WO2024256696A1 - Nouvelles compositions pharmaceutiques injectables à effet retard - Google Patents

Nouvelles compositions pharmaceutiques injectables à effet retard Download PDF

Info

Publication number
WO2024256696A1
WO2024256696A1 PCT/EP2024/066678 EP2024066678W WO2024256696A1 WO 2024256696 A1 WO2024256696 A1 WO 2024256696A1 EP 2024066678 W EP2024066678 W EP 2024066678W WO 2024256696 A1 WO2024256696 A1 WO 2024256696A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
particles
coated
coating
oxide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/066678
Other languages
English (en)
Inventor
Stefan GRUDÉN
Joel HELLRUP
Amanda BÅHLSTRÖM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanexa AB
Original Assignee
Nanexa AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanexa AB filed Critical Nanexa AB
Publication of WO2024256696A1 publication Critical patent/WO2024256696A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes

Definitions

  • This invention relates to new pharmaceutical formulations for use in the field of drug delivery.
  • a release profile is provided that shows minimal initial rapid release of active ingredient, that is a large concentration of drug in plasma shortly after administration. Such a 'burst' release will result in unwanted, high concentrations of active ingredient, and may be hazardous in the case of drugs that have a narrow therapeutic window or drugs that are toxic at high plasma concentrations.
  • an injectable suspension of an active ingredient it is also important that the size of the suspended particles is controlled so that they can be injected through a needle. If large, aggregated particles are present, they will not only block the needle, through which the suspension is to be injected, but also will not form a stable suspension within (i.e. they will instead tend to sink to the bottom of) the injection liquid.
  • Atomic layer deposition is a technique that is employed to deposit thin films comprising a variety of materials, including organic, biological, polymeric and, especially, inorganic materials, such as metal oxides, on solid substrates. It is an enabling technique for atomic and close-to-atomic scale manufacturing (ACSM) of materials, structures, devices and systems in versatile applications (see, for example, Zhang et al. Nanomanuf. Metro!. 2022, https://doi.org/10.1007/s41871-022-00136- 8). Based on its self-limiting characteristics, ALD can achieve atomic-level thickness that is only controlled by adjusting the number of growth cycles. Moreover, multilayers can be deposited, and the properties of each layer can be customized at the atomic level.
  • ALD Atomic layer deposition
  • ALD is used as a key technique for the manufacturing of, for example, next-generation semiconductors, or in atomic-level synthesis of advanced catalysts as well as in the precise fabrication of nanostructures, nanoclusters, and single atoms (see, for example, Zhang et a/, supra).
  • Film coatings are produced by alternating exposure of solid substrates within an ALD reactor chamber to vaporized reactants in the gas phase.
  • Substrates can be silicon wafers, granular materials or small particles (e.g. microparticles or nanoparticles).
  • the coated substrate is protected from chemical reactions (decomposition) and physical changes by the solid coating.
  • ALD can also potentially be used to control the rate of release of the substrate material within a solvent, which makes it of potential use in the formulation of active pharmaceutical ingredients.
  • a first precursor which can be metal-containing, is fed into an ALD reactor chamber (in a so called 'precursor pulse'), and forms an adsorbed atomic or molecular monolayer at the surface of the substrate.
  • first precursor is then purged from the reactor, and then a second precursor, such as water, is pulsed into the reactor. This reacts with the first precursor, resulting in the formation of a monolayer of e.g. metal oxide on the substrate surface.
  • a subsequent purging pulse is followed by a further pulse of the first precursor, and thus the start of a new cycle of the same events (a so called 'ALD cycle').
  • the thickness of the film coating is controlled by inter alia the number of ALD cycles that are conducted.
  • the particles were then loaded back into the reactor and the steps of ALD coating of the powder, and deagglomerating the powder were repeated 3 times, to a total of 4 series of cycles. This process has been found to allow for the formation of coated particles that are, to a large extent, free of pinholes (see also, Hellrup et al., Int. J. Pharm., 529, 116 (2017)).
  • thermogel-forming excipient within the aqueous medium in essentially the same aqueous suspension of coated drug microparticles.
