Novel process for the manufacture of pharmaceutical compositions

Abstract

Processes are provided for preparing compositions in the form of a plurality of particles having an average diameter by weight, number, and / or volume of from 10 nm to about 700 μm, the particles comprising: (a) a solid core, preferably comprising a biologically active agent; and (b) two or more sequentially applied, discrete layers, each comprising at least one separately applied coating material, the two or more layers together surrounding, enclosing, and / or encapsulating the core. The process includes the sequential steps of: (1) applying a first layer of at least one coating material to the solid core by a vapor deposition technique; (2) removing the coated particles from the vapor deposition reactor and agitating the coated particles to deagglomerate particle aggregates formed during step (1) by a mechanical sieving technique; (3) reintroducing the deagglomerated coated particles from step (2) into the vapor deposition reactor and applying an additional layer of at least one coating material to the reintroduced particles; and (1), optionally repeating steps (2) and (3) one or more times to increase the total thickness of the at least one coating material surrounding the solid core. The vapor deposition technique is preferably atomic layer deposition. If 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 a novel process for producing compositions that are useful in the field of drug delivery. [Background technology]

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

[0003] In the field of drug delivery, the ability to control the profile of drug release is of great importance. To ensure 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] WO 2014 / 187995 describes a process in which several ALD cycles are performed, after which the resulting coated substrate is periodically removed from the reactor and a redispersion / agitation step is performed to present new surfaces available for precursor adsorption.

[0014] The agitation step is primarily used to address a problem 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 a solvent (e.g., water or hydrocarbon) and sonicating it, resulting in deagglomeration and breaking down the contact points between individual particles of the coated active material.

[0015] The particles were then reloaded into the reactor, and the powder ALD coating and powder deagglomeration steps were repeated three times (for a total of four successive cycles). This process has been shown to enable the formation of pinhole-free coated particles (see also Hellrup et al., Int. J. Pharm., 529, 116 (2017)).

[0016] 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.

[0017] We have found it advantageous to deagglomerate the agglomerated particles to primary particles outside the reactor by a dry process involving a combination of mechanical forcing and sieving. This avoids the need to use invasive deagglomeration techniques such as sonication, as well as the need to dry the particles before returning them to the reactor for further coating. By performing the deagglomeration step in this manner, we have found it is possible to present coated particles that are essentially completely pinhole-free in a form that can be easily processed into pharmaceutical formulations. Summary of the Invention

[0018] According to a first aspect of the present invention, there is provided a process for preparing a composition in the form of a plurality of particles having an average diameter based on weight, number, and / or volume in an amount of from 10 nm to about 700 μm, the particles comprising: (a) a solid core, preferably comprising a biologically active agent; (b) comprising (i.e., consisting of) two or more sequentially applied individual layers, each of which comprises at least one distinct (i.e., separately applied) coating material, and which together surround, enclose, and / or encapsulate the core; This process involves the following steps: (1) applying an initial layer of at least one coating material to the solid core by a vapor deposition technique; (2) removing the coated particles from the vapor deposition reactor and subjecting the coated particles to agitation to deagglomerate particle agglomerates formed during step (1) by mechanical sieving techniques; (3) reintroducing the deagglomerated coated particles from step (2) into a vapor deposition reactor and applying at least one additional layer of coating material to the reintroduced particles; and (4) optionally repeating steps (2) and (3) one or more times to increase the total thickness of the at least one coating material surrounding the solid core; This process is hereinafter referred to as the "process of the present invention." [Brief explanation of the drawings]

[0019] [Figure 1] Figure 1 is a TEM image. [Figure 2] Figure 2 is a TEM image. [Figure 3] FIG. 3 shows the drug release profile versus time of the samples obtained according to the examples. [Figure 4] FIG. 4 shows the drug release profile versus time of the samples obtained according to the examples. DETAILED DESCRIPTION OF THE INVENTION

[0020] 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.

[0021] The process of the present invention is preferably used to prepare 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.

[0022] 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.

[0023] "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.

[0024] 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.

