New Process

Abstract

A process for preparing a composition in the form of a plurality of particles having an average diameter based on weight, number, and / or volume in an amount of from 10 nm to about 700 μm, the particles comprising: (a) a solid core, preferably comprising a biologically active agent; and (b) two or more sequentially applied discrete layers, each of which comprises at least one separately applied coating material, the two or more layers together surrounding, enclosing, and / or encapsulating the core, the process comprising the sequential steps of: (1) depositing a first layer of at least one coating material by a vapor deposition technique onto the solid core; (2) subjecting the coated particles to agitation to deagglomerate particle aggregates formed during step (1) by a sieving step; (3) applying at least one additional layer of coating material to the deagglomerated particles; and (4) optionally repeating steps (2) and (3) one or more times to increase the total thickness of the at least one coating material surrounding the solid core, wherein at least one of the sieving steps includes a vibration sieving technique, which includes powering a vibration motor coupled to the sieve. The vapor deposition technique is preferably atomic layer deposition. If the core includes a biologically active agent, the composition may provide a delayed or sustained release of the active agent without a burst effect.

Description

[Technical field]

[0001] The present invention relates to a novel process for producing compositions that are useful 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 a more 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 sustained release compositions, it is also very important that the drug delivery composition provides a release profile that exhibits an initial minimal rapid release of the active ingredient (high plasma concentration of drug immediately after administration). For drugs with narrow therapeutic windows or that are toxic at high plasma concentrations, such a "burst" release can be dangerous.

[0005] In the particular case of injectable suspensions, it is also important to ensure that the suspended particle size is controlled so that they can be injected through a needle: if large aggregated 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). Based on its self-limiting properties, ALD can achieve atomic-level thicknesses that are controlled only by adjusting the number of growth cycles. Moreover, 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, for example, as a key technique in the production of next generation semiconductors, or for 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, which could potentially be used to formulate active pharmaceutical ingredients.

[0011] In ALD, a first precursor, which may be metal-containing, is delivered to 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, for example of 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] Alternatively, in "spatial ALD," separate reactor chambers contain each precursor, and the substrate being coated is moved from one reactor chamber to another for the coating to form. In this method, or other methods of ALD, the introduction of a precursor to the substrate being coated (or vice versa) can be considered equivalent to a "precursor pulse," and the separation of a precursor from the substrate being coated (or vice versa) can be considered equivalent to a "purging pulse."

[0013] The thickness of the film coating is controlled, among other things, by the number of ALD cycles performed.

[0014] In a typical ALD process, only monolayers of atoms or molecules are produced during a single cycle, so that no discernible physical interfaces form between these monolayers, resulting in essentially continuous bands across the surface of the substrate.

[0015] 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.

[0016] The agitation step is performed to solve a problem observed mainly with nano- and microparticles, namely, particle agglomeration during the ALD coating process, which results in the formation of "pinholes" due to the contact points between such particles. The redispersion / agitation step is performed by placing the coated substrate in water and sonicating, which results in deagglomeration and the destruction of the contact points between the individual particles of the coated active material.

[0017] The particles were then reloaded into the reactor and the steps of 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)).

[0018] As described in WO2014 / 187995, the process of performing a "set" of ALD coating cycles followed by intermittent dispersion results in transparent, distinct layers of coating defined by a transparent, visible physical interface between such coating layers. Such interfaces are more distinct than interfaces that may be seen between layers of different coating materials. The interfaces formed by such intermittent dispersion of particles are clearly visible as regions of high electron transparency by techniques such as transmission electron microscopy (TEM). As will be explained below, similar interfaces are not visible when a coating of the same material builds up from the surface of a substrate one atomic layer at a time.

[0019] As described in unpublished International Patent Application No. PCT / GB2020 / 053129, we have more recently found that it is advantageous to deagglomerate the agglomerated particles to primary particles outside the reactor by a dry process involving a combination of mechanical forcing means and sieving, particularly sonic sieving devices. This avoids the need to use invasive deagglomeration techniques such as sonication, as well as the need to dry the particles before returning them to the reactor for further coating. By carrying out the deagglomeration step in this manner, we have found that it is possible to present essentially completely pinhole-free coated particles in a form that can be readily processed into pharmaceutical formulations.

[0020] Attempts to scale up the process described in International Patent Application No. PCT / GB2020 / 053129 were found to have insufficient throughput for the amount of coated particles required for a commercially viable process, a problem that has been unexpectedly solved by the process described herein. Summary of the Invention

[0021] According to a first aspect of the present invention, there is provided a process for preparing a composition in the form of a plurality of particles having an average diameter based on weight, number and / or volume in an amount of from 10 nm to about 700 μm, the particles comprising: (a) a solid core, preferably comprising a biologically active agent; (b) two or more sequentially applied separate layers, each of which comprises at least one distinct (i.e., separately applied) coating material, and the two or more layers together surround, enclose, and / or encapsulate the core; The process consists of the following steps: (1) applying an initial layer of at least one coating material to the solid core by a vapor deposition technique; (2) subjecting the coated particles to agitation to deagglomerate particle agglomerates formed during step (1) by a sieving step; (3) applying at least one additional layer of coating material to the deagglomerated particles; and (4) optionally repeating steps (2) and (3) one or more times to increase the total thickness of the at least one coating material surrounding the solid core; At least one of the screening steps includes a vibration screening technique, the vibration screening technique including providing power to a vibration motor coupled to a screen; This process is hereinafter referred to as the "process of the invention." [Brief description of the drawings]

[0022] [Figure 1] Figures 1 and 2 show the respective azacitidine release profiles (percentage of azacitidine released per minute versus sampling time in a Sotax device for samples obtained according to Comparative Example 1 and Example 1, respectively). [Diagram 2] Figures 1 and 2 show the respective azacitidine release profiles (percentage of azacitidine released per minute versus sampling time in a Sotax device for samples obtained according to Comparative Example 1 and Example 1, respectively). [Diagram 3] Figures 3 and 4 show the respective indomethacin release profiles (percentage of indomethacin cumulatively released versus sampling time in a Sotax device for samples obtained according to Comparative Example 3 and Example 4, respectively). [Figure 4] Figures 3 and 4 show the respective indomethacin release profiles (percentage of indomethacin cumulatively released versus sampling time in a Sotax device for samples obtained according to Comparative Example 3 and Example 4, respectively). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] 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 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.

[0024] The process of the present invention is preferably used to prepare a pharmaceutical composition, where the composition may contain a pharmacologically effective amount of a biologically active agent, and further, the solid core preferably contains the biologically active agent.

[0025] In this regard, the solid core may consist essentially of or 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"). Biologically active agents also include biopharmaceuticals and / or biologics. Biologically active agents may also include mixtures of different APIs, either as different API particles or as particles containing multiple APIs.

[0026] "Consisting essentially of" a biologically active agent includes that the solid core contains essentially only the biologically active agent, i.e., is free of non-biologically active substances such as excipients, carriers (see below), and other active substances. This means that the core may contain less than about 5%, such as less than about 3%, such as less than about 2%, such as less than about 1% of such other excipients and / or active substances.

[0027] Alternatively, the core containing a biologically active agent may contain such an agent mixed with one or more pharmaceutical ingredients, which may include pharma- ceutically acceptable excipients such as adjuvants, diluents, or carriers, and / or may include other biologically active ingredients.

[0028] The biologically active agent may be presented 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 (and optionally other pharmaceutical ingredients described herein) should also remain in solid form while being coated, for example, in the ALD reactor, and should not physically or chemically degrade to a significant extent (i.e., about 10% w / w or less) while being coated or after being covered by at least one of the coating materials. The biologically active agent may further be presented in combination (e.g., as a mixture or as a complex) with another active material.

[0029] As used herein, the term "biologically active agent" or similar and / or related phrases generally refers to any agent or drug capable of producing some sort of physiological effect (whether in therapeutic or prophylactic capacity for a particular disease state or condition) in a living subject, including particularly mammalian and especially human subjects (patients).

[0030] 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, topoisomerases, immunomodulators, immunostimulants, immunosuppressants, anabolic steroids, anticoagulants, antiplatelet agents, anticonvulsants, antidementia agents, antidepressants, antidotes, antihyperlipidemic agents, antigout agents, antimalarials, antimigraine agents, anti-inflammatory agents, antiparkinsonian agents, antipruritics, antipsoriatic agents, antiemetics, antiobesity agents, anthelmintics, anti Asthmatics, Antibiotics, Antidiabetics, Antiepileptics, Antifibrinolytics, Antihemorrhagic, Antihistamines, Antitussives, Antihypertensives, Antimuscarinics, Antimycobacterials, Antioxidants, Antipsychotics, Antipyretics, Antirheumatics, Antiarrhythmics, Anxiolytics, Aphrodisiacs, Cardiac glycosides, Cardiac stimulants, Entheogens, Entactogens, Euphoric, Orexigenics, Antithyroids, Anxiolytics, Hypnotics, Neuroleptics, Astringents, Bacteriostatics, Beta-blockers, Calcium channel blockers, ACE inhibitors, Angiotensin II receptor antagonists, Renin inhibitors, Beta-adrenergic receptor blockers, Blood products products, blood substitutes, bronchodilators, cardiac arrhythmia drugs, 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 removers, glucocorticoids, mineralocorticoids, hemostatic agents, hallucinogens, hypothalamic-pituitary hormones, immune agents, laxatives, antidiarrheals, lipid regulators, muscle relaxants, parasympathomimetics, parathyroid calcitonin, selenics, statins, Stimulants, wake enhancers, decongestants, dietary minerals, biphosphonates, cough suppressants, ophthalmic drugs, ontological drugs, H1 antagonists, H2 antagonists, proton pump inhibitors, prostaglandins, radiopharmaceuticals, hormones, sedatives, antiallergic drugs, appetite stimulants, steroids, sympathomimetics, thrombolytic drugs, thyroid drugs, vaccines, vasodilators, xanthines, erectile dysfunction drugs, gastrointestinal drugs, histamine receptor antagonists, keratolytics, antianginal drugs, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, leukotriene inhibitors, macrolides, NSAIDs, nutritional supplements, opioid analgesics,The therapeutic agent may be selected from an opioid antagonist, a potassium channel activator, a protease inhibitor, an anti-osteoporosis drug, an anti-obesity drug, a cognitive enhancer, an anti-urinary incontinence drug, a nutritional oil, an anti-benign prostatic hyperplasia drug, an essential fatty acid, a non-essential fatty acid, a cytokine, a peptidomimetic, a peptide, a protein, a radiopharmaceutical, a geriatric drug, a toxoid, a serum, an antibody, a nucleoside, a nucleotide, a vitamin, a portion of genetic material, a nucleic acid, or a mixture of any of these.

[0031] 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, golimumab, belatacept, buserelin, velaglucerase alfa, tesamorelin, brentuximab vedotin, taliglucerase alfa, belimumab, aflibercept, asparaginase erwinia chrysanthemi, ocriplas amine, glucarpidase, teduglutide, raxibacumab, certolizumab astimlimab pegol, insulin isophane, epoetin zeta, obinutuzumab, fibrinolysin, also known as plasmin, 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, beractant, 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 (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.

[0032] 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, and the like. Mycin, 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.

[0033] The compositions made by the process 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.

[0034] The anesthetics that may also be used in the compositions made by the process of the present invention may be local or systemic. Local anesthetics that may be mentioned include amylocaine, ambucaine, articaine, benzocaine, benzonatate, bupivacaine, butacaine, butanilicaine, chloroprocaine, cinchocaine, cocaine, cyclomethycaine, dibucaine, diperodon, dimethocaine, eucaine, etidocaine, hexylcaine, fomocaine, photocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine, mepivacaine, mepricaine, cyclomethy ... Examples of such medicaments include rucaine, metabutoxycaine, nitracaine, orthocaine, oxetacaine, oxybuprocaine, paraethoxycaine, phenacaine, piperocaine, pyridocaine, pramocaine, prilocaine, procaine, procainamide, proparacaine, propoxycaine, pyrrocaine, quinisocaine, ropivacaine, trimecaine, tricaine, tropacocaine, or a pharma- ceutically acceptable salt of any of these.

[0035] Psychiatric drugs may also be used in the compositions made by the process 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, aripiprazole, asenapine, atomoxetine, baclofen, benperidol, bromperidol, bupropion, buspirone, butobarbital, carbamazepine, chloral hydrate, chlorpromazine, chlorprothixene, citalopram, clomethiazole, clominamide, clomid ... pramine, 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, hydrochloride, azithromycin, 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, peridiazine perphenazine, phenelzine, phenobarbital, pimozide, pregabalin, promethazine, prothipendyl, protriptyline, quetiapine, ramelteon, reboxetine, reserpine, risperidone, rubidium chloride, secobarbital, selegiline, sertindole, sertraline, sodium oxybate, 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.

[0036] Opioid analgesics that may be used in the compositions made by the processes 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.

[0037] Opioid antagonists that may be used in the compositions made by the processes 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.

[0038] Anticancer drugs that may be included in the compositions made by the process of the 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, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, erlotinib, estramustine, etoposide, everolimus, fludarabine, fluorouracil, gefitinib, guadecitabine, gemcitabine, hydroxycarbamide, hydroxyurea, idarubicin Cinnamon, idelalisib, ifosfamide, imatinib, irinotecan, ixazomib, cabozantinib, carfilzomib, crizotinib, lapatinib, lomustine, mechlorethamine, melphalan, mercaptopurine, mesna, methotrexate, mitotane, mitoxantrone, nelarabine, nilotinib, niraparib, olaparib, oxaliplatin, paclitaxel, panobinostat, pazopanib, pemetrexed, pixa Intolone, ponatinib, procarbazine, 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. A preferred biologically active agent is azacitidine.

[0039] 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, colorectal 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 disease 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.

[0040] 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 transfusion), refractory anemia with excess blasts, refractory anemia with excess blasts in transition, and chronic myelogenous leukemia (myelomonocytic leukemia).

[0041] Other drugs that may be mentioned for use in the compositions made by the process of the invention include immunomodulatory imide drugs such as thalidomide, and analogs thereof such as pomalidomide, lenalidomide, and apremilast, and pharmaceutically acceptable salts of any of these. Other drugs that are often 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.

[0042] Pharmaceutically 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 compound of the present invention 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 compound of the present invention in the form of a salt with another counterion using a suitable ion exchange resin.

[0043] Particular salts which may be mentioned include, for example, acid addition salts of hydrochloric acid, L-lactic acid, acetic acid, phosphoric acid, (+)-L-tartaric acid, citric acid, propionic acid, butyric acid, hexanoic acid, L-aspartic acid, L-glutamic acid, succinic acid, ethylenediaminetetraacetic acid (EDTA), maleic acid, methanesulfonic acid, etc.

[0044] The compositions made by the process of the present invention may contain a pharmacologically effective amount of a biologically active agent. The term "pharmacologically effective amount" refers to an amount of such an active ingredient, whether administered alone or in combination with another active ingredient, that is capable of imparting a desired physiological change (such as a therapeutic effect) to 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.

[0045] 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.

[0046] Administration of the compositions made by the process of the present invention can be continuous or intermittent (eg, by bolus injection). The dosage of the active ingredient can also be determined by the timing and frequency of administration.

[0047] In any event, a physician or other person skilled in the art will be able to routinely determine the actual dosage of any particular active ingredient which will be most suitable for an individual patient.

[0048] Alternatively, the compositions 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 condition, such as contrast agents or contrast media for bioimaging).

[0049] Non-biologically active adjuvants, diluents and carriers that may be used in the cores coated according to 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 specific peptides / proteins mentioned above, including vaccines. Thus, embedding the macromolecule complex in an excipient often results in a larger core for coating, and therefore a larger coated particle.

[0050] It is not a requirement that the core of the composition made by the process of the present invention contain a biologically active agent. Whether or not the core contains one or more biologically active agents, the core may contain and / or consist essentially of one or more non-biologically active adjuvants, diluents, and carriers (including emollients), and / or other excipients with functional properties (e.g., buffers and / or pH modifiers (e.g., citric acid)).

[0051] When injected, the formulations produced by the processes of the invention provide depot formulations that release the biologically active agent over an extended period of time, which can be at least about 3 days, e.g., about 5 days, or about 7 days, and up to about a year, e.g., about 3 weeks (e.g., about 2 weeks or about 4 weeks), or about 12 weeks (e.g., about 10 weeks or about 14 weeks).

[0052] The solid core is provided in the form of nanoparticles, or more preferably microparticles, with a preferred average diameter by weight, number, or volume of about 50 nm (e.g., about 100 nm, about 250 nm, etc.) to about 30 μm, for example, about 500 nm to about 100 μm, more specifically, about 1 μm to about 50 μm (e.g., about 25 μm, for example, about 20 μm).

[0053] As used herein, the term "weight-based average diameter" is understood by those skilled in the art to include the average 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 average diameter" is understood by those skilled in the art to include the average 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 average diameter" is understood by those skilled in the art to include the average 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 average diameter, such as area-based average diameter, and these other expressions of average 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).

[0054] 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.

[0055] Nevertheless, the present invention also allows for coating of particles of any shape. For example, irregularly shaped (e.g., "raisin" shaped), needle-shaped, flaky or rectangular 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, gaps, etc., such as fibrous or "entangled" particles, can also be coated according to the present invention.

[0056] 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., crushing, shearing, milling, or grinding to a particular weight-based average diameter (as described above), 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, spray drying including the use of supercritical fluids, precipitation, 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). Alternatively, nanoparticles may be made by well-known techniques such as gas condensation, attrition, chemical precipitation, ion implantation, pyrolysis, hydrothermal synthesis, and the like.

[0057] The particles may need to be washed and / or cleaned to remove impurities that may result from their production, and then dried (depending on the method by which the particles containing the cores are initially provided). 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. Once 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.

[0058] 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 create favorable adsorption / nucleation sites on the core for the ALD precursors.

[0059] Two or more layers of coating material are applied sequentially to the core. Preferred vapor deposition techniques include vapor 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 with each pulse instead of atoms), molecular layer epitaxy (MLE), chemical vapor deposition (CVD), atomic layer CVD, molecular layer CVD, physical vapor deposition (PVD), sputtering PVD, reactive sputtering PVD, evaporation PVD, and binary reaction sequence chemistry. ALD is the preferred coating method according to the present invention.

[0060] When ALD is used, the coating material may be prepared by feeding a precursor into the ALD reactor chamber (in a so-called "precursor pulse") to form a monolayer of atoms or molecules adsorbed on the surface of the particle. A second precursor is then pulsed into the reactor and reacts with the first precursor to form a monolayer of the compound 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").

[0061] In most cases, the first of the reaction sequence will involve the presence of some functional groups or free electron pairs or radicals on the surface to be coated (e.g., hydroxy groups). (-OH) or a primary or secondary amino group (-NH2 or -NHR, where R is, for example, an aliphatic group such as 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.

[0062] 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 (i.e., "separately applied") to a solid core containing a biologically active agent. Such "separate application" of a "separate layer, coating, or shell" means that the solid core is coated with a first layer of coating material, which layer is formed by two or more (e.g., a plurality or set of) cycles as described herein, each cycle producing a monolayer of coating material, and then the resulting coated core is subjected to some form of sieving step, such as a vibratory sieving technique, step, or process, as described herein.

[0063] 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 set of cycles, the coated cores are subjected to some form of sieving step, such as the vibratory sieving techniques, steps, or processes described herein, followed by a further set of cycles.

[0064] This process may be repeated as many times as necessary, in that the number of distinct layers of coating material as defined herein corresponds to the number of these intermittent screening steps, with the proviso that at least one of these screening steps comprises a vibratory screening step in accordance with the present invention. It is preferred that at least the final screening step comprises an essential vibratory screening step that is performed prior to application of the final layer (series of cycles) of coating material. However, it is further preferred that two or more (including each) of the screening steps comprise the vibratory screening technique, step or process described herein.

[0065] The vibratory sieving technique which is an essential part of the process of the present invention comprises a vibratory motor coupled to a sieve, providing a means for vibratory passing of the solid product mass formed by coating the cores through a sieve which may be located inside or (preferably) outside (i.e., outside) the reactor, and is 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 is repeated as many times as necessary and / or appropriate prior to applying the final layer(s) of coating material.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] The sieve and vibrating motor may be suspended from the mount (e.g., a frame that can be placed on the floor, etc.) 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 the process of the present invention include, for example, Russell Finex, SWECO, Filtra Vibracion, VibraScreener, Gough Engineering, and Farley Greene.

[0070] 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.

[0071] 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.

[0072] Where each screening step does not include an essential vibration screening technique, step, or process according to the present invention, the screening step may nevertheless be performed by one or more other means of forcing the coated mass through a screen, in a manual, mechanical, and / or automated manner. Thus, the mechanical force may take the form of tapping, vibration, application of a pressure gradient (e.g., a jet), horizontal rotation, mechanized cyclic displacement of a screen, centrifugal force, screening, or combinations thereof (e.g., vibration and tapping, rotation and tapping, etc.).

[0073] Such alternative forcing means is preferably mechanical and may be vibration, with suitable alternative means of applying a vibrational force (i.e., not including a vibrating motor coupled to a sieve) forcing the coated powder mass through a mesh or sieve. Alternative mechanical means of generating vibrations about the equilibrium point may include acoustic waves (including sound and ultrasound), or may be mechanical (e.g., tapping), or other methods including combinations thereof (e.g., ultrasound and sound, sound and tapping, ultrasound and tapping, etc.).

[0074] In such cases, at least one of these alternative mechanical sieving steps is preferably performed by a sonic sifter, as described below. Manufacturers of suitable sonic sifters include Advantech Manufacturing, Endecott, and Tsutsui.

[0075] 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.

[0076] 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.

[0077] Any one of the above throughputs represents 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 vibration sieving technique integral to the process of the present invention, 20 g of coated particles can be continuously sieved in a maximum of 20 minutes, or more preferably in only 5 minutes or less.

[0078] 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.

[0079] Surprisingly, the use of stainless steel mesh within a vibratory sieving technique is as gentle on particle coating as the use of softer polymeric sieving as part of a mechanical sieving technique such as sonic sieving, as demonstrated by the examples below.

[0080] 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.

[0081] 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 is not present for the vibration sifting technique, since it does not rely on sound waves to create vibrations in the sieve. Thus, the vibration sifting technique that is an essential part of the process of the present invention allows for sifting of larger particles than would be possible if alternative mechanical sifting techniques were used.

[0082] When the sieve is located external to the reactor (i.e., outside the reactor), step (2) of the process of the present invention involves discharging the coated particles from the vapor deposition reactor prior to subjecting the coated particles to agitation, and step (3) involves reintroducing the deagglomerated coated particles from step (2) into the vapor deposition reactor and applying at least one additional layer of coating material to the reintroduced particles.

[0083] Alternatively, the coated cores may be subjected to the aforementioned vibrosieving step internally without being removed from the apparatus in a continuous process. Such a process involves a means for vibratory passing the solid product mass formed by coating the cores through a sieve disposed within the reactor, configured to deagglomerate any particle agglomerates during said vibrosieving of the coated cores by passing 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.

[0084] Placing the sieve 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 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 and reduces the risk of contamination.

[0085] 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.

[0086] In ALD coating processes, such distinct physical interfaces are typically more difficult to observe because the coating occurs at the atomic level.

[0087] 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.

[0088] 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.

[0089] Thus, whether performed inside or outside the reactor, particle agglomerates are broken down by means of vibrating 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 size is so small (i.e., <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.

[0090] 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 a gas phase coating mechanism to the particles after such de-agglomeration by vibrating sieving means forms a complete coating on the particles, thus meaning that fully coated particles (individual or agglomerates of the desired size) are formed.

[0091] Whether carried out inside or outside a reactor, the process of the present invention may be carried out in a manner which involves carrying out steps (2) and (3) of the process at least once, preferably twice, more preferably three times, such as four times (including five times), more particularly six times, such as seven times, and not more than about 100 times, such as not more than about 50 times, such as not more than about 40 times (including not more than about 30 times), for example from 2 to 20 times, such as from 3 to 15 times, for example 10 times, such as 9 or 8 times, more preferably 6 or 7 times, especially 4 or 5 times.

[0092] 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 the final screening step comprises a vibratory screening step performed prior to application of the final layer (series of cycles) of coating material. However, it is further preferred that two or more (including each) of the screening steps comprise the vibratory screening techniques, steps or processes described herein.

[0093] The preferred repetition of the coating and deagglomeration steps further benefits from the improved throughput of the vibratory screening technique.

[0094] 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.

[0095] The minimum thickness of each individual layer / coating / shell is in the range of about 0.1 nm on average (eg, about 0.5 nm, or about 0.75 nm, for example 1 nm).

[0096] 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.

[0097] 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.

[0098] It has been found that applying a coating / shell followed by one or more deagglomeration 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 elements as deagglomeration occurs.

[0099] For example, if it is intended to provide the sample in a suspension prior to administration to a patient, it is necessary to provide deaggregated 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.

[0100] We have discovered that performing one or more of the deagglomeration steps described herein results in particles with 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.

[0101] In this regard, the (e.g., inorganic) material coating typically completely surrounds, encloses, and / or encapsulates the solid core containing the biologically active drug, thus minimizing the risk of an initial drug concentration burst resulting from direct drug contact with a solvent in which the associated 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.

[0102] Thus, in a further embodiment of the present 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%, such as at least about 99%, for example approximately or about 100% of the surface of the core, wherein the coating essentially completely surrounds, surrounds and / or encapsulates the core.

[0103] 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.

[0104] Quite surprisingly, we have also found that when using the vibratory sieving technique according to the invention, the above-mentioned low frequency pinholes, gaps, or cracks in the coating material can be maintained. This was surprising given that the technique described herein uses stainless steel sieves (rather than the softer polymeric sieves used in the mechanical sieving process described in International Patent Application No. PCT / GB2020 / 053129), which may be preferred for such vibratory sieving techniques. Previous attempts to manually pass particles through metal sieves caused significant formation of pinholes, gaps, or cracks in the coating material.

[0105] As described below, the process of the present invention results in deagglomerated coated particles that are essentially free of such cracks through which the active ingredient may be released in an uncontrolled manner. By the coating being "essentially free of such cracks" it is meant 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 may potentially be exposed (e.g., to the elements).

[0106] The layers of coating material can be collectively essentially uniform in thickness across the surface area of ​​the particle. By "essentially uniform" thickness is meant that the degree of variation in coating thickness of at least about 10%, e.g., about 25%, e.g., about 50% of the coated particles present in the compositions of the invention is no more than about ±20% (including no more than ±50%) of the average thickness as measured by TEM.

[0107] The coating materials that may be applied to the cores are pharma- ceutically acceptable, in that they should be essentially non-toxic.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] As noted above, because the compositions made by the processes of the present invention include two or more separate layers of inorganic coating material, the nature and chemical composition of those layers can vary from layer to layer.

[0112] 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.

[0113] 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.

[0114] The layers of coating material (individually or collectively) in the compositions made by the processes of the present invention may consist essentially of (e.g., greater than about 80%, e.g., greater than about 90%, e.g., about 95%, e.g., about 98%) iron oxide, titanium dioxide, or more preferably zinc oxide, silicon oxide, and / or aluminum oxide.

[0115] The process of the present invention is particularly useful where the coating material applied to the core comprises zinc oxide, silicon dioxide and / or aluminum oxide.

[0116] Thus, 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.

[0117] Non-limiting examples of precursors are as follows: zinc oxide precursors can be water and di-C1-C5 alkyl zinc, such as diethyl zinc; aluminum oxide precursors can be water and tri-C1-C5 alkyl aluminum, such as trimethyl aluminum; silicon oxide (silica) precursors can be water as oxygen precursor, and silane, alkyl silane, amino silane, and orthosilicate tetraethyl ester; iron oxide precursors 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.

[0118] It is further preferred that the inorganic coating material comprises a mixture of: (i) zinc oxide (ZnO); (ii) one or more other metal and / or metalloid oxides. The atomic ratio ((i):(ii)) is between at least about 1:6 and at most about 6:1.

[0119] Preferably, the atomic ratio ((i):(ii)) is between at least about 1:1 and at most about 6:1.

[0120] 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 materials.

[0121] Thus, the biologically active agent-containing core may be coated with a coating material comprising a mixture of zinc oxide and one or more other metal and / or metalloid oxides in an atomic ratio of zinc oxide to other oxides of at least about 1:6 (e.g., at least about 1:4, e.g., at least 1:2), preferably at least about 1:1 (e.g., at least about 1.5:1, e.g., at least about 2:1) (including at least about 2.25:1, e.g., at least about 2.5:1 (e.g., at least about 3.25:1 or at least about 2.75:1 (including 3:1)), and up to (i.e., up to) about 6:1 (including up to about 5.5:1), or up to about 5:1, e.g., up to 4.5:1 (including up to about 4:1) (e.g., up to about 3.75:1).

[0122] To produce 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, about one to about six 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, followed by one pulse of the other metal and / or metalloid-containing precursor, followed by a second precursor pulse to form one monolayer of the other metal and / or metalloid oxide. 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 produce the relevant oxides is not important, so long as the resulting atomic ratios are ultimately within the relevant range.

[0123] We have found that when coatings including zinc oxide are applied using ALD at low temperatures, such as from about 50° C. to about 100° C., the coating material is largely crystalline in nature (unlike other coating materials such as aluminum oxide and titanium oxide, which form amorphous layers).

[0124] 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.

[0125] We have found that these problems can be alleviated by making mixed oxide coatings as described herein. In particular, we have found that these problems can be alleviated by making a mixture of two or more metal and / or metalloid oxide (mixed oxide) coatings as described herein. In particular, by forming a mixed oxide coating as described herein, which may be composed primarily, but not entirely, 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 ingress of injection vehicles such as water. In this regard, it appears that the presence of the aforementioned perceived interfaces can be reduced or avoided entirely by employing the mixed oxide aspects of the 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).

[0126] In addition to the inorganic coatings employed in the formulations of the present invention, other coating materials, such as pharma- ceutically acceptable and essentially non-toxic coating materials, may also be applied either 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 layers.

[0127] The additional coating material may include organic or polymeric materials such as polyamides, polyimides, polyureas, polyurethanes, polythioureas, polyesters, or polyimines. The additional coating material may also include hybrid materials (such as between organic and inorganic materials), including materials that are combinations 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.

[0128] 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 stationary during use to carry out a vapor deposition technique, excluding negligible movement and / or vibration, such as caused by associated machinery, for example.

[0129] Furthermore, a so-called "stop-flow" process can be employed. Using the stop-flow process, the first precursor is fed into the reactor chamber and allowed to contact the core in the reactor chamber for a predetermined period of time (which can 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 a pump that can cause gas flow and / or a substantial absence of mechanical agitation of the core.

[0130] The employment of a stop-flow process can enhance the uniformity of the coating by allowing each gas to conform and diffuse into high aspect ratio substrates such as powders. The advantage can be even more pronounced when using slower reacting precursors, since the precursors are given more time to react on the surface. This can be particularly evident when depositing mixed oxide coatings according to the invention. For example, when depositing mixed zinc oxide / aluminum oxide coatings as described below, we have found that zinc-containing precursors, such as diethylzinc (DEZ), have a lower reaction probability towards the surface of the substrate than aluminum-containing precursors, such as trimethylaluminum (TMA).

[0131] 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.

[0132] 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.

[0133] 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.

[0134] Using such multi-pulse techniques, each precursor may be delivered to the reactor chamber as multiple "sub-pulses," each lasting 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 contacted with 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.

[0135] 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, for example about 50°C to about 100°C. The optimal process temperature depends on the reactivity of the precursors and / or substances (including biologically active agents) employed in the core and / or the melting point of the core material. If the core to be coated contains a biologically active component, lower temperatures such as about 30°C to about 100°C are preferably employed. In particular, temperatures of about 20°C to about 80°C, such as about 30°C to about 70°C, for example about 40°C to about 60°C, for example about 50°C are employed.

[0136] 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 would potentially be exposed (e.g., to the elements), two further optional steps may be applied to the coated particles before subjecting them to further processing of the pharmaceutical formulation.

[0137] 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").

[0138] 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.

[0139] The role of the 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 their 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.

[0140] For reasons described herein, the sealing shell preferably does not include zinc oxide, although it may include silicon dioxide or, more preferably, aluminum oxide.

[0141] A second optional step may include subjecting the few remaining particles having broken and / or cracked shells / coatings to a process in which all particles are suspended in a solvent (wherein the active ingredient is soluble, e.g., with a solubility of at least about 1 mg / mL, while the least soluble material of 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, e.g., by centrifugation, sedimentation, flocculation, and / or filtration, thereby ensuring that primarily intact particles remain.

[0142] The above optional step, as previously discussed, provides a means of further potentially reducing the possibility of a (possibly) undesirable initial peak (burst) in plasma concentration of the active ingredient.

[0143] 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).

[0144] Alternatively, at the end of the process, the separated particles may be resuspended in a solvent (e.g., water, with or without the presence of one or more pharma- ceutically acceptable excipients as defined herein) for subsequent storage and / or administration to a patient.

[0145] 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 an inorganic material) 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 / deposition process, to enhance coating efficiency, or to reduce agglomeration.

[0146] 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.

[0147] Alternatively, 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 may then be applied.

[0148] The outer surface of the particles of the compositions made by the process 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.

[0149] Alternatively, the moiety can be an anchoring group, such as a moiety containing silane functionality (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 anchoring group by covalent or non-covalent bonds (including hydrogen bonds or van der Waals bonds), or a combination thereof.

[0150] The presence of such an anchoring group may provide a versatile tool for targeted delivery to specific sites in the body. Alternatively, compounds such as PEG may be used to allow the 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).

[0151] The composition made by the process of the invention is suitable for administration to a patient as it is prepared (i.e., as a plurality of particles) or, preferably, is formulated with one or more pharma- ceutically acceptable excipients, including adjuvants, diluents, or carriers for use in the human or veterinary fields (including in therapy and / or in diagnosis, where the core contains diagnostic material).

[0152] Further provided are compositions made by the processes of the invention for use in medical, diagnostic and / or veterinary practice, and pharmaceutical (or veterinary) formulations comprising the compositions of the invention and a pharma- ceutically (or veterinarily) acceptable adjuvant, diluent or carrier.

[0153] The compositions of the invention may be administered locally, topically, or systemically, for example orally (enterally), by injection or infusion, intravenously or intra-arterially (including intravascular or other perivascular devices / formulations (e.g., stents)), intramuscularly, intraosseously, intracerebrally, intraventricularly, intrasynovially, intrasternally, intrathecally, intralesional, intracranially, intratumorally, dermal, intradermal, subcutaneously, transmucosally (e.g., sublingual or buccal), rectally, transdermal, nasal, pulmonary (e.g., inhalation, tracheal or bronchial), topically, or by any other parenteral route (e.g., subcutaneously or intramuscularly), optionally in the form of a pharmaceutical (or veterinary) formulation comprising the compound in a pharma- ceutically (or veterinarily) acceptable dosage form.

[0154] Incorporation of the compositions made by the process of the present invention into pharmaceutical formulations can be accomplished with due consideration of the intended route of administration and standard pharmaceutical practice. Pharmaceutically acceptable excipients, such as carriers, may be chemically inert to the biologically active agent and may have no adverse side effects or toxicity under the conditions of use. Such pharma-ceutically acceptable carriers may also impart immediate or modified release to the compositions made by the process of the present invention.

[0155] Pharmaceutical (or veterinary) formulations comprising compositions made by the processes 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.

[0156] For oral administration (i.e., administration to the gastrointestinal tract by oral administration accompanied by swallowing), the compositions made by the process of the present invention can be formulated in various dosage forms. The pharma- ceutically acceptable carrier or diluent can be solid or liquid. Solid formulations include granules (which may contain some or all of the particles of the compositions of the present invention in the presence of, for example, carriers and other excipients such as binders or pH adjusters), compressed tablets, pills, lozenges, capsules, cachets, and the like. Carriers include those previously described for formulating biologically active agents in the core, as well as materials well known to those skilled in the art, including magnesium carbonate, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, lactose, microcrystalline cellulose, low crystalline cellulose, and the like.

[0157] Solid dosage forms may contain additional excipients such as flavorants, lubricants, binders, preservatives, disintegrants, and / or encapsulating materials, For example, the compositions made by the processes of the present invention may be encapsulated, for example, in a soft or hard shell capsule, such as a gelatin capsule.