  • a formulation comprising: (a) a plurality of particles having a weight-, number-, or volume-based mean diameter that is between about 10 nm and about 700 pm, which particles comprise solid cores coated with at least one coating material; (b) a pharmaceutically-acceptable aqueous carrier system, in which said coated particles are suspended; and
  • thermogelling agent which formulations are hereinafter referred to as 'the formulations of the invention'.
  • the term 'solid' will be well understood by those skilled in the art to include any form of matter that retains its shape and density when not confined, and/or in which molecules are generally compressed as tightly as the repulsive forces among them will allow.
  • the solid cores have at least a solid exterior surface onto which a layer of coating material can be deposited.
  • the interior of the solid cores may be also solid or may instead be hollow. For example, if the particles are spray dried before they are placed into the reactor vessel, they may be hollow due to the spray drying technique.
  • Cores may in the alternative comprise agglomerates of smaller 'primary' particles, i.e. secondary particles of a size range defined herein, which are subsequently coated as described herein.
  • the extended-release of the biologically-active agent following injection is obtained by encapsulating small, injectable (e.g. micro) particles comprising said biologically-active agent with at least one coating material applied by way of a gas phase deposition technique.
  • Formulations of the invention are preferably pharmaceutical or veterinary formulations, in which case the formulations may comprise a pharmacologically-or veterinarily- effective amount of a biologically-active agent.
  • the solid cores of the formulation of the invention preferably comprise said biologically- active agent.
  • the term 'biologically-active agent' may hereinafter be referred to interchangeably as a 'drug', and 'active pharmaceutical ingredient (API)' and/or an 'active ingredient', and also includes biopharmaceuticals and/or biologies.
  • Biologically- active agents can also comprise a mixture of two or more different APIs, either as different API particles or as particles comprising more than one API.
  • the solid cores may consist essentially of biologically-active agent, by which we include that the aforementioned solid core is essentially comprised only of biologically-active agent(s), i.e. it is free from non-biologically active substances, such as excipients, carriers and the like vide infra). This means that the core may comprise less than about 5%, such as less than about 3%, including less than about 2%, e.g. less than about 1% of such other excipients and/or other active substances.
  • solid cores comprising biologically-active agent may include such an agent in admixture with one or more pharmaceutical ingredients, such as one or more pharmaceutically-acceptable excipients, such as adjuvants, diluents or carriers, and/or may include other biologically-active ingredients.
  • Biologically-active agents may thus be presented in combination (e.g. in admixture or as a complex) with another active substance.
  • Biologically-active agents may be presented in a crystalline, a part-crystalline and/or an amorphous state. Biologically-active agents may further comprise any substance that is in the solid state, or which may be converted into the solid state, at about room temperature (e.g. about 18°C) and about atmospheric pressure, irrespective of the physical form. Such agents (and optionally other pharmaceutical ingredients as mentioned hereinbefore) should also remain in the form of a solid whilst being coated in the gas phase deposition (e.g. ALD) reactor and also should not decompose physically or chemically to an appreciable degree (i.e. no more than about 10% w/w) whilst being coated, or after having been covered by at least one of the aforementioned layers of coating materials.
  • gas phase deposition e.g. ALD
  • biologically active agent' or similar and/or related expressions, generally refer(s) to any agent, or drug, capable of producing some sort of physiological effect (whether in a therapeutic or prophylactic capacity against a particular disease state or condition) in a living subject, including, in particular, mammalian and especially human subjects (patients).
