New Injectable Oily Pharmaceutical Composition

Abstract

A pharmaceutical or veterinary formulation is provided, comprising: (a) a plurality of particles having an average diameter by weight, number, or volume in an amount of 10 nm to about 700 μm, the particles comprising a solid core coated with zinc oxide and suspended in (b); and (b) an oleaginous carrier system comprising a pharmaceutically or veterinarily acceptable oil, the zinc oxide-coated particles comprising: (1) a solid core comprising a biologically active agent; and (2) one or more discrete layers surrounding the core, each of the one or more layers comprising at least one distinct zinc oxide coating. The zinc oxide-coated particles are preferably synthesized via a vapor-phase coating technique, such as atomic layer deposition. When the core comprises a biologically active agent and the particles are suspended in an oleaginous carrier system, the formulation 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 Art

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

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

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

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

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

[0007] Atomic layer deposition (ALD) is a technique used to deposit thin films containing various materials, including organic materials, biological materials, polymer materials, and particularly inorganic materials such as metal oxides, on a solid substrate.

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

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

[0010] In ALD, a first precursor, which may contain metal, is supplied to the ALD reactor chamber (in a so-called "precursor pulse") to form a monolayer of atoms or molecules adsorbed on the substrate surface. Then, any excess first precursor is purged from the reactor, and a second precursor, such as water, is pulsed into the reactor. This reacts with the first precursor to form a monolayer on the substrate surface, for example, a metal oxide. After the subsequent purge pulse, further pulses of the first precursor follow, thus initiating a new cycle of the same event (the so-called "ALD cycle").

[0011] The thickness of the film coating is controlled, in particular, by the number of ALD cycles performed.

[0012] In typical ALD processes, only monolayers of atoms or molecules are produced in a single cycle, so no discernible physical interfaces are formed between these monolayers, and they essentially form a continuum on the substrate surface.

[0013] International Patent Application No. 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 / stirring step is performed to present a new surface available for the adsorption of precursors.

[0014] The stirring step is performed to address a problem primarily observed with nanoparticles and microparticles. Specifically, particle aggregation occurs during the ALD coating process, and "pinholes" are formed by the contact points between such particles. The redispersion / stirring step is carried out by placing the coated substrate in a solvent (e.g., water or hydrocarbons) and sonicating it, which results in deaggregation and the breakdown of contact points between individual particles of the coated active material.

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

[0016] This method significantly reduces the rapid release of the active ingredient and minimizes the risk of burst release; however, it has been found that when small particles of the biologically active ingredient are coated with zinc oxide and then mixed with an aqueous medium for injection, the burst release effect is not suppressed to the expected degree. The applicants have found that this problem can be significantly reduced by using an oily carrier system instead. [Overview of the project]

[0017] According to a first aspect of the present invention, a pharmaceutical preparation or a veterinary preparation, (a) Multiple particles having an average diameter based on weight, number, or volume, ranging in quantity from 10 nm to approximately 700 μm, wherein each particle comprises a solid core coated with a zinc oxide coating, and the particles are suspended in (b) below. (b) A pharmaceutical or veterinary preparation is provided which comprises an oily carrier system containing a pharmaceutically acceptable or veterinarily acceptable oil, This formulation will hereafter be referred to as "the formulation of the present invention." [Brief explanation of the drawing]

[0018] [Figure 1] Figure 1 shows in vivo azacitidine release from zinc oxide-coated particles suspended in 0.1% (w / w) polysorbate 20, 0.25% (w / w) carboxymethylcellulose sodium, and medium-chain triglycerides in phosphate-buffered saline (pH 7.4). [Modes for carrying out the invention]

[0019] Those skilled in the art will understand that the term “solid” includes all forms of matter that retain their shape and density when not confined, and / or whose molecules are generally compressed as strongly as the repulsive forces between them allow. A solid core has at least a solid outer surface on which layers of coating material can be deposited. The interior of a solid core may also be solid, or it may be hollow instead. For example, if particles are spray-dried before being placed in a reaction vessel, they may be hollow for spray-drying purposes.

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

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

[0022] By "consisting essentially of" a biologically active agent is meant that the solid core consists essentially of only the biologically active agent, i.e., does not contain substances that are not biologically active such as excipients, carriers, etc. (hereinafter). This means that the core can contain less than about 5%, such as less than about 3%, for example less than about 2%, such as less than about 1% of such other excipients.

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

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

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

[0026] Biologically active drugs include, for example, analgesics, anesthetics, anti-ADHD agents, appetite suppressants, antitoxic agents, antibacterial agents, antimicrobial agents, antifungal agents, antiviral agents, antiparasitic agents, antiprotozoal agents, anthelmintics, ectoparasitic agents, vaccines, anticancer agents, antimetabolites, alkylating agents, antitumor agents, topoisomerases, immunomodulators, immunostimulants, immunosuppressants, anabolic steroid solutions, anticoagulants, antiplatelet agents, anticonvulsants, antidementia agents, antidepressants, antitoxinizers, antihyperlipidemic agents, antigout agents, antimalarial agents, antimigraine agents, anti-inflammatory agents, antiparkinsonian agents, antipruritic agents, antipsoriasis agents, antiemetics, antiobesity agents, antiasthma agents, Antibiotics, antidiabetic drugs, antiepileptic drugs, antifibrinolytic drugs, antihemorrhagic drugs, antihistamines, antitussives, antihypertensive drugs, antimuscarinic drugs, antimycobacterial drugs, antioxidants, antipsychotics, antipyretics, antirheumatic drugs, antiarrhythmic drugs, anti-anxiety drugs, aphrodisiacs, cardiac glycosides, cardiac stimulants, enterogens, enteractogens, anesthetics, orexogenics, antithyroid drugs, anxiolytics, hypnotics, nerve relaxants, astringents, bacteriostatic drugs, beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, renin inhibitors, beta-adrenergic receptor blockers, blood products Blood substitutes, bronchodilators, cardiac antiarrhythmics, chemotherapy drugs, coagulants, corticosteroids, cough suppressants, diuretics, deliant agents, expectorants, fertilizers, sex hormones, mood stabilizers, mucolytics, neuroprotective agents, nootropics, neurotoxins, dopamine agonists, antiparkinson's disease drugs, free radical scavengers, growth factors, fibrates, bile acid blockades, desarcolytics, glucocorticoids, mineralocorticoids, hemostatic agents, hallucinogens, hypothalamic-pituitary hormones, immunosuppressants, laxatives, antidiarrheal agents, lipid regulators, muscle relaxants, parasympathomimetic agents, parathyroid calcitonin, celenic, statins, Stimulants, stimulants, decongestants, dietary minerals, biphosphonates, cough suppressants, ophthalmic drugs, ontology drugs, H1 antagonists, H2 antagonists, proton pump inhibitors, prostaglandins, radiopharmaceuticals, hormones, sedatives, anti-allergic drugs, appetite stimulants, steroids, sympathomimetic drugs, thrombolytics, thyroid drugs, vaccines, vasodilators, xanthines, erectile dysfunction drugs, gastrointestinal drugs, histamine receptor antagonists, keratolytics, antianginal agents, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, leukotriene inhibitors, macrolides, NSAIDs, nutritional supplements, opioid analgesics,The following may be selected from opioid antagonists, potassium channel activators, protease inhibitors, anti-osteoporosis drugs, anti-obesity drugs, cognitive enhancers, anti-urinary incontinence drugs, nutritional oils, anti-benign prostatic hyperplasia drugs, essential fatty acids, non-essential fatty acids, cytokines, peptide mimetic drugs, peptides, proteins, radiopharmaceuticals, anti-senile drugs, toxoids, serum, antibodies, nucleosides, nucleotides, vitamins, parts of genetic material, nucleic acids, or mixtures thereof.