[0025] 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 an agent should also remain in a solid form while being coated in the reactor, and should not physically or chemically decompose to a significant extent (i.e., about 10% w / w or more) while being coated or after being covered with at least one of the aforementioned coatings. The biologically active agent may further be presented in combination with another active substance (e.g., as a mixture or as a complex).

[0026] 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).

[0027] 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, 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, bacteriostatics, beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, renin inhibitors, beta-adrenergic receptor antagonists Body 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, serotonin, Drugs, statins, stimulants, wake-promoting drugs, 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, steroids, sympathomimetics, thrombolytic drugs, thyroid drugs, vaccines, vasodilators, xanthines, drugs to improve erectile dysfunction, gastrointestinal drugs, histamine receptor antagonists, keratolytics, antianginal drugs, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, leukotriene inhibitors, macrolides, NSAIDs, nutritional supplements,The compound may be selected from an opioid analgesic, an opioid antagonist, a potassium channel activator, a protease inhibitor, an anti-osteoporosis agent, an anti-obesity agent, a cognition 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.

[0028] 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.

[0029] 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.

[0030] The compositions made by the processes of the invention may include benzodiazepines such as alprazolam, chlordiazepoxide, clobazam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, quazepam, temazepam, triazolam, and pharmaceutically acceptable salts of any of these.

[0031] The anesthetics that may be used in the compositions made by the process of the present invention may be local or systemic. Local anesthetics that may be mentioned include amylocaine, ambucaine, articaine, benzocaine, benzonatate, bupivacaine, butacaine, butanilicaine, chloroprocaine, cinchocaine, cocaine, cyclomethicaine, 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.

[0032] Psychiatric drugs may also be used in the compositions made by the process of the present invention. Psychiatric drugs that may be mentioned include 5-HTP, acamprosate, agomelatine, alimemazine, amphetamine, dextroamphetamine, amisulpride, amitriptyline, amobarbital, amobarbital / secobarbital, amoxapine, amphetamine, aripiprazole, asenapine, atomoxetine, baclofen, benperidol, bromperidol, bupropion, buspirone, butobarbital, carbamazepine, chloral hydrate, chlorpromazine, chlorprothixene, citalopram, clomethiazole, fluproex, clomipramine, 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 hydroxyzine, 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, penetrazol radiazine, pericyazine, perphenazine, phenelzine, phenobarbital, pimozide, pregabalin, promethazine, prothipendyl, protriptyline, quetiapine, ramelteon, reboxetine, reserpine, risperidone, rubidium chloride, secobarbital, selegiline, sertindole, sertraline, sodium oxybate, sodium valproate, sulpiride, thioridazine, thiothixene, tianeptine, tizanidine, topiramate, tranylcypromine, trazodone,These include 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.

[0033] Opioid analgesics that may be used in the compositions made by the processes of the present invention include buprenorphine, butorphanol, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, nomethadone, opium, oxycodone, oxymorphone, pentazocine, tapentadol, tramadol, and pharmaceutically acceptable salts of any of these.

[0034] Opioid antagonists that may be used in the compositions made by the processes of the present invention include naloxone, nalorphine, niconalorphine, diprenorphine, levallorphan, samidorphan, nalodain, alvimopan, methylnaltrexone, naloxegol, 6β-naltrexone, axerophrine, bebenoplan, methylsamidorphan, naldemedine, preferably nalmefene, especially naltrexone, and pharmaceutically acceptable salts of any of these.

[0035] Anti-cancer drugs that may be included in the compositions made by the processes of the present invention include: actinomycin, afatinib, all-trans retinoic acid, amsacrine, anagrelide, arsenic trioxide, axitinib, azacitidine, azathioprine, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, chlorambucil, Cladribine, clofarabine, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, erlotinib, estramustine, etoposide, everolimus, fludarabine, fluorouracil, gefitinib, guadecitabine, gemcitabine, hydroxycarbamide, hydroxyurea, idarubicin ib, idelalisib, ifosfamide, imatinib, irinotecan, ixazomib, cabozantinib, carfilzomib, crizotinib, lapatinib, lomustine, mechlorethamine, melphalan, mercaptopurine, mesna, methotrexate, mitotane, mitoxantrone, nelarabine, nilotinib, niraparib, olaparib, oxaliplatin, paclitaxel, panobinostat, pazopanib, pemetrexed, pixan toron, 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.

[0036] 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.

[0037] Cancers that may be mentioned include myelodysplastic syndromes and subtypes, such as acute myeloid leukemia, refractory anemia or refractory anemia with ringed sideroblasts (with neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transition, and chronic myelogenous leukemia (myelomonocytic leukemia).

[0038] Other drugs that may be mentioned for use in the compositions made by the processes 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 are often mentioned include angiotensin II receptor type 2 agonists, such as Compound 21 (C21; 3-[4-(1H-imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophene-2-[(N-butyloxylcarbamate)-sulfonamide], and pharmaceutically acceptable (e.g., sodium) salts thereof.

[0039] The compositions made by the processes 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 is capable of producing 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 a cure or prevention of said disease or disorder.

[0040] 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.

[0041] Administration of the compositions made by the processes of the present invention can be continuous or intermittent (e.g., by bolus injection). The dosage of the active ingredient can also be determined by the timing and frequency of administration.

[0042] 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.

[0043] 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).

[0044] 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 complex macromolecule, such as a peptide, protein, or portion of genetic material, as generally described, and / or the specific peptides / proteins mentioned above, including vaccines. Embedding the macromolecule complex in an excipient in this way often results in a larger core for coating, and therefore a larger coated particle.

[0045] It is not a requirement that the core of the composition made by the process of the present invention contain a biologically active agent. Whether or not the core contains a biologically active agent, the core may comprise and / or consist essentially of one or more non-biologically active adjuvants, diluents, and carriers (including emollients), and / or other excipients with functional properties (e.g., buffers and / or pH modifiers (e.g., citric acid)).

[0046] 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).

[0047] 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).

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] Two or more layers of coating material are applied sequentially to the core. Preferred vapor deposition techniques 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 with each pulse instead of atoms), molecular layer epitaxy (MLE), chemical vapor deposition (CVD), atomic layer CVD, molecular layer CVD, physical vapor deposition (PVD), sputtering PVD, reactive sputtering PVD, evaporation PVD, and binary reactive sequence chemistry. ALD is the preferred coating method according to the present invention.

[0054] Two or more distinct layers or coating materials (also referred to herein as "coatings" or "shells," all of which terms are used interchangeably herein) are applied (i.e., "separately applied") to a solid core containing a biologically active agent. Such "separate application" of "separate layers, coatings, or shells" means that the solid core is coated with a first layer of coating material, and then the resulting coated core is subjected to some form of mechanical sieving technique, step, or process. In this regard, the number of distinct layers of coating material, as defined herein, corresponds to the number of these intermittent mechanical sieving steps, with the final mechanical sieving step occurring before the application of the final layer of coating material.

[0055] Mechanical sieving techniques that are an essential part of the process will involve mechanically forcing the solid product mass formed by coating the cores through a sieve located external (i.e., outside) of the reactor, configured to deagglomerate any particle agglomerates upon such mechanical forcing of the coated cores prior to subjecting them to a second and / or further layer of coating material, this process being repeated as many times as necessary and / or appropriate before applying a final layer of coating material.

[0056] Thus, the mechanical forcing means can include one or more of any means for forcing the coated mass through a sieve in a mechanical and / or automated manner, where the forcing means is not manually applied by human force. Thus, the mechanical force can take the form of tapping, vibration, application of a pressure gradient (e.g., a jet), horizontal rotation, mechanized cyclic displacement of a sieve, centrifugal force, sieving, or combinations thereof (e.g., vibration and tapping, rotation and tapping, etc.).

[0057] Preferably, however, the mechanical forcing means is vibrational. Here, a suitable means of applying a vibrational force (i.e., shaking) is forcing the coated powder mass through a mesh or sieve. The vibration or shaking can be provided by any mechanical means that generates vibrations about an equilibrium point, which can be via acoustic waves (including sonic and ultrasonic waves), or mechanical (tapping), or other methods including combinations thereof (e.g., ultrasonic and sonic, sonic and tapping, ultrasonic and tapping, etc.).

[0058] Suitable sieve meshes may include perforated plates, microplates, grids, diamonds, but are preferably made from thread or wire (woven wire sieves).

[0059] At least one of the mechanical sieving steps in the process of the present invention is preferably performed by sonic sieving, as described below. Manufacturers of suitable sonic sifters include Advantech Manufacturing, Endecott, and Tsutsui.

[0060] 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).

[0061] 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.

[0062] 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.

[0063] 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.

[0064] Thus, particle agglomerates are broken down by mechanical forcing through a sieve, 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.

[0065] 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 mechanical sieving will form a complete coating on the particles, thus meaning that fully coated particles (individual or agglomerates of the desired size) are formed.

[0066] The process of the present invention may be carried out in a manner which comprises carrying out steps (2) and (3) of the process at least once, preferably twice, more preferably three times, such as four, 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, up to about 30 times, for example, 2 to 20 times, such as 3 to 15 times, for example, 10 times, such as 9 or 8 times, more preferably 6 or 7 times, especially 4 or 5 times.

[0067] The total thickness of the coating (meaning all separate layers / coatings / shells) ranges on average from about 0.5 nm to about 2 μm.

[0068] The minimum thickness of each individual layer / coating / shell is in the range of about 0.5 nm on average (eg, about 0.75 nm, about 1 nm, etc.).

[0069] The maximum thickness of each individual layer / coating / shell will depend on the size of the core (initially) and subsequently the size of the core with previously applied coatings, and may be on average about 1 / 100th the mean diameter (i.e., mean diameter based on weight, number, or volume) of the core, or cores to which the coatings have been previously applied.

[0070] Preferably, for particles having an average diameter of about 100 nm to about 1 μm, the coating thickness 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.

[0071] It has been found that applying a coating / shell followed by one or more deagglomeration steps, such as sonication, can result in wear, pinholes, breaks, gaps, cracks, and / or voids (hereinafter "cracks") in the layer / coating because the coated particles 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.

[0072] As described herein, it has surprisingly been discovered that carrying out a mechanical sieving process in accordance with the present invention (as opposed to sonication as described in WO 2014 / 187995 or manually passing the particles through a sieve by hand) results in particles that are not only completely covered by the layer / coating, with significantly fewer pinholes, gaps or cracks in the final layer of coating material, but also in a manner in which the particles can be easily de-agglomerated (e.g., using non-invasive techniques such as vortexing) in a manner that does not disrupt the layer of coating material formed prior to and / or during pharmaceutical formulation.

[0073] For example, if it is intended to provide the sample in a suspension prior to administration to a patient, it is necessary to provide deaggregated primary particles without pinholes or cracks in the coating, which would result in an undesirable initial peak (burst) in the plasma concentration of the active ingredient immediately after administration.

[0074] As described below, the process of the present invention results in deagglomerated coated particles that are essentially free of cracks through which the active ingredient may be released in an uncontrolled manner. By "essentially free of cracks" in the coating, we mean 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).

[0075] The layers of coating material can be collectively of essentially uniform thickness across the surface area of ​​the particle. By "essentially uniform" thickness is meant that the degree of variation in coating thickness is at least about 10%, e.g., about 25%, e.g., about 50% (including about ±20% or less, including ±50% or less of the average thickness, as measured by TEM) of the coated particles present in the compositions of the present invention.

[0076] Coating materials that may be applied to the cores are pharmaceutically acceptable in that they must be essentially non-toxic.

[0077] 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.

[0078] 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.

[0079] Metals that may be mentioned include alkali metals, alkaline earth metals, noble metals, transition metals, post-transition metals, lanthanides, etc. Metals and metalloids that may be mentioned include aluminum, titanium, magnesium, iron, gallium, zinc, zirconium, niobium, hafnium, tantalum, lanthanum, and / or silicon, more preferably aluminum, titanium, magnesium, iron, gallium, zinc, zirconium, and / or silicon, especially aluminum, titanium, and / or zinc.

[0080] As noted above, because the compositions made by the process of the present invention include two or more separate layers of inorganic coating material, the nature and chemical composition of those layers can vary from layer to layer.

[0081] 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.

[0082] Coating materials that may be mentioned include aluminum oxide (Al2O3), titanium dioxide (TiO2), iron oxide (Fe x 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.

[0083] The layers of coating material (individually or collectively) in the compositions made by the processes of the present invention can consist essentially of (e.g., greater than about 80%, e.g., greater than about 90%, e.g., about 95%, e.g., about 98%) iron oxide, aluminum oxide, zinc oxide, or titanium dioxide.

[0084] The process of the present invention is particularly useful when the coating material applied to the core comprises zinc oxide.

[0085] In ALD, the layer of coating material can be applied at a process temperature of about 20°C to about 800°C, or about 40°C to about 200°C, e.g., about 40°C to about 150°C, e.g., about 50°C to about 100°C. The optimal process temperature depends on the reactivity of the precursors and / or materials (including biologically active agents) used in the core and / or the melting point of the core material. If the core to be coated contains a biologically active component, lower temperatures, such as about 30°C to about 100°C, are preferably used.

[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 steps provide a means to further potentially reduce the likelihood of a (possibly) undesirable initial peak (burst) in plasma concentration of the active ingredient, as discussed herein.

[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 made by the process 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 made by the process of the invention is suitable for administration to a patient as it is prepared (i.e., as a plurality of particles) or, preferably, is formulated with one or more 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 made by the processes of the invention for use in medical, diagnostic and / or veterinary practice, and pharmaceutical (or veterinary) formulations comprising the compositions of the invention and a 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 produced by the process 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 the biologically active agent and may not have adverse side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate or modified release to the composition produced by the process of the present invention.

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

[0102] For oral administration (i.e., administration to the gastrointestinal tract orally with swallowing), the compositions made by the process of the present invention can be formulated in a variety of 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 made by the processes of the present invention may be encapsulated, for example, in soft or hard shell capsules, e.g., gelatin capsules.

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

[0105] For parenteral administration, such as subcutaneous and / or intramuscular injection, the compositions made by the process 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 made by the process 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 made by the processes of the invention that are 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, such as a needle, catheter, etc., to form a depot formulation. Use of compositions made by the processes of the invention can control the dissolution rate and pharmacokinetic profile by reducing any burst effect, as discussed above, and / or by lowering the Cmax in the plasma concentration-time profile, thus increasing the length of release of the biologically active ingredient from the formulation.

[0109] The compositions made by the processes of the present invention may be contained within reservoirs and injection or infusion devices, with the coated particles and carrier system housed separately and mixing occurring before and / or during injection or infusion.

[0110] Compositions made by the processes of the invention can also be formulated for inhalation, e.g., as inhalation powders for use in dry powder inhalers (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 compositions of the invention for use in pulmonary inhalation range from about 2 to about 10 μm.

[0111] The compositions produced by the process of the present invention can also be formulated for topical administration to the skin or mucosa. For topical application, pharmaceutical preparations can be provided in the form of, for example, 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 esters wax, cetaryl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0112] 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.

[0113] In any event, the compositions made by the processes of the present invention may be 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). rdedition(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, for example, the "Publication Number 10 ...

[0114] According to a further aspect of the present invention there is provided a process for preparing a pharmaceutical or veterinary formulation comprising mixing a coated particle prepared as described herein together with a pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier.

[0115] Such formulations are preferably injectable and / or infusible and thus comprise one or more compositions made by the process of the invention suspended in a pharmaceutically or veterinarily acceptable aqueous and / or oily carrier.

[0116] Additionally, injectable and / or injectable dosage forms, and injection or infusion means, are provided that include the compositions made by the processes of the present invention contained within a reservoir. In this regard, the compositions made by the processes of the present invention can be stored prior to loading into a suitable injectable and / or injectable dosage means (e.g., a syringe equipped with a needle for injection) or can be prepared immediately prior to loading into such a dosage means.

[0117] therefore, (a) a composition made by the process of the present invention; (b) a pharmaceutically or veterinarily acceptable carrier system. And, the kit of parts includes the composition made by the process of the present invention along with instructions for the end user to mix these particles with a pharmaceutically or veterinarily acceptable aqueous and / or oily carrier system.

[0118] Further provided are pre-loaded injectable and / or injectable dosage forms as described above, but modified by including at least two chambers, in one of which a composition made by the process of the invention is placed, and in the other chamber a pharmaceutically or veterinarily acceptable carrier system, which upon mixing form a suspension or otherwise before and / or during injection or infusion.

[0119] 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%).

[0120] The compositions made by the process 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.

[0121] The compositions made by the process of the present invention can 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.

[0122] Furthermore, the compositions made by the processes of the present invention can be stored under normal storage conditions and maintain their physical and / or chemical integrity.

[0123] The phrase "maintaining physical and chemical integrity" essentially means chemical and physical stability.

[0124] "Chemical stability" includes the ability of any composition made by the process of the invention to be stored (with or without appropriate pharmaceutical packaging) under normal storage conditions with minimal chemical degradation or decomposition.

[0125] "Physical stability" includes that any composition made by the process of the invention may be stored (with or without appropriate pharmaceutical packaging) under normal storage conditions with only a small degree of physical transformation (e.g., precipitation as described above) or change in the properties and / or integrity of the coated particles, e.g., the coating itself or the active ingredient (including dissolution, solvation, solid-state phase transitions, etc.).

[0126] Examples of "normal storage conditions" for compositions made by the processes of the present invention include temperatures of about -50°C to about +80°C (preferably about -25°C to about +75°C, e.g., about 50°C) for extended periods of time (i.e., about 12 months or more, e.g., about 6 months), and / or pressures of about 0.1 to about 2 bar (preferably atmospheric pressure), and / or exposure to about 460 lux of ultraviolet / visible light, and / or relative humidity of about 5 to about 95% (preferably about 10 to about 40%).

[0127] Under such conditions, compositions made by the processes of the present invention may optionally be found to be less than about 15%, more preferably less than about 10%, and especially less than about 5% chemically and / or physically degraded / decomposed. Those skilled in the art will appreciate that the above upper and lower limits of temperature and pressure represent the extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g., a temperature of 50°C and a pressure of 0.1 bar).

[0128] Additionally, compositions made by the processes of the present invention may provide a release and / or pharmacokinetic profile that minimizes any burst effect and / or Cmax characterized by a maximum concentration shortly after administration.

[0129] 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.

[0130] The present invention is illustrated, but in no way limited, by the following examples with reference to the accompanying figures, in which Figures 1 and 2 are TEM images showing the clear, visible physical interface (regions of greater electron transparency) formed by using the processes described herein, and Figures 3 and 4 show drug release profiles versus time for samples obtained according to the examples. [Example]

[0131] Comparative Example 1 Coated Azacitidine Microparticles I Azacitidine microparticles (Olon SpA, Rodano, Italy) were prepared by jet milling (Catalent, Malvern, PA, USA). The mean diameter of the jet-milled azacitidine particles was 1.2 μm as determined by laser diffraction (Sympatec, Helos (H1672) and Rodos, R3, Clausthal-Zellerfeld, Germany).

[0132] The powder was loaded into an ALD reactor (Picosun, SUNALE™ R-series, Espoo, Finland). 35 ALD cycles were performed at a reactor temperature of 50°C. Diethyl zinc and water were used as precursors to form a first layer of zinc oxide. The thickness of the first layer was approximately 5 nm (estimated from the number of ALD cycles).

[0133] The powder was removed from the reactor and deagglomerated by using a rubber spatula to force the powder through a metal sieve with a mesh size of 20 μm.

[0134] The resulting deagglomerated powder was reloaded into the ALD reactor and subjected to 35 more ALD cycles as before to form a second layer of zinc oxide, extracted from the reactor, deagglomerated by manual sieving as above, reloaded to form a third layer, deagglomerated, and reloaded for a final fourth layer.

[0135] To determine the drug loading (i.e., w / w% azacitidine in the powder), a 4.6 x 250 mm, 3 μm particle, C18 column (Luna, Phenomenex, USA) was used with a diode array detector (Shimadzu) set at 210 nm using a HPLC (Prominence-i, Shimadzu, Japan). The nanoshell coating was dissolved in 1 M phosphoric acid, and the slurry was diluted with 1 g / L sodium bisulfite in water to dissolve the azacitidine. The solution was then filtered (0.2 μm RC, Lab Logistics Group, Germany) and further analyzed by HPLC (n=2). The drug loading was determined to be 64.7%.

[0136] Example 1 Coated Azacitidine Microparticles II The corresponding coated microparticles of azacitidine were prepared as described in Comparative Example 1 above, except that the powder was supplied by MSN Labs (India). The particles had an average diameter of 5.5 μm (determined by laser diffraction (Shimadzu, SALD-7500 nano, Kyoto, Japan)). Deagglomeration was performed by sieving through a nylon sieve with a mesh size of 20 μm using a sonic sifter (Tsutsui Scientific Instruments Co., Ltd., SW-20AT, Tokyo, Japan) to shake the powder through the sieve. The drug loading was determined to be 74.5%.

[0137] Example 2 In vitro drug release In vitro release testing of the particles of Comparative Example 1 and Example 1 was carried out using a Sotax CE7 smart USP4 apparatus (Sotax AG, Switzerland) connected to a CP7-35 piston pump (Sotax AG, Switzerland) and a C613 fraction collector (Sotax AG, Switzerland).

[0138] A 22.6 mm diameter flow-through cell was prepared using a 5 mm ruby ​​bead at the tip of the cell cone, into which the suspended sample was introduced.

[0139] Samples were analyzed in duplicate, with a sample amount corresponding to 50 mg of azacitidine per cell. Samples (33.3 mg azacitidine / mL) were dispersed by vortexing in 0.1% Tween 20 + 0.25% sodium CMC in saline (0.9% NaCl) phosphate buffer, pH 7.2.

[0140] The device was used in an open-loop setup, with fresh 20 mM PIPES (pH 7.2) dissolution medium continuously introduced into the system. The water bath temperature was set at 37°C ± 0.5°C, and the medium flow rate was set at 16 mL / min. Two Whatman glass microfiber filters, GF / F and GF / D (d = 25 mm, Sigma-Aldrich / Merck KGaA, Germany), were used to filter the medium before it left the flow-through cell. Collected fractions of the released medium were analyzed for azacitidine content using HPLC with the same settings as those used for the drug loading analysis described above.

[0141] Figures 3 and 4 show the respective azacitidine release profiles (percentage of azacitidine released per minute versus sampling time in a Sotax device for samples obtained according to Comparative Example 1 and Example 1, respectively).

[0142] It can be seen that Comparative Example 1 has a higher initial (burst) release than Example 1.

Claims

1. 1. A method for preparing a composition in the form of a plurality of particles having an average diameter based on weight, number, and / or volume of 10 nm to 700 μm, said particles comprising: (a) a solid core containing a biologically active agent; (b) two or more sequentially applied individual layers, each comprising at least one distinct coating material, said two or more layers together surrounding, enclosing, and / or encapsulating said core; The method comprises the steps of: (1) applying an initial layer of at least one coating material to the solid core by a vapor deposition technique; (2) removing the coated particles from the vapor deposition reactor and subjecting the coated particles to agitation to deagglomerate particle agglomerates formed during step (1) by mechanical sieving techniques; (3) reintroducing the deagglomerated coated particles from step (2) into the vapor deposition reactor and applying an additional layer of at least one coating material to the reintroduced particles; and (4) repeating steps (2) and (3) one or more times to increase the total thickness of the at least one coating material surrounding the solid core; wherein the mechanical sieving technique comprises mechanically and / or automatically passing the coated particles through a sieve located outside the reactor; method.

2. The method of claim 1 , wherein the core comprises a pharmaceutically acceptable excipient.

3. The method described in claim 2, wherein the pharmaceutically acceptable excipient is a sugar or sugar alcohol, and / or a pH modifier.

4. The method of claim 1 , wherein the core consists essentially of a biologically active agent.

5. 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 antiasthmatic agent ... Respiratory, antibiotic, 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-adrenergic receptor blocker, hemostatic Fluid products, blood substitutes, bronchodilators, cardiac arrhythmia drugs, chemotherapy drugs, coagulants, corticosteroids, cough suppressants, diuretics, deliriants, expectorants, fertility drugs, sex hormones, mood stabilizers, mucolytics, neuroprotective agents, 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, immunomodulators, laxatives, antidiarrheals, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, selenics, steroids Tatins, 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, 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, NSAIDs, nutritional supplements, opioid analgesics,5. The method of any one of claims 2 to 4, wherein the compound is selected from an opioid antagonist, a potassium channel activator, a protease inhibitor, an anti-osteoporosis agent, a cognition 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.

6. 6. The method of any one of claims 1 to 5, wherein the average diameter of the cores based on weight, number or volume is in the amount of 1 μm to 50 μm.

7. A method according to any one of claims 1 to 6, wherein 3 to 10 individual layers of coating material are applied sequentially to the core.

8. 8. The method according to any one of claims 1 to 7, wherein the total thickness of the individual layers of coating material is between 0.5 nm and 2 μm.

9. 9. The method of any one of claims 1 to 8, wherein the maximum thickness of each individual layer of coating material is 1 / 100 of the average diameter based on weight, number, or volume of the core (including any other previously applied individual layers of coating material located between the each individual layer and the outer surface of the core).

10. The method of claim 1 , wherein the coating material of the one or more individual layers comprises one or more inorganic materials.

11. The method of claim 10 , wherein the coating material comprises one or more metal-containing or metalloid-containing compounds.

12. The method of claim 11 , wherein the compound comprises a hydroxide and / or an oxide.

13. 13. The method of claim 11 or 12, wherein the one or more coating materials comprise aluminum oxide, titanium dioxide, zinc sulfide, and / or zinc oxide.

14. The method of claim 13 , wherein the one or more coating materials comprise zinc oxide.

15. 15. A method according to any one of claims 1 to 14, comprising applying the distinct layers of coating material to the core and / or previously coated core by atomic layer deposition.

16. 16. The method of claim 15, wherein the mechanical sieving comprises vibrating or shaking the sieve.

17. 17. The method of claim 16, wherein the mechanical sieving comprises sonic sieving.

18. 18. The method of any one of claims 1 to 17, comprising the further step of resuspending the separated particles in a solvent, with or without the presence of one or more pharmaceutically acceptable excipients.

19. 19. The method of any one of claims 2 to 18, wherein the biologically active agent is an anti-cancer agent.

20. 20. The method of claim 19, wherein the biologically active agent is azacitidine.

21. A composition obtainable by the method defined in any one of claims 1 to 20.

22. 22. A composition according to claim 21 for use in medical or veterinary practice.

23. A pharmaceutical formulation comprising the composition defined in claim 21 and a pharmaceutically acceptable adjuvant, diluent, or carrier.

24. 24. The formulation according to claim 23 in the form of a sterile injectable and / or injectable dosage form.

25. 25. The formulation of claim 23 or 24 in the form of a liquid, sol, or gel that can be administered via a surgical administration device to form a depot formulation.

26. A veterinary formulation comprising the composition defined in claim 21 and a veterinarily acceptable adjuvant, diluent, or carrier.

27. The formulation of claim 26 in the form of a sterile injectable and / or injectable dosage form.

28. The formulation of claim 26 or 27 in the form of a liquid, sol, or gel that can be administered via a surgical administration device to form a depot formulation.

29. 26. A method for the preparation of a formulation as defined in any one of claims 23 to 25, comprising mixing the composition as defined in claim 21 with said pharmaceutically acceptable adjuvant, diluent or carrier.

30. A method for preparing a formulation as defined in any one of claims 26 to 28, comprising mixing the composition as defined in claim 21 with the veterinarily acceptable adjuvant, diluent, or carrier.

31. 22. The composition of claim 21 for use in the treatment of cancer.

32. 32. The composition for use of claim 31, wherein the cancer is a myelodysplastic syndrome or one or more of its subtypes.

33. A formulation according to any one of claims 23 to 25 for use in the treatment of cancer.

34. The formulation for use according to claim 33, wherein the cancer is one or more of myelodysplastic syndromes or subtypes thereof.

Images