  • Biologically-active agents may, for example, be selected from an analgesic, an anaesthetic, an anti-ADHD agent, an anorectic agent, an antiaddictive 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 antineoplastic agent, a topoisomerase inhibitor, an immunomodulator, an immunostimulant, an immunosuppressant, an anabolic steroid, an anticoagulant agent, an antiplatelet agent, an anticonvulsant agent, an antidementia agent, an antidepressant agent, an antidote, an antihyperlipidemic agent, an antigout agent, an antimalarial, an antimigraine agent, an antiparkinson agent, an antipruritic agent,
  • 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 as follows: lepirudin, cetuximab, dornase alfa, denileukin diftitox, etanercept, bivalirudin, leuprolide, alteplase, interferon alfa-nl, darbepoetin alfa, reteplase, epoetin alfa, salmon calcitonin, interferon alfa-n3, pegfilgrastim, sargramostim, secretin, peginterferon alfa-2b, asparaginase, thyrotropin alfa, antihemophilic factor, anakinra, gramicidin D, intravenous immunoglobulin, anistreplase, insulin (regular), tenecteplase, menotropins, interferon gamma-lb, interferon alfa-2a (recombinant), coagulation factor Vil
  • Non-limiting examples of drugs which may be used according to the present invention are all-trans retinoic acid (tretinoin), alprazolam, allopurinol, amiodarone, amlodipine, asparaginase, astemizole, atenolol, azathioprine, azelatine, beclomethasone, bendamustine, bleomycin, budesonide, buprenorphine, butalbital, capecitabine, carbamazepine, carbidopa, carboplatin, cefotaxime, cephalexin, chlorambucil, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clonazepam, clozapine, cyclophosphamide, cyclosporin, cytarabine, dacarbazine, dactinomycin, daunorubicin, diazepam
  • Formulations of the invention may comprise benzodiazipines, such as alprazolam, chlordiazepoxide, clobazam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, quazepam, temazepam, triazolam and pharmaceutically- acceptable salts of any of these.
  • Anaesthetics that may also be employed in the formulations of the invention may be local or general.
  • Local anaesthetics that may be mentioned include amylocaine, ambucaine, articaine, benzocaine, benzonatate, bupivacaine, butacaine, butanilicaine, chloroprocaine, cinchocaine, cocaine, cyclomethycaine, dibucaine, diperodon, dimethocaine, eucaine, etidocaine, hexylcaine, fomocaine, fotocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine, meta butoxycaine, nitracaine, orthocaine, oxetacaine, oxybu procaine, paraethoxycaine, phenacaine, piperocaine, piridocaine, pramocaine, prilocaine, primacaine, procaine, procainamide, proparacaine, propoxycaine, pyrrocaine, qui
  • Psychiatric drugs may also be employed in the formulations of the invention.
  • Psychiatric drugs that may be mentioned include 5-HTP, acamprosate, agomelatine, alimemazine, amfetamine, dexamfetamine, amisulpride, amitriptyline, amobarbital, amobarbital/secobarbital, amoxapine, amphetamine(s), aripiprazole, asenapine, atomoxetine, baclofen, benperidol, bromperidol, bupropion, buspirone, butobarbital, carbamazepine, chloral hydrate, chlorpromazine, chlorprothixene, citalopram, clomethiazole, clomipramine, clonidine, clozapine, cyclobarbital/diazepam, cyproheptadine, cytisine, desipramine, desvenlafaxine,
  • Opioid analgesics that may be employed in formulations of the 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.
  • Opioid antagonists that may be employed in formulations of the invention include naloxone, nalorphine, niconalorphine, diprenorphine, levallorphan, samidorphan, nalodeine, alvimopan, methylnaltrexone, naloxegol, 60-naltrexol, axelopran, bevenopran, methylsamidorphan, naldemedine, preferably nalmefene and, especially, naltrexone, as well as pharmaceutically-acceptable salts of any of these.
  • Anticancer agents that may be included in formulations of the invention include the following: actinomycin, afatinib, all-trans retinoic acid, amsakrin, anagrelid, arseniktrioxid, axitinib , azacitidine, azathioprine, bendamustine, bexaroten, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, chlorambucil, cladribine, clofarabine, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, erlotinib, estramustin, etoposide, everolimus, fludarabine
  • Such compounds may be used in any one of the following cancers: adenoid cystic carcinoma, adrenal gland cancer, amyloidosis, anal cancer, ataxia-telangiectasia, atypical mole syndrome, basal cell carcinoma, bile duct cancer, Birt-Hogg Dube, tube syndrome, bladder cancer, bone cancer, brain tumor, breast cancer (including breast cancer in men), carcinoid tumor, 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 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 lymphom
  • myelodysplastic syndrome and sub-types such as acute myeloid leukemia, refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myeloid (myelomonocytic) leukemia.
  • Osteporosis drugs that may be mentioned include the bisphosphonates, such as clodronate, ibandronate, pamidronate, zoledronic acid, etidronate, alendronate, risedronate, tiludronate, bondronate and derivatives (e.g. acid derivatives of these compounds).
  • bisphosphonates such as clodronate, ibandronate, pamidronate, zoledronic acid, etidronate, alendronate, risedronate, tiludronate, bondronate and derivatives (e.g. acid derivatives of these compounds).
  • drugs that may be mentioned for use in formulations of the invention include immunomodulatory imide drugs, such as thalidomide and analogues thereof, such as pomalidomide, lenalidomide and apremilast, and pharmaceutically-acceptable salts of any of these.
  • immunomodulatory imide drugs such as thalidomide and analogues thereof, such as pomalidomide, lenalidomide and apremilast
  • drugs that many be mentioned include angiotensin II receptor type 2 agonists, such as Compound 21 (C21; 3-[4-(lH-imidazol-l-ylmethyl)phenyl]- 5-(2-methylpropyl)thiophene-2-[(N-butyloxylcarbamate)-sulphonamide] and pharmaceutically-acceptable (e.g. sodium) salts thereof.
  • Preferred anticancer agents include lenalidomide, which is useful in the treatment of multiple myeloma and anaemia in low to intermediate risk myelodysplastic syndrome and, especially, azacitidine, which is useful in the treatment of certain subtypes of myelodysplastic syndrome.
  • cisplatin which is a chemotherapeutic agent useful in numerous cancers, including testicular, cervical, ovarian cancer, bladder cancer, lung, esophageal and head and neck cancers, as well as brain tumors, neuroblastoma and mesothelioma.
  • liraglutide which is useful in the treatment of type 2 diabetes mellitus and prevention of cardiovascular complications associated with diabetes.
  • Particular drugs that may be mentioned in this regard include the glucagon-like peptide-1 receptor agonists, such as exenatide, lixisenatide, albiglutide, dulaglutide, more preferably tirzepatide and semaglutide, and especially liraglutide.
  • formulations as described herein may also comprise, instead of (or in addition to) biologically-active agents, diagnostic agents (i.e. agents with no direct therapeutic activity perse, but which may be used in the diagnosis of a condition, such as a contrast agents or contrast media for bioimaging).
  • diagnostic agents i.e. agents with no direct therapeutic activity perse, but which may be used in the diagnosis of a condition, such as a contrast agents or contrast media for bioimaging.
  • Formulations of the invention may include one or more of any of the aforementioned biologically active agents, particularly in view of the fact that any component, or combination of components, of a formulation of the invention (including the coatings or carrier system) may cause an inflammatory response after injection, e.g. subcutaneously.
  • biologically active agents that may in particular be mentioned include those in which the biologically active agent may, on its own or in the form of a formulation of the invention, produce an inflammatory response when administered to a patient, or may be expected to produce such a response.
  • biologically active agents that may in particular be mentioned for use in formulations of the invention include, for example, antineoplastic agents, topoisomerase inhibitors, immunomodulators (such as thalidomide, pomalidomide, lenalidomide and apremilast), immunostimulants, immunosuppressants, chemotherapeutics, growth factors, vasodilators and radiopharmaceuticals.
  • immunomodulators such as thalidomide, pomalidomide, lenalidomide and apremilast
  • immunostimulants such as thalidomide, pomalidomide, lenalidomide and apremilast
  • immunostimulants such as thalidomide, pomalidomide, lenalidomide and apremilast
  • immunosuppressants such as thalidomide, pomalidomide, lenalidomide and apremilast
  • chemotherapeutics such as chemotherapeutics, growth factors, vasod
  • Particular biologically active agents include any one or more of the specific anticancer agents listed above and, in particular, actinomycin, azacitidine, azathioprine, bendamustine, bexaroten, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, capecitabine, carboplatin, chlorambucil, cladribine, clofarabine, cytarabine, dabrafenib, dacarbazine, dactinomycin, daunorubicin, decitabine, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, estramustin, etoposide, everolimus, fludarabine, fluorouracil, guadecitabine, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan
  • biologically active agents include certain cytokines, proteins, and vaccines, as well as therapeutic peptides/proteins such as daratumumab and isatuximab.
  • drugs that may be mentioned in this regard include bendamustine, bleomycin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cyclosporin, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, everolimus, fluorouracil, gemcitabine, ifosfamide, irinotecan, mercaptopurine, mesna, methotrexate, midazolam, mitomycin, oxaliplatin, paclitaxel, procarbazine, temsirolimus, thioguanine, vinblastine, vincristine, vinorelbine or pharmaceutically acceptable salts of any of these.
  • Non-biologically active adjuvants, diluents and carriers that may be employed in cores to be coated in accordance with the relevant aspects of the invention may 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, a protein or portions of genetic material or the like, for example as described generally and/or the specific peptides/proteins described hereinbefore including vaccines. Embedding complex macromolecules in excipients in this way will often result in larger cores for coating, and therefore larger coated particles.
  • a complex macromolecule such as a peptide, a protein or portions of genetic material or the like, for example as described generally and/or the specific peptides/proteins described hereinbefore including vaccines.
  • the cores of the formulations of the invention comprise a biologically-active agent. Whether the cores do or do not comprise a biologically-active agent, the cores may comprise and/or consist essentially of one or more non- biologically active adjuvants, diluents and carriers, including emollients, and/or other excipients with a functional property, such as a buffering agent and/or a pH modifying agent (e.g. citric acid).
  • a buffering agent e.g. citric acid
  • the cores as described hereinbefore are provided in the form of nanoparticles or, more preferably, microparticles.
  • Preferred weight-, number-, or volume- based mean diameters are between about 50 nm (e.g. about 100 nm, such as about 250 nm) and about 30 pm, for example between about 500 nm and about 100 pm, more particularly between about 1 pm (such as about 5 pm, including about 7 pm or about 9 pm) and up to about 50 pm, such as about 25 pm, e.g. about 20 pm.
  • the term 'weight based mean diameter' will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by weight, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the weight fraction, as obtained by e.g. sieving (e.g. wet sieving).
  • the term 'number based mean diameter' will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by number, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the number fraction, as measured by e.g. microscopy.
  • volume based mean diameter will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by volume, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the volume fraction, as measured by e.g. laser diffraction.
  • the person skilled in the art will also understand there are other suitable ways of expressing mean diameters, such as area based mean diameters, and that these other expressions of mean diameter are interchangeable with those used herein.
  • Other instruments that are well known in the field may be employed to measure particle size, such as equipment sold by e.g. Malvern Instruments, Ltd (Worcestershire, UK) and Shimadzu (Kyoto, Japan).
  • Particles may be spherical, that is they possess an aspect ratio smaller than about 20, more preferably less than about 10, such as less than about 4, and especially less than about 2, and/or may possess a variation in radii (measured from the centre of gravity to the particle surface) in at least about 90% of the particles that is no more than about 50% of the average value, such as no more than about 30% of that value, for example no more than about 20% of that value.
  • the coating of particles on any shape is also possible in accordance with the invention. For example, irregular shaped (e.g. 'raisin'-shaped), needle-shaped, flake-shaped or cuboid-shaped particles may be coated.
  • the size may be indicated as the size of a corresponding spherical particle of e.g. the same weight, volume or surface area.
  • Hollow particles, as well as particles having pores, crevices etc., such as fibrous or 'tangled' particles may also be coated in accordance with the invention.
  • Particles may be obtained in a form in which they are suitable to be coated or be obtained in that form, for example by particle size reduction processes (e.g. crushing, cutting, milling or grinding) to a specified weight based mean diameter (as hereinbefore defined), for example by wet grinding, dry grinding, air jet-milling (including cryogenic micronization), ball milling, such as planetary ball milling, as well as making use of end-runner mills, roller mills, vibration mills, hammer mills, roller mill, fluid energy mills, pin mills, etc.
  • particle size reduction processes e.g. crushing, cutting, milling or grinding
  • a specified weight based mean diameter as hereinbefore defined
  • wet grinding dry grinding
  • air jet-milling including cryogenic micronization
  • ball milling such as planetary ball milling, as well as making use of end-runner mills, roller mills, vibration mills, hammer mills, roller mill, fluid energy mills, pin mills, etc.
  • particles may be prepared directly to a suitable size and shape, for example by spray-drying, freeze-drying, spray-freeze- drying, vacuum-drying, precipitation, including the use of supercritical fluids or other top-down methods (i.e. reducing the size of large particles, by e.g. grinding, etc.), or bottom-up methods (i.e. increasing the size of small particles, by e.g. sol-gel techniques, crystallization, etc.).
  • Nanoparticles may alternatively be made by well- known techniques, such as gas condensation, attrition, chemical precipitation, ion implantation, pyrolysis, hydrothermal synthesis, etc.
  • cores may then be deagglomerated by grinding, screening, milling and/or dry sonication.
  • cores may be treated to remove any volatile materials that may be absorbed onto its surface, e.g. by exposing the particle to vacuum and/or elevated temperature.
  • Surfaces of cores may be chemically activated prior to applying the first layer of coating material, e.g. by treatment with hydrogen peroxide, ozone, free radical-containing reactants or by applying a plasma treatment, in order to create free oxygen radicals at the surface of the core.
  • This in turn may produce favourable adsorption/nucleation sites on the cores for (e.g. ALD) precursors.
  • Preferred methods of applying the coating(s) to the cores e.g.
  • those comprising biologically-active agents include gas phase techniques, such as ALD or related technologies, such as atomic layer epitaxy (ALE), molecular layer deposition (MLD; a similar technique to ALD with the difference that molecules (commonly organic molecules) are deposited in each pulse instead of atoms), molecular layer epitaxy (MLE), chemical vapor deposition (CVD), atomic layer CVD, molecular layer CVD, physical vapor deposition (PVD), sputtering PVD, reactive sputtering PVD, evaporation PVD and binary reaction sequence chemistry.
  • ALD is the preferred method of coating according to the invention.
  • Coating materials that may be applied to said cores may be pharmaceutically- acceptable, in that they should be essentially non-toxic.
  • Coating materials may comprise organic or polymeric materials, such as a polyamide, a polyimide, a polyurea, a polyurethane, a polythiourea, a polyester or a polyimine. Coating materials may also comprise hybrid materials (as between organic and inorganic materials), including materials that are a combination between a metal, or another element, and an alcohol, a carboxylic acid, an amine or a nitrile. Such additional organic, polymeric and/or hybrid organic-inorganic coatings are preferably applied using a coating technique that comprises MLD as described hereinbefore.
  • Such polymeric coatings can be polyimides, polyazomethines, polyureas, polyamides, nylons, metalcones, alucones, titanicones, zincones, metal-organic framework polymers, oxycarbides and hybrid nanolaminates.
  • the coating materials comprise inorganic materials.
  • Inorganic coating materials may comprise one or more metals or metalloids, or may comprise one or more metal-containing, or metalloid-containing, compounds, such as metal, or metalloid, oxides, nitrides, sulphides, selenides, carbonates, and/or other ternary compounds, etc.
  • Metal, and metalloid, hydroxides and, especially, oxides are preferred, especially metal oxides.
  • Metals that may be mentioned include alkali metals, alkaline earth metals, noble metals, transition metals, post-transition metals, lanthanides, etc.
  • Metal and metalloids that may be mentioned include aluminium, titanium, magnesium, iron, gallium, zinc, zirconium, niobium, hafnium, tantalum, lanthanum, and/or silicon; more preferably aluminium, titanium, magnesium, iron, gallium, zinc, zirconium, and/or silicon; especially aluminium, silicon, titanium and/or zinc.
  • formulations of the invention may comprise two or more discrete layers of (e.g. inorganic) coating materials, the nature and chemical composition(s) of those layers may differ from layer to layer.
  • Individual layers may also comprise a mixture of two or more inorganic materials, such as metal oxides or metalloid oxides, and/or may comprise multiple layers or composites of different inorganic or organic materials, to modify the properties of the layer.
  • inorganic materials such as metal oxides or metalloid oxides
  • Coating materials that may be mentioned include those comprising aluminium oxide (AI2O3), titanium dioxide (TiOz), iron oxides (Fe x O y , e.g. FeO and/or FezOs and/or FesC ), gallium oxide (GazCh), magnesium oxide (MgO), zinc oxide (ZnO), niobium oxide (NbzOs), hafnium oxide (HfOz), tantalum oxide (TazOs), lanthanum oxide (LazOs), zirconium dioxide (ZrOz) and/or silicon dioxide (SiOz).
  • Preferred coating materials include aluminium oxide, titanium dioxide, iron oxides, gallium oxide, magnesium oxide, zinc oxide, zirconium dioxide and silicon dioxide. More preferred coating materials include iron oxide, titanium dioxide, zinc sulphide, more preferably zinc oxide, silicon dioxide and/or aluminium oxide.
  • Layers of coating materials (on an individual or a collective basis) in coated cores of said relevant formulations of the invention may consist essentially (e.g. may be greater than about 80%, such as greater than about, 90%, e.g. about 95%, such as about 98%) of iron oxides, titanium dioxide, or more preferably zinc oxide, silicon oxide and/or aluminium oxide.
  • the processes described herein are particularly useful when the coating material(s) that is/are applied to the cores comprise zinc oxide, silicon dioxide and/or aluminium oxide.
  • the inorganic coating material comprises zinc oxide, and, when is does comprise zinc oxide, it is more particularly a mixture of:
  • the atomic ratio ((i) : (ii)) is between at least about 1 : 10 (e.g. about 1 :6) and up to and including about 10: 1 (e.g. about 6: 1). It is preferred that the atomic ratio ((i):(ii)) is between at least about 1 : 1 and up to and including about 6: 1.
  • the coating comprising a mixture of zinc oxide and one or more other metal and/or metalloid oxides is referred to hereinafter as a 'mixed oxide' coating or coating material(s).
  • the biologically active agent-containing cores may thus be coated, at least in part, with a coating material that comprises a mixture of zinc oxide, and one or more other metal and/or metalloid oxides, at an atomic ratio of zinc oxide to the other oxide(s) that is at least about 1 : 10 (e.g. at least about 1 :6, including at least about 1:4, such as at least about 1:2), preferably at least about 1 : 1 (e.g. at least about 1.5: 1, such as at least about 2: 1), including at least about 2.25: 1, such as at least about 2.5: 1 (e.g. at least about 3.25: 1 or least about 2.75: 1 (including 3: 1)), and is up to (i.e. no more than) and including about 10: 1, such as about 6: 1, including up to about 5.5: 1, or up to about 5: 1, such as up to about 4.5: 1, including up to about 4: 1 (e.g. up to about 3.75: 1).
  • a coating material that comprises a mixture of zinc oxide, and one or
  • the first of the consecutive reactions will involve some functional group or free electron pairs or radicals at the surface to be coated, such as a hydroxy group (-OH) or a primary or secondary amino group (-NH2 or -NHR where R e.g. is an aliphatic group, such as an alkyl group).
  • the individual reactions are advantageously carried out separately and under conditions such that all excess reagents and reaction products are essentially removed before conducting the subsequent reaction.
  • the above-described mixed oxide coating may be prepared by feeding a first, zinc-, other metal- or metalloid-containing precursor into an ALD reactor chamber (in a so called 'precursor pulse') to form the adsorbed atomic or molecular zinc-, other metal- or metalloid-containing monolayer at the surface of the particle.
  • a second precursor e.g. water
  • a subsequent purging pulse is followed by a further pulse of the first precursor, and thus the start of a new cycle of the same events, which is an ALD cycle.
  • an organic, polymeric and/or hybrid organic-inorganic coating may be prepared by using an MLD precursor, for example an organic molecule comprising a difunctional group, such as a diol, diamine, diisocyanate, dichloride, dialdehyde.
  • an MLD precursor for example an organic molecule comprising a difunctional group, such as a diol, diamine, diisocyanate, dichloride, dialdehyde.
  • a mixed oxide coating with an atomic ratio of (for example) between about 1: 1 and up to and including about 6: 1 of zinc oxide relative to the one or more other metal and/or metalloid oxides the skilled person will appreciate that for every one ALD cycle (i.e. monolayer) of the other oxide(s), between about 1 and about 6 ALD cycles of zinc oxide must also be deposited.
  • 3 zinc-containing precursor pulses may each be followed by second precursor pulses, forming 3 monolayers of zinc oxide, which will then be followed by 1 pulse of the other metal and/or metalloid-containing precursor followed by second precursor pulse, forming 1 monolayer of oxide of the other metal and/or metalloid.
  • 6 monolayers of zinc oxide may be followed by 2 monolayers of the other oxide, or any other combination so as to provide an overall atomic ratio of about 3: 1.
  • the order of pulses to produce the relevant oxides is not critical, provided that the resultant atomic ratio is in the relevant range in the end.
  • the other metal or metalloid oxide material preferably comprises one or other or both of aluminium oxide (AI2O3) and/or silicon dioxide (SiOz).
  • one or more coatings comprises zinc oxide, or a mixed oxide layer comprising zinc oxide in one or more of the above-mentioned ratios
  • the single metal and/or metalloid oxide may include iron oxide, titanium dioxide, zinc sulphide, zinc oxide, silicon dioxide and/or aluminium oxide, preferably aluminium oxide, but is preferably different to zinc oxide, such as silicon dioxide or, preferably, aluminium oxide.
  • the priming layer may be applied to the core prior to application of at least one coating material comprising zinc oxide, or a mixture of zinc oxide and one or more other metal and/or metalloid oxide.
  • the primer layer may be applied to core particles immediately before any subsequent coating step(s) of e.g. mixed metal oxide, which may take place before or after carrying out a deagglomeration step, either internally or externally to the reactor, as described hereinafter.
  • the primer layer is itself a discrete, separate layer as defined herein.
  • a method of preparing of plurality of coated particles in accordance with the invention wherein the coated particles are made by applying precursors of at least two metal and/or metal oxides forming a mixed oxide on the solid cores, and/or previously-coated solid cores, by a gas phase deposition technique.
  • Precursors for forming a metal oxide or a metalloid oxide often include an oxygen precursor, such as water, oxygen, ozone and/or hydrogen peroxide; and a metal and/or metalloid compound, typically an organometal compound or an organometalloid compound.
  • Non-limiting examples of precursors are as follows: Precursors for zinc oxide may be water and diCi-Csalkylzinc, such as diethylzinc. Precursors for aluminium oxide may be water and triCi-Csalkylaluminium, such as trimethylaluminium. Precursors for silicon oxide (silica) may be water as the oxygen precursor and silanes, alkylsilanes, aminosilanes, and orthosilicic acid tetraethyl ester. Precursors for iron oxide includes oxygen, ozone and water as the oxygen precursor; and di Ci-Csalkyl-iron, dicyclopropyl-iron, and FeCh. It will be appreciated that the person skilled in the art is aware of what precursors are suitable for the purpose as disclosed herein.
  • layers of coating materials may be applied at process temperatures from about 20°C to about 800°C, or from about 40°C to about 200°C, e.g. from about 40°C to about 150°C, such as from about 50°C to about 100°C.
  • the optimal process temperature depends on the reactivity of the precursors and/or substances (including biologically-active agents) that are employed in the core and/or melting point of the core substance(s). It is preferred that a lower temperature, such as from about 30°C to about 100°C is employed.
  • a temperature from about 20°C to about 80°C is employed, such as from about 30°C to about 70°C, such as from about 40°C to about 60°C, such as about 50°C.
  • coatings comprising zinc oxide are applied using ALD at a lower temperature, such as from about 50°C to about 100°C, unlike other coating materials, such as aluminium oxide, titanium oