New composition

Abstract

To provide a novel formulation to be used in the field of drug delivery.SOLUTION: Provided is a composition comprising a plurality of particles with an average diameter of 10 nm to approximately 700 μm, based on weight, number, or volume. The particles are composed of: (a) a solid core, preferably, containing a biologically active agent; (b) one or more discrete layers surrounding the core, each comprising at least one separated coating material; and (c) a final overcoating layer made of the coating material, the overcoating layer surrounding and / or encapsulating the core and a previously applied layer(s), and having a thickness thinner than that of the previously applied layer(s). The layers (b) and (c) are preferably applied using a gaseous phase coating technology including atomic layer deposition. When the core contains a biologically active agent, the composition may provide delayed or sustained release of the active agent with no burst effect.SELECTED DRAWING: Figure 8

Description

Technical Field

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

Background Art

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

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

[0004] In the case of sustained release compositions, it is also very important for the drug delivery composition to provide a release profile that minimizes the initial rapid release of the active ingredient (high concentration of the drug in plasma immediately after administration). In the case of drugs with a narrow therapeutic window, such burst release can be dangerous.

[0005] In the specific case of injectable suspensions, it is also important to ensure that the suspended particle sizes are controlled so that they can be injected through a needle. In the case of large aggregated particles, they will not only clog the needle (through which the suspension is injected), but will not form a stable suspension in the injection solution (i.e., they will tend to sink to the bottom of the injection solution).

[0006] Therefore, 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 containing various materials, including organic materials, biological materials, polymeric materials, and especially inorganic materials such as metal oxides, onto a solid substrate.

[0008] This technique is typically carried out at low pressure and high temperature. The film coating is produced by alternately exposing a solid substrate within an ALD reactor chamber to reactants vaporized in the gas phase. The substrate can be a silicon wafer, granular material, or small particles (e.g., microparticles or nanoparticles).

[0009] The coated substrate is protected from chemical reactions (decomposition) and physical changes by the solid coating. ALD may also be used to control the release rate of substrate materials within a solvent, which could potentially be used in the formulation of pharmaceutical active ingredients.

[0010] In ALD, a first precursor, which can be a metal-containing substance, is supplied to the ALD reactor chamber (in a so-called "precursor pulse") to form a monolayer of adsorbed atoms or molecules on the surface of the substrate. Next, the excess first precursor is purged from the reactor, and then a second precursor, such as water, is pulse-injected into the reactor. This reacts with the first precursor to form a monolayer, for example, of metal oxide on the substrate surface. After subsequent purge pulses, a further pulse of the first precursor follows, and thus a new cycle of the same events (a so-called "ALD cycle") is initiated.

[0011] The thickness of the film coating is controlled, among other things, by the number of ALD cycles carried out.

[0012] In a normal ALD process, only a monolayer of atoms or molecules is produced during one cycle, so no distinguishable physical interface is formed between these monolayers, and it essentially forms a continuous band on the surface of the substrate.

[0013] In International Patent Application No. 2014 / 187995, a process is described in which several ALD cycles are carried out, and then the resulting coated substrate is periodically removed from the reactor and redispersed / stirred to present a new surface available for precursor adsorption.

[0014] The stirring step is performed mainly to solve problems observed mainly with nanoparticles and microparticles. That is, particle aggregation occurs during the ALD coating process, and "pinholes" are formed by such contact points between particles. The redispersion / stirring step is carried out by placing the coated substrate in water and subjecting it to ultrasonic treatment, as a result of which deaggregation occurs and the contact points between the individual particles of the coated active material are broken.

[0015] As described in WO2014 / 187995, the process of performing a "set" of ALD coating cycles and subsequently dispersing intermittently results in transparent and distinct coating layers defined by a visible physical interface between such coating layers. Such an interface can be clearly seen as a highly electron-transparent region by techniques such as transmission electron microscopy (TEM). As will be explained below, when the coating builds up one atomic layer at a time from the surface of the substrate, no such interface is visible. This also applies when different precursors are supplied to the ALD reactor in successive ALD cycles.

[0016] After the final redispersion step, it has been found to be advantageous to provide a final thinner "sealing" shell of the inorganic coating material. This allows the particles to be deaggregated into primary particles without using invasive deaggregation techniques such as ultrasonic treatment and presents them in a form that can be easily processed into pharmaceutical formulations.

SUMMARY OF THE INVENTION

[0017] According to a first aspect of the present invention, there is provided a composition in the form of a plurality of particles in an amount having an average diameter based on weight, number, and / or volume of from 10 nm to about 700 μm, wherein the particles are: (a) A solid core, preferably a solid core containing a biologically active agent, and (b) One or more individual layers surrounding the core (or, if there are a plurality of such layers, sequentially surrounding), each layer containing at least one distinct (i.e., applied separately) coating material, and (c) An outer (i.e., final) overcoating layer (a "sealing shell") of the coating material that surrounds, encloses, and / or encapsulates the core and / or the previously applied layers of the coating material, and the thickness of the final layer is thinner than the previously applied layers, an overcoating layer, and is included (i.e., composed of). These compositions are hereinafter collectively referred to as "the compositions of the present invention."

Brief Description of the Drawings

[0018]

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Mode for Carrying Out the Invention

[0019] The term "solid" is well understood by those skilled in the art to include any form of a substance that retains its shape and density when not confined and / or in which the molecules are generally compressed as strongly as the repulsive forces between them allow. The solid core has at least a solid outer surface on which a layer of coating material can be deposited. The interior of the solid core 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 for spray drying technology.

[0020] The composition of the present invention is preferably a pharmaceutical composition, in which case the composition may comprise a pharmacologically effective amount of a biologically active agent. Further, the solid core preferably contains the biologically active agent.

[0021] In this regard, the solid core may consist essentially of or contain a biologically active agent (this agent may hereinafter be referred to interchangeably as "drug" as well as "active pharmaceutical ingredient (API)" and / or "active ingredient"). Biologically active agents also include biopharmaceuticals and / or biologics. The biologically active agent may also include a mixture of different APIs, as different API particles or particles containing multiple APIs.

[0022] "Consisting essentially of" a biologically active agent means that the solid core contains essentially only the biologically active agent, i.e., does not contain biologically inactive agents such as excipients, carriers, etc. (hereinafter). This means that the core may contain less than about 5%, for example less than about 3% and for example less than about 1% of such other excipients.

[0023] Alternatively, a core containing a biologically active agent may contain such an agent mixed with one or more pharmaceutical ingredients, which may include pharmaceutically acceptable excipients such as adjuvants, diluents, or carriers, and / or other biologically active components. such an agent may contain pharmaceutically acceptable excipients such as adjuvants, diluents, or carriers, and / or other biologically active components.

[0024] Biologically active agents can be presented in crystalline, semi-crystalline, and / or amorphous states. Biologically active agents, regardless of their physical form, can further include any substance that is in a solid state or can be converted to a solid state at approximately room temperature (e.g., about 18 °C) and approximately atmospheric pressure. Such agents should also remain in solid form while being coated in a reactor and should not decompose physically or chemically to a significant extent (i.e., by about 10% w / w or less) while being coated or after being covered by at least one of the layers of the aforementioned coating material. Biologically active agents can be further presented in combination with another active substance (e.g., as a mixture or as a complex).

[0025] As used herein, the term "biologically active agent" or similar and / or related expressions generally refer to any agent or drug that can produce a certain physiological effect (whether it has a therapeutic or preventive ability against a specific medical condition or state) in a living subject, including in particular mammalian and especially human subjects (patients).

[0026] Biologically active agents include, for example, analgesics, anesthetics, anti-ADHD agents, anorectics, anti-toxic agents, antibacterial agents, antimicrobial agents, antifungal agents, antiviral agents, antiparasitic agents, antiprotozoal agents, anthelmintics, ectoparasiticides, vaccines, anti-cancer agents, antimetabolites, alkylating agents, antitumor agents, topoisomerases, immunomodulators, immunostimulants, immunosuppressants, anabolic steroids, anticoagulants, antiplatelet agents, antiepileptic agents, anti-dementia agents, antidepressants, antidotes, antihyperlipidemic agents, antigout agents, antimalarial agents, antimigraine agents, anti-inflammatory agents, anti-Parkinson agents, anti-itch agents, antipsoriatic agents, antiemetics, anti-obesity agents, anthelmintics, antiarrhythmic agents, anti-asthmatic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptic drugs, antifibrinolytics, antihemorrhagic agents, antihistamines, antitussives, antihypertensives, antimuscarinic agents, antimycobacterial agents, antioxidants, antipsychotics, antipyretics, antirheumatic agents, antiarrhythmic agents, anxiolytics, aphrodisiacs, cardiac glycosides, cardiotonics, entheogens, entactogens, deliriants, orexigenics, antithyroid agents, anxiolytics, hypnotics, neuroleptics, astringents, bacteriostatics, beta blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, renin inhibitors, beta adrenergic receptor blockers, blood products, blood substitutes, bronchodilators, cardiac arrhythmia drugs, chemotherapeutic agents, coagulants, corticosteroids, antitussives, diuretics, deliriants, expectorants, fertilisers, sex hormones, mood stabilisers, mucolytics, neuroprotective agents, nootropics, neurotoxins, dopamine agonists, anti-Parkinson's disease drugs, free radical scavengers, growth factors, fibrates, bile acid sequestrants, blood stasis removing agents, glucocorticoids, mineralocorticoids, haemostatics, hallucinogens, hypothalamic-pituitary hormones, immunising agents, cathartics, antidiarrhoeals, lipid regulators, muscle relaxants, parasympathomimetics, parathyroid calcitonin, selenic, statins, stimulants, wakefulness promoters, congestion removing agents, dietary minerals, bisphosphonates, cough suppressants, ophthalmic drugs, ontological drugs, H1 antagonists, H2 antagonists, proton pump inhibitors, prostaglandins, radiopharmaceuticals, hormones, sedatives, anti-allergy agents, appetite stimulants, appetite suppressants, steroids, sympathomimetics, thrombolytics, thyroid agents, vasodilators, xanthines, erectile dysfunction improving agents, gastrointestinal drugs, histamine receptor antagonists, keratolytics, anti-anginal agents, non-steroidal anti-inflammatory agents, COX-2 inhibitors, leukotriene inhibitors, macrolides,It may be selected from NSAIDs, nutritional agents, 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, portions of genetic material, nucleic acids, or mixtures of any of these.,

[0027] Biologically active agents can also be cytokines, peptidomimetics, peptides, proteins, toxoids, sera, antibodies, vaccines, nucleosides, nucleotides, a portion of genetic material, nucleic acids, or mixtures thereof. Non-limiting examples of therapeutic peptides / proteins are as follows: repirudin, cetuximab, dornase alfa, denileukin diftitox, etanercept, vibralazine, leuprorelin, alteplase, interferon alpha-n1, darbepoetin alpha, reteplase, epoetin alpha, salmon calcitonin, interferon alpha-n3, pegfilgrastim, sargramostim, secretin, peginterferon alpha-2b, asparaginase, thyrotropin alpha, antihemophilic factor, anakinra, gramicidin D, intravenous immunoglobulin, anisoylated plasminogen streptokinase activator complex (APSAC), insulin (regular), tenecteplase, menotropins, interferon gamma-1b, interferon alpha-2a (recombinant), coagulation factor VIIa, oprelvekin, parathyroid hormone (1-34), glucagon (recombinant), aldesleukin, botulinum toxin type B, omalizumab, lutropin alpha, insulin lispro, insulin glargine, collagenase, rasburicase, adalimumab, imiglucerase, abciximab, alpha-1-proteinase inhibitor, pegaspargase, interferon beta-1a, pegademase bovine, human serum albumin, eptifibatide, iodinated serum albumin, infliximab, follitropin beta, vasopressin, interferon beta-1b, hyaluronidase, rituximab, basiliximab, muromonab-CD3, digoxin immune Fab (ovine), ibritumomab, daptomycin, tositumomab, pegvisomant, botulinum toxin type A, pancrelipase, streptokinase, alemtuzumab, agalsidase beta, interferon alpha-2b, oxytocin, enfuvirtide, palivizumab, daclizumab, bevacizumab, alcitumomab, eculizumab, panitumumab, ranibizumab,Idursulfase, Alglucosidase Alfa, Exenatide, Mecasermin, Pramlintide, Galactosidase Alfa, Abatacept, Cosyntropin, Corticotropin, Insulin Aspart, Insulin Detemir, Insulin Glargine, Pegaptanib, Nesiritide, Thymalfasin, Defibrotide, Natural Alpha Interferon / Multiferon, Glatiramer Acetate, Periostat, Teicoplanin, Canakinumab, Ipilimumab, Sulfoxide, Tocilizumab, Teriparatide, Pertuzumab, Rilonacept, Denosumab, Liraglutide, Golgimab, Belatacept, Buserelin, Velaglucerase Alfa, Tesamorelin, Brentuximab Vedotin, Taliglucerase Alfa, Belimumab, Aflibercept, Asparaginase Erwinia Chrysanthemi, Ocriplasmin, Glucarpidase, Teduglutide, Laxibacumab, Certolizumab Pegol, Insulin Isophane, Epoetin Zeta, Obinutuzumab, Fibrinolysin, Also Known As Plasmin, Follitropin Alfa, Romiplostim, Lucinactant, Natalizumab, Aliskiren, Ragweed Pollen Extract, Secukinumab, Somatropin (Recombinant), Drotrecogin Alfa, Alefacept, OspA Lipoprotein, Urokinase, Abarelix, Sermorelin, Aprotinin, Gemtuzumab Ozogamicin, Satsuma Monoclonal Antibody, Albiglutide, Antithrombin Alfa, Antithrombin III (Human), Asfotase Alfa, Atezolizumab, Autologous Cultured Chondrocytes, Beractant, Blinatumomab, C1 Esterase Inhibitor (Human), Coagulation Factor XIII A Subunit (Recombinant), Corn Starch Alfa, Daratumumab, Desirudin, Dulaglutide, Elosulfase Alfa, Ebolucumab, Fibrinogen Concentrate (Human), Filgrastim - sndz, Intrinsic Factor, Hepatitis B Immunoglobulin, Human Calcitonin, Human Clostridium Tetani Toxoid Immunoglobulin, Human Rabies Virus Immunoglobulin, Human Rho(D) Immunoglobulin, Human Rho(D) Immunoglobulin, Hyaluronidase (Human, Recombinant), Idarucizumab, Immunoglobulin (Human), Vedolizumab, U, Stemiximab, Turuktogualfa, tuberculin purified protein derivative, Shimoktogualfa, Siltuximab, Seberipase Alfa, Sacrosidase, Ramucirumab, Prothrombin Complex Concentrate, Poractant Alfa, Pembrolizumab, Peginterferon Beta-1a, Ofatumumab, Obinutuzumab, Nivolumab, Necitumumab, Methylprednisolone, Methoxypolyethylene glycol-epoetin beta, Mepolizumab, Ixekizumab, Insulin Degludec, Insulin (Porcine), Insulin (Bovine), Thyroglobulin, Anthrax Immune Globulin (Human), Anti-Inhibitor Coagulation Complex, Brodalumab, C1 Esterase Inhibitor (Recombinant), Chorionic Gonadotropin (Human), Chorionic Gonadotropin (Recombinant), Coagulation Factor X (Human), Dinutuximab, Emicizumab, Factor IX Complex (Human), Hepatitis A Vaccine, Human Varicella Zoster Immune Globulin, Ibritumomab Tiuxetan, Lenograstim, Pegloticase, Protamine Sulfate, Protein S (Human), Sipuleucel-T, Somatropin (Recombinant), Susoctogualfa, and Thrombomodulin Alfa.

[0028] Non-limiting examples of drugs that can be used in accordance with the present invention are all-trans retinoic acid (tretinoin), alprazolam, allopurinol, amiodarone, amlodipine, asparaginase, astemizole, atenolol, azathioprine, azelaic acid, beclomethasone, bendamustine, bleomycin, budesonide, buprenorphine, butalbital, capecitabine, carbamazepine, carbidopa, carboplatin, cefotaxime, cephalexin, chlorambucil, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clonazepam, clozapine, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin, diazepam, diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine, docetaxel, doxorubicin, doxazosin, enalapril, epirubicin, erlotinib, estradiol, etodolac, etoposide, everolimus, famotidine, felodipine, fentanyl citrate, fexofenadine, filgrastim, finasteride, fluconazole, flunisolide, fluorouracil, flurbiprofen, fluticasone, fluvoxamine, furosemide, gemcitabine, glipizide, glibride, ibuprofen, ifosfamide, imatinib, indomethacin, irinotecan, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen, lamotrigine, lansoprazole, loperamide, loratadine, lorazepam, lovastatin, medroxyprogesterone, mefenamic acid, mercaptopurine, mesna, methotrexate, methylprednisolone, midazolam, mitomycin, mitoxantrone, moxidectin, mometasone, nabumetone, naproxen, nicergoline, nifedipine, norfloxacin, omeprazole, oxaliplatin, paclitaxel, phenytoin, piroxicam, procarbazine, quinapril, ramipril, risperidone, rituximab, sertraline, simvastatin, sulindac, sunitinib, temsirolimus, terbinafine, terfenadine, thioguanine, trastuzumab, triamcinolone, valproic acid, vincristine, vinblastine, vinorelbine, zolpidem,Or a pharmaceutically acceptable salt of any of these.

[0029] The composition of the present invention may contain benzodiazepines such as alprazolam, chlordiazepoxide, clobazam, chlorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, quazepam, temazepam, triazolam, and pharmaceutically acceptable salts of any of these.

[0030] The anesthetic agents that can also be used in the composition of the present invention can be local or general. Local anesthetics that can be mentioned include amylocaine, ambucaine, articaine, benzocaine, benzonatate, bupivacaine, butacaine, butanilicaine, chloroprocaine, cinchocaine, cocaine, cyclomethycaine, dibucaine, diperodon, dimethocaine, eu -caine, ethylidocaine, hexylcaine, fomocaine, photocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine, mepivacaine, meprilocaine, metabutoxycaine, nitrocaine, orthocaine, oxethacaine, oxybuprocaine, paraethoxycaine, phenacaine, piperocaine, pyridocaine, pramocaine,prilocaine, procaine, procaine amide, propalacaine, propoxycaine, pyrocaine, quiniso-caine, ropivacaine, trimecaine, tricaine, tropacocaine, or pharmaceutically acceptable salts of any of these.

[0031] Psychiatric drugs can also be used in the composition of the present invention. Psychiatric drugs that may be mentioned include 5-HTP, acamprosate, agomelatine, amisulpride, amitriptyline, amobarbital, amobarbital / secobarbital, amoxapine, amphetamine, aripiprazole, asenapine, atomoxetine, baclofen, benperidol, bromperidol, bupropion, buspirone, butabarbital, carbamazepine, chloral hydrate, chlorpromazine, chlorprothixene, citalopram, chlormethiazole, clomipramine, clonidine, clozapine, cyclobarbital / diazepam, cyproheptadine, cytisine, desipramine, desvenlafaxine, dexamphetamine, dextromethamphetamine, diphenhydramine, disulfiram, divalproex sodium, doxepin, doxylamine, duloxetine, enanthic acid, escitalopram, eszopiclone, fluoxetine, flupentixol, fluphenazine, fluspirilene, fluvoxamine, gabapentin, glutethimide, guanfacine, haloperidol, hydroxyzine, iloperidone, imipramine, lamotrigine, levetiracetam, levomepromazine, levomilnacipran, lisdexamfetamine, lithium salts, lurasidone, melatonin, melperone, meprobamate, methamphetamine, netamidone, methylphenidate, mianserin, mirtazapine, moclobemide, nalmefene, naltrexone, niaprazine, nortriptyline, olanzapine, ondansetron, oxcarbazepine, paliperidone, paroxetine, penfluridol, pentobarbital, perazine, periciazine, perphenazine, phenelzine, phenobarbital, pimozide, pregabalin, promethazine, prothipendyl, protriptyline, quetiapine, ramelteon, reboxetine, reboxetine, reserpine, risperidone, rubidium chloride, secobarbital, selegiline, sertindole, sertraline, sodium oxybate, sodium valproate, sodium valproate, sulpiride, thioridazine, thiothixene, tianeptine, tizanidine, topiramate, tranylcypromine, trazodone, trifluoperazine, trimipramine,It contains tryptophan, valerian, valproic acid (in a ratio of 2.3:1), varenicline, venlafaxine, vilazodone, vortioxetine, zaleplon, diprasidone, zolpidem, zopiclone, zotepine, zuclopenthixol, and pharmaceutically acceptable salts of any of these.