[0027] Biologically active agents can also be cytokines, peptide mimes, peptides, proteins, toxoids, serum, antibodies, vaccines, nucleosides, nucleotides, parts of genetic material, nucleic acids, or mixtures thereof. Non-limiting examples of therapeutic peptides / proteins include: repiridine, cetuximab, dorunase alfa, denileukin difutox, etanercept, bivalirudin, leuprolide, alteplase, interferon alfa-n1, darbepoetin alfa, leteplase, epoetin alfa, salmon calcitonin, interferon alfa-n3, pegfilgrastim, salgramostim, secretin, peginterferon alfa-2b, asparaginase Thyrotropin alpha, antihemophilic factor, anakinra, gramicidin D, intravenous immunoglobulin, anistreplase, insulin (usual), tenecteplase, menotropin, interferon gamma-1b, interferon alpha-2a (recombinant), coagulation factor VIIa, oprelbequin, palifermin, glucagon (recombinant), aldesleukin, botulinum toxin type B, omalizumab, lutropin alpha, insulin lispro, insulin glargine, collagenase, rasburicase, A Darimumab, imiglucerase, absiximab, alpha-1 proteinase inhibitor, pegaspargase, interferon beta-1a, pegademase, human serum albumin, eptifibatide, iodized serum albumin, infliximab, follitropin beta, vasopressin, interferon beta-1b, hyaluronidase, rituximab, basiliximab, muromonab, digoxin immunofa (sheep), ibritumomab, daptomycin, tositumomab, pegvisomant, bo Turinus toxin type A, pancrelipase, streptokinase, alemtuzumab, alglucerase, capromab, laronidase, urofolitropin, efalizumab, serum albumin, choriogonadotropin alpha, antithymocyte globulin, filgrastim, coagulation factor IX, becapremin, agalsidase beta, interferon alpha-2b, oxytocin, enfuvirtide, palivizumab, daclizumab, bevacizumab, alsitumomab, eculizumab, panitumumab, ranibizumabIdursulfase, alglucosidase alfa, exenatide, mecasermin, plumrintide, galsulfase, abatacept, cosintropin, corticotropin, insulin aspert, insulin detemir, insulin glulisin, pegaptanib, nesiritide, thymalfacin, defibrotide, natural alpha interferon / multiferon, glatiramer acetate, perotact, teicoplanin, canakinumab, ipilimumab, thulodexide, tocilizumab, teriparatide, pertuzumab, lilonacept, denosumab, liraglutide, golimumab, belatacept, buserelin, veraglucerase alfa, tesamorelin, brentuximab vedotin, taliglucerase alfa, belimumab, aflibercept, asparaginase erwinia chrysanthemi, occliplus Min, glucarpidase, teduglutide, laxibakumab, certolizumab astimulimab pegol, insulin isophane, epoetinzeta, obinutuzumab, fibrinolysin, also known as plasmin, follitropin alfa, romiplostim, lucinactant, natalizumab, aliskiren, ragweed pollen extract, secukinumab, somatotropin (recombinant), drolecogin alfa, alefacept, OspA lipoprotein, urokinase, abarelix, selmorelin, aprotinin, gemtuzumab ozogamicin, satumomab pendetide, albiglutide, antithrombin alfa, antithrombin III (human), asfotase alfa, atezolizumab, autologous cultured chondrocytes, belacant, blinatumomab, C1 esterase inhibitor (human), coagulation factor XIII A subunit (recombinant), Cornstat alfa, daratumumab, decildin, dulaglutide, erosulfase alfa, evolocumab, fibrinogen concentrate (human), filgrastim-sndz, gastric endogenous factor, hepatitis B immunoglobulin, human calcitonin, human Clostridium tetanythoxoid immunoglobulin, human rabies virus immunoglobulin, human Rho(D) immunoglobulin, human Rho(D) immunoglobulin, hyaluronidase (human, recombinant), idarucizumab, immunoglobulin (human), vedolizumab, ustekinumab, tuloctocog alfa, tuberculin purified protein derivative,Simoctocog alfa, siltuximab, seberipase alfa, sacrosidase, ramucirumab, prothrombin complex concentrate, polactant alfa, pembrolizumab, pegylated interferon 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), human chorionic gonadotropin, human chorionic gonadotropin, coagulation factor X, dinutuximab, efmoloctocog alfa, human factor IX complex, hepatitis A vaccine, human varicerazoster immunoglobulin, ibritumomab tiuxetan, lenograstim, pegroticase, protamisulfate, protein S (human), cyplucel-T, somatropin (recombinant), susoctocog 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, butarvital, capecitabine, carbamazepine, carbidopa, carboplatin, cefotaxime, cephalexin, chlorambucil, cholestyramine, ciprofloxacin, cisapride, cisplatin, and clarithromycin. Mycin, clonazepam, clozapine, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin, diazepam, diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine, docetaxel, doxorubicin, doxazosin, enalapril, epirubicin, erlotinib, estradiol, etodrug, etoposide, everolimus, famotidine, felodipine, fentanyl citrate, fexofenadine, filgrastim, finasteride, fluconazole, flunicorn Solid, fluorouracil, flurbiprofen, fluralaner, fluvoxamine, furosemide, gemcitabine, glipizide, glibride, ibuprofen, ifosfamide, imatinib, indomethacin, irinotecan, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen, lamotrigine, lansoprazole, loperamide, loratadine, lorazepam, lovastatin, medroxyprogesterone, mefenamic acid, mercaptopurine, mesna, methotrexate, methylprednisolone, midazolam Mitomycin, Mitoxantrone, Moxidectin, Mometasone, Nabumeton, Naproxen, Nicergoline, Nifedipine, Norfloxacin, Omeprazole, Oxaliplatin, Paclitaxel, Pheniloin, Piroxicam, Procarbazine, Quinapril, Ramipril, Risperidone, Rituximab, Sertraline, Simvastatin, Slindac, Sunitinib, Temsirolimus, Terbinafine, Terfenadine, Thioguanine, Trastuzumab, Triamcinolone, Valproic acid, Vinblastine, Vincristine, Vinorelbine, Zolpidemor any pharmaceutically acceptable salt thereof.

[0029] The formulations of the present invention may include benzodiadipines such as alprazolam, chlordiazepoxide, clobazam, chlorazepic acid, diazepam, estazolam, flurazepam, lorazepam, oxazepam, quazepam, temazepam, triazolam, and pharmaceutically acceptable salts thereof.

[0030] Furthermore, the anesthetics that can be used in the formulations of the present invention may be local or systemic. Local anesthetics that may be mentioned include amylocaine, ambucaine, alticaine, benzocaine, benzonate, bupivacaine, butacaine, butanilicaine, chloroprocaine, cincocaine, cocaine, cyclomethicaine, dibucaine, diperodone, dimethocaine, eukaine, etidocaine, hexylcaine, phomokaine, photocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine, mepivacaine, and mepri. Examples include lucaine, metabutoxycaine, nitracaine, orthocaine, oxetacaine, oxybuprocaine, paraethoxycaine, phenacaine, pipelocaine, pyridocaine, pramocaine, prilocaine, prilocaine, procaine, procainamide, propalacaine, propoxycaine, pyrocaine, quinisocaine, ropivacaine, trimecaine, tricaine, tropacocaine, or any pharmaceutically acceptable salt thereof.

[0031] Psychotropic drugs can also be used in the formulations of the present invention. Psychotropic drugs that can be mentioned include 5-HTP, acamprosate, agomelatine, alimazine, amfetamine, dextroamphetamine, amisulpride, amitriptyline, amobarbital, amobarbital / secobarbital, amoxapine, amphetamine, aripiprazole, asenapine, atomoxetine, baclofen, bemperidol, bromperidol, bupropion, buspirone, butobarbital, carbamazepine, chloral hydrate, chlorpromazine, chlorprothixen, citalopram, clomethiazole, and Lomipramine, clonidine, clozapine, cyclobarbital / diazepam, cyproheptadine, cyticine, desipramine, desvenlafaxine, dexamfetamine, dextromethylphenidate, diphenhydramine, disulfiram, divalproex sodium, doxepin, doxylamine, duloxetine, enanthic acid, escitalopram, ezopiclone, fluoxetine, flupentixol, fluphenazine, fluspirylene, fluvoxamine, gabapentin, glutethimid, guanfacine, haloperidol, hydroxy Zin, Iloperidone, Imipramine, Lamotrigine, Levetiracetam, Levomepromazine, Levomilnacipran, Lisdexamfetamine, Lithium salt, Lurasidone, Melatonin, Merperone, Meprobamate, Metamfetamine, Netadon, Methylphenidate, Mianserin, Mirtazapine, Moclobemide, Nalmefene, Naltrexone, Niaprazine, Nortriptyline, Olanzapine, Ondansetron, Oxycarbazepine, Paliperidone, Paroxetine, Penfluridol, Pentobarbital, Perazine, Periciazine, Per Phenazine, phenelzine, phenobarbital, pimozide, pregabalin, promethazine, protipendyl, protriptyline, quetiapine, ramelteon, reboxetine, reboxetine, reserpine, risperidone, rubidium chloride, secobarbital, selegiline, certindol, sertraline, sodium oxybate, sodium valproate, sodium valproate, sulpiride, thioridazine, thiothixen, thianeptine, tizanidine, topiramate, tranylcypromine, trazodone, trifluoperazine, trimipramine,Examples include tryptophan, valerian, valproic acid (in a 2.3:1 ratio), varenicline, venlafaxine, virazodone, vortioxetine, zaleplon, ziprasidone, zolpidem, zopiclone, zotepine, zuclopentixol, and any pharmaceutically acceptable salts thereof.

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

[0033] Examples of opioid antagonists that can be used in the formulations of the present invention include naloxone, nalorphine, niconalorphine, dyprenorphine, levallorphan, samidolphan, nalodeine, albimopan, methylnaltrexone, naloxegol, 6β-naltrexone, axeroplan, bebenoplan, methylsamidolphan, naldemedine, preferably nalmefene, particularly naltrexone, and any pharmaceutically acceptable salts thereof.

[0034] Anticancer agents that may be included in the formulation of the present invention include actinomycin, afatinib, all-trans retinoic acid, amsacrin, anagrelide, arsenic trioxide, axitinib, azacitidine, azathioprine, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, chlorambucil, cladribine, clofarabine, and sita. Rabin, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, docetaxel, doxyfluuridine, doxorubicin, epirubicin, epotilon, erlotinib, estramustine, etoposide, everolimus, fludarabine, fluorouracil, gefitinib, guadecitabine, gemcitabine, hydroxycarbamide, hydroxyurea, idarubicin, idelalisib, ifos Famide, imatinib, irinotecan, ixazomib, cabozantinib, carfilzomib, crizotinib, lapatinib, lomustine, mechloretamine, melphalan, mercaptopurine, mesna, methotrexate, mitotane, mitoxantrone, nelarabine, nilotinib, niraparib, olaparib, oxaliplatin, paclitaxel, panobinostat, pazopanib, pemetrexed, pixantrone, ponatinib, Examples include procarbazine, regorafenib, ruxolitinib, sonidegib, sorafenib, sunitinib, tegafur, temozolomide, teniposide, thioguanine, thiotepa, topotecan, trabectedin, barrubicin, vandetanib, vemurafenib, venetoclax, vinblastine, vincristine, vindesine, vinflunin, vinorelbine, bismodegib, and any pharmaceutically acceptable salts thereof. The preferred bioactive agent is azacitidine.

[0035] Such compounds may be used in any one of the following cancers: adenocystic carcinoma, adrenal carcinoma, amyloidosis, anal cancer, ataxic telangiectasia, atypical mole syndrome, basal cell carcinoma, cholangiocarcinoma, Birt-Hogg Dube, ductal syndrome, bladder cancer, bone cancer, brain tumor, breast cancer (including male breast cancer), cancerous tumors, cervical cancer, colorectal cancer, ductal carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, HER2-positive breast cancer, islet cell tumor, juvenile polyposis syndrome, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, all types of acute lymphoblastic leukemia, acute myeloid leukemia, adult leukemia, childhood leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lobular carcinoma, lung cancer, small cell lung cancer, Hodgkin's disease Lymphoma, non-Hodgkin lymphoma, malignant glioma, melanoma, meningioma, multiple myeloma, myelodysplastic syndrome, nasopharyngeal cancer, neuroendocrine tumor, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor, parathyroid cancer, penile cancer, peritoneal cancer, Puts-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] Cancers that may be mentioned include myelodysplastic syndromes and subtypes, such as acute myeloid leukemia, refractory anemia or refractory anemia with ring sideroblasts (with neutropenia or thrombocytopenia, or requiring blood transfusions), refractory anemia with blast cell proliferation, refractory anemia with blast cell proliferation in the transitional phase, and chronic myeloid leukemia (myelomonocytic leukemia).

[0037] Other drugs that may be mentioned for use in the formulations of the present invention include immunomodulatory imide drugs such as thalidomide, as well as analogs thereof such as pomalidomide, lenalidomide, and apremilast, and pharmaceutically acceptable salts of any of these. Other drugs that may be mentioned include angiotensin II receptor type 2 agonists such as compound 21(C21;3-[4-(1H-imidazole-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophene-2-[(N-butyloxylcarbamate)-sulfonamide] and pharmaceutically acceptable (e.g., sodium) salts thereof.

[0038] The formulations of the present invention may contain a pharmacologically effective amount of a biologically active agent. The term "pharmacologically effective amount" means the amount of such active agent that can produce a desired physiological change (such as a therapeutic effect) in a patient being treated, whether administered alone or in combination with another active agent. Such biological or medical response in a patient, or such effect, may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows or feels an effect) and may include at least partial relief of the symptoms of the disease or disorder being treated, or the cure or prevention of such disease or disorder.

[0039] Therefore, the dose of the active ingredient that can be administered to a patient must be sufficient to influence the therapeutic response over a reasonable and / or relevant timeframe. Those skilled in the art recognize that the precise dose and composition, as well as the selection of the most suitable delivery regimen, are influenced not only by the properties of the active ingredient, but also, in particular, by the pharmacological properties of the formulation, the route of administration, the nature and severity of the condition being treated, the physical and mental state of the recipient, and the age, condition, weight, sex, and response of the patient being treated, the stage / severity of the disease, and genetic differences among patients.

[0040] The formulation of the present invention may be administered continuously or intermittently (e.g., by bolus injection). The dose of the active ingredient may also be determined by the timing and frequency of administration.

[0041] In any case, a physician or other person skilled in the art will be able to routinely determine the actual dosage of any particular active ingredient that is most suitable for an individual patient.

[0042] Alternatively, the formulations described herein may also include, instead of (or in addition to) biologically active agents, diagnostic agents (i.e., agents that do not have direct therapeutic activity of their own but can be used to diagnose conditions, such as contrast agents or contrast media for bioimaging).

[0043] Nonbiologically active adjuvants, diluents, and carriers that can be used in cores coated according to the present invention may include carbohydrates, such as sugars like lactose and / or trehalose, and water-soluble pharmaceutically acceptable substances such as sugar alcohols like 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 polymer, such as a peptide, protein, or part of genetic material as generally described, and / or the aforementioned specific peptide / protein, including vaccines. Thus, embedding polymer complexes in excipients often results in larger cores for coating and, consequently, larger coated particles.

[0044] It is not a requirement that the core of the formulation of the present invention contain a biologically active agent. Whether or not the core contains a biologically active agent, the core may contain, and / or be essentially composed of, one or more non-biologically active adjuvants, diluents, and carriers (including emollients), and / or other excipients having functional properties (e.g., buffers and / or pH modifiers (e.g., citric acid)).

[0045] The core is provided in the form of nanoparticles, or more preferably microparticles. Preferred average diameters based on weight, number, or volume are 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).

[0046] As used herein, the term “weight-based average diameter” will be understood by those skilled in the art to include, and is defined by, a weight-based particle size distribution, i.e., a distribution characterized by existing fractions (relative amounts) in each size class, defined, for example, as weight fractions obtained by sieving (e.g., wet sieving). As used herein, the term “number-based average diameter” will be understood by those skilled in the art to include, and is defined by, a number-based particle size distribution, i.e., a distribution characterized by existing fractions (relative amounts) in each size class, defined, for example, as fractions measured by microscopic examination. As used herein, the term “volume-based average diameter” will be understood by those skilled in the art to include, and is defined by, a volume-based particle size distribution, i.e., a distribution characterized by existing fractions (relative amounts) in each size class, defined, for example, as volume fractions measured by laser diffraction. For example, particle size can be measured using other instruments well-known in this field, such as those sold by Malvern Instruments, Ltd (Worcestershire, UK) and Shimadzu (Kyoto, Japan).

[0047] The particles may be spherical, that is, they have an aspect ratio of less than about 20, more preferably less than about 10, for example less than about 4, and especially less than about 2, and / or at least about 90% of the particles, less than or equal to about 50% of the mean, for example less than or equal to about 30% of that value, for example less than or equal to about 20% of that value, in terms of radius (measured from the center of mass to the particle surface).

[0048] Nevertheless, according to the present invention, it is also possible to coat particles of any shape. For example, irregularly shaped (e.g., "raisin" shaped), needle-shaped, or rectangular parallelepiped-shaped particles can be coated. In the case of non-spherical particles, the size may be expressed, for example, as the corresponding spherical particle size for the same weight, volume, or surface area. Hollow particles, as well as particles having pores, gaps, etc., such as fibrous or "tangled" particles, can also be coated according to the present invention.

[0049] The particles may be obtained in a form suitable for coating, or in that form, by particle size reduction processes (e.g., grinding, cutting, milling, or abrasive grinding) to a specific weight-based average diameter (as previously defined), for example, by utilizing ball milling such as wet grinding, dry grinding, air jet milling (including cryogenic pulverization), planetary ball milling, and end runner mills, roller mills, vibratory mills, hammer mills, roller mills, fluid energy mills, pin mills, etc. Alternatively, the particles may be directly prepared to a suitable size and shape by, for example, spray drying, precipitation, or other top-down methods (i.e., reducing larger particle sizes by grinding, etc.), including the use of supercritical fluids, or by bottom-up methods (i.e., increasing smaller particle sizes by sol-gel techniques, etc.). Alternatively, nanoparticles may be produced by well-known techniques such as gas condensation, abrasion, chemical precipitation, ion implantation, pyrolysis, and hydrothermal synthesis.

[0050] The particles may need to be washed and / or cleaned to remove impurities that may originate from their formation, and then dried (depending on how the particles, including the core, are initially supplied). Drying can be carried out by many techniques known to those skilled in the art, including evaporation, spray drying, vacuum drying, freeze-drying, fluidized bed drying, microwave drying, IR radiation, drum drying, etc. Once dried, the core can then be deaggregated by grinding, screening, milling, and / or dry ultrasonic treatment. Alternatively, the core can be treated, for example, by exposing the particles to vacuum and / or high temperatures to remove any volatile substances that may be absorbed onto its surface.

[0051] The core surface can be chemically activated before applying the first layer of coating material, for example, by treating it with hydrogen peroxide, ozone, or a free radical-containing reactant, or by applying plasma treatment to create free oxygen radicals on the core surface. This can generate favorable adsorption / nucleation sites on the core of the ALD precursor.

[0052] Preferred methods for coating a core containing a biologically active agent include vapor phase techniques such as ALD, or related techniques such as atomic layer epitaxy (ALE), molecular layer deposition (MLD, a technique similar to ALD but differing in that molecules (usually organic molecules) are deposited in each pulse instead of atoms), molecular layer epitaxy (MLE), chemical vapor deposition (CVD), atomic layer CVD, molecular layer CVD, physical vapor deposition (PVD), sputtering PVD, reactive sputtering PVD, vapor deposition PVD, and binary reaction sequence chemistry. ALD is a preferred coating method according to the present invention.

[0053] A composition containing a biologically active agent is coated with one or more separate layers, at least one of which comprises at least one separate zinc oxide coating.

[0054] Preferably, two or more separate layers, coatings, or shells (these terms are used interchangeably herein) are applied (i.e., “applied separately”) to a solid core containing a biologically active agent, and more preferably, all or most of the separate layers, coatings, or shells contain zinc oxide.

[0055] In "separate layers, coatings, or shells," "separate application" means that a solid core is coated with a first layer of coating material, and the resulting coated core is then subjected to some form of de-agglomeration process. In this regard, the number of separate layers of coating material as defined herein corresponds to the number of these intermittent de-agglomeration steps, with the final mechanical de-agglomeration taking place before the application of the final layer of coating material.

[0056] The coated core may be subjected to the aforementioned deaggregation process without being removed from the apparatus by a continuous process. Such a process involves forcing the solid product mass formed by coating the core through a sieve placed in the reactor, and is configured to deaggregate particle aggregates by forcing the coated core with the forcing means applied in the reactor before being subjected to a second coating and / or further coating. This process is continued for the required and / or appropriate number of times before applying the final coating, as described herein.

[0057] Placing a sieve inside the reaction vessel means that the coating can be applied by a continuous process that does not require removing particles from the reactor. Therefore, there is no need to handle particles manually, and no external machinery is needed to deagglomerate agglomerated particles. This not only significantly reduces the time required to carry out the coating process, but also makes it more convenient and reduces the risk of harmful (e.g., toxic) materials being handled by personnel. Furthermore, limiting manual work improves process reproducibility and reduces the risk of contamination.

[0058] Alternatively, the coated core may be removed from the coating apparatus, such as an ALD reactor, and subsequently subjected to an external deagglomeration step, for example, as described in International Patent Application No. 2014 / 187995. Such an external deagglomeration step may include stirring, such as sonication in a wet or dry state, or preferably, the resulting solid product mass removed from the reactor may be sieved, for example by passing it through a sieve or mesh, to deagglomerate the particles before returning the particles to the coating apparatus for the next coating step, for example, as described below. Here again, this process may be continued for as many times as necessary and / or appropriate before applying the final coating.

[0059] In an external deagglomeration process, deagglomeration can alternatively be performed by subjecting the coated particles, either wet or dry, to one or more of the following: nozzle aerosol generation, 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 previously described with respect to the core) before the next coating step.

[0060] However, in such external processes, the deagglomeration step may include one or more sieving steps, which may include jet sieving, manual sieving, vibrating sieving, horizontal sieving, tap sieving, or (preferably) ultrasonic sieving as described below, or any combination of these sieving steps. Suitable manufacturers of ultrasonic sifters include Advantech Manufacturing, Endecott, and Tsutsui.

[0061] Without being limited by theory, it is believed that removing coated particles from an ALD reactor under vacuum conditions and exposing the newly coated surface to the atmosphere would result in structural reorganization through relaxation and reconstruction of the outermost atomic layer. Such a process is thought to involve the reorganization of atoms on (and near) the surface, driven by a thermodynamic tendency to decrease the free energy of the surface.

[0062] Furthermore, surface adsorption of species (e.g., hydrocarbons that are always present in the air) may contribute to this phenomenon, as may the reactions of the hydrocarbon-formed coating and surface modification by atmospheric oxygen. Therefore, chemical analysis of such interfaces may reveal the presence of trace amounts of contaminants not originating from coating processes such as ALD.

[0063] Whether carried out inside or outside the reactor, particle aggregates are preferably broken down by a forceful means of passing them through a sieve, thus separating the aggregates into individual particles or aggregates of a desired and predetermined size (thereby achieving deaggregation). With regard to the latter, in some cases, it is impossible to achieve “complete” deaggregation (i.e., the aggregates are broken down into individual particles) because the individual primary particle size is very small (i.e., <1 μm). Instead, deaggregation is achieved by breaking down larger aggregates into smaller aggregates of secondary particles of the desired size, as determined by the mesh size of the sieve. The smaller aggregates are then coated using a gas-phase technique to form “particles” that are completely coated in the form of smaller aggregate particles. Thus, the term “particles” in the context of this invention refers to both individual (primary) particles and aggregated (secondary) particles of the desired size.

[0064] In any case, the desired particle size (whether it be individual particles or aggregates of the desired size) is maintained, and furthermore, the continuous application of the gas-phase coating mechanism to such deaggregated particles via sieving forms a complete coating on the particles, thus meaning that completely coated particles (individual particles or aggregates of the desired size) are formed.

[0065] The repeated coating and de-aggregation processes described above may be carried out at least once, preferably twice, more preferably three times, for example four or five times, more specifically six times, for example seven times, and about 100 times or less, for example about 50 times or less, for example about 40 times or less, for example about 30 times or less, for example 2 to 20 times, for example 3 to 15 times, for example 10 times, for example 9 or 8 times, more preferably 6 or 7 times, in particular 4 or 5 times, regardless of whether they are carried out inside or outside the reactor.

[0066] The total thickness of the coating (meaning all separate layers / coatings / shells) is in the range of approximately 0.5 nm to 2 μm on average.

[0067] The minimum thickness of each individual layer / coating / shell is in the range of approximately 0.1 nm on average (e.g., approximately 0.75 nm, approximately 1 nm, etc.).

[0068] The maximum thickness of each individual layer / coating / shell will depend on the size of the core (initially) and thereafter on the size of the core with the pre-coated coating, and may be approximately 1 / 100th of the average diameter (i.e., average diameter based on weight, number, or volume) of that core or the pre-coated core.

[0069] Preferably, for particles with an average diameter of about 100 nm to about 1 μm, the coating thickness should be about 1 nm to about 5 nm on average; for particles with an average diameter of about 1 μm to about 20 μm, the coating thickness should be about 1 nm to about 10 nm on average; and for particles with an average diameter of about 20 μm to about 700 μm, the coating thickness should be about 1 nm to about 100 nm on average.

[0070] The applicants have found that when one or more deaggregation steps, such as sonication, are performed after the application of a coating / shell, the coated particles essentially "bond" or "adhere" more tightly immediately after the application of a thicker coating, resulting in wear, pinholes, breakage, gaps, cracks, and / or voids (hereinafter "cracks") in the layer / coating. As a result, when deaggregation occurs, the core containing biologically active components may be exposed to elements.

[0071] The applicants have found that by performing the deaggregation step described in the present invention (which significantly reduces pinholes, gaps, or cracks in the final layer of the coating material), particles are produced that are not only completely covered by the layer / coating, but also covered in such a way that the particles can be easily deaggregated (e.g., using non-invasive techniques such as vortexing) without destroying the layer of coating material formed before and / or during pharmaceutical formulation.

[0072] For example, if the intention is to provide a sample in a suspension before administration to a patient, it is necessary to provide deaggregated primary particles without pinholes or cracks in the coating. Such cracks can cause undesirable initial peaks (bursts) in the plasma concentration of the active ingredient immediately after administration.

[0073] As described below, the process of the present invention yields deaggregated coated particles that are essentially free of cracks through which the active ingredients can be released in an uncontrolled manner. “Essentially free of cracks” in the coating means that less than approximately 1% of the surface of the coated particles contains wear, pinholes, fractures, gaps, cracks and / or voids (through which the active ingredients are potentially exposed (e.g., to elements)).

[0074] The coating material layer can, collectively, have an essentially uniform thickness across the surface area of ​​the particles. "Essentially uniform" thickness means that the degree of variation in coating thickness is such that at least about 10%, e.g., about 25%, e.g., about 50% (including about ±20% or less of the average thickness, or ±50% or less, as measured by TEM) of the coated particles present in the composition of the present invention.

[0075] The coating material applied to the core must contain zinc oxide, but in addition to zinc oxide, other coating materials that are pharmaceutically acceptable and essentially non-toxic may be applied either between separate coatings of zinc oxide (e.g., between separate de-aggregation steps) and / or while the zinc oxide coating is applied (i.e., individual layers may also contain mixtures of zinc oxide and one or more additional coating materials), and / or multiple layers or composites of zinc oxide and one or more different inorganic or organic materials may be included to modify the properties of the layers.

[0076] The additional coating material may include organic or polymer materials such as polyamide, polyimide, polyurea, polyurethane, polythiourea, polyester, or polyimine. The additional coating material may also include hybrid materials (such as those between organic and inorganic materials) which are combinations of a metal or another element with an alcohol, carboxylic acid, amine, or nitrile. However, it is preferable that the coating material includes an inorganic material.

[0077] The additional inorganic coating material may contain one or more metals or metalloids, or one or more metal-containing or metalloid-containing compounds such as metals or metalloids, oxides, nitrides, sulfides, selenides, carbonates, and / or other ternary compounds. Metals and metalloids, hydroxides, oxides in particular, and metal oxides in particular are preferred.

[0078] Other metals that may be mentioned include alkali metals, alkaline earth metals, precious metals, transition metals, post-transition metals, and lanthanides. Metals and metalloids that may be mentioned include aluminum, titanium, magnesium, iron, gallium, zirconium, niobium, hafnium, tantalum, lanthanum, and / or silicon, more preferably aluminum, titanium, magnesium, iron, gallium, zinc, zirconium, and / or silicon, and especially aluminum and / or titanium.

[0079] Additional coating materials that may be mentioned include aluminum oxide (Al2O3), titanium dioxide (TiO2), and iron oxide (Fe x O y Examples include those containing FeO and / or Fe2O3 and / or Fe3O4, gallium oxide (Ga2O3), magnesium oxide (MgO), niobium oxide (Nb2O5), hafnium oxide (HfO2), tantalum oxide (Ta2O5), lanthanum oxide (La2O3), zirconium dioxide (ZrO2), and / or silicon dioxide (SiO2). Preferred additional coating materials include aluminum oxide, titanium dioxide, iron oxide, gallium oxide, magnesium oxide, zirconium dioxide, and silicon dioxide. More preferred additional coating materials include iron oxide, as well as titanium dioxide, zinc sulfide, and aluminum oxide.

[0080] In most cases, the first in a series of reactions involves several functional groups, free electron pairs, or radicals on the surface to be coated, such as a hydroxyl group (-OH) or a primary or secondary amino group (-NH2 or -NHR, where R is an aliphatic group such as an alkyl group). Each reaction is advantageously carried out separately under conditions that all excess reagents and reaction products are essentially removed before proceeding to the next reaction.

[0081] In ALD, the coating material layer can be applied at a process temperature of approximately 20°C to 800°C, or approximately 40°C to 200°C, for example, approximately 40°C to 150°C. The optimal process temperature depends on the reactivity of the precursor and / or substance (including biologically active agents) used in the core, and / or the melting point of the core material. If the core to be coated contains biologically active components, it is preferable to use a lower temperature, such as approximately 30°C to 100°C.

[0082] The coating material layers (individually or aggregated) in the formulation of the present invention may essentially consist of zinc oxide (for example, more than about 80%, more than about 90%, more than about 95%, or more than 98%).

[0083] The plurality of zinc oxide-coated particles according to the present invention do not inherently contain the aforementioned cracks in the applied coating that potentially expose the active ingredient (e.g., to the element), but further optional steps may be applied to the plurality of coated particles before subjecting them to further pharmaceutical formulation processes. This optional step may include subjecting the few remaining particles having broken and / or cracked shells / coatings to a process in which all particles are suspended in a solvent (the active ingredient is, for example, soluble at a solubility of at least about 0.1 mg / mL, while the least soluble material of the coating is, for example, insoluble at a solubility of about 0.1 μg / mL or less), and subsequently separating the solid particles from the solvent by, for example, centrifugation, sedimentation, agglomeration, and / or filtration, thereby ensuring that mainly intact particles remain.

[0084] The optional steps described above, as discussed herein, provide means to further potentially reduce the possibility of (possibly) undesirable early peaks (bursts) in the plasma concentration of the active ingredient.