[0158] Compositions made by the processes of the invention formulated for rectal administration may include suppositories which may contain suitable non-irritating excipients, such as, for example, cocoa butter, synthetic glyceride esters, or polyethylene glycols, which are solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release particles of the compositions made by the processes of the invention.

[0159] For parenteral administration, such as subcutaneous and / or intramuscular injection, the compositions made by the process of the present invention may be presented in a sterile injectable and / or infusible form, for example, in the form of a sterile aqueous or oleaginous suspension of the compositions made by the process of the present invention.

[0160] Sterile aqueous suspensions of particles of the formulation of the invention can be formulated 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 homogenous 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.

[0161] The oily or oil-based carrier system may include one or more pharma- tically 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, propylene glycol, polyethylene glycol, glycols, such as polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and / or natural and / or refined pharma- tically 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, oleic acid ... 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.

[0162] 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.

[0163] Compositions made by the processes of the invention suitable for injection may also be in the form of a liquid, sol, paste, or gel that can be administered via a surgical administration device, e.g., a syringe with an injection needle, catheter, or the like, to form a depot formulation.

[0164] The use of the compositions made by the processes of the present invention may be advantageous in reducing any burst effect (e.g., concentration maxima immediately following administration) as discussed above, and / or in reducing the C in the plasma concentration-time profile.max By decreasing the dissolution rate and thus increasing the length of release of the biologically active ingredient from the formulation, the dissolution rate and pharmacokinetic profile can be controlled.

[0165] These factors not only reduce the frequency or frequency at which a formulation according to the process of the present invention needs to be administered to a subject, but also allow the subject more time as an outpatient, thus improving their quality of life.

[0166] The compositions made by the process of the present invention also have the advantage that by controlling the release of the active ingredient at a steady rate over an extended period of time, they provide lower daily exposure to potentially toxic drugs, which is expected to reduce undesirable side effects.

[0167] The compositions made by the processes of the invention may be contained within a reservoir and injection or infusion means, where the coated particles and carrier system are contained separately and mixing occurs before and / or during injection or infusion.

[0168] Compositions made by the processes of the invention may also be formulated for inhalation, e.g., as an inhalation powder for use in a dry powder inhaler (see, e.g., Kumaresan et al, Pharma Times, 44, 14 (2012) and Mack et al., Inhalation, 6, 16 (2012), the relevant disclosures of which are incorporated herein by reference). Suitable particle sizes for the plurality of particles in the compositions of the invention for use in pulmonary inhalation range from about 2 to about 10 μm.

[0169] The compositions made by the process of the present invention can also be formulated for topical administration to the skin or mucosa. For topical application, pharmaceutical preparations can be provided in the form of, for example, lotions, gels, pastes, tinctures, transdermal patches, gels for transmucosal delivery, all of which can include the compositions of the present invention. The compositions can also be formulated in a suitable ointment containing the compositions of the present invention suspended in a carrier such as mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, or water. Suitable carriers for lotions or creams include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetaryl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0170] The pharmaceutical formulation may comprise 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 pharma- ceutically acceptable excipients.

[0171] Compositions of the present invention suitable for injection may also include compositions in the form of a liquid, sol, or gel that can be administered via a surgical administration device, such as a needle, catheter, etc., to form a depot preparation.

[0172] In any case, the compositions made by the process of the present invention 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, 3rd edition (1986); 'Remington: The Science and Practice of Pharmacy', Troy (ed.), University of the Sciences in Philadelphia, 21st edition (2006); and / or 'Aulton's Pharmaceutics: The Design and Manufacture of Medicines', Aulton and Taylor (eds.), Elsevier, 4th edition, 2013), and documents referred to therein, all relevant disclosures of which are incorporated herein by reference. Otherwise, the preparation of suitable formulations can be achieved non-inventively by those skilled in the art using routine techniques.

[0173] According to a further aspect of the invention there is provided a process for preparing a pharmaceutical or veterinary formulation comprising mixing a coated particle prepared as described herein together with a pharma- ceutically or veterinarily acceptable adjuvant, diluent or carrier.

[0174] Such formulations are preferably injectable and / or infusible and thus comprise one or more compositions made by the process of the invention suspended in a pharma- ceutically or veterinarily acceptable aqueous and / or oily carrier.

[0175] Additionally, injectable and / or injectable dosage forms are provided that include the formulations made by the processes 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).

[0176] Alternatively, compositions made by the processes of the invention may be stored prior to loading into a suitable injectable and / or injectable dosage device (e.g., a syringe with a needle for injection) or may be prepared immediately prior to loading into such a dosage device.

[0177] Thus, the 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 aqueous carrier system are separately contained and mixing occurs prior to and / or during injection or infusion.

[0178] therefore, (a) a composition made by the process of the present invention; (b) a pharma- ceutically or veterinarily acceptable carrier system. And, the kit of parts includes compositions made by the process of the present invention along with instructions for the end user to mix these particles with a pharma- ceutically or veterinarily acceptable aqueous and / or oil-based carrier system.

[0179] 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 is placed the composition made by the process of the invention, and in the other chamber is placed a pharma- ceutically or veterinarily acceptable carrier system, which upon mixing form a suspension or otherwise prior to and / or during injection or infusion.

[0180] Whenever the word "about" is used herein, for example in the context of an amount (e.g., concentration, dimension (size and / or weight), dose, duration, pharmacokinetic parameter, etc.), relative amount (percentage, weight ratio, atomic ratio, size ratio, aspect ratio, proportion, multiple or 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 is anywhere from 8.5% to 11.5%).

[0181] The compositions made by the process of the present invention allow for the formulation of a wide variety of pharma- ceutical active compounds, which may be used to effectively treat a wide variety of disorders, depending on the biologically active agent contained therein.

[0182] The compositions made by the process of the present invention may further be formulated in the form of an injectable suspension of coated particles having a size distribution that is capable of forming a homogenous and stable (i.e., non-settling) suspension in the injection fluid and that is capable of being injected through a needle. In this regard, the formulations of the present invention may include an aqueous medium containing inactive ingredients that has sufficient viscosity to prevent premature gelation of the formulations of the present invention and / or to prevent settling that would result in the suspension not being "homogeneous" and thus risking under- or overdosing of the active ingredient.

[0183] Moreover, the compositions made by the process of the present invention can be stored under normal storage conditions and maintain their physical and / or chemical integrity.

[0184] The phrase "maintaining physical and chemical integrity" essentially means chemical stability and physical stability.

[0185] "Chemical stability" includes the ability of any composition made by the process of the invention to be stored (with or without appropriate pharmaceutical packaging) under normal storage conditions with only slight chemical degradation or decomposition.

[0186] "Physical stability" includes that any composition made by the process of the 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.).

[0187] Examples of "normal storage conditions" for compositions made by the process of the invention include temperatures of about -50°C to about +80°C (preferably, about -25°C to about +75°C, e.g., about 50°C) for extended periods 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 UV / visible light, and / or relative humidity of about 5 to about 95% (preferably, about 10 to about 40%).

[0188] Under such conditions, compositions made by the process of the present 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).

[0189] Additionally, the compositions made by the processes of the present invention may exhibit any burst effect and / or C max The present invention may provide a release and / or pharmacokinetic profile that minimizes

[0190] The compositions and processes described herein may have advantages for the physician and / or patient in treating the relevant condition with a particular biologically active agent that may be more effective, less toxic, have a broader spectrum of activity, be more potent, produce 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.

[0191] The present invention is illustrated, but in no way limited, by the following examples with reference to the accompanying figures in which Figures 1 to 4 show drug release profiles versus time for samples obtained according to the examples. EXAMPLES

[0192] Comparative Example 1 Coated Azacitidine Microparticles I Azacitidine microparticles (Olon SpA, Rodano, Italy) were prepared by jet milling (Catalent, Malvern, PA (USA)). The weight-based (D50) mean diameter of the jet-milled azacitidine particles was 1.2 μm as determined by laser diffraction (Sympatec, Helos (H1672) and Rodos, R3, Clausthal-Zellerfeld, Germany).

[0193] The powder was loaded into an ALD reactor (Picosun, SUNALE™ R-series, Espoo, Finland). 35 ALD cycles were performed at a reactor temperature of 50° C. Diethylzinc and water were used as precursors to form a first layer of zinc oxide. The thickness of the first layer was about 5 nm (estimated from the number of ALD cycles).

[0194] The powder was removed from the reactor and deagglomerated by forcing it through a metal sieve with a mesh size of 20 μm using a rubber spatula.

[0195] The resulting deagglomerated powder was reloaded into the ALD reactor and subjected to 35 additional ALD cycles as before to form a second layer of zinc oxide, extracted from the reactor, deagglomerated by manual sieving as above, reloaded to form a third layer, deagglomerated, and reloaded for a final, fourth layer.

[0196] 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 210 nm was used using a 4.6 x 250 mm, 3 μm particles, C18 column (Luna, Phenomenex, USA). The nanoshell coating was dissolved in 1 M phosphoric acid, the slurry was diluted, and azacitidine was dissolved by diluting with 1 g / L sodium bisulfite in water, followed by filtration (0.2 μm RC, Lab Logistics Group, Germany) and further analysis by HPLC (n=2). The drug loading was determined to be 64.7%.

[0197] Comparative Example 2 Coated Azacitidine Microparticles II The corresponding coated microparticles of azacitidine were prepared as described in Comparative Example 1 above, except that the powder was supplied by MSN Labs (India). The particles had an average diameter of 5.5 μm, as determined by laser diffraction (Shimadzu, SALD-7500nano, Kyoto, Japan). Deagglomeration was performed by sieving through a nylon sieve with a mesh size of 20 μm, using a sonic sifter (Tsutsui Scientific Instruments Co., Ltd., SW-20AT, Tokyo, Japan) to shake the powder through the sieve. The drug loading was determined to be 74.5%.

[0198] Comparative Example 3 Coated indomethacin microparticles I Using a process similar to that described in Comparative Example 2 above, coated microparticles of indomethacin were prepared using four ALD sets of 33 cycles each with a 2:1 ratio of ZnO:Al2O3 (i.e., two ZnO cycles followed by one Al2O3 cycle repeated 11 times). Between each ALD set, samples were deagglomerated using a sonic sifter (Tsutsui Sonic Agitated Sifting Machine SW-20AT) equipped with a nylon sieve and a sieve with a 20 μm mesh size. The particles had an average diameter of 8 μm as determined by laser diffraction (Shimadzu SALD-7500nano).

[0199] Example 4 Coated indomethacin microparticles II Coated microparticles of indomethacin were prepared as described in Comparative Example 3 above, up to the point of the final sieving step.

[0200] At that point, the coated diclofenac microparticles were finally sieved using a vibratory sifter (Russell Finex Mini Sifter 400) equipped with a vibratory motor, a stainless steel sieve, and a 25 μm mesh size sieve, and then coated with a fourth set of ALD cycles, as described in Comparative Example 3 above.

[0201] Comparative Example 5 In vitro drug release I In vitro release studies of the coated azacitidine particles of Comparative Examples 1 and 2 were carried out using a Sotax CE7 smart USP4 instrument (Sotax AG, Switzerland) connected to a CP7-35 piston pump (Sotax AG, Switzerland) and a C613 fraction collector (Sotax AG, Switzerland).

[0202] A 22.6 mm diameter flow-through cell was prepared with a 5 mm ruby ​​bead at the tip of the cell cone, into which the suspended sample was introduced.

[0203] Samples were analyzed in duplicate with a sample amount corresponding to 50 mg of azacytidine per cell. Samples (33.3 mg azacytidine / mL) were dispersed by vortexing in 0.1% Tween 20 + 0.25% sodium CMC in saline (0.9% NaCl) phosphate buffer, pH 7.2.

[0204] The device was used in an open loop setup, with fresh 20 mM PIPES (pH 7.2) dissolution medium continuously introduced into the system. The water bath temperature was set at 37°C ± 0.5°C and the medium flow rate was set at 16 mL / min. Two Whatman glass microfiber filters, GF / F and GF / D (d = 25 mm, Sigma-Aldrich / Merck KGaA, Germany), were used to filter the medium before leaving the flow-through cell. The collected fractions of released medium were analyzed for azacitidine content using HPLC, using the same settings as those used for the drug loading analysis above.

[0205] Figures 1 and 2 show the respective azacitidine release profiles (percentage of azacitidine released per minute versus sampling time in a Sotax device for samples obtained according to Comparative Example 1 and Example 1, respectively).

[0206] It can be seen that Comparative Example 1 has a higher initial (burst) release than Comparative Example 2.

[0207] Example 6 In vitro drug release II In vitro release testing of the particles of Comparative Example 3 and Example 4 was carried out according to the method described above for Comparative Example 5 above.

[0208] Figures 3 and 4 show the respective indomethacin release profiles (percentage of indomethacin cumulatively released versus sampling time in a Sotax device for samples obtained according to Comparative Example 3 and Example 4, respectively).

[0209] The two samples had nearly identical release profiles, demonstrating that the vibratory sieving technique used to prepare the coated indomethacin microparticles of Example 4 above does not exhibit an initial (burst) increase in release of the active ingredient compared to those prepared using a sonic sifter alone.

[0210] Taken together, the results of Comparative Example 5 and Example 6 show that not only can the vibratory sifter with a stainless steel sieve produce fewer pinholes, gaps, or cracks in the coating material than the manual sieving process used to prepare Comparative Example 1, but also cannot produce more pinholes, gaps, or cracks in the coating material than the sonic sifter with a softer nylon sieve as a tool for deagglomeration between ALD sets.

Claims

1. A process for preparing a composition in the form of a plurality of particles having an average diameter based on weight, number, and / or volume in an amount from 10 nm to about 700 μm, wherein the particles comprise: (a) a solid core; and (b) two or more sequentially applied individual layers, each of which comprises at least one distinct coating material, and the two or more layers together surround, enclose, and / or encapsulate the core, two or more sequentially applied individual layers; The process comprising sequential steps: (1) applying a first layer of at least one coating material to the solid core by a vapor deposition technique; (2) subjecting the coated particles to agitation to deaggregate particle aggregates formed during step (1) by a sieving step; (3) applying a further layer of at least one coating material to the deaggregated particles; and (4) optionally repeating steps (2) and (3) one or more times to increase the total thickness of the at least one coating material surrounding the solid core; wherein at least one of the sieving steps comprises a vibratory sieving technique, and the vibratory sieving technique comprises supplying power to a vibration motor coupled to the sieve. A process.

2. The process according to claim 1, wherein the vibration motor is a piezoelectric vibration motor or an eccentric rotating mass vibration motor.

3. The process according to claim 1 or 2, wherein the vibration motor and the sieve are suspended from a mount via a suspension means.

4. The process according to claim 3, wherein the suspension means comprises a spring or a bellows.

5. The process according to claim 1 or 2, wherein the vibratory sieving technique further comprises controlling a vibration probe coupled to the sieve.

6. The process according to claim 1 or 2, wherein the vibratory sieving technique comprises sieving the coated particles at a throughput of at least 1 g / min.

7. The process according to claim 1 or 2, wherein the sieve is formed of stainless steel.

8. Step (2) includes discharging the coated particles from the vapor deposition reactor before subjecting the coated particles to agitation, and step (3) includes reintroducing the deagglomerated coated particles from step (2) into the vapor deposition reactor and applying a further layer of at least one coating material to the reintroduced particles. The process according to claim 1 or 2.

9. The process according to claim 1, wherein the core comprises a biologically active agent and / or a pharmaceutically acceptable excipient.

10. The process according to claim 9, wherein the carrier / excipient material is a sugar or sugar alcohol and / or a pH modifier.

11. The process according to claim 1 or 2, wherein the core consists essentially of a biologically active agent.

12. The biologically active agent is an analgesic, anesthetic, anti-ADHD agent, anorectic agent, anti-addictive agent, antibacterial agent, antimicrobial agent, antifungal agent, antiviral agent, antiparasitic agent, antiprotozoal agent, anthelmintic, ectoparasiticide, vaccine, anticancer agent, antimetabolite, alkylating agent, antitumor agent, topoisomerase, immunomodulator, immunostimulant, immunosuppressant, anabolic steroid solution, anticoagulant, antiplatelet agent, antiepileptic agent, anti-dementia agent, antidepressant, antidote, antihyperlipidemic agent, antigout agent, antimalarial agent, antimigraine agent, anti-inflammatory agent, antiparkinson agent, anti-itch agent, antipsoriatic agent, antiemetic agent, anti-obesity agent, vermifuge, anti-asthmatic agent, antibiotic, antidiabetic agent, antiepileptic drug, antifibrinolytic agent, antihemorrhagic agent, antihistamine drug, antitussive agent, antihypertensive agent, antimuscarinic agent, antimycobacterial agent, antioxidant, antipsychotic agent, antipyretic agent, antirheumatic agent, antiarrhythmic agent, anxiolytic agent, aphrodisiac, cardiac glycoside, cardiotonic agent, entheogen, entactogen, deliriant, orexigenic, antithyroid agent, anxiolytic drug, hypnotic drug, neuroleptic drug, astringent, bacteriostatic agent, beta blocker, calcium channel blocker, ACE inhibitor, angiotensin II receptor antagonist, renin inhibitor, beta adrenergic receptor blocker, blood product, blood substitute, bronchodilator, cardiac arrhythmia drug, chemotherapeutic agent, coagulant, corticosteroid, antitussive, diuretic agent, deliriant agent, expectorant, fertilizing agent, sex hormone, mood stabilizer, mucolytic agent, neuroprotective agent, nootropic agent, neurotoxin, dopaminergic agent, antiparkinson disease drug, free radical scavenger, growth factor, fibrate, bile acid sequestrant, stasis remover, glucocorticoid, mineralocorticoid, hemostatic agent, hallucinogenic agent, hypothalamic-pituitary hormone, immunizing agent, cathartic, antidiarrheal agent, lipid regulator, muscle relaxant, parasympathomimetic agent, parathyroid calcitonin, selenic, statin, stimulant, wakefulness promoter, congestion remover, dietary mineral, bisphosphonate, cough suppressant, ophthalmic drug, ontological drug, H1 antagonist, H2 antagonist, proton pump inhibitor, prostaglandin, radiopharmaceutical, hormone, sedative, anti-allergic agent, appetite stimulant, steroid, sympathomimetic agent, thrombolytic agent, thyroid agent, vasodilator, xanthine, erectile dysfunction improver, gastrointestinal drug, histamine receptor antagonist, keratolytic agent, anti-anginal agent, non-steroidal anti-inflammatory agent, COX-2 inhibitor, leukotriene inhibitor, macrolide, NSAID, nutrient,The process according to claim 9, selected from opioid analgesics, opioid antagonists, potassium channel activators, protease inhibitors, anti-osteoporosis drugs, cognitive enhancers, anti-incontinence agents, nutritional oils, anti-benign prostatic hyperplasia agents, essential fatty acids, non-essential fatty acids, cytokines, peptidomimetics, peptides, proteins, radiopharmaceuticals, geriatric therapeutics, toxoids, sera, antibodies, nucleosides, nucleotides, vitamins, a portion of genetic material, nucleic acids, or any mixture thereof.

13. The process according to claim 1 or 2, wherein the average diameter based on the weight, number, or volume of the core is in the amount of 1 μm to about 50 μm.

14. The process according to claim 1 or 2, wherein 3 to 10 individual layers of coating material are sequentially applied to the core.

15. The process according to claim 1 or 2, wherein the total thickness of the individual layers of coating material is from about 0.5 nm to about 2 μm.

16. The process according to claim 1 or 2, wherein the maximum thickness of an individual layer of coating material is about 1 / 100 of the average diameter based on the weight, number, or volume of the core (including any other previously applied individual layers of coating material located between the individual layer and the outer surface of the core).

17. The process according to claim 1 or 2, wherein the coating material for the one or more individual layers comprises one or more inorganic coating materials.

18. The process according to claim 17, wherein the coating material comprises one or more metal-containing or metalloid-containing compounds.

19. The process according to claim 18, wherein the compound comprises a hydroxide and / or an oxide.

20. The process according to claim 18, wherein the one or more coating materials comprise silicon oxide, aluminum oxide, titanium dioxide, zinc sulfide, and / or zinc oxide.

21. The process according to claim 20, wherein the one or more coating materials comprise a mixture of zinc oxide and one or both of silicon dioxide and aluminum oxide.

22. The process according to claim 1 or 2, comprising applying separate layers of a coating material to a core and / or a previously coated core by atomic layer deposition.

23. The process according to claim 1 or 2, further comprising the step of resuspending the separated particles in a solvent in the presence or absence of one or more pharmaceutically acceptable excipients.

24. The process according to claim 9, wherein the biologically active agent is an anti-cancer agent.

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

26. A composition obtained by the process according to claim 1.

27. The composition according to claim 26, for use in medical or veterinary diagnosis.

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

29. The formulation according to claim 28 in the form of a sterile injectable and / or infusible dosage form.

30. The formulation according to claim 28 in the form of a liquid, sol, or gel, administrable via a surgical administration device for forming a depot formulation.

31. A process for preparing the formulation according to claim 28, comprising mixing the composition according to claim 26 with a relevant pharmaceutically acceptable or veterinarily acceptable adjuvant, diluent, or carrier.

32. The composition according to claim 26 for use in the treatment of cancer, wherein the biologically active agent is as described in claim 24.

33. The composition according to claim 26 for use in the manufacture of a medicament for the treatment of cancer, wherein the biologically active agent is as described in claim 24.

34. A method for treating cancer, comprising administering to a patient in need thereof the composition according to claim 26, wherein the biologically active agent is as described in claim 24.

35. The composition according to claim 32, wherein the biologically active agent is as described in claim 25 and the cancer is one or more of myelodysplastic syndromes or subtypes thereof.

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