[0032] Opioid analgesics that can be used in the composition of the present invention include buprenorphine, butorphanol, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, normethadone, opium, oxycodone, oxymorphone, pentazocine, tapentadol, tramadol, and pharmaceutically acceptable salts of any of these.

[0033] Opioid antagonists that can be used in the composition of the present invention include naloxone, nalorphine, nicomorphine, diprenorphine, levallorphan, samidorphan, nalodeine, alvimopan, methylnaltrexone, naloxegol, 6β-naltrexone, axelopran, bebenopran, methylsamidorphan, naldemedine, preferably nalmefene, particularly naltrexone, and pharmaceutically acceptable salts of any of these.

[0034] The anti-cancer agents that can be included in the composition of the present invention include the following: actinomycin, afatinib, all-trans retinoic acid, amsacrine, anagrelide, arsenic trioxide, axitinib, azacitidine, azathioprine, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, chlorambucil, cladribine, clofarabine, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, erlotinib, estramustine, etoposide, everolimus, fludarabine, fluorouracil, gefitinib, guadecitabine, gemcitabine, hydroxycarbamide, hydroxyurea, idarubicin, idelalisib, ifosfamide, imatinib, irinotecan, ixazomib, cabozantinib, carfilzomib, crizotinib, lapatinib, lomustine, mechlorethamine, melphalan, mercaptopurine, mesna, methotrexate, mitotane, mitoxantrone, nelarabine, nilotinib, niraparib, olaparib, oxaliplatin, paclitaxel, panobinostat, pazopanib, pemetrexed, pixantrone, ponatinib, procarbazine, regorafenib, luxolitinib, sonidegib, sorafenib, sunitinib, tegafur, temozolomide, teniposide, thioguanine, thiotepa, topotecan, trabectedin, valrubicin, vandetanib, vemurafenib, venetoclax, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, visimodegib, and pharmaceutically acceptable salts of any of these. A preferred biologically active agent is azacitidine.

[0035] Such compounds can be used in any one of the following cancers: adenocystic carcinoma, adrenal cancer, amyloidosis, anal cancer, ataxia-telangiectasia, atypical mole syndrome, basal cell carcinoma, bile duct cancer, Birt-Hogg Dube, duct syndrome, bladder cancer, bone cancer, brain tumor, breast cancer (including male breast cancer), cancer-like tumor, cervical cancer, colorectal cancer, ductal carcinoma of the breast, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, HER2-positive breast cancer, islet cell tumor, juvenile polyposis syndrome, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, all types of acute lymphoblastic leukemia, acute myeloid leukemia, adult leukemia, pediatric leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lobular carcinoma, lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, malignant glioma, melanoma, meningioma, multiple myeloma, myelodysplastic syndrome, nasopharyngeal cancer, neuroendocrine tumor, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor, parathyroid cancer, penile cancer, peritoneal cancer, Peutz-Jeghers syndrome, pituitary tumor, polycythemia vera, prostate cancer, renal cell carcinoma, retinoblastoma, salivary gland cancer, sarcoma, Kaposi sarcoma, skin cancer, small intestine cancer, gastric cancer, testicular cancer, thymoma, thyroid cancer, uterine (endometrial) cancer, vaginal cancer, Wilms tumor.

[0036] Other drugs that may be mentioned for use in the compositions of the present invention include immunomodulatory imide drugs such as thalidomide, and their analogs such as pomalidomide, lenalidomide, and apremilast, and pharmaceutically acceptable salts of any of these. Other drugs that have been much mentioned include angiotensin II type 2 receptor 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.

[0037] The composition of the present invention may contain a pharmacologically effective amount of a biologically active agent. The term "pharmacologically effective amount" refers to that amount of such an active ingredient which, whether administered alone or in combination with another active ingredient, is capable of producing the desired physiological change (such as a therapeutic effect) in the treated patient. Such a biological or medical response, or such an effect, in a patient may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives indication of, or feels, an effect), and includes at least partial alleviation of the symptoms of the disease or disorder being treated, or cure or prevention of the disease or disorder. It may include at least partial alleviation of the symptoms of the disease or disorder being treated, or cure or prevention of the disease or disorder.

[0038] Accordingly, the dosage of the active ingredient to be administered to a patient must be sufficient to produce a therapeutic response over a reasonable and / or relevant time frame. Those skilled in the art will recognize that the selection of the exact dosage and composition and the most suitable delivery regimen depends not only on the nature of the active ingredient, but also, inter alia, on the pharmacological properties of the formulation, the route of administration, the nature and severity of the condition being treated, the physical and mental condition of the recipient, and the age, condition, weight, sex, and response of the patient being treated, the stage / severity of the disease, and genetic differences among patients.

[0039] Administration of the composition of the present invention can be continuous or intermittent (e.g., by bolus injection). The dosage of the active ingredient can also be determined by the timing and frequency of administration.

[0040] 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 that is most suitable for an individual patient.

[0041] Alternatively, the compositions described herein may also include, instead of (or in addition to) the biologically active agent, a diagnostic agent (i.e., an agent that itself has no direct therapeutic activity but can be used for the diagnosis of conditions such as contrast agents or contrast media for bioimaging).

[0042] Non-biologically active adjuvants, diluents, and carriers that can be used for the core coated according to the present invention include pharmaceutically acceptable substances soluble in water, such as carbohydrates, for example sugars such as lactose and / or trehalose, and sugar alcohols such as mannitol, sorbitol, and xylitol, or pharmaceutically acceptable inorganic salts such as sodium chloride. Preferred carrier / excipient materials include sugars and sugar alcohols. Such carrier / excipient materials are particularly useful when the biologically active agent is a macromolecular complex, such as a peptide, protein, or part of a genetic material as generally described, and / or when it is the aforementioned specific peptide / protein. Thus, embedding the macromolecular complex in the excipient often results in a larger core for coating, and thus larger coated particles. For example, it is more beneficial to apply a sealing shell that may contain aluminum oxide.

[0043] It is not a requirement that the core of the composition of the present invention contain a biologically active agent. Whether or not the core contains a biologically active agent, the core may include and / or consist essentially of non-biologically active adjuvants, diluents, and carriers (including emollients), and / or other excipients having functional properties (e.g., buffers and / or pH modifiers such as citric acid).

[0044] The core is provided in the form of nanoparticles, or more preferably microparticles. The average diameter based on preferred weight, number, or volume is from about 50 nm (e.g., about 100 nm, about 250 nm, etc.) to about 30 μm, for example, from about 500 nm to about 100 μm, more specifically, from about 1 μm to about 50 μm (such as about 25 μm, for example, about 20 μm).

[0045] As used herein, the term "weight-based average diameter" is understood by those skilled in the art to include that the average particle size is characterized and defined from a particle size distribution by weight, i.e., the existing fraction (relative amount) in each size class is defined as the weight fraction obtained, for example, by sieving (e.g., wet sieving). As used herein, the term "number-based average diameter" is understood by those skilled in the art to include that the average particle size is characterized and defined from a particle size distribution by number, i.e., specifically, the existing fraction (relative amount) in each size class is characterized and defined from a distribution defined as the number fraction measured, for example, by microscopy. As used herein, the term "volume-based average diameter" is understood by those skilled in the art to include that the average particle size is characterized and defined from a particle size distribution by volume, i.e., the existing fraction (relative amount) in each size class is defined as the volume fraction measured, for example, by laser diffraction. The particle size can be measured using other well-known devices in this field, such as those sold by Malvern Instruments, Ltd (Worcestershire, UK) and Shimadzu (Kyoto, Japan).

[0046] The particles can be spherical, i.e., they have an aspect ratio of less than about 20, more preferably less than about 10, for example less than about 4, especially less than about 2, and / or can have a variation in radius (measured from the center of gravity to the particle surface) of at least about 90% of the particles, less than about 50% of the average value, for example, less than about 30% of that value, for example, less than about 20% of that value.

[0047] Nevertheless, according to the present invention, it is also possible to coat particles into any shape. For example, particles having an irregular shape (e.g., "raisin" shape), needle shape, or rectangular parallelepiped shape can be coated. In the case of non-spherical particles, the size can be expressed, for example, as the corresponding spherical particle diameter of the same weight, volume, or surface area. Hollow particles, as well as particles having pores, gaps, etc., such as fibrous or "entangled" particles, can also be coated according to the present invention.

[0048] The particles can be obtained in a form suitable for their coating, or in that form, for example, by a particle size reduction process (e.g., by grinding, cutting, milling, or grinding to a specific weight-based average diameter (as described above), such as wet grinding, dry grinding, air jet milling (including cryogenic micronization), ball milling such as planetary ball milling, and using an end runner mill, roller mill, vibration mill, hammer mill, roller mill, fluid energy mill, pin mill, etc. Alternatively, the particles can be directly prepared in a suitable size and shape by, for example, spray drying, precipitation, or other top-down methods (i.e., reducing large particle sizes, e.g., by grinding, etc.) including the use of supercritical fluids, or bottom-up methods (i.e., increasing small particle sizes, e.g., by sol-gel technology, etc.). Alternatively, the nanoparticles can be produced by well-known techniques such as gas condensation, attrition, chemical precipitation, ion implantation, pyrolysis, hydrothermal synthesis, etc.

[0049] The particles may need to be washed and / or cleaned to remove impurities that may be derived from their production and then dried (depending on the method by which the particles including the core are initially provided). Drying can 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 core can then be deagglomerated by grinding, screening, milling, and / or dry sonication. Alternatively, the core can be treated to remove any volatile substances that may be adsorbed on its surface, for example, by exposing the particles to a vacuum and / or high temperature.

[0050] The surface of the core can be chemically activated, for example, by treatment with hydrogen peroxide, ozone, free radical-containing reactants, or by applying plasma treatment to create free oxygen radicals on the surface of the core. This can create favorable adsorption sites / nucleation sites on the core for ALD precursors.

[0051] Preferably, two or more layers of the coating material are sequentially applied to the core. Preferred methods for applying a coating to a core containing a biologically active agent include vapor phase techniques such as ALD, or related techniques such as atomic layer epitaxy (ALE), molecular layer deposition (MLD, which is a technique similar to ALD but differs in that molecules (usually organic molecules) are deposited in each pulse instead of atoms), molecular layer epitaxy (MLE), chemical vapor deposition (CVD), atomic layer CVD, molecular layer CVD, physical vapor deposition (PVD), sputtering PVD, reactive sputtering PVD, evaporation PVD, and binary reaction sequence chemistry. ALD is a preferred coating method according to the present invention.

[0052] Preferably, two or more separate layers, coatings or shells (these terms are used interchangeably herein) are applied to a solid core containing a biologically active agent (i.e., "applied separately"). Such "separate application" of "separate layers, coatings or sub - shells" means that the solid core is coated with a first layer of coating material and then the resulting coated core is subjected to some form of de - aggregation process. In this regard, the number of individual layers of coating material (also referred to as "sub - shells") as defined herein corresponds to the number of these intermittent de - aggregation steps, and the final de - aggregation step is performed prior to the application of an over - coating layer on the outside of the coating material.

[0053] The coated core can be subjected to the aforementioned de - aggregation process without being removed from the apparatus by a continuous process. Such a process involves forcing a solid product mass formed by coating the core through a sieve disposed within the reactor, and when the coated core is forced by the forcing means applied within the reactor prior to being subjected to a second coating and / or further coatings, it is configured to de - aggregate agglomerates of particles. This process is continued the necessary number and / or appropriate number of times prior to applying the final over - coating as described herein.

[0054] Placing a sieve within the reaction vessel means that the coating can be applied by a continuous process that does not require removal of the particles from the reactor. Thus, there is no need to manually handle the particles and no external machinery is required to de - aggregate the agglomerated particles. This not only significantly reduces the time taken to carry out the coating process but also makes it more convenient and reduces the risk of harmful (e.g., toxic) materials being handled by personnel. Also, by limiting manual operations, the reproducibility of the process is enhanced and the risk of contamination is reduced.

[0055] Alternatively, the coated core is removed from a coating apparatus such as an ALD reactor and can then be subjected to an external deagglomeration step, for example, as described in International Patent Application No. 2014 / 187995. Such an external deagglomeration step may include agitation such as sonication in the wet or dry state, or preferably sieving the resulting solid product mass removed from the reactor to deagglomerate the particles, for example, by passing through a sieve or mesh, before returning the particles to the coating apparatus for coating in the next coating step. Again, this process can be continued the necessary number and / or appropriate number of times before applying the final overcoating described herein.

[0056] In an external deagglomeration process, deagglomeration can alternatively be performed by subjecting the coated particles in the wet or dry state to one or more of nozzle aerosol generation, milling, grinding, agitation, high shear mixing and / or homogenization. If the deagglomeration step is performed on particles in the wet state, the deagglomerated particles should be dried (as described above with respect to the core) before the next coating step.

[0057] However, in such an external process, the deagglomeration step includes one or more sieving steps, which can include jet sieving, manual sieving, vibratory sieve shaking, horizontal sieve shaking, tap sieving, or preferably sonic sieving as described below, or similar processes including any combination of these sieving steps.

[0058] The inventors have found that after external deagglomeration, applying separate layers of coating material results in a visible and distinguishable interface. This can be observed by analyzing the coated particles according to the present invention, for example, observed as regions of higher electron transmissivity by TEM (as can be seen in Figures 1 and 2).

[0059] This is in contrast to a continuous ALD process where the coated particles are not removed from the reactor prior to recoating. In an ALD coating process, even when different coating materials are used sequentially (e.g., switching from one metal oxide precursor to another between ALD cycles), since the coating occurs at the atomic level, distinct physical interfaces such as those shown in FIGS. 1 and 2 are not observed. Thus, the thickness of the layer between the interfaces shown in FIGS. 1 and 2 directly corresponds to the number of cycles in each series that are carried out within the ALD reactor and between individual external agitation steps.

[0060] Without being limited by theory, it is thought that removing the coated particles from an ALD reactor under vacuum conditions and exposing the newly coated surface to air results in a restructuring of the surface due to relaxation and reconstruction of the outermost atomic layer. Such a process is thought to involve a rearrangement of the atoms at the surface (and near the surface) that is driven by the thermodynamic tendency to reduce the free energy of the surface.

[0061] Furthermore, surface adsorption of species (e.g., hydrocarbons that are always present in air) may contribute to this phenomenon, similar to reactions of coatings formed by hydrocarbons and surface modification by oxygen in air, etc. Thus, chemically analyzing such an interface may contain trace contaminants not originating from coating processes such as ALD.

[0062] Regardless of whether it is carried out inside or outside the reactor, the particle aggregates are preferably broken down by means of forced passage through a sieve, thereby separating the aggregates into individual particles or aggregates of a desired and predetermined size (thereby achieving deaggregation). With regard to the latter, in some cases, since the individual primary particle sizes are very small (i.e., <1 μm), it is impossible to achieve "complete" deaggregation (i.e., the aggregates are broken down into individual particles). Instead, deaggregation is achieved by breaking down larger aggregates into smaller aggregates of secondary particles of the desired size, as determined by the size of the sieve mesh. The smaller aggregates are then coated by a vapor-phase technique to form "particles" that are completely coated in the form of small aggregate particles. Thus, the term "particle", when referring to deaggregated and coated particles in the context of the present invention, refers to both individual (primary) particles and aggregated (secondary) particles of the desired size.

[0063] In any case, the desired particle size (whether it be individual particles or aggregates of the desired size) is maintained, and furthermore, the continued application of the vapor-phase coating mechanism to the particles after such deaggregation by the sieve forms a complete coating on the particles, thus meaning that completely coated particles (individual or aggregates of the desired size) are formed.

[0064] The above-described repeated coating and deaggregation processes are carried out inside or outside the reactor regardless of whether it is carried out inside or outside the reactor, at least once, preferably twice, more preferably three times, for example four times, five times, more specifically six times, for example seven times, and up to about 100 times, for example about 50 times or less, for example about 40 times or less, about 30 times or less, for example 2 to 20 times, for example 3 to 15 times, for example 10 times, for example 9 or 8 times, more preferably 6 or 7 times, particularly 4 or 5 times.

[0065] The total thickness of the coating (meaning all separate layers / coatings / shells) ranges on average from about 0.5 nm to about 2 μm.

[0066] The minimum thickness of each individual subshell ranges on average from about 0.5 nm (e.g., about 0.75 nm, about 1 nm, etc.).

[0067] The maximum thickness of the individual subshells will depend on the size of the core (initially), and then the size of the core with the previously applied coatings, and can be on average about 1 / 100 of the average diameter (i.e., the average diameter based on the weight, number, or volume of that core or the core with the previously applied coatings).

[0068] Preferably, for particles with an average diameter from about 100 nm to about 1 μm, the subshells must be on average from about 1 nm to about 5 nm, and for particles with an average diameter from about 1 μm to about 20 μm, the thickness of the coating must be on average from about 1 nm to about 10 nm, and for particles with an average diameter from about 20 μm to about 700 μm, the thickness of the coating must be on average from about 1 nm to about 100 nm.

[0069] The thickness of the final outer overcoating layer / coating, or sealing shell (these terms are used interchangeably herein) must be thinner than the subshell. Thus, the thickness can be on average about 0.7 times or less (e.g., about 0.6 times) the average of the thickest previously applied subshell. Alternatively, the thickness can be on average about 0.7 times or less (e.g., about 0.6 times) the average of the thickness of the last subshell applied, and / or on average about 0.7 times or less (e.g., about 0.6 times) the average of the average thickness of all previously applied subshells. The thickness can range on average from about 0.3 nm to about 10 nm for particles up to about 20 μm in size. For larger particles, the thickness can be on average about 1 / 1000 or less of the average diameter based on the weight, number, or volume of the coated particles.

[0070] After applying the subshell and performing one or more deaggregation steps such as sonication, it has been found that in the subshell coating, abrasion, pinholes, breakage, gaps, cracks, and / or voids (hereinafter "cracks") occur because the coated particles are "bonded" or "adhered" more tightly essentially immediately after applying a thicker coating. As a result, when deaggregation occurs, the core containing the biologically active ingredient may be exposed to the elements.

[0071] The role of the sealing shell is to provide a "sealing" overcoating layer to the particles and cover those cracks, so that the particles occur in a manner such that they can be easily deaggregated (e.g., using non-invasive techniques such as vortexing) without destroying the subshell formed below before and / or during pharmaceutical formulation and while being completely covered by that sealing shell.

[0072] For example, if it is intended to provide a sample in a suspension before administration to a patient, it is necessary to provide deaggregated primary particles without pinholes or cracks in the coating.

[0073] If the final thinner sealing shell is not applied, it has been found that in many cases, an acceptable suspension for administering properly deaggregated particles cannot be obtained unless invasive techniques such as sonication are applied. Such methods introduce the aforementioned cracks in the coating and / or the sample, and some of the shells are completely destroyed. This results in an undesirable initial peak (burst) in the plasma concentration of the active ingredient immediately after administration.

[0074] Conversely, it has been found that when a thinner outer coating (sealing shell) is applied, the particles can be resuspended in the solvent without such previously applied invasive deaggregation steps.

[0075] Instead, it is sufficient to subject the suspension to a less intense process such as vortexing, stirring, or gentle sonication, whereby deagglomerated coated particles are obtained that are essentially free of such cracks (through which the active ingredient could be released in an uncontrolled manner). By "essentially free of such cracks" in the coating is meant that less than about 1% of the surface of the coated particles contains abrasions, pinholes, breaks, gaps, cracks and / or voids (through which the active ingredient could potentially be exposed (e.g., to the elements)).

[0076] The subshell and the thinner outer shell can together be of essentially uniform thickness over the surface area of the particle. By "essentially uniform" thickness is meant that the degree of variation in the thickness of the inorganic coating is at least about 10%, such as about 25%, such as about 50% (when measured by TEM, about ±20% or less) of the coated particles present in the compositions of the present invention.

[0077] Coating materials that can be applied to the core can be pharmaceutically acceptable in that they must be essentially non-toxic.

[0078] Coating materials can include organic or polymeric materials such as polyamides, polyimides, polyureas, polyurethanes, polythioureas, polyesters, or polyimines. Coating materials can also include hybrid materials (such as between organic and inorganic materials) that are materials that are a combination between a metal or another element and an alcohol, carboxylic acid, amine, or nitrile. However, the coating materials preferably include inorganic materials.

[0079] Inorganic coating materials can include one or more metals or metalloids, or one or more metal-containing or metalloid-containing compounds such as metal or metalloid oxides, nitrides, sulfides, selenides, carbonates, and / or other ternary compounds. Metals, and metalloids, hydroxides, particularly oxides, particularly metal oxides are preferred.

[0080] Metals that may be mentioned include alkali metals, alkaline earth metals, noble metals, transition metals, and post-transition metals. Metals and metalloids that may be mentioned include aluminum, titanium, magnesium, iron, gallium, zinc, zirconium, niobium, hafnium, tantalum, lanthanum, and / or silicon, more preferably aluminum, titanium, magnesium, iron, gallium, zinc, zirconium, and / or silicon, particularly aluminum, titanium, and / or zinc.

[0081] As described above, since the composition of the present invention includes one or more individual layers of an inorganic coating material, the properties and chemical compositions of those layers may differ from layer to layer.

[0082] Individual layers may also include a mixture 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.

[0083] Coating materials that may be mentioned include those containing aluminum oxide (Al2O3), titanium dioxide (TiO2), iron oxide (Fe x 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, as well as titanium dioxide, zinc sulfide, zinc oxide, and aluminum oxide.

[0084] The layer of coating material (on an individual or collective basis) in the composition of the present invention can consist essentially of (e.g., more than about 80%, e.g., more than about 90%, e.g., about 95%, e.g., about 98%) iron oxide, aluminum oxide, zinc oxide, or titanium dioxide. The coating of zinc oxide (and iron oxide) can be thicker than the corresponding coating of aluminum oxide or titanium (because they are more soluble). Thus, when the coating material used, for example, contains zinc oxide, a thicker coating of the material can be used, larger coated particles are obtained, and it is more beneficial to apply a sealing shell that can contain the same material or a different material (e.g., aluminum oxide).

[0085] In ALD, the layer of coating material can be applied at a process temperature of about 20°C to about 800°C, or about 40°C to about 200°C, e.g., about 40°C to about 150°, e.g., 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) used for the core, and / or the melting point of the core material.

[0086] In most cases, at the beginning of successive reactions, the surface to be coated will be associated with some functional groups or lone electron pairs or radicals (e.g., hydroxy groups (-OH) or primary or secondary amino groups (-NH2 or -NHR, where R is an aliphatic group such as an alkyl group, for example). Each reaction is preferably carried out separately under conditions such that all excess reagents and reaction products are essentially removed before the next reaction is carried out.

[0087] The plurality of coated particles according to the present invention are, in the applied coating, essentially free of the aforementioned cracks, through which the active ingredient is potentially (e.g., to the element) exposed, and before subjecting it to further processing of a pharmaceutical formulation, further optional steps can be applied to the plurality of coated particles. This optional step involves subjecting a small number of the remaining particles having a broken and / or cracked shell / coating to a process in which all the particles are suspended in a solvent (the active ingredient is soluble, for example, with a solubility of at least about 1 mg / mL, but the least soluble material of the coating is insoluble, for example, with a solubility of about 0.1 μg / mL or less), and subsequently separating the solid particles from the solvent, for example, by centrifugation, sedimentation, aggregation, and / or filtration, so as to ensure that mainly intact particles remain.

[0088] As previously discussed, the above-mentioned optional step further potentially provides a means to reduce the likelihood of an (presumably) undesirable initial peak (burst) in the plasma concentration of the active ingredient.

[0089] At the end of the process, the coated particles can be dried using one or more of the aforementioned techniques for drying the core. Drying can occur in the absence or presence of one or more pharmaceutically acceptable excipients (e.g., sugars or sugar alcohols).

[0090] Alternatively, at the end of the process, the separated particles can be resuspended in a solvent (e.g., water, with or without the presence of one or more pharmaceutically acceptable excipients as defined herein) for subsequent storage and / or administration to a patient.

[0091] ​Before applying the first layer of the coating material or between successive coatings, the core and / or partially coated particles can be subjected to one or more alternative and / or preparatory surface treatments. In this regard, one or more intermediate layers comprising different materials (i.e., other than inorganic materials) can be applied to the relevant surfaces, for example, to protect the core or partially coated particles from unwanted reactions with precursors during the coating step / deposition process, to enhance coating efficiency, or to reduce aggregation.

[0092] The intermediate layer can, for example, contain one or more surfactants for the purpose of reducing aggregation of the particles to be coated and providing a hydrophilic surface suitable for subsequent coating. In this regard, suitable surfactants include well-known non-ionic, anionic, cationic, or zwitterionic surfactants such as the Tween series (e.g., Tween 80). Alternatively, if the active ingredient used as part of the core (or as the core) is prone to react with one or more precursor compounds that can be present in the gas phase during the coating (e.g., ALD) process, the core can be subjected to a preparatory surface treatment.

[0093] Alternatively, the application of this "intermediate" layer / surface treatment of this nature can alternatively be achieved 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 the coating material can then be applied.

[0094] The outer surface of the particles of the composition of the present invention can also be derivatized or functionalized, for example, by attaching one or more chemical compounds or moieties to the outer surface of the final layer of the coating material, using, for example, chemical compounds or moieties that enhance the targeted delivery of the particles within the patient to whom the nanoparticles are administered. Such compounds can be organic molecule (e.g., PEG) polymers, antibodies or antibody fragments, or receptor-binding proteins or peptides, etc.

[0095] Alternatively, that portion can be an anchoring group such as a portion containing silane functionality (see, for example, 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 a covalent or non-covalent bond (including hydrogen bonds or van der Waals bonds), or a combination thereof.

[0096] The presence of such a moiety can provide a versatile tool for targeted delivery to a specific site in the body. Alternatively, the use of a compound such as PEG can allow the particles to circulate longer in the bloodstream and avoid accumulation in the liver or spleen (a natural mechanism by which the body eliminates particles that could prevent delivery to diseased tissue).

[0097] The composition of the present invention is suitable for administration to a patient when it is prepared (i.e., as a plurality of particles), or, preferably, formulated with one or more pharmaceutically acceptable excipients including adjuvants, diluents, or carriers for use in the medical or veterinary fields (including during therapy and / or during diagnosis if the core contains diagnostic material). Further provided are compositions of the present invention for use in medical, diagnostic, and / or veterinary practice, and pharmaceutical (or veterinary) formulations comprising the compositions of the present invention and a pharmaceutically (or veterinarily) acceptable adjuvant, diluent, or carrier.

[0098]

[0099] ​The composition of the present invention can be administered, optionally, in the form of a pharmaceutical (or veterinary) preparation containing a compound in a pharmaceutically (or veterinarily) acceptable dosage form, by local, topical, or systemic routes, such as oral (enteral), injection or infusion, intravenous or intra - arterial (including intravascular or other perivascular devices / formulations, e.g., stents), intramuscular, intra - osseous, intracerebral, intraventricular, intrasynovial, intrasternal, intramedullary, intralesional, intracranial, intratumoral, cutaneous, intradermal, subcutaneous, transmucosal (e.g., sublingual or buccal), rectal, transdermal, nasal, pulmonary (e.g., inhalation, tracheal or bronchial), local, or any other parenteral route (e.g., subcutaneous or intramuscular).

[0100] The incorporation of the composition of the present invention into a pharmaceutical preparation can be achieved by fully considering the intended route of administration and standard pharmaceutical practices. Pharmaceutically acceptable excipients, such as carriers, may be chemically inert to the biologically active agent and may have no harmful side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers can also impart immediate release or controlled release of the composition of the present invention.

[0101] A pharmaceutical (or veterinary) preparation containing the composition of the present invention can include different types of particles, e.g., particles containing different active ingredients with different functionalizations (as described above), particles with different sizes, and / or particles with layers of coating materials of different thicknesses, or combinations thereof. By combining particles with different coating thicknesses and / or different core sizes in a single pharmaceutical preparation, the drug release after administration to a patient can be controlled (e.g., varied or extended) over a specific period.

[0102] For oral administration (i.e., oral administration to the gastrointestinal tract with swallowing), the compositions of the present invention can be formulated in various dosage forms. Pharmaceutically acceptable carriers or diluents can be solid or liquid. Solid formulations include granules (which can contain some or all of the plurality of particles of the composition of the present invention in the presence of, for example, a carrier and other excipients such as binders or pH adjusters), compressed tablets, pills, lozenges, capsules, cachets, and the like. Carriers include those described above with respect to the formulation of the biologically active agent in the core, and materials well known to those skilled in the art, including magnesium carbonate, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, lactose, microcrystalline cellulose, low crystalline cellulose, and the like.

[0103] Solid dosage forms can include additional excipients such as flavoring agents, lubricants, binders, preservatives, disintegrants, and / or encapsulating materials. For example, the compositions of the present invention can be encapsulated, for example, in soft or hard shell capsules, such as gelatin capsules.

[0104] The compositions of the present invention formulated for rectal administration can include suppositories containing suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters, or polyethylene glycols, which are solid at room temperature but liquefy and / or dissolve in the rectal cavity to release the particles of the compositions of the present invention.

[0105] In the case of parenteral administration such as subcutaneous injection and / or intramuscular injection, the compositions of the present invention are in a sterile injectable and / or infusible dosage form, for example, a sterile aqueous or oily suspension form of the composition of the present invention.

[0106] Such suspensions can be formulated according to techniques well known to those skilled in the art by using suitable dispersing or wetting agents (such as Tweens, for example, Tween 80) and suspending agents.

[0107] Non-toxic parenterally acceptable diluents include 1,3-butanediol, mannitol, Ringer's solution, isotonic sodium chloride solution, solutions of sterile fixed oils (including any minimally irritating fixed oil such as synthetic monoglycerides or diglycerides), natural pharmaceutically acceptable oils such as olive oil or castor oil, as well as fatty acids such as oleic acid and its glyceride derivatives, and their polyoxyethylated versions and pH adjusters that can be used in the preparation. These oil suspensions may also contain long-chain alcohol diluents or dispersants.

[0108] The compositions of the present invention suitable for injection may also include compositions in the form of liquids, sols, or gels (e.g., containing hyaluronic acid) that can be administered via a surgical administration device, such as a needle, catheter, etc., to form a depot formulation. The use of the compositions of the present invention can control the dissolution rate and pharmacokinetic profile by reducing any burst effect as described above and / or by increasing the length of release of the biologically active ingredient from the formulation.

[0109] The compositions of the present invention can also be formulated for inhalation as an inhalation powder for use, for example, 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 are incorporated herein by reference). Suitable particle sizes for the plurality of particles in the compositions of the present invention for use in inhalation into the lungs are in the range of about 2 to about 10 μm.

[0110] The composition of the present invention can also be formulated for topical administration to the skin or mucosa. For topical application, the pharmaceutical preparation can be provided, for example, in the form of a lotion, a gel, a paste, a tincture, a transdermal patch, a gel for transmucosal delivery, all of which can contain the composition of the present invention. The composition can also be formulated in a suitable ointment containing the composition of the present invention suspended in a carrier such as mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, or water. Suitable carriers for lotions or creams include mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0111] The pharmaceutical preparation can contain from about 1 wt% to about 99 wt%, such as from about 10 wt% (such as about 20 wt%, for example, about 50 wt%) to about 90 wt% of the composition of the present invention, the remainder being constituted by pharmaceutically acceptable excipients.

[0112] In any case, the composition of the present invention is formulated with conventional pharmaceutical additives and / or excipients used in the art for the preparation of pharmaceutical preparations, and then by standard techniques (e.g., Lachman et al, "The Theory and Practice of Industrial Pharmacy", Lea & Febiger, 3 rd edition (1986); "Remington: The Science and Practice of Pharmacy", Troy (ed.), University of the Sciences in Philadelphia, 21 st edition (2006); and / or "Aulton’s Pharmac eutics: The Design and Manufacture of Medicines", Aulton and Taylor (eds.), Elsevier, 4 th(see edition, 2013) and can be incorporated into various types of pharmaceutical formulations and / or dosage forms using the documents referred to therein, and the relevant disclosures in all documents are incorporated herein by reference. Otherwise, the preparation of suitable formulations can be achieved non-inventively by a person skilled in the art using routine techniques.

[0113] Whenever the term "about" is used herein, for example, in the context of a quantity (e.g., concentration, dimension (size and / or weight), size ratio, aspect ratio, ratio, or fraction), temperature or pressure, such variables are approximate and thus it will be understood that they can vary by ±15%, for example ±10%, for example ±5%, preferably ±2% (e.g., ±1%) from the numerical values specified herein. This also applies where such numerical values are expressed as percentages (e.g., "about 15%" can mean ±15% of the numerical value 10, which can be either 8.5% or 11.5%).

[0114] The compositions of the present invention enable the formulation of a variety of pharmaceutically active compounds. The compositions of the present invention can be used to effectively treat a wide variety of disorders depending on the biologically active agents contained therein.

[0115] The compositions of the present invention can form a homogeneous and stable (i.e., non-settling) suspension in an injection solution and can be further formulated in the form of an injection suspension of coated particles having a size distribution that can be injected through a needle.

[0116] Furthermore, the compositions of the present invention can provide a release and / or pharmacokinetic profile that minimizes any burst effect characterized by a maximum concentration immediately after administration.

[0117] The compositions and processes described herein can have the advantage of being more effective, less toxic, having a broader range of activity, being more potent, being more convenient for physicians and / or patients in the treatment of related conditions with certain biologically active agents, or having other useful pharmacological properties than any similar treatment that may be described in the prior art for the same active ingredients, and may result in fewer side effects.

[0118] The present invention is illustrated by the following examples, with reference to the accompanying drawings, but is in no way limited thereto. Figures 1 and 2 are TEM images showing distinct physical interfaces (regions with higher electron permeability) formed using the processes described herein. Figures 3 and 4 show in vitro indomethacin release from aluminum oxide-coated particles before (Figure 3) and after (Figure 4) application of the sealing shell. Figure 5 shows indomethacin release from particles with a sealing shell that were also subjected to the final washing step. Figure 6 shows indomethacin release from particles without a sealing shell that were subjected to the final washing step. Figure 7 shows a comparison of in vivo plasma concentration-time profiles in rats injected with coated indomethacin particles with (white squares) and without (black triangles) the sealing shell. Figure 8 shows a comparison of in vivo plasma concentration-time profiles in rats injected with coated indomethacin particles at different doses. Figure 9 shows a comparison of in vivo plasma concentration-time profiles in rats injected with the same dose of coated indomethacin particles prepared by the same process with and without being subjected to the washing step. Figures 10 and 11 show in vitro indomethacin release from particles coated with a zinc oxide sub-shell before (Figure 10) and after (Figure 11) application of the aluminum oxide sealing shell. Figures 12 and 13 show before (Figure 12) and after (Figure 13) application of the aluminum oxide sealing shell, of titanium oxide It shows the in vitro indomethacin release from particles coated with a tantalum subshell. Figures 14 and 15 show the in vitro release of phenylalanine-glycine-glycine tripeptide from the coated particles before (Figure 14) and after (Figure 15) the application of the sealing shell.

Example

[0119] Example 1 Coated indomethacin microparticles I Microparticles of indomethacin (Hangzhou APIChem Technology Co., Ltd., China) were prepared by a wet ball mill (Fritsch, Premium line, Pulverisette 7, IDar-Oberstein, Germany). The average diameter of the indomethacin particles pulverized by the ball mill was 5.9 μm as determined by laser diffraction (Shimadzu, SALD-7500nano, Kyoto, Japan).

[0120] After pulverization, the suspension was washed and dried to form a powder consisting of indomethacin microparticles. The dried microparticles were dispersed using a dry sieve (100 μm mesh).

[0121] The powder was loaded into an ALD reactor (Picosun, SUNALE® R-series, Espoo, Finland). At a reactor temperature of 50 °C, 15 ALD cycles were performed. Trimethylaluminum and water were used as precursors to form the first subshell of aluminum oxide. The thickness of the first subshell was approximately 4 - 5 nm (estimated from the number of ALD cycles).

[0122] The powder was extracted from the reactor and deagglomerated by sieving through a 100 μm mesh sieve, followed by a 20 μm mesh sieve.

[0123] The powder was loaded into the ALD reactor. At a reactor temperature of 50 °C, 15 ALD cycles were performed. Trimethylaluminum and water were used as precursors to form a second sub-shell of aluminum oxide. The thickness of the second sub-shell was approximately 4 - 5 nm (estimated from the number of ALD cycles).

[0124] The powder was extracted from the reactor and de-aggregated by sieving, first through a 100 μm mesh sieve and then through a 20 μm mesh sieve. The degree of de-aggregation was measured by laser diffraction and the average particle size was measured to be 6 μm.

[0125] The coating - de-aggregation step was repeated two more times to form the third and fourth sub-shells of the same thickness on the particles.

[0126] 40 mg of the powder was placed in a test tube and 3 mL of a dispersion containing water with 0.5% Tween - 80 (Merck, Kenilworth, NJ, USA) was added. The suspension was gently vortexed for 1 minute (Vortex - Genie 2 (Scientific Industries Ltd., New York, USA)) and the particle size distribution was measured by laser diffraction. The average particle size was measured to be 6 μm.

[0127] The suspension was added to a dissolution bath containing 1 L of phosphate buffer (pH 7.2, 25 mM, 37 °C). Samples were removed from the bath at 2, 5, 10, 20, 60, and 120 minutes and filtered through a 0.2 μm filter. The filtered samples were analyzed for indomethacin content using a UV / vis spectrometer (Ultrospec 2100 pro (Amersham Biosciences, Little Chalfont, UK)) operating at a wavelength of 320 nm. The release of indomethacin determined by the absorbance over time is plotted in Figure 3.

[0128] After drying, the powder was loaded into the ALD reactor. Using trimethylaluminum and water as precursors, 10 additional ALD cycles were performed at a reactor temperature of 50 °C to form an aluminum oxide "sealing" shell. The thickness of the resulting sealing shell was approximately 3 nm (estimated from the number of ALD cycles).

[0129] The resulting 40 mg of powder was placed in a test tube, and 3 mL of the same dispersion was added. The suspension was vortexed for 1 minute, and the degree of deaggregation was measured by laser diffraction. The average particle size was measured to be 6 μm.

[0130] The suspension was added to a dissolution bath containing 1 L of phosphate buffer (pH 7.2, 25 mM, 37 °C). Samples were removed from the bath at 2, 5, 10, 20, 60, and 120 minutes and filtered through a 0.2 μm filter. The filtered samples were analyzed for indomethacin content using a UV / vis spectrometer operating at 320 nm. Again, the release of indomethacin over time is plotted in Figure 4.

[0131] Between Figures 3 and 4, a clear difference is seen between the release profiles, with the profile shown in Figure 4 being much slower. This suggests that after applying the sealing shell, the subshell is more highly intact and less indomethacin is exposed to the dissolution solution.

[0132] Example 2 Coated Indomethacin Fine Particles II The sample from Example 1 was washed, 40 mg of the sample was placed in a test tube, and 10 mL of dimethyl sulfoxide was added. The suspension thus formed was vortexed for 1 minute and then centrifuged at 7000×g (Biofuge primo R (Heraeus, Hanau, Germany)) for 5 minutes. The solvent was decanted, and the wet powder was kept in the test tube.

[0133] 10 mL of 99.7% ethanol was added, and the steps of vortexing, centrifuging, and decanting were repeated.

[0134] 3 mL of the same dispersion as described in Example 1 was added. The suspension was gently vortexed for 1 minute, and the degree of deaggregation was measured by laser diffraction. The average particle size was measured to be 6 μm.

[0135] The suspension was added to a dissolution bath containing 1 L of phosphate buffer (pH 7.2, 25 mM, 37 °C). Samples were collected as in Example 1. The release profile is shown in Figure 5.

[0136] Comparing Figure 4 and Figure 5, it can be seen that when the samples were subjected to the above washing, the release of indomethacin was further delayed, suggesting that during washing, indomethacin was removed from the particles with cracks, and only the particles with intact and high-density shells remained in the samples.

[0137] Example 3 Comparison between particles with and without a sealing shell Samples with a sealing shell were prepared as described in Example 1, but the final step of applying the sealing shell was omitted. The washing, dissolution, and analysis of the samples were carried out as described in Example 2, and the release profile is shown in Figure 6.

[0138] By comparing the release profiles between Figure 5 and Figure 6, it is shown that the indomethacin content of the washed samples is higher in the samples with a sealing shell. The amount of "wasted" indomethacin is about 4 times that of the samples without a sealing shell (15.5% vs. 4%).

[0139] Example 4 In vivo rat model I Samples similar to those described in Example 1 (four sub-shells without a sealing shell) were suspended in a 0.5% Tween-80 solution. A second suspension was prepared using samples with four sub-shells having a sealing shell as described above.

[0140] Both suspensions were subcutaneously injected into the dorsal region of male Sprague-Dawley rats, and plasma samples were extracted. The indomethacin content was measured by HPLC-MS / MS (Xeco TDS-micro (Waters, Milford, MA, USA)) using a diode array detector (Shimadzu) set at 254 nm. Separation was performed using a phenylhexyl column with dimensions of 4.6 * 150 mm and a particle size of 2.6 μm in a column oven set at 40 °C. Mobile phase A was water with 10 g / L acetic acid, and mobile phase B was acetonitrile. A gradient elution program was applied, reducing mobile phase A from 70% to 30%. Quantification was performed using a linear equation from a six-point calibration curve in the range of 0.5 - 100 μg / mL. The analysis run time was 31 minutes.

[0141] The solid line of the square points in Figure 7 shows the plasma concentration profile of this first test group, and the dotted line of the triangular points shows the plasma concentration profile of the second test group.

[0142] The peaks in the figure represent the initial burst release of indomethacin in the first few hours after administration of the suspension. It can be seen that the sealing shell on the particles of the first suspension reduces the burst release by about a quarter.

[0143] Example 5 In Vivo Rat Model II Samples (four subshells and a sealing shell) were prepared according to the method described in Example 1.

[0144] Suspensions were subcutaneously injected into the dorsal region of male Sprague-Dawley rats (6 rats per group at doses of 1, 10, and 100 mg / kg body weight (BW)) and compared to an injection of neat indomethacin (1 mg / kg BW). Plasma samples were extracted at different times. The indomethacin content was analyzed by HPLC-MS / MS (Xeco TDS-micro (Waters, Milford, MA, USA)).

[0145] Figure 8 shows the results of plasma sample analysis. The plasma concentration-time profile on the left shows the comparison between neat indomethacin and the sample coated at 1 mg / kg. The profile on the right shows the comparison between different coated samples. The plasma concentration-time profile of indomethacin coated with nanoshells showed sustained release over 12 weeks when administered subcutaneously at 10 or 100 mg / kg. Neat indomethacin was completely eliminated within one week.

[0146] Example 6 In vivo rat model III Samples were prepared according to the method described in Example 2 (4 subshells and sealing shells, then washed).

[0147] The suspension of the sample was used in the rat model (10 mg / kg BW) described in Example 5.

[0148] The results of plasma sample analysis of this test are shown in Figure 9. For comparison, Figure 9 also includes the results of 10 mg / kg in Example 5.

[0149] From the plasma concentration profile, it can be seen that washing of the sample significantly reduces the initial burst of drug release.

[0150] Example 7 Coated indomethacin microparticles III The microparticles of indomethacin were prepared, washed, dried, and dispersed as described in Example 1 above.

[0151] The powder was loaded into the same ALD reactor as described in Example 1. Using diethylzinc (DEZ) and water as precursors, 15 ALD cycles were performed at a reactor temperature of 50 °C to form the first subshell of zinc oxide. The thickness of the first subshell was approximately 4 - 5 nm (estimated from the number of ALD cycles).

[0152] The powder was extracted from the reactor and deagglomerated using a 20 μm nylon mesh sieve (Tsutsui Scientific, China) by a sonic shifter (Tsutsui Scientific SW-20AT, China).

[0153] The powder was loaded back into the ALD reactor and an additional 15 ALD cycles were performed to form a second subshell of zinc oxide. The thickness of the second subshell was estimated to be approximately 4 - 5 nm.

[0154] The powder was extracted from the reactor and deagglomerated using the sonic shifter as described above.

[0155] The coating - deagglomeration step was repeated two more times to form third and fourth subshells of the same thickness on the particles, forming a sample without a sealing shell.

[0156] The total indomethacin content in the samples produced without a sealing shell was measured by HPLC as described in Example 4 above.

[0157] Samples of 41.09 mg and 39.74 mg (duplicate tests) were placed into test tubes. 3 mL of the dispersion was added and the suspension was vortexed as described in Example 1.

[0158] The two suspensions were added to the dissolution bath, the samples were removed and filtered through a 0.2 μm filter as described in Example 1. The filtered samples were analyzed for indomethacin content as described in Example 1. Figure 10 plots the average values of indomethacin release from the two samples (error bars are not shown as the analytical data are nearly the same with standard deviations).

[0159] ​The sample was reloaded into the ALD reactor and 15 additional ALD cycles were performed at a reactor temperature of 50 °C using trimethylaluminum and water as precursors to form a sealing shell of aluminum oxide. The thickness of the resulting sealing shell was approximately 4 - 5 nm (estimated from the number of ALD cycles).

[0160] The total indomethacin content in the generated sample with the sealing shell was measured by HPLC as described in Example 4 above.

[0161] Samples of 40.41 mg and 40.18 mg (duplicate test) with the sealing shell were placed into test tubes, 3 mL of the dispersion was added, and the suspension was vortexed as described above.

[0162] The suspension was then added to the dissolution bath and the release of indomethacin was analyzed and plotted in Figure 11 as described above.

[0163] Between Figures 10 and 11, a clear difference was seen between the release profiles, with the release shown in Figure 11 being much slower. This suggests that after applying the aluminum oxide sealing shell to the four sub - shells of zinc oxide, the sub - shells are much more highly intact and less indomethacin is exposed to the dissolution solution.

[0164] Example 8 Coated Indomethacin Particles IV The same procedure as described in Example 7 above was repeated, but titanium tetrachloride was used instead of DEZ to provide four separate sub - shells of titanium dioxide.

[0165] The release profiles of indomethacin are shown in Fig. 12 (without the aluminum oxide sealing shell) and Fig. 13 (with the sealing shell). A difference is seen, and what is shown in Fig. 13 is initially slow and the in vitro burst release is much lower. Again, this suggests that after applying the aluminum oxide sealing shell to the four sub-shells of titanium dioxide, the sub-shells are more highly intact and there is less indomethacin exposed to the dissolution solution.

[0166] Example 9 Coated peptide microparticles Microparticles containing trehalose and phenylalanine-glycine-glycine (PGG) (both from Sigma-Aldrich Co., St. Louis, USA) were prepared by spray drying using a mini spray dryer B-290 (Buchi, Switzerland).

[0167] 130 mL of an aqueous solution of PGG (0.5%), trehalose (9.7%), and Tween 80® (0.2%). Thereby, microparticles containing 4.7% of PGG were obtained. The spray drying was carried out at an inlet temperature of 125 °C, a pump flow rate of 4.2 mL / min, and a resulting outlet temperature of 73 °C.

[0168] The powder of the microparticles was loaded into an ALD reactor (Picosun, SUNALE™ R-series, Espoo, Finland). At a reactor temperature of 50 °C, 25 ALD cycles were carried out. Trimethylaluminum and water were used as precursors to form the first sub-shell of aluminum oxide. The thickness of the first sub-shell was about 7 - 8 nm (estimated from the number of ALD cycles).

[0169] The powder was extracted from the reactor and deaggregated using a sonic shifter as described in Example 7 above.

[0170] Three more coating - deaggregation steps were carried out to provide a total of four sub-shells of the same thickness.

[0171] The total PGG content in the sample thus generated was measured by HPLC as described in Example 4 above.

[0172] Next, 199.22 mg of the sample was placed in a test tube, 3 mL of the dispersion was added, the suspension was vortexed for 1 minute, added to the dissolution bath, and the release of indomethacin was measured as described in Example 1 above.

[0173] The released PGG was analyzed by HPLC and plotted in Figure 14.

[0174] The remaining sample was reloaded into the ALD reactor and, as described above, an additional 15 ALD cycles were performed to form an aluminum oxide "sealing" shell (estimated to be about 4 - 5 nm thick based on the number of ALD cycles).

[0175] The total PGG content in the generated sample with the sealing shell was measured by HPLC.

[0176] 199.12 mg and 200.28 mg of the powder (duplicate test) were added to a test tube, 3 mL of the dispersion was added, and subsequently the resulting suspension was gently vortexed for 1 minute, the suspension was added to the dissolution bath, and the released PGG content was analyzed as described above. The release of PGG versus time is plotted in Figure 15 (average value of the two values).

[0177] There are clear differences between the release profiles between Figure 14 and Figure 15, with the profile shown in Figure 15 being much slower, again suggesting that the sealing shell on the four sub - shells keeps them more intact and less indomethacin is exposed to the dissolution solution.

Claims

1. 1. A composition in the form of a plurality of particles having an average diameter based on volume that is from about 500 nm to about 50 μm, said particles comprising: (a) a spray-dried solid core comprising a biologically active agent and / or a pharmaceutically acceptable excipient; (b) one or more discrete layers surrounding the core, each comprising at least one distinct coating material; (c) an outer overcoating layer of coating material that surrounds, surrounds, and / or encapsulates the core of coating material and the previously applied individual layers, the outer overcoating layer having a thickness less than the previously applied individual layers; the thickness of the outer overcoating layer is less than or equal to about 1 / 1000 of the average volumetric diameter of the core and any previously applied individual layers of coating material; composition.

2. 10. The composition of claim 1, wherein the carrier / excipient material is a sugar or sugar alcohol, and / or a pH modifier.

3. The composition of claim 1 , wherein the core consists essentially of a biologically active agent.

4. The biologically active agent may be an analgesic, an anesthetic, an anti-ADHD agent, an anorectic, an anti-addictive agent, an antibacterial agent, an antimicrobial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, an antiprotozoal agent, an anthelmintic, an ectoparasiticide, a vaccine, an anticancer agent, an antimetabolite, an alkylating agent, an antitumor agent, a topoisomerase, an immunomodulatory agent, an immunostimulant, an immunosuppressant, an anabolic steroid, an anticoagulant, an antiplatelet agent, an anticonvulsant, an antidementia agent, an antidepressant, an antidote, an antihyperlipidemic agent, an antigout agent, an antimalarial agent, an antimigraine agent, an anti-inflammatory agent, an antiparkinsonian agent, an antipruritic agent, an antipsoriatic agent, an antiemetic, an anti-obesity agent, an anthelmintic, an antidysrhythmic agent, an anti-dysrhythmic agent, an anti-dyslipide ... Antithrombotic, antiasthmatic, antibiotic, anticoagulant, antidepressant, antidiabetic, antiepileptic, antifibrinolytic, antihemorrhagic, antihistamine, antitussive, antihypertensive, antimuscarinic, antimycobacterial, antioxidant, antipsychotic, antipyretic, antirheumatic, antiarrhythmic, anxiolytic, aphrodisiac, cardiac glycoside, cardiac stimulant, entheogen, entactogen, euphoric, orexigenic, antithyroid, anxiolytic, hypnotic, neuroleptic, astringent, bacteriostatic, beta-blocker, calcium channel blocker, ACE inhibitor, angiotensin II receptor antagonist, renin inhibitor, beta-blocker Adrenergic receptor blocking agents, blood 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, dopaminergic agents, antiparkinsonian drugs, free radical scavengers, growth factors, fibrates, bile acid sequestrants, scar removers, glucocorticoids, mineralocorticoids, hemostatic agents, hallucinogens, hypothalamic-pituitary hormones, immunological agents, laxatives, antidiarrheals, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid Calcitonin, selenics, statins, stimulants, wake-promoting agents, decongestants, dietary minerals, biphosphonates, cough suppressants, ophthalmic drugs, ontology drugs, H1 antagonists, H2 antagonists, proton pump inhibitors, prostaglandins, radiopharmaceuticals, hormones, sedatives, antiallergic drugs, appetite stimulants, appetite suppressants, steroids, sympathomimetics, thrombolytic drugs, thyroid drugs, vasodilators, xanthines, erectile dysfunction drugs, gastrointestinal drugs, histamine receptor antagonists, keratolytics, antianginal drugs, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, leukotriene inhibitors, macrolides,4. The composition of any one of claims 1 to 3, wherein the compound is selected from an NSAID, a nutritional supplement, an opioid analgesic, an opioid antagonist, a potassium channel activator, a protease inhibitor, an anti-osteoporosis agent, a cognitive enhancer, an anti-urinary incontinence agent, a nutritional oil, an anti-benign prostatic hyperplasia agent, an essential fatty acid, a non-essential fatty acid, a 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.

5. 5. The composition of claim 1, wherein the core has an average diameter based on volume of from about 1 μm to about 50 μm.

6. 6. The composition of claim 1, wherein two or more separate layers of coating material are applied sequentially to the core.

7. The composition of claim 6 wherein 3 to 10 individual layers of coating material are applied.

8. The composition of any one of claims 1 to 7, wherein the total thickness of the individual layers of coating material is from about 0.5 nm to about 2 µm.

9. 9. The composition of claim 1, wherein the maximum thickness of each individual layer of coating material is, on average, about 1 / 100 of the average volumetric diameter of the core or core with any previously applied individual layers of coating material.

10. 10. The composition of claim 1, wherein the thickness of the outer overcoating layer is no more than about 0.7 times the thickness of the thickest previously applied individual layer of coating material.

11. 11. The composition of claim 10, wherein for particles up to about 20 μm, the outer overcoating layer has a thickness of from about 0.3 nm to about 10 nm.

12. 12. The composition of any one of claims 1 to 11, wherein the thickness of the outer overcoating layer is no more than about 0.7 times the thickness of the last individual layer of coating material applied.

13. 13. The composition of any one of claims 1 to 12, wherein the outer overcoating layer results in particles that are essentially free of abrasions, pinholes, breaks, gaps, cracks, and / or voids through which the active ingredient may potentially be exposed, if present.

14. 14. The composition of claim 1, wherein the coating material of the one or more individual layers and / or the coating material of the outer overcoating layer comprises one or more inorganic materials.

15. The composition of claim 14 , wherein the coating material comprises one or more metal- or metalloid-containing compounds.

16. 16. The composition of claim 15, wherein the compound comprises a hydroxide and / or an oxide.

17. 17. The composition of claim 15 or 16, wherein the compound comprises aluminum oxide, titanium dioxide, and / or zinc oxide.

18. 18. The composition of any one of claims 1 to 17, wherein the coating material of the outer overcoating layer comprises aluminum oxide.

19. The composition of any one of claims 1 to 18, wherein the biologically active agent is selected from 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 of any of these.

20. A composition according to any one of claims 1 to 19, wherein the biologically active agent is a peptide.

21. A composition according to any one of claims 1 to 19, wherein the biologically active agent is a toxoid.

22. A composition according to any one of claims 1 to 19, wherein the biologically active agent is a vaccine.

23. A composition according to any one of claims 1 to 19, wherein the biologically active agent is part of genetic material.

24. A composition according to any one of claims 1 to 19, wherein the biologically active agent is a nucleic acid.

25. A composition according to any one of claims 1 to 19, wherein the biologically active agent is an anti-obesity agent and / or an anti-diabetic agent.

26. The composition of any one of claims 2 to 19, wherein the pharmaceutically acceptable excipient is a sugar or sugar alcohol and the biologically active agent is a polymer complex.

27. The composition of claim 26, wherein the macromolecular complex is selected from a peptide, a protein, and a portion of genetic material.

28. 28. A composition as defined in any one of claims 1 to 27 for use in medical or veterinary practice.

29. The composition of claim 28 for use in the treatment of obesity and / or diabetes.

30. 28. A pharmaceutical or veterinary formulation comprising a composition as defined in any one of claims 1 to 27 and a pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier.

31. 31. The formulation of claim 30 in the form of a sterile injectable and / or injectable dosage form.

32. 31. The formulation of claim 30 in the form of a liquid, sol, or gel that can be administered via a surgical administration device to form a depot formulation.

33. A formulation according to any one of claims 30 to 32 for use in the treatment of obesity and / or diabetes.

34. 28. A process for preparing a composition as defined in any one of claims 1 to 27, comprising: A process comprising applying a layer of coating material by atomic layer deposition to a spray dried core and / or a separate layer of previously applied coating material on said core.

35. (i) coating the spray-dried solid cores with a first discrete layer of a coating material; (ii) the coated cores from step (i) are then subjected to a deagglomeration process step; (iii) then coating the deagglomerated coated cores from step (ii) with a second, discrete layer of coating material; (iv) repeating steps (ii) and (iii) to obtain the required number of individual layers; (v) subjecting the coated particles from step (iv) to a final deagglomeration process step; 35. The process of claim 34, wherein (vi) applying an outer overcoating layer of coating material to the deagglomerated coated particles from step (v).

36. 36. The process of claim 35, wherein the deagglomeration step performed during application of the coating comprises sieving.

37. 35. The process of claim 34, wherein the sieving comprises sonic sieving.

38. 38. The process of any one of claims 34 to 37, wherein the particles are subjected to a final vortexing step after application of the outer overcoating layer.

39. 33. A process for the preparation of a formulation as defined in any one of claims 30 to 32, comprising:

28. A process comprising mixing a composition according to any one of claims 1 to 27 with the relevant pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier.

40. 40. The process of any one of claims 34 to 39, comprising the further step of suspending the coated particles in a solvent in which the biologically active agent is soluble, followed by separating the particles from the solvent to provide separated particles.

41. 41. The process of claim 40, comprising the further step of resuspending the separated particles in a solvent.

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