agent is a cytokine, a protein, a vaccine, or a peptide.

17. The biologically active agent is selected from the group consisting of daratumumab, isatuximab, actinomycin, azacitidine, azathioprine, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, chlorambucil, cladribine, clofarabine, cytarabine, dabrafenib, dacarbazine, dactinomycin, daunorubicin, decitabine, docetaxel, docetaxel, Xifluridine, 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, oxazomib Liplatin, paclitaxel, panobinostat, pemetrexed, pixantrone, procarbazine, tegafur, temozolomide, teniposide, thioguanine, thiotepa, topotecan, trabectedin, valrubicin, venetoclax, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, bendamustine, bleomycin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cycloheximide 15. The formulation of claim 14, wherein the active ingredient is selected from the group consisting of rosporin, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, mercaptopurine, midazolam, mitomycin, oxaliplatin, temsirolimus, thioguanine, thalidomide, pomalidomide, lenalidomide, apremilast, pharmaceutically acceptable salts of any of these active ingredients, and combinations thereof.

18. 18. The formulation of claim 17, wherein the biologically active agent is selected from the group of azacitidine and lenalidomide.

19. 10. The formulation of claim 1, wherein the anti-inflammatory agent is selected from butylpyrazolidine, acetic acid derivatives or related substances, oxicams, propionic acid derivatives, fenamates, coxibs, nonsteroidal anti-inflammatory agents, corticosteroids, quinolines, gold preparations, antihistamines, and combinations thereof.

20. The anti-inflammatory agent is selected from the group consisting of phenylbutazone, mofebutazone, oxyphenbutazone, clofezone, kebuzone, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpyramide, oxametacin, proglumetacin, ketorolac, aceclofenac, bufexamac, piroxicam, tenoxicam, droxicam, lornoxicam, meloxicam, ibuprofen, naproxen, ketoprofen, fenoprofen, and fenbufen. , benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen, alminoprofen, dexketoprofen, vedaprofen, carprofen, tepoxalin, mefenamic acid, tolfenamic acid, flufenamic acid, meclofenamic acid, flunixin, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, firocoxib, robenacoxib, mavacoxib, cimicoxib buprenorphine, nabumetone, niflumic acid, azapropazone, glucosamine, benzydamine, glycosaminoglycan polysulfate, proquazone, orgotein, nimesulide, feprazone, diacerein, morniflumate, tenidap, oxaceprol, chondroitin sulfate, pentosan polysulfate, aminopropionitrile, 11-dehydrocorticosterone, 11-deoxycorticosterone, 11-deoxycortisol, 11-ketoprogesterone, 11β-hydroxypregnenolone, 11β-hydroxyprogesterone, 11β,17α,21-trimethylolpropanediol Hydroxypregnenolone, 17α,21-dihydroxypregnenolone, 17α-hydroxypregnenolone, 17α-hydroxyprogesterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxycorticosterone, 18-hydroxyprogesterone, 21-deoxycortisol, 21-deoxycortisone, 21-hydroxypregnenolone (prevediolone), aldosterone, corticosterone (17-deoxycortisol), cortisol (hydrocortisone), cortisone, pregnenolone, progesterone,Flugestone (flurogestone), fluorometholone, medrysone (hydroxymethylprogesterone), prebedilone acetate (21-acetoxypregnenolone), chloroprednisone, cloprednol, difluprednate, fludrocortisone, fluocinolone, fluperolone, fluprednisolone, loteprednol, methylprednisolone, prednicarbate, prednisolone, prednisone, tixocortol, triamcinolone, alclometasone, beclomethasone, betamethasone, clobetasol, clobetasone, clocort lon, desoximetasone, dexamethasone, diflorasone, difluocortolone, fluchlororone, flumethasone, fluocortin, fluocortolone, fluprednidene, fluticasone, fluticasone furoate, halometasone, meprednisone, mometasone, mometasone furoate, paramethasone, prednylidene, rimexolone, urobetasol (halobetasol), amcinonide, budesonide, ciclesonide, deflazacort, desonide, formocortal fluchloronone acetonide (flucloronide), fludroxycortide (flurandoles) fluocinolone, flurandrenolide), flunisolide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, oxycinchophen, gold sodium thiomalate, gold sodium thiosulfate, auranofin, aurothioglucose, aurotioprol, penicillamine, bucillamine, acrivastine, alimemazine, antazoline, astemizole, azatadine, azelastine, bamipine, bilastine, bromdiphenhydramine, brompheniramine, buclizine, cetirizine, cinnarizine, cyclizine, cyproheptadine , deptropine, desloratadine, dexbrompheniramine, dexchlorpheniramine, diphenylpyraline, dimenhydrinate, dimethindene, doxylamine, ebastine, epinastine, phenindamine, pheniramine, fexofenadine, histapirodine, hydroxyethylpromethazine, isothipendyl, carbinoxamine, ketotifen, kifenadine, clemastine, chlorcyclizine, chlorphenamine, chlorphenoxamine, chloropyramine, levocetirizine, loratadine,2. The formulation of claim 1, wherein the active ingredient is selected from the group consisting of mebhydroline, mequitazine, meclozine, mepyramine, methapyrilene, methdilazine, mizolastine, oxatomide, oxomemazine, pimethixene, promethazine, pyrobutamine, rupatadine, sequifenadine, talastine, thenarizine, terfenadine, thiazinam, thiethylperazine, thonzylamine, trimethobenzamide, tripelennamine, triprolidine, tritocubaline, pharmaceutically acceptable salts of any of these active ingredients, and combinations thereof.