[0085] At the end of the process, the coated particles can be dried using one or more of the aforementioned techniques for drying the core. Drying may occur in the absence or presence of one or more pharmaceutically acceptable excipients (e.g., sugars or sugar alcohols).

[0086] Before applying the first layer of the coating material, or during sequential coating, 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 containing different materials (i.e., non-inorganic materials) may be applied to the relevant surface, for example, to protect the core or partially coated particles from undesirable reactions with precursors during the coating step / deposition process, to enhance coating efficiency, or to reduce aggregation.

[0087] The intermediate layer may contain one or more surfactants, for example, to reduce aggregation of the particles to be coated 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 part of) the core readily reacts 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.

[0088] Alternatively, the application of an “intermediate” layer / surface treatment of this nature may provide the particles with a surface layer to which a coating material can subsequently be applied, achieved by liquid-phase non-coating techniques followed by freeze-drying, spray-drying, or other drying methods.

[0089] The outer surface of the particles of the formulation of the present invention may also be derivatized or functionalized, for example, by attaching one or more chemical compounds or parts to the outer surface of the final layer of a coating material, using compounds or parts that enhance the targeted delivery of particles in a patient to whom the nanoparticles are administered. Such compounds may be organic molecular (e.g., PEG) polymers, antibodies or antibody fragments, or receptor-binding proteins or peptides.

[0090] Alternatively, the moiety may be an anchoring group, such as a moiety containing silane functionality (see, for example, Herrera et al, J. Mater. Chem., 18, 3650 (2008) and US8, 097, 742). Another compound (e.g., the desired targeting compound) may be bonded to such an anchoring group by covalent or non-covalent bonds (including hydrogen bonds or van der Waals bonds), or a combination thereof.

[0091] The presence of such immobilizing groups can provide a versatile tool for targeted delivery to specific sites within the body. Alternatively, compounds such as PEG can be used to allow particles to circulate in the bloodstream for longer periods, preventing accumulation in the liver or spleen (a natural mechanism by which the body eliminates particles, potentially preventing delivery to diseased tissue).

[0092] A core coated with one or more separate layers, coatings, or shells (at least one of which contains zinc oxide) is hereinafter referred to as "coated particles of the formulation of the present invention."

[0093] The formulations of the present invention can be used, for example, in the practice of medicine, diagnosis, and / or veterinary medicine.

[0094] The pharmaceutical (or veterinary) formulations of the present invention may include different types of particles, for example, particles containing different active ingredients including different functionalizations (as described above), particles with layers of coating material of different sizes and / or thicknesses, or combinations thereof. In a single pharmaceutical formulation, by combining particles having different coating thicknesses and / or different core sizes, drug release after administration to a patient can be controlled (e.g., variable or prolonged) over a specific period of time.

[0095] The formulations of the present invention may be administered systemically in a pharmaceutically (or veterinarily) acceptable dosage form, for example, by injection or infusion, intravenously or intra-arterially (including by intravascular or other perivascular devices / dosage forms (e.g., stents)), intramuscularly, intraosseously, intracerebrally, intraventricularly, intrasynovally, intrasternally, intrathecally, intrafocally, intracranially, intratumorally, cutaneously, intradermally, subcutaneously, or percutaneously.

[0096] The preparation of the formulations of the present invention involves incorporating the coated particles described herein into a suitable pharmaceutically or veterinarily acceptable oily carrier system, which can be achieved considering the intended route of administration and standard pharmaceutical practices. Therefore, the suitable oily carrier system must be chemically inert to the biologically active agent (if used) and free from harmful side effects or toxicity under the conditions of use. Such a pharmaceutically acceptable carrier may also confer immediate or controlled release to the formulations of the present invention.

[0097] For parenteral administration such as subcutaneous and / or intramuscular injection, the formulation of the present invention may be in the form of a sterile injection and / or infusion dosage form, in which case the dosage form may be contained in a reservoir and in the injection or infusion means, and the coated particles and carrier system are contained separately, with mixing occurring before and / or between injection or infusion.

[0098] The formulations of the present invention, which are suitable for injection, may also be in the form of a liquid, sol, or gel (e.g., containing hyaluronic acid) that can be administered via a surgical administration device, such as a needle or catheter, to form a depot formulation. The use of the formulations of the present invention can control the dissolution rate and pharmacokinetic profile by reducing any burst effect as previously defined and / or by reducing Cmax in the plasma concentration-time profile, and thus increasing the length of release of the biologically active component from the formulation.

[0099] When a zinc oxide-containing coating is applied using ALD at low temperatures such as approximately 50°C to 100°C, it was found that, unlike other coating materials such as aluminum oxide and titanium oxide which form an amorphous layer, the coating material is predominantly crystalline by its properties.

[0100] Without being limited by theory, the coated particles of the formulation of the present invention are substantially primary particles with no physical pinholes or cracks in the coating because zinc oxide is crystalline, before being prepared and suspended in a carrier system for injection. However, interfaces may exist between adjacent crystals of zinc oxide deposited by ALD, thereby allowing a carrier system, medium, or solvent (e.g., an aqueous solvent system) in which zinc oxide is partially dissolved to penetrate thereafter suspension.

[0101] This can cause these interfaces to "broaden," resulting in the formation of pinholes after the preparation of a composition in which zinc oxide-coated particles are suspended in such a carrier system, thus leading to the penetration of such carrier / solvent, and / or the creation of more and / or wider physical pinholes or cracks (as described above), thereby potentially exposing the active ingredient to the carrier suspension medium in such a formulation after its preparation. This further, as will be discussed later, can expose the active ingredient to the carrier system before injection, and thus partially dissolve in the carrier system, resulting in an unexpected burst effect.

[0102] As shown below, the applicants have found that this problem can be solved by suspending the coated particles in an oily solvent system.

[0103] Therefore, the pharmaceutically or veterinarily acceptable carrier system according to the present invention is oily or oleophilic. Accordingly, the carrier system may contain one or more pharmaceutically or veterinarily acceptable liquid lipids, which may include fixed oils such as mono-, di-, or triglycerides, including migliol (e.g., 812N), propylene glycol dicaprylocate (migliol 840, C8 / C10 ester), tricaprylin (migliol oil), gelcile 43 / 01, colisolve GTA, and labrafil. The carrier system may also include polysorbates such as polysorbate 20, polysorbate 60, and polysorbate 80; glycols such as propylene glycol, polyethylene glycol, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600; and / or natural and / or refined pharmaceutically acceptable oils, such as olive oil, peanut oil, soybean oil, corn oil, cottonseed oil, sesame oil, castor oil, oleic acid, and their polyoxyethylated versions (e.g., sorbitan trioleate, lauroglycol 90, capryol PGMC, PEG-60 hydrogenated castor oil, polyoxyl 35 castor oil). More preferred carrier systems include mono-, di-, and / or triglycerides, including alkyl chain triglycerides (e.g., C6-C6). 12 Medium-chain triglycerides, such as alkyl chain triglycerides, are most preferred.

[0104] In addition, the coated particles of the formulation of the present invention can be formulated according to techniques well known to those skilled in the art by using a suitable dispersant or wetting agent (e.g., Tweens such as Tween 80) and a suspending agent.

[0105] Otherwise, the formulations of the present invention and dosage forms containing them are formulated with conventional pharmaceutical excipients 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, 3 rd edition (1986), "Remington: The Science and Practice of Pharmacy", Troy (ed.), University of the Sciences in Philadelphia, 21 st edition (2006), and / or "Aulton's Pharmaceutics: The Design and Manufacture of Medicines," Aulton and Taylor (eds.), Elsevier, 4 th The preparations may be incorporated into various types of pharmaceutical preparations and / or dosage forms using the documents referred to therein (see edition, 2013) and the documents referred therein, and the relevant disclosures in all of them are incorporated herein by reference. Otherwise, the preparation of suitable formulations can be achieved non-originally by those skilled in the art using routine techniques.

[0106] The formulation of the present invention may contain about 1% to about 99% coated particles, such as about 10% by weight (about 20% by weight, for example, about 50% by weight) to about 90% by weight, with the remainder consisting of a carrier system and / or other excipients.

[0107] A further aspect of the present invention provides a process for preparing a formulation of the present invention, comprising mixing the coated particles described herein with an oily carrier system after coating as described herein.

[0108] Furthermore, an injectable and / or injectable dosage form is provided, comprising a reservoir and the formulation of the present invention contained in an injection or injection means.

[0109] In this regard, the formulations of the present invention may be stored before being loaded into a suitable injectable and / or infusion dispensing means (e.g., a syringe equipped with an injection needle), or may be prepared immediately before being loaded into such dispensing means.

[0110] therefore, (a) Coated particles of the formulation of the present invention, (b) A kit of components comprising a carrier system for the formulation of the present invention is further provided. The kit of components also includes coated particles of the formulation of the present invention, along with instructions for the end user on how to mix those particles with the carrier system according to the present invention.

[0111] As described above, pre-loaded injection and / or infusion dosage forms are further provided, but are modified to include at least two chambers, in which coated particles of the formulation of the present invention are placed, and in the other chamber, a carrier system of the formulation of the present invention is placed, and mixing takes place before and / or between injection or infusion.

[0112] Whenever the term “approximately” is used herein, it will be understood that, for example, in the context of quantity (e.g., concentration, dimensions (size and / or weight), size ratio, aspect ratio, ratio, or fraction), temperature, or pressure, such variables are approximate and therefore may vary by ±15%, e.g., ±10%, e.g., ±5%, preferably ±2% (e.g., ±1%) from the numerical value specified herein. This is true even if such a numerical value is expressed as a percentage in the first place (for example, “approximately 15%” may mean ±15% of the numerical value 10, which is any of 8.5% to 11.5%).

[0113] The formulations of the present invention enable the formulation of a wide variety of pharmaceutically active compounds. Depending on the biologically active agents contained, the formulations of the present invention can be used to effectively treat a wide variety of disorders.

[0114] The formulations of the present invention can be further formulated into an injectable suspension of coated particles having a size distribution that can form a uniform and stable (i.e., non-settling) suspension in an injection solution and can be injected through a needle.

[0115] In this regard, the formulations of the present invention may include an oily medium having sufficient viscosity to prevent sedimentation, which would result in the suspension becoming non-homogeneous and thus pose a risk of under- or over-dosing of the active ingredient. For any given number of coated particles, this can be achieved by adding known viscosity modifiers (such as polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose, or sodium starch glycolate), or more preferably by providing a more viscous carrier system itself.

[0116] Furthermore, the formulations can be stored under normal storage conditions, maintaining their physical and / or chemical integrity.

[0117] The phrase "maintain physical and chemical integrity" essentially means chemical stability and physical stability.

[0118] "Chemical stability" means that any formulation of the present invention can be stored under normal storage conditions with minimal chemical alteration or degradation (whether or not appropriate pharmaceutical packaging is used).

[0119] "Physical stability" means that any formulation of the present invention can be stored under normal storage conditions with minimal physical transformation, such as sedimentation as described above, or changes in the properties and / or integrity of coated particles, such as the coating itself or the active ingredient (including dissolution, solvation, solid phase transition, etc.), with or without appropriate pharmaceutical packaging.

[0120] Examples of "normal storage conditions" for the formulation of the present invention include long-term storage (i.e., about 12, for example, about 6 months or more) at a temperature of about -50°C to about +80°C (preferably about Examples include a temperature of -25°C to approximately +75°C (for example, approximately 50°C), and / or a pressure of approximately 0.1 to approximately 2 bar (preferably atmospheric pressure), and / or exposure to UV / visible light of approximately 460 lux, and / or a relative humidity of approximately 5 to approximately 95% (preferably approximately 10 to approximately 40%).

[0121] Under such conditions, the formulations of the present invention may be found to be chemically and / or physically altered / degraded by, as necessary, less than about 15%, more preferably less than about 10%, and particularly less than about 5%. Those skilled in the art will understand that the above upper and lower limits of temperature and pressure represent extremes of normal storage conditions, and that certain combinations of these extremes are not experienced during normal storage (e.g., 50°C and 0.1 bar pressure).

[0122] Furthermore, the formulations of the present invention may provide a release and / or pharmacokinetic profile that minimizes any burst effects characterized by a maximum concentration immediately after administration, and / or minimizes Cmax.

[0123] The formulations and processes described herein may have advantages in treating a particular biologically active drug for a relevant condition, such as being more convenient, more effective, less toxic, having a broader range of activity, being more potent, having fewer side effects, or having other useful pharmacological properties that surpass any similar treatment that may be described in the prior art for the same active ingredient.

[0124] The present invention is illustrated by the following examples with reference to the accompanying figures, but is not limited thereto: Figure 1 shows in vivo azacitidine release from zinc oxide-coated particles suspended in 0.1% (w / w) polysorbate 20, 0.25% (w / w) carboxymethylcellulose sodium, and medium-chain triglycerides in phosphate-buffered saline (pH 7.4). [Examples]

[0125] Example 1 Coated azacitidine microparticles Azacitidine (MSN Labs, India) microparticle samples were prepared by jet milling. The average diameter of the jet-milled azacitidine particles was 4 μm, as determined by laser diffraction provided by the provider.

[0126] The powder was loaded into an ALD reactor (Picosun, SUNALE® R-series, Espoo, Finland) and 30 ALD cycles were performed at a reactor temperature of 50°C. Diethylzinc and water were used as precursors to form a first layer of zinc oxide. The thickness of the first layer was approximately 5 nm (estimated from the number of ALD cycles).

[0127] The powder was removed from the reactor and deaggregated by passing it through a polymer sieve with a mesh size of 20 μm using an ultrasonic sifter.

[0128] The resulting deaggregated powder was reloaded into the ALD reactor and subjected to 30 more ALD cycles, similar to the process before forming the second layer of zinc oxide. The powder was then extracted from the reactor, deaggregated by sonic shift as described above, reloaded to form the third layer, deaggregated, and then reloaded to form the final fourth layer.

[0129] To determine the drug load (i.e., the w / w% of azacitidine in the powder), HPLC (Prominence-i (Shimadzu, Japan)) was performed using a 4.6 × 250 mm, 3 μm particle, C18 column (Luna, Phenomenex, USA) with a diode array detector (Shimadzu, Japan) set to 210 nm. The nanoshell coating was dissolved in 1 M phosphoric acid, the slurry was diluted, and azacitidine was dissolved in water with 1 g / L sodium bisulfite. The mixture was then filtered (0.2 μm RC, Lab Logistics Group, Germany) and further analyzed by HPLC (n=2). The drug load was determined to be 74%.

[0130] Example 2 In vivo drug release of suspension Two samples were prepared according to the procedure described below.

[0131] A first sample containing azacitidine microparticles (prepared according to the process described in Example 1 above) was suspended in 0.1% (w / w) polysorbate 20 and 0.25% (w / w) carboxymethylcellulose sodium in phosphate-buffered saline (pH 7.4). A second sample containing azacitidine microparticles was suspended in medium-chain triglycerides (Crodamol GTCC).

[0132] The concentration of azacitidine particles in each formulation was adjusted to 13.5 mg / kg (rat body weight). Samples were prepared immediately before administration and injected within 10 minutes of preparation.

[0133] The vial containing the sample was gently tapped at least 10 times to remove any material that may have settled at the bottom. The vial was then vortexed and inverted for 30–60 seconds. To avoid sample sedimentation, all vials were inverted three times immediately before each injection.

[0134] Eight male Sprague Dawley rats were provided by Charles River Laboratories (UK), where the experiment was conducted.

[0135] Rats were randomly divided into two groups of four, with body weights ranging from 294 to 327 g on the day of administration. Hair in the intended administration area was shaved before injection, and the injection site was marked. Each animal was administered the drug by subcutaneous injection. In both groups, the formulation was drawn into a 1 mL BD syringe, and the dose was administered to the flank through a 20 G needle (BD Microlance). The injection site area was kept hairless throughout the study.

[0136] Blood samples (approximately 0.2 mL) were collected from the tail vein at the following time points: 0.5, 1, 3, 6, 12, 24, 48, 72, 120, and 168 hours, into tubes containing 5 μL of THU (25 μL / mL blood; tetrahydrouridine, a competitive cytidine deaminase inhibitor) stabilizer (1 mg / mL aqueous solution) and K2EDTA (dipotassium ethylenediaminetetraacetic acid). The collected blood samples were centrifuged (1500 g, 4°C for 10 minutes) to separate the plasma, which was then stored at -80°C until analysis.

[0137] Bioanalysis was performed by Lablytica Life Science AB (an external research institution based in Uppsala) to determine the concentration of azacitidine in heparin sodium rat plasma using LC-MSMS.

[0138] Figure 1 shows the release profiles from different samples. The dotted line shows the release profile of the sample suspended in 0.1% (w / w) polysorbate 20 and 0.25% (w / w) carboxymethylcellulose sodium in phosphate-buffered saline (pH 7.4), while the solid line shows the release profile of the sample suspended in medium-chain triglycerides.

[0139] Samples suspended in phosphate-buffered saline exhibit a higher initial burst release than samples suspended in medium-chain triglycerides.

Claims

1. A pharmaceutical or veterinary preparation in the form of a sterile injectable dosage form, (a) A plurality of particles having an average diameter based on weight, number, or volume, ranging in quantity from 1 μm to about 50 μm, wherein the particles comprise a solid core containing a biologically active agent, the core is coated with a zinc oxide coating, and the plurality of particles are suspended in (b) below. (b) an oily carrier system comprising a pharmaceutically acceptable or veterinarily acceptable oil, Pharmaceutical preparations or veterinary preparations.

2. The zinc oxide-coated particles are The formulation according to claim 1, comprising one or more separate layers surrounding the core, each of which comprises at least one separate zinc oxide coating.

3. The formulation according to claim 2, wherein the core essentially consists of a biologically active agent.

4. The aforementioned biologically active drugs include analgesics, anesthetics, anti-ADHD agents, appetite suppressants, antitoxic agents, antibacterial agents, antimicrobial agents, antifungal agents, antiviral agents, antiparasitic agents, antiprotozoal agents, anthelmintics, ectoparasitic agents, vaccines, anticancer agents, antimetabolites, alkylating agents, antitumor agents, topoisomerases, immunomodulators, immunostimulants, immunosuppressants, anabolic steroid solutions, anticoagulants, antiplatelet agents, anticonvulsants, antidementia agents, antidepressants, antitoxin agents, antihyperlipidemic agents, antigout agents, antimalarial agents, antimigraine agents, anti-inflammatory agents, antiparkinsonian agents, antipruritic agents, antipsoriasis agents, antiemetics, antiobesity agents, antiasthma agents, Antibiotics, antidiabetic drugs, antiepileptic drugs, antifibrinolytic drugs, antihemorrhagic drugs, antihistamines, antitussives, antihypertensive drugs, antimuscarinic drugs, antimycobacterial drugs, antioxidants, antipsychotics, antipyretics, antirheumatic drugs, antiarrhythmic drugs, anti-anxiety drugs, aphrodisiacs, cardiac glycosides, cardiac stimulants, enterogens, enteractogens, anesthetics, orexogenics, antithyroid drugs, anxiolytics, hypnotics, nerve relaxants, astringents, bacteriostatic drugs, beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, renin inhibitors, beta-adrenergic receptor blockers, hematologics Products, blood substitutes, bronchodilators, cardiac antiarrhythmic drugs, chemotherapy drugs, coagulants, corticosteroids, cough suppressants, diuretics, deliant agents, expectorants, fertilizers, sex hormones, mood stabilizers, mucolytics, neuroprotective agents, nootropics, neurotoxins, dopamine agonists, antiparkinson's disease drugs, free radical scavengers, growth factors, fibrates, bile acid blockades, desarcolytics, glucocorticoids, mineralocorticoids, hemostatic agents, hallucinogens, hypothalamic-pituitary hormones, immunosuppressants, laxatives, antidiarrheal agents, lipid regulators, muscle relaxants, parasympathomimetic agents, parathyroid calcitonin, Celenic, Sta Chin, stimulants, stimulants, decongestants, dietary minerals, biphosphonates, cough suppressants, ophthalmic drugs, ontology drugs, H1 antagonists, H2 antagonists, proton pump inhibitors, prostaglandins, radiopharmaceuticals, hormones, sedatives, anti-allergic drugs, appetite stimulants, steroids, sympathomimetic drugs, thrombolytics, thyroid drugs, vasodilators, xanthines, erectile dysfunction drugs, gastrointestinal drugs, histamine receptor antagonists, keratolytics, antianginal agents, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, leukotriene inhibitors, macrolides, NSAIDs, nutritional supplements, opioid analgesics,The formulation according to claim 3, selected from opioid antagonists, potassium channel activators, protease inhibitors, anti-osteoporosis drugs, cognitive enhancers, anti-urinary incontinence drugs, nutritional oils, anti-benign prostatic hyperplasia drugs, essential fatty acids, non-essential fatty acids, cytokines, peptide mimetic drugs, peptides, proteins, radiopharmaceuticals, anti-senile drugs, toxoids, serum, antibodies, nucleosides, nucleotides, vitamins, parts of genetic material, nucleic acids, or mixtures thereof.

5. The aforementioned biologically active drug is azacitidine, liraglutide, or lenalidomide. The formulation according to claim 4.

6. The formulation according to any one of claims 1 to 5, wherein two or more separate layers of zinc oxide coating are sequentially applied to the core.

7. The formulation according to claim 6, wherein 3 to 10 individual layers of zinc oxide coating are applied.

8. The formulation according to any one of claims 1 to 7, wherein the total thickness of the zinc oxide coating is approximately 0.5 nm to approximately 2 μm.

9. The formulation according to any one of claims 6 to 8, wherein the maximum thickness of each individual layer of the zinc oxide coating, including any other individual layers pre-applied to the core, is about 1 / 100th of the average diameter of the core based on its weight, number, or volume.

10. The formulation according to any one of claims 1 to 9, wherein the carrier system comprises one or more medium-chain triglycerides.

11. The aforementioned medium-chain triglycerides are C ６ ~C １２ The formulation according to claim 10, comprising an alkyl chain triglyceride.

12. A formulation according to any one of claims 1 to 11, in the form of an injectable dosage form.

13. The formulation according to claim 12, in the form of a liquid, sol, or gel that can be administered via a surgical administration device that forms a depot formulation.

14. The formulation according to any one of claims 1 to 11, wherein the zinc oxide coating is applied by atomic layer deposition.

15. A process for preparing the formulation according to any one of claims 1 to 14, wherein the coated particles are produced by applying a layer of the zinc oxide coating material to the core and / or a pre-coated core by atomic layer deposition.

16. (i) The solid core is coated with a first separate layer of the coating material, (ii) Next, the coated core from step (i) is subjected to a de-aggregation process step, (iii) Next, the de-aggregated coated core from step (ii) is coated with a second separate layer of the coating material. (iv) The process according to claim 15, wherein steps (ii) and (iii) are repeated to obtain the required number of individual layers.

17. The process according to claim 16, wherein the de-aggregation step performed during the application of the coating includes sieving.

18. The process according to claim 17, wherein the sieving includes ultrasonic sieving.

19. A process for preparing the formulation according to any one of claims 1 to 14, wherein the coated particles are mixed with the carrier system after coating.

20. An injectable and / or injectable dosage form comprising a reservoir and an injection or infusion means containing the formulation according to any one of claims 1 to 14.

21. The dosage form according to claim 20, which can be administered via a surgical administration device that forms a depot preparation.

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