New Regulations

Abstract

Compositions are provided that include a plurality of particles having an average diameter of 10 nm to about 700 μm by weight, number, or volume, comprising: (a) a solid core, preferably containing a biologically active agent; (b) one or more discrete layers surrounding the core, each comprising at least one distinct coating material; and (c) a final overcoating layer of coating material that surrounds, encloses, and / or encapsulates the core and any previously applied layers of coating material, the final layer having a thickness less than the previously applied layers. Layers (b) and (c) are preferably applied by a vapor-phase coating technique, such as atomic layer deposition. When the core contains a biologically active agent, the composition can provide delayed or sustained release of the active agent without a burst effect.

Description

[Technical Field]

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

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

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

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

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

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

[0007] Atomic layer deposition (ALD) is a technique used to deposit thin films onto solid substrates, including a variety of materials, including organic, biological, polymeric, and, especially, inorganic materials such as metal oxides.

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

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

[0010] In ALD, a first precursor, which may be metal-containing, is supplied to the ALD reactor chamber (in a so-called "precursor pulse") and forms a monolayer of atoms or molecules adsorbed on the surface of the substrate. Excess first precursor is then purged from the reactor, and a second precursor, such as water, is then pulsed into the reactor. This reacts with the first precursor to form a monolayer of, for example, a metal oxide on the substrate surface. A subsequent purge pulse is followed by a further pulse of the first precursor, thus initiating a new cycle of the same events (a so-called "ALD cycle").

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

[0012] In a typical ALD process, only monolayers of atoms or molecules are produced during a single cycle, resulting in essentially continuous bands across the surface of the substrate, with no discernible physical interfaces between them.

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

[0014] The agitation step is performed to address a problem primarily observed with nanoparticles and microparticles: particle agglomeration occurs during the ALD coating process, resulting in the formation of "pinholes" at the contact points between such particles. The redispersion / agitation step is performed by placing the coated substrate in water and sonicating it, resulting in deagglomeration and breaking down the contact points between individual particles of the coated active material.

[0015] As described in WO 2014 / 187995, the process of performing a "set" of ALD coating cycles, followed by intermittent dispersal, results in clear, distinct layers of coating defined by clear, visible physical interfaces between such coating layers. Such interfaces are clearly visible by techniques such as transmission electron microscopy (TEM) as regions of high electron transparency. As discussed below, similar interfaces are not visible when the coating builds up from the surface of the substrate one atomic layer at a time. This is true even when different precursors are fed to the ALD reactor in successive ALD cycles.

[0016] It has been found to be advantageous to provide a final thinner "sealing" shell of inorganic coating material after the final redispersion step, which allows the particles to be de-agglomerated into primary particles without the use of invasive de-agglomeration techniques such as sonication, presenting 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 having an average diameter by weight, number, and / or volume in an amount of from 10 nm to about 700 μm, the particles comprising: (a) a solid core, preferably comprising a biologically active agent; (b) one or more separate layers surrounding (or, if there is more than one such layer, surrounding, in turn, the core), each of which comprises at least one distinct (i.e., separately applied) coating material; and (c) an outer (i.e., final) overcoating layer ("sealing shell") of coating material that surrounds, encloses, and / or encapsulates the core and / or previously applied layers of coating material, the final layer having a thickness less than the previously applied layers. These compositions are hereinafter collectively referred to as "the compositions of the present invention." [Brief explanation of the drawings]

[0018] [Figure 1] Figure 1 is a TEM image. [Figure 2] Figure 2 is a TEM image. [Figure 3] FIG. 3 shows the in vitro release of indomethacin from particles coated with aluminum oxide prior to application of a sealing shell. [Figure 4] FIG. 4 shows the in vitro release of indomethacin from aluminum oxide coated particles after application of a sealing shell. [Figure 5] FIG. 5 shows the release of indomethacin from particles with a sealing shell that were also subjected to a final washing step. [Figure 6] FIG. 6 shows the release of indomethacin from particles that were subjected to a final washing step but did not have a sealing shell. [Figure 7] Figure 7 shows a comparison between the in vivo plasma concentration-time profiles in rats injected with coated indomethacin particles in the presence (white squares) and absence (black triangles) of a sealing shell. [Figure 8] FIG. 8 shows a comparison between the in vivo plasma concentration-time profiles in rats injected with different doses of coated indomethacin particles. [Figure 9] FIG. 9 shows a comparison between the in vivo plasma concentration-time profiles in rats injected with the same dose of coated indomethacin particles made by the same process, with and without a washing step. [Figure 10] FIG. 10 shows the in vitro release of indomethacin from particles coated with a zinc oxide subshell prior to application of an aluminum oxide sealing shell. [Figure 11] FIG. 11 shows the in vitro release of indomethacin from particles coated with zinc oxide subshells after application of an aluminum oxide sealing shell. [Figure 12] FIG. 12 shows the in vitro release of indomethacin from particles coated with a titanium oxide subshell prior to application of an aluminum oxide sealing shell. [Figure 13] FIG. 13 shows the in vitro release of indomethacin from particles coated with a titanium oxide subshell after application of an aluminum oxide sealing shell. [Figure 14] FIG. 14 shows the in vitro release of phenylalanine-glycine-glycine tripeptide from coated particles prior to application of a sealing shell. [Figure 15] FIG. 15 shows the in vitro release of phenylalanine-glycine-glycine tripeptide from coated particles after application of a sealing shell. DETAILED DESCRIPTION OF THE INVENTION

[0019] Those skilled in the art will appreciate that the term "solid" includes any form of matter that retains its shape and density when unconfined and / or whose molecules are generally as tightly packed as the repulsive forces between them allow. The solid core has at least a solid outer surface onto which a layer of coating material can be deposited. The interior of the solid core may also be solid, or alternatively, may be hollow. For example, if the particles are spray-dried before being placed in a reaction vessel, they may be hollow due to the spray-drying technique.

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

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

[0022] "Consisting essentially of" a biologically active agent includes that the solid core contains essentially only the biologically active agent, i.e., does not contain non-biologically active agents such as excipients, carriers, etc. (see below). This means that the core may contain less than about 5%, e.g., less than about 3%, e.g., less than about 1%, including less than about 2%, of such other excipients.

[0023] Alternatively, the 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 ingredients.

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

[0025] As used herein, the term "biologically active agent," or similar and / or related phrases, generally refers to any agent or drug capable of producing some kind of physiological effect (whether therapeutic or prophylactic for a particular disease state or condition) in a living subject, including particularly mammalian and especially human subjects (patients).

[0026] Biologically active agents include, for example, analgesics, anesthetics, anti-ADHD agents, appetite suppressants, anti-addictive agents, antibacterial agents, antimicrobial agents, antifungal agents, antiviral agents, antiparasitic agents, antiprotozoal agents, anthelmintics, ectoparasiticides, vaccines, anticancer agents, antimetabolites, alkylating agents, antitumor agents, topoisomerases, immunomodulators, immunostimulants, immunosuppressants, anabolic steroids, anticoagulants, antiplatelet agents, anticonvulsants, antidementia agents, antidepressants, detoxifiers, antihyperlipidemic agents, antigout agents, antimalarials, antimigraine agents, anti-inflammatory agents, antiparkinsonian agents, antipruritics, antipsoriatic agents, antiemetics, anti-obesity agents, anthelmintics, anti Antiarrhythmics, antiasthmatics, antibiotics, anticoagulants, antidepressants, antidiabetics, antiepileptics, antifibrinolytics, antihemorrhagic agents, antihistamines, antitussives, antihypertensives, antimuscarinics, antimycobacterials, antioxidants, antipsychotics, antipyretics, antirheumatics, antiarrhythmics, anxiolytics, aphrodisiacs, cardiac glycosides, cardiac stimulants, entheogens, entactogens, euphoric agents, orexigenics, antithyroid agents, anxiolytics, hypnotics, neuroleptics, astringents, bacteriostatic agents, beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, renin inhibitors, beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, renin inhibitors, Adrenergic receptor blockers, 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 drugs, 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, ontological 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, keratolytic agents, antianginal drugs, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, leukotriene inhibitors, macrolides,The therapeutic agent may be selected from an NSAID, a nutritional agent, an opioid analgesic, an opioid antagonist, a potassium channel activator, a protease inhibitor, an anti-osteoporosis agent, a cognitive enhancer, an anti-urinary incontinence agent, a nutritional oil, an anti-benign prostatic hyperplasia agent, an essential fatty acid, a non-essential fatty acid, a 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.

[0027] The biologically active agent may also be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, or a mixture thereof. Non-limiting examples of therapeutic peptides / proteins are: lepirudin, cetuximab, dornase alfa, denileukin diftitox, etanercept, bivalirudin, leuprolide, alteplase, interferon alfa-n1, darbepoetin alfa, reteplase, epoetin alfa, salmon calcitonin, interferon alfa-n3, pegfilgrastim, sargramostim, secretin, peginterferon alfa-2b, asparaginase. , thyrotropin alfa, antihemophilic factor, anakinra, gramicidin D, intravenous immunoglobulin, anistreplase, insulin (regular), tenecteplase, menotropin, interferon gamma-1b, interferon alfa-2a (recombinant), coagulation factor VIIa, oprelvekin, palifermin, glucagon (recombinant), aldesleukin, botulinum toxin type B, omalizumab, lutropin alfa, insulin lispro, insulin glargine, collagenase, rasburicase, a Dalimumab, imiglucerase, abciximab, alpha-1-proteinase inhibitor, pegaspargase, interferon beta-1a, pegademase bovine, human serum albumin, eptifibatide, iodinated serum albumin, infliximab, follitropin beta, vasopressin, interferon beta-1b, hyaluronidase, rituximab, basiliximab, muromonab, digoxin immune Fab (ovine), ibritumomab, daptomycin, tositumomab, pegvisomant, vomit Turinum toxin type A, pancrelipase, streptokinase, alemtuzumab, alglucerase, capromab, laronidase, urofollitropin, efalizumab, serum albumin, choriogonadotropin alfa, antithymocyte globulin, filgrastim, coagulation factor IX, becapremin, agalsidase beta, interferon alfa-2b, oxytocin, enfuvirtide, palivizumab, daclizumab, bevacizumab, arcitumomab, eculizumab, panitumumab, ranibizumab,Idursulfase, alglucosidase alfa, exenatide, mecasermin, pramlintide, galsulfase, abatacept, cosyntropin, corticotropin, insulin aspart, insulin detemir, insulin glulisine, pegaptanib, nesiritide, thymalfasin, defibrotide, natural alpha interferon / multiferon, glatiramer acetate, perotact, teicoplanin, canakinumab, ipilimumab, sulodexide, tocilizumab, teriparatide, pertuzumab, rilonacept, denosumab, liraglutide, golimumab, belatacept, buserelin, velaglucerase alfa, tesamorelin, brentuximab vedotin, taliglucerase alfa, belimumab, aflibercept, asparaginase Erwinia chrysanthemis, ocriplas Glucarpidase, teduglutide, raxibacumab, certolizumab, astimlimab pegol, insulin isophane, epoetin zeta, obinutuzumab, fibrinolysin, also known as plasmin, follitropin alfa, romiplostim, lucinactant, natalizumab, aliskiren, ragweed pollen extract, secukinumab, somatotropin (recombinant), drotrecogin alfa, alefacept, OspA lipoprotein, urokinase, abarelix, sermorelin, aprotinin, gemtuzumab ozogamicin, satumomab pendetide, albiglutide, antithrombin alfa, antithrombin III (human), asfotase alfa, atezolizumab, autologous cultured chondrocytes, beractant, blinatumomab, C1 esterase inhibitor (human), coagulation factor XIII A subunit (recombinant), cornstat alfa, daratumumab, desirudin, dulaglutide, elosulfase alfa, evolocumab, fibrinogen concentrate (human), filgrastim-sndz, gastric intrinsic factor, hepatitis B immunoglobulin, human calcitonin, human clostridial tetani toxoid immunoglobulin, human rabies virus immunoglobulin, human Rho(D) immunoglobulin, human Rho(D) immunoglobulin, hyaluronidase (human, recombinant), idarucizumab, immunoglobulin (human), vedolizumab, ustekinumab, turoctocog alfa, tuberculin purified protein derivative,Simoctocog alfa, siltuximab, sebelipase alfa, saclosidase, ramucirumab, prothrombin complex concentrate, poractant alfa, pembrolizumab, peginterferon beta-1a, ofatumumab, obiltoxaximab, nivolumab, necitumumab, metreleptin, methoxypolyethylene glycol-epoetin beta, mepolizumab, ixekizumab, insulin degludec, insulin (porcine), insulin (bovine), thyroglobulin, anthrax immunoglobulin (human), anti- Inhibitor coagulation complex, brodalumab, C1 esterase inhibitor (recombinant), chorionic gonadotropin (human), chorionic gonadotropin (recombinant), coagulation factor X (human), dinutuximab, efmoloctocog alfa, factor IX complex (human), hepatitis A vaccine, human varicella-zoster immune globulin, ibritumomab tiuxetan, lenograstim, pegloticase, protamoxifen sulfate, protein S (human), sipuleucel-T, somatropin (recombinant), sucoctocog alfa, and thrombomodulin alfa.

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

[0029] The compositions of the present invention may include benzodiazepines such as alprazomal, chlordiazepoxide, clobazam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, quazepam, temazepam, triazolam, and pharmaceutically acceptable salts of any of these.

[0030] The anesthetics that can be used in the compositions of the present invention can be local or systemic.Local anesthetics that can be mentioned include amylocaine, ambucaine, articaine, benzocaine, benzonatate, bupivacaine, butacaine, butanilicaine, chloroprocaine, cinchocaine, cocaine, cyclomethicane, dibucaine, diperodon, dimethocaine, eucaine, etidocaine, hexylcaine, fomocaine, photocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine, mepivacaine, mepryl and quinisocaine, ropivacaine, trimecaine, tolicaine, tropacocaine, or a pharmaceutically acceptable salt of any of these.

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

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

[0033] Opioid antagonists that may be used in the compositions of the present invention include naloxone, nalorphine, niconalorphine, diprenorphine, levallorphan, samidorphan, nalodain, alvimopan, methylnaltrexone, naloxegol, 6β-naltrexone, axerophrine, bebenoplan, methylsamidorphan, naldemedine, preferably nalmefeme, especially naltrexone, and pharmaceutically acceptable salts of any of these.

[0034] Anticancer drugs that may be included in the compositions of the present invention include actinomycin, afatinib, all-trans retinoic acid, amsacrine, anagrelide, arsenic trioxide, axitinib, azacitidine, azathioprine, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, chlorambucil, cladribine, clotrimazole, cyclosporine ... arabine, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, erlotinib, estramustine, etoposide, everolimus, fludarabine, fluorouracil, gefitinib, guadecitabine, gemcitabine, hydroxycarbamide, hydroxyurea, idarubicin, idelari Sib, 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, ruxolitinib, sonidegib, sorafenib, sunitinib, tegafur, temozolomide, teniposide, thioguanine, thiotepa, topotecan, trabectedin, valrubicin, vandetanib, vemurafenib, venetoclax, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, and pharmaceutically acceptable salts of any of these. A preferred biologically active agent is azacitidine.

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

[0036] Other drugs that may be mentioned for use in the compositions of the invention include immunomodulatory imide drugs such as thalidomide, and analogs thereof such as pomalidomide, lenalidomide, and apremilast, as well as pharmaceutically acceptable salts of any of these. Other drugs that have been mentioned include angiotensin II receptor type 2 agonists, such as Compound 21 (C21; 3-[4-(1H-imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophene-2-[(N-butyloxylcarbamate)-sulfonamide], and pharmaceutically acceptable (e.g., sodium) salts thereof.

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

[0038] Therefore, the dosage of active ingredient that can be administered to patient should be sufficient to bring about therapeutic response in reasonable and / or relevant time frame.Those skilled in the art know that the selection of exact dosage and composition and most suitable delivery regimen is not only influenced by the nature of active ingredient, but also by the pharmacological properties of preparation, route of administration, the nature and severity of the pathological condition that is being treated, the physical condition and mental state of recipient, and the age, condition, weight, sex and response of the patient that is being treated, the stage / severity of disease and the genetic difference between patients.

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

[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 which will be most suitable for an individual patient.

[0041] Alternatively, the compositions described herein may also include, instead of (or in addition to) a biologically active agent, a diagnostic agent (i.e., an agent that does not itself have direct therapeutic activity but can be used in the diagnosis of a condition, such as contrast agents or contrast media for bioimaging).

[0042] Non-biologically active adjuvants, diluents, and carriers that can be used in the cores coated according to the present invention can include pharmaceutically acceptable substances that are soluble in water, such as carbohydrates, e.g., sugars such as lactose and / or trehalose, and sugar alcohols such as mannitol, sorbitol, and xylitol, or 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 portion of genetic material, as generally described, and / or the specific peptide / protein described above. Embedding the macromolecular complex in an excipient in this way often results in a larger core for coating, and therefore larger coated particles, making it more advantageous to apply a sealing shell, which can include, for example, aluminum oxide.

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

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

[0045] As used herein, the term "weight-based average diameter" is understood by those skilled in the art to include the average particle size characterized and defined by a particle size distribution by weight, i.e., a distribution in which 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 the average particle size characterized and defined by a particle size distribution by number, i.e., a distribution in which the existing fraction (relative amount) in each size class is 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 the average particle size characterized and defined by a particle size distribution by volume, i.e., a distribution in which the existing fraction (relative amount) in each size class is defined as the volume fraction measured, for example, by laser diffraction. Other instruments well known in the art can be used to measure particle size, for example, instruments sold by Malvern Instruments, Ltd. (Worcestershire, UK) and Shimadzu (Kyoto, Japan).

[0046] The particles may be spherical, i.e., they have an aspect ratio of less than about 20, more preferably less than about 10, such as less than about 4, especially less than about 2, and / or at least about 90% of the particles may have a variation in radius (measured from the center of gravity to the particle surface) of not more than about 50% of the mean value, such as not more than about 30% of that value, for example not more than about 20% of that value.

[0047] Nevertheless, the present invention also allows for coating of particles of any shape. For example, particles of irregular shape (e.g., "raisin" shape), needle shape, or rectangular parallelepiped shape can be coated. For non-spherical particles, the size can be expressed as the particle size of a corresponding sphere of the same weight, volume, or surface area, for example. Hollow particles, as well as particles with pores, gaps, etc., such as fibrous or "tangled" particles, can also be coated according to the present invention.

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

[0049] The particles may need to be washed and / or cleaned to remove impurities that may result from their production, and then dried (depending on how the core-containing particles were originally prepared). 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 cores can then be deagglomerated by grinding, screening, milling, and / or dry sonication. Alternatively, the cores can be treated to remove any volatile materials that may be absorbed onto their surface, for example, by exposing the particles to vacuum and / or elevated temperatures.

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

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

[0052] Preferably, two or more distinct layers, coatings, or shells (these terms are used interchangeably herein) are applied (i.e., "separately applied") to the solid core containing the biologically active agent. Such "separate application" of "separate layers, coatings, or subshells" 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 deagglomeration process. In this regard, The number of individual layers (also referred to as "subshells") of coating material as defined herein is , corresponding to a number of these intermittent deagglomeration steps, with a final deagglomeration step occurring prior to application of an outer overcoating layer of coating material.

[0053] The coated cores may be subjected to the aforementioned deagglomeration process without being removed from the apparatus in a continuous process. Such a process may involve forcing the solid product mass formed by coating the cores through a sieve disposed within the reactor, configured to deagglomerate particle agglomerates upon forcing the coated cores by a forcing means applied within the reactor prior to being subjected to a second and / or further coating. This process may be continued as many times as necessary and / or appropriate before applying a final overcoat, as described herein.

[0054] Placing the sieve inside the reactor vessel means that the coating can be applied in a continuous process without the need to remove the particles from the reactor. Therefore, there is no need for manual handling of the particles, and no external machinery is required to deagglomerate agglomerated particles. This not only significantly reduces the time the coating process takes to be carried out, but also makes it more convenient and reduces the risk of personnel handling harmful (e.g., toxic) materials. Limiting manual handling also increases the reproducibility of the process and reduces the risk of contamination.

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

[0056] In the external deagglomeration process, deagglomeration can alternatively be performed by subjecting the wet or dry coated particles to one or more of nozzle aerosolization, milling, grinding, stirring, high shear mixing and / or homogenization. If the deagglomeration step is performed on wet particles, the deagglomerated particles should be dried (as described above for the cores) before the next coating step.

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

[0058] The inventors have found that applying separate layers of coating material after external deagglomeration results in a visible and discernible interface, which can be observed by analyzing the coated particles in accordance with the present invention, for example, by TEM as an area of ​​higher electron transparency (as can be seen in Figures 1 and 2).

[0059] This is in contrast to sequential ALD processes, in which coated particles are not removed from the reactor before recoating. In ALD coating processes, even when different coating materials are used sequentially (e.g., switching from one metal oxide precursor to another between ALD cycles), no distinct physical interfaces, such as those shown in Figures 1 and 2, are observed because coating occurs at the atomic level. Therefore, the layer thickness between interfaces, as shown in Figures 1 and 2, directly corresponds to the number of cycles performed in each series within the ALD reactor and between individual external agitation steps.

[0060] Without being limited by theory, it is believed that removing the coated particles from the vacuum conditions of the ALD reactor and exposing the newly coated surface to the atmosphere leads to structural rearrangement due to relaxation and restructuring of the outermost atomic layers. Such a process is believed to involve a reorganization of atoms at (and near) the surface, driven by a thermodynamic tendency to reduce the surface free energy.

[0061] Furthermore, surface adsorption of species (e.g., hydrocarbons, which are always present in air) may contribute to this phenomenon, as may reactions of coatings formed with hydrocarbons, as well as surface modification by atmospheric oxygen, etc. Therefore, chemical analysis of such interfaces may reveal traces of contaminants that do not originate from coating processes such as ALD.

[0062] Whether performed inside or outside the reactor, particle agglomerates are preferably broken down by forcing them through a sieve, thus separating the agglomerates into individual particles or agglomerates of a desired and predetermined size (thereby achieving deagglomeration). Regarding the latter, in some cases, the individual primary particle sizes are so small (i.e., <1 μm) that it is not possible to achieve "complete" deagglomeration (i.e., agglomerates broken down into individual particles). Instead, deagglomeration is achieved by breaking down larger agglomerates into smaller agglomerates of secondary particles of the desired size, as determined by the mesh size of the sieve. The smaller agglomerates are then coated using a gas-phase technique to form fully coated "particles" in the form of small agglomerate particles. Thus, the term "particles," when referring to deagglomerated and coated particles in the context of the present invention, refers to both individual (primary) particles and agglomerated (secondary) particles of the desired size.

[0063] In either case, the desired particle size (whether it be individual particles or agglomerates of the desired size) is maintained, and furthermore, continued application of the gas phase coating mechanism to the particles after such deagglomeration by sieving means that a complete coating is formed on the particles, and thus fully coated particles (individuals or agglomerates of the desired size) are formed.

[0064] The repeated coating and deagglomeration process described above, whether carried out inside or outside the reactor, may be carried out at least once, preferably twice, more preferably three times, such as four times, including five times, more particularly six times, such as seven times, and up to about 100 times, such as up to about 50 times, such as up to about 40 times, including up to about 30 times, 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, especially 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 is in the range of about 0.5 nm on average (eg, about 0.75 nm, about 1 nm, etc.).

[0067] The maximum thickness of an individual subshell will depend on the size of the core (initially) and subsequently the size of the core with any previously applied coatings, and can be on average about 1 / 100th of the average diameter (i.e. (Average diameter based on weight, number, or volume of the core or cores with a previously applied coating).

[0068] Preferably, for particles having an average diameter of about 100 nm to about 1 μm, the subshell should average about 1 nm to about 5 nm; for particles having an average diameter of about 1 μm to about 20 μm, the coating thickness should average about 1 nm to about 10 nm; and for particles having an average diameter of about 20 μm to about 700 μm, the coating thickness should average 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), should be thinner than the subshells. Thus, the thickness can be about 0.7 times (e.g., about 0.6 times) or less, on average, the thickness of the widest previously applied subshell. Alternatively, the thickness can be about 0.7 times (e.g., about 0.6 times) or less, on average, the thickness of the last subshell applied and / or about 0.7 times (e.g., about 0.6 times) or less, on average, the average thickness of all previously applied subshells. The thickness can range from about 0.3 nm to about 10 nm, on average, for particles up to about 20 μm. For larger particles, the thickness can be about 1 / 1000 or less, on average, of the average diameter of the coated particles based on weight, number, or volume.

[0070] It has been found that applying a subshell followed by one or more deagglomeration steps, such as sonication, can result in wear, pinholes, breaks, gaps, cracks, and / or voids (hereinafter "cracks") in the subshell coating because the coated particles essentially become more tightly "bonded" or "glued" together immediately after applying the thicker coating, potentially exposing the core containing the biologically active component to elements upon deagglomeration.

[0071] The role of the sealing shell is to provide a "sealing" overcoating layer to the particles, covering their cracks, so that the particles are not only completely covered with their sealing shell, but also in a manner that allows them to be easily de-aggregated (e.g., using non-invasive techniques such as vortexing) in a manner that does not disrupt the underlying sub-shells formed before and / or during pharmaceutical formulation.

[0072] For example, if it is intended that the sample will be provided in a suspension prior to administration to a patient, it is necessary to provide de-agglomerated primary particles without pinholes or cracks in the coating.

[0073] It has been found that if a final, thinner sealing shell is not applied, it is often impossible to obtain an acceptable suspension for administration of properly deaggregated particles unless invasive techniques such as sonication are applied. Such methods introduce cracks into the coating and / or sample, and some shells are completely destroyed. This results in an undesirable initial peak (burst) in plasma concentrations of the active ingredient immediately after administration.

[0074] Conversely, it was found that applying a thinner outer coating (sealing shell) allowed the particles to be resuspended in solvent without such an invasive deagglomeration step previously applied.

[0075] Instead, it has been found that subjecting the suspension to a less vigorous process, such as vortexing, stirring, or mild sonication, is sufficient to result in de-agglomerated coated particles that are essentially free of such cracks through which the active ingredient may be released in an uncontrolled manner. By "essentially free of such cracks" in the coating, it is meant that less than about 1% of the surface of the coated particle contains abrasions, pinholes, breaks, gaps, cracks, and / or voids through which the active ingredient may potentially be exposed (e.g., to the elements).

[0076] The subshell and thinner outer shell, collectively, can be of essentially uniform thickness across 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%, e.g., about 25%, e.g., about 50% (no more than about ±20% as measured by TEM) of the coated particles present in the compositions of the present invention.

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

[0078] The coating material may comprise an organic or polymeric material, such as a polyamide, polyimide, polyurea, polyurethane, polythiourea, polyester, or polyimine. The coating material may also comprise a hybrid material (such as between an organic and an inorganic material), including a material that is a combination between a metal or another element and an alcohol, a carboxylic acid, an amine, or a nitrile. However, it is preferred that the coating material comprise an inorganic material.

[0079] The inorganic coating material may include one or more metals or metalloids, or may include one or more metal-containing or metalloid-containing compounds such as metals or metalloids, oxides, nitrides, sulfides, selenides, carbonates, and / or other ternary compounds, etc. Metals and metalloids, hydroxides, especially oxides, especially metal oxides, are preferred.

[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, especially aluminum, titanium, and / or zinc.

[0081] As noted above, because the compositions of the present invention include one or more individual layers of inorganic coating material, the nature and chemical composition of those layers can vary from layer to layer.

[0082] Individual layers may also include mixtures of two or more inorganic materials, such as metal oxides or metalloid oxides, and / or may include multiple layers or composites of different inorganic or organic materials to modify the properties of the layer.

[0083] Coating materials that may be mentioned include aluminum oxide (Al2O3), titanium dioxide (TiO2), iron oxide (Fex O y Examples of suitable coating materials include those containing FeO and / or FeO and / or FeO, gallium oxide (GaO), magnesium oxide (MgO), zinc oxide (ZnO), niobium oxide (NbO), hafnium oxide (HfO), tantalum oxide (TaO), lanthanum oxide (LaO), zirconium dioxide (ZrO), and / or silicon dioxide (SiO). Preferred coating materials include aluminum oxide, titanium dioxide, iron oxide, gallium oxide, magnesium oxide, zinc oxide, zirconium dioxide, and silicon dioxide. More preferred coating materials include iron oxide, titanium dioxide, zinc sulfide, zinc oxide, and aluminum oxide.

[0084] The coating material layer (individually or collectively) 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. Zinc oxide (and iron oxide) coatings can be thicker than corresponding coatings of aluminum oxide or titanium oxide (because they are more soluble). Thus, when the coating material used includes, for example, zinc oxide, a thicker coating of the material can be used, resulting in larger coated particles, making it more beneficial to apply a sealing shell that can include the same material or a different material (e.g., aluminum oxide).

[0085] In ALD, the layer of coating material may be applied at a process temperature of about 20° C. to about 800° C., or about 40° C. to about 200° C., e.g., about 40° C. to about 150° C., e.g., about 50° C. to about 100° C. The optimal process temperature will depend on the reactivity of the precursors and / or materials (including biologically active agents) used in the core and / or the melting point of the core material.

[0086] In most cases, the first of the reaction sequence will involve the addition of some functional groups or free electron pairs or radicals to the surface to be coated (e.g., hydroxy groups). (-OH) or a primary or secondary amino group (-NH or -NHR, where R is an aliphatic group such as, for example, an alkyl group). Each reaction is advantageously carried out separately under conditions such that essentially all excess reagents and reaction products are removed before the next reaction is carried out.

[0087] A plurality of coated particles according to the present invention are essentially free of the aforementioned cracks in the applied coating through which the active ingredient is potentially exposed (e.g., to the elements), and a further optional step may be applied to the plurality of coated particles before subjecting them to further processing in the pharmaceutical formulation. This optional step may include subjecting the few remaining particles having broken and / or cracked shells / coatings to a treatment in which all particles are suspended in a solvent (wherein the active ingredient is soluble, e.g., with a solubility of at least about 1 mg / mL, while the least soluble material of the coating is insoluble, e.g., with a solubility of about 0.1 μg / mL or less), followed by separation of the solid particles from the solvent, e.g., by centrifugation, sedimentation, flocculation, and / or filtration, thereby ensuring that primarily intact particles remain.

[0088] The above optional step, as previously discussed, provides a means of further potentially reducing the likelihood of a (possibly) undesirable initial peak (burst) in 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 techniques described above for drying cores. 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 may 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] Prior to applying the first layer of coating material, or between successive coatings, the core and / or partially coated particles may be subjected to one or more alternative and / or preliminary surface treatments. In this regard, one or more intermediate layers comprising a different material (i.e., other than an inorganic material) may be applied to the relevant surface, for example, to protect the core or partially coated particles from undesired reactions with precursors during the coating step / deposition process, to enhance coating efficiency, or to reduce agglomeration.

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

[0093] Alternatively, application of an "intermediate" layer / surface treatment of this nature may alternatively be accomplished by a liquid phase non-coating technique followed by freeze drying, spray drying, or other drying method to provide the particles with a surface layer onto which a coating material may then be applied.

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

[0095] Alternatively, the moiety can be an anchoring group, such as a moiety containing silane functionality (see, e.g., Herrera et al., J. Mater. Chem., 18, 3650 (2008) and US 8,097,742). Another compound (e.g., a desired targeting compound) can be bound to such an anchoring group by covalent or non-covalent bonds (including hydrogen bonds or van der Waals bonds), or a combination thereof.

[0096] The presence of such an anchoring group can provide a versatile tool for targeted delivery to specific sites in the body. Alternatively, compounds such as PEG can be used to allow particles to circulate longer in the bloodstream and prevent them from accumulating in the liver or spleen (the body's natural mechanisms for eliminating particles, potentially preventing delivery to diseased tissues).

[0097] The composition of the present invention is suitable for administration to a patient as it is prepared (i.e., as a plurality of particles) or, preferably, is formulated with one or more pharmaceutically acceptable excipients, including adjuvants, diluents, or carriers for use in the human or veterinary fields (including in therapy and / or in diagnosis if the core contains diagnostic material).

[0098] Further provided are compositions of the invention for use in medical, diagnostic and / or veterinary practice, and pharmaceutical (or veterinary) formulations comprising a composition of the invention and a pharmaceutically (or veterinarily) acceptable adjuvant, diluent, or carrier.

[0099] The compositions of the invention may be administered locally, regionally, or systemically, for example orally (enterally), by injection or infusion, intravenously or intra-arterially (including by intravascular or other perivascular device / dosage form (e.g., stent)), intramuscularly, intraosseously, intracerebrally, intraventricularly, intrasynovially, intrasternally, intrathecally, intralesionally, intracranially, intratumorally, cutaneously, intradermally, subcutaneously, transmucosally (e.g., sublingually or bucally), rectally, transdermally, nasally, pulmonary (e.g., inhalation, tracheal or bronchial), topically, or by any other parenteral route (e.g., subcutaneously or intramuscularly), optionally in the form of a pharmaceutical (or veterinary) formulation comprising the compound in a pharmaceutically (or veterinarily) acceptable dosage form.

[0100] The incorporation of the composition of the present invention into a pharmaceutical preparation can be achieved by taking into full consideration the intended route of administration and standard pharmaceutical practice. Pharmaceutically acceptable excipients such as carriers may be chemically inert to biologically active agents and may not have adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also provide immediate release or modified release of the composition of the present invention.

[0101] Pharmaceutical (or veterinary) formulations comprising the compositions of the invention may contain particles of different types, e.g., particles containing different active ingredients with different functionalization (as described above), particles of different sizes and / or layers of coating material of different thicknesses, or combinations thereof. By combining particles with different coating thicknesses and / or different core sizes in a single pharmaceutical formulation, drug release after administration to a patient can be controlled (e.g., varied or extended) over a particular period of time.

[0102] For oral administration (i.e., oral administration to the gastrointestinal tract accompanied by 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 may contain some or all of the particles of the compositions of the present invention in the presence of, for example, a carrier and other excipients such as a binder or pH adjuster), compressed tablets, pills, lozenges, capsules, cachets, and the like. Carriers include those previously described for formulating biologically active agents in cores, as well as materials well known to those skilled in the art, including magnesium carbonate, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, lactose, microcrystalline cellulose, low-crystalline cellulose, and the like.

[0103] Solid dosage forms may contain additional excipients such as flavorings, lubricants, binders, preservatives, disintegrants, and / or encapsulating materials. For example, the compositions of the present invention may be encapsulated in, for example, a soft or hard shell capsule, such as a gelatin capsule.

[0104] Compositions of the invention formulated for rectal administration may include suppositories, which may contain suitable non-irritating excipients such as, for example, cocoa butter, synthetic glyceride esters, or polyethylene glycols, which are solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release particles of the composition of the invention.

[0105] For parenteral administration, such as subcutaneous and / or intramuscular injection, the compositions of the present invention may be in the form of a sterile injectable and / or infusible dosage form, for example, a sterile aqueous or oleaginous suspension of the compositions of the present invention.

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

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

[0108] Compositions of the invention suitable for injection may also include compositions in the form of a liquid, sol, or gel (e.g., comprising hyaluronic acid) that can be administered via a surgical administration device, e.g., a needle, catheter, etc., to form a depot formulation. Use of compositions of the invention can control the dissolution rate and pharmacokinetic profile by reducing any burst effect, as discussed 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, e.g., as an inhalation powder for use in a dry powder inhaler (see, e.g., Kumaresan et al., Pharma Times, 44, 14 (2012) and Mack et al., Inhalation, 6, 16 (2012), the relevant disclosures of which are incorporated herein by reference). Suitable particle sizes for the plurality of particles in the compositions of the present invention for use in pulmonary inhalation range from about 2 to about 10 μm.

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

[0111] The pharmaceutical formulation may comprise from about 1% to about 99% by weight, such as from about 10% by weight (such as about 20% by weight, e.g., about 50% by weight) to about 90% by weight of the composition of the invention, with the remainder made up of pharmaceutically acceptable excipients.

[0112] In any event, the compositions of the present invention are formulated with conventional pharmaceutical additives and / or excipients used in the art for the preparation of pharmaceutical formulations, and then processed using standard techniques (e.g., Lachman et al., "The Theory and Practice of Industrial Pharmacy," Lea & Febiger, 2003). 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 Pharmaceutics: The Design and Manufacture of Medicines", Aulton and Taylor (eds.), Elsevier, 4 th(See, e.g., 1999 IEEE International Conference on Pharmaceuticals and Medical Devices, Vol. 1, No. 10, pp. 111-113, 2013) and the documents cited therein, the relevant disclosures of all documents being incorporated herein by reference. Otherwise, the preparation of suitable formulations can be accomplished non-inventively by those skilled in the art using routine techniques.

[0113] Whenever the word "about" is used herein, for example, in the context of an amount (e.g., concentration, dimension (size and / or weight), size ratio, aspect ratio, proportion, or fraction), temperature, or pressure, it will be understood that such variable is approximate and may therefore vary from the numerical value specified herein by ±15%, for example ±10%, for example ±5%, preferably ±2% (e.g., ±1%). This is true even when such numerical values ​​are expressed as percentages (e.g., "about 15%" may mean ±15% of the numerical value 10, which may be anywhere from 8.5% to 11.5%).

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

[0115] The compositions of the present invention may further be formulated in the form of an injectable suspension of coated particles having a size distribution that is capable of forming a homogeneous and stable suspension in injection fluid (i.e., does not settle) and that can be injected through a needle.

[0116] Additionally, the compositions of the present invention may 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 may have advantages for the physician and / or patient in treating the relevant condition with a particular biologically active agent that may be more effective, less toxic, have a broader spectrum of activity, be more potent, produce fewer side effects, or have other useful pharmacological properties than any similar treatment that may be described in the prior art for the same active ingredient.

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

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

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

[0121] The powder was loaded into an ALD reactor (Picosun, SUNALE® R-series, Espoo, Finland). 15 ALD cycles were performed at a reactor temperature of 50 °C. Trimethylaluminum and water were used as precursors to form the initial subshell of aluminum oxide. The thickness of the initial 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 followed by a 20 μm mesh.

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

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

[0125] The coating-deagglomeration step was repeated two more times to form third and fourth subshells of equal thickness on the particles.

[0126] 40 mg of powder was placed in a test tube and 3 mL of a dispersion solution containing 0.5% Tween-80 (Merck, Kenilworth, NJ, USA) in water 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 min 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, as determined by absorbance versus time, is plotted in Figure 3.

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

[0129] 40 mg of the resulting 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 deagglomeration 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] A clear difference can be seen between the release profiles of Figures 3 and 4, with the profile shown in Figure 4 being much slower. This suggests that after application of the sealing shell, the subshell is more intact and less indomethacin is exposed to the dissolution medium.

[0132] Example 2 Coated indomethacin microparticles II The sample from Example 1 was washed, and 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 retained in the test tube.

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

[0134] 3 mL of the same dispersion liquid as described in Example 1 was added. The suspension was gently vortexed for 1 minute and the degree of deagglomeration 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 taken as in Example 1. Figure 5 shows the release profile.

[0136] Comparing Figures 4 and 5, it can be seen that the release of indomethacin was even slower when the sample was subjected to the above washing, suggesting that during washing, indomethacin was removed from the cracked particles, leaving only particles with an intact, dense shell in the sample.

[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 without the final step of applying a sealing shell. Washing, dissolution, and analysis of the samples were performed as described in Example 2, and the release profiles are shown in Figure 6.

[0138] Comparison of the release profiles between Figures 5 and 6 shows that the indomethacin content of the washed samples is higher in the samples with a sealing shell. The amount of "wasted" indomethacin is about four times that of the samples without a sealing shell (15.5% vs. 4%).

[0139] Example 4 In vivo rat model I A sample similar to that described in Example 1 (four subshells without sealing shells) was suspended in a 0.5% Tween-80 solution. A second suspension was prepared using the sample with four subshells with sealing shells, as described above.

[0140] Both suspensions were injected subcutaneously into the dorsal region of male Sprague-Dawley rats, and plasma samples were extracted. 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 4.6 x 150 mm, 2.6 μm particle size phenylhexyl column with the column oven set at 40 °C. Mobile phase A was 10 g / L acetic acid in water, and mobile phase B was acetonitrile. A gradient elution program was applied, decreasing mobile phase A from 70% to 30%. Quantitation was performed using a linear equation from a six-point calibration curve ranging from 0.5 to 100 μg / mL. The analytical run time was 31 min.

[0141] The solid line with square dots in Figure 7 shows the plasma concentration profile for this first test group, and the dotted line with triangle dots shows the plasma concentration profile for the second test group.

[0142] The peak in the figure represents the initial burst release of indomethacin during 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 four-fold.

[0143] Example 5 In vivo rat model II The samples (four subshells and a sealing shell) were prepared according to the method described in Example 1.

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

[0145] Figure 8 shows the results of the plasma sample analysis. The plasma concentration-time profile on the left shows a comparison between neat indomethacin and the coated sample at 1 mg / kg. The profile on the right shows a comparison between the different coated samples. The plasma concentration-time profile of nanoshell-coated indomethacin 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 The samples were prepared according to the method described in Example 2 (four subshells and a sealing shell, which were then washed).

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

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

[0149] The plasma concentration profiles show that washing the sample significantly reduces the initial burst of drug release.

[0150] Example 7 Coated indomethacin microparticles III 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. Fifteen ALD cycles were performed using diethylzinc (DEZ) and water as precursors at a reactor temperature of 50°C to form a zinc oxide first subshell. 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 mesh nylon sieve (Tsutsui Scientific, China) by a sonic sifter (Tsutsui Scientific SW-20AT, China).

[0153] The powder was again loaded into the ALD reactor and subjected to 15 more ALD cycles to form a second zinc oxide subshell, the thickness of which was estimated to be approximately 4–5 nm.

[0154] The powder was extracted from the reactor and deagglomerated using a sonic sifter 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 samples produced without a sealing shell was determined by HPLC as described in Example 4 above.

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

[0158] The two suspensions were added to a dissolution bath, and 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 release of indomethacin from the two samples (with standard deviation; error bars are not shown because the analytical data were nearly identical).

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

[0160] The total indomethacin content in the resulting samples with sealing shells was determined by HPLC as described in Example 4 above.

[0161] Duplicate samples of 40.41 mg and 40.18 mg with sealing shells were placed in test tubes, 3 mL of dispersion liquid was added, and the suspensions were vortexed as above.

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

[0163] A clear difference can be seen between the release profiles in Figures 10 and 11, with the release shown in Figure 11 being much slower. This suggests that after applying the aluminum oxide sealing shell to the four zinc oxide subshells, the subshells are much more intact, exposing less indomethacin to the dissolution medium.

[0164] Example 8 Coated indomethacin microparticles IV The same procedure as described in Example 7 above was repeated, but using titanium tetrachloride instead of DEZ to provide four separate subshells of titanium dioxide.

[0165] The release profiles of indomethacin are shown in Figure 12 (without an aluminum oxide sealing shell) and Figure 13 (with a sealing shell). A difference is seen, with Figure 13 showing an initially slower and much lower burst release in vitro. Again, this suggests that after applying the aluminum oxide sealing shell to the four titanium dioxide subshells, the subshells are more intact and less indomethacin is exposed to the dissolution medium.

[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%). This resulted in microparticles containing 4.7% PGG. Spray drying was performed 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 fine particle powder was loaded into an ALD reactor (Picosun, SUNALE™ R-series, Espoo, Finland). 25 ALD cycles were performed at a reactor temperature of 50 °C. Trimethylaluminum and water were used as precursors to form the first subshell of aluminum oxide. The thickness of the first subshell was approximately 7–8 nm (estimated from the number of ALD cycles).

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

[0170] Three more coating-disaggregation steps were performed to provide a total of four subshells of the same thickness.

[0171] The total PGG content in the samples so produced was measured by HPLC as described in Example 4 above.

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

[0173] The released PGG was analyzed by HPLC and is plotted in FIG.

[0174] The remaining sample was reloaded into the ALD reactor and subjected to 15 additional ALD cycles as described above to form an aluminum oxide “sealing” shell (approximately 4–5 nm thick, as estimated from the number of ALD cycles).

[0175] The total PGG content in the produced samples with sealing shells was measured by HPLC.

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

[0177] A clear difference can be seen between the release profiles in Figures 14 and 15, with the profile shown in Figure 15 being much slower, again suggesting that the sealing shell on the four subshells makes them more intact and exposes less indomethacin to the dissolution medium.

Claims

1. 1. A composition in the form of a plurality of particles having an average diameter based on volume that is from about 1 μm to about 50 μm, said particles comprising: (a) a 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. The composition described in claim 1, wherein the pharmaceutically acceptable excipient 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 two or more separate layers of coating material are applied sequentially to the core.

6. The composition of claim 5 wherein 3 to 10 individual layers of coating material are applied.

7. The composition of any one of claims 1 to 6, wherein the total thickness of the individual layers of coating material is from about 0.5 nm to about 2 µm.

8. 8. 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.

9. 9. 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.

10. 10. The composition of claim 9, 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.

11. 11. 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 last individual layer of coating material applied.

12. 12. The composition of any one of claims 1 to 11, 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.

13. 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.

14. The composition of claim 13 , wherein the coating material comprises one or more metal- or metalloid-containing compounds.

15. The composition of claim 14 , wherein the compound comprises a hydroxide and / or an oxide.

16. 16. The composition of claim 14 or 15, wherein the compound comprises aluminum oxide, titanium dioxide, and / or zinc oxide.

17. 17. The composition of any one of claims 1 to 16, wherein the coating material of the outer overcoating layer comprises aluminum oxide.

18. 18. A composition as defined in any one of claims 1 to 17 for use in medical or veterinary practice.

19. 18. A pharmaceutical or veterinary formulation comprising a composition as defined in any one of claims 1 to 17 and a pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier.

20. 20. The formulation according to claim 19 in the form of a sterile injectable and / or injectable dosage form.

21. 21. The formulation of claim 20 in the form of a liquid, sol, or gel that can be administered via a surgical administration device to form a depot formulation.

22. A process for preparing a composition as defined in any one of claims 1 to 17, comprising: A process comprising applying a layer of coating material to a core and / or a separate layer of previously applied coating material on said core by atomic layer deposition.

23. (i) coating a solid core with a first discrete layer of a coating material; (ii) the coated cores from step (i) are then subjected to a deagglomeration process step; (iii) then coating the deagglomerated coated cores from step (ii) with a second, discrete layer of coating material; (iv) repeating steps (ii) and (iii) to obtain the required number of individual layers; (v) subjecting the coated particles from step (iv) to a final deagglomeration process step; 23. The process of claim 22, wherein (vi) applying an outer overcoating layer of coating material to the deagglomerated coated particles from step (v).

24. 24. The process of claim 23, wherein the deagglomeration step performed during application of the coating comprises sieving.

25. 25. The process of claim 24, wherein the sieving comprises sonic sieving.

26. 26. The process of any one of claims 22 to 25, wherein the particles are subjected to a final vortexing step after application of the outer overcoating layer.

27. 22. A process for the preparation of a formulation as defined in any one of claims 19 to 21, comprising:

18. A process comprising mixing a composition according to any one of claims 1 to 17 with the relevant pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier.

28. 28. The process of any one of claims 22 to 27, 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.

29. 30. The process of claim 28, comprising the further step of resuspending the separated particles in a solvent.

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