21. 10. The formulation of claim 1, wherein the anti-inflammatory agent is formulated with the biologically active agent within the solid core that forms part of the formulation of the present invention.

22. 10. The formulation of claim 1, wherein the anti-inflammatory agent is dissolved and / or suspended within the carrier system.

23. 23. The formulation of claim 22, wherein the anti-inflammatory agent is provided in the form of additional particles having an average diameter by weight, number, or volume of about 500 nm to about 100 μm, comprising a core comprising the anti-inflammatory agent, the core being at least partially coated with one or more coating materials that allow release of the anti-inflammatory agent over the same or a different time scale as the biologically active agent.

24. 24. The formulation of claim 23, wherein the coating is as described in claim 3.

25. 10. A process for preparing the formulation of claim 1, wherein the coated particles are made by applying the layer(s) of coating material to the core and / or previously coated cores by vapor deposition techniques.

26. (i) coating a solid core with a first discrete layer of a coating material; (ii) the coated cores from step (i) are then subjected to a deagglomeration process step; (iii) then coating the deagglomerated coated cores from step (ii) with a second, discrete layer of coating material; (iv) repeating steps (ii) and (iii) to obtain as many individual layers as required.

27. 27. The process of claim 26, wherein the deagglomeration step performed between applications of the coating comprises sieving.

28. 28. The process of claim 27, wherein the sieving comprises vibratory sieving.

29. 30. The process of claim 28, wherein the vibrating screening comprises controlling a vibrating probe coupled to a screen.

30. 28. The process of claim 27, wherein the sieving comprises sonic sieving.

31. 10. A process for preparing the formulation of claim 1, wherein the coated particles are mixed with the carrier system after coating.

32. 10. An injectable and / or infusible dosage form comprising the formulation of claim 1 contained within a reservoir connected to and / or associated with an injection or infusion means.

33. 33. The dosage form of claim 32, which is a surgical administration device forming a depot formulation.

34. 33. The dosage form of claim 32, wherein the coated particles of claim 1 and the carrier system are contained separately and mixing occurs before and / or during injection or infusion.

35. 34. Use of the formulation of claim 1 or the dosage form of claim 32 for the manufacture of a medicament for treating a disease or condition in a patient, comprising: A use comprising administering said formulation or dosage form, wherein said biologically active agent employed in said formulation or dosage form is suitable for use in said disease or condition.

36. 34. Use of the formulation of claim 1 or the dosage form of claim 32 for the manufacture of a medicament for treating a disease or condition in a patient, comprising: (A) the formulation, the formulation of claim 1 provided that it does not contain an anti-inflammatory agent, or the dosage form containing any such formulation, wherein the biologically active agent used in the formulation or dosage form is suitable for use in the disease or condition; and (B) A pharmaceutical formulation comprising an anti-inflammatory agent as defined above or in admixture with one or more pharmaceutically or veterinarily acceptable excipients, such as a carrier system according to the present invention; comprising administering Use wherein components (A) and (B) are each provided in a form suitable for administration in conjunction with one another.

37. 37. Use according to claim 36, comprising associating component (A) according to claim 36 with component (B) according to claim 36, thus making the two components suitable for administration together.

38. (i) administering component (A) according to claim 36 to a patient having a relevant disease or condition; (ii) if the patient exhibits an inflammatory response after such administration; a. the formulation; b. The dosage form, or c. Administering component (B) of claim 36 to the patient; 37. The use of claim 36, comprising:

39. 37. The use of claim 36, wherein the disease or condition is cancer and the biologically active agent used in the formulation is an injectable anti-cancer drug.

40. A parts kit, (I) one of components (A) and (B) according to claim 36, (II) A kit of parts containing that component together with instructions for use in conjunction with the other of the two components.

41. 37. A kit of parts comprising components (A) and (B) of claim 36 packaged and presented together as separate components of a combination pack for use in conjunction with one another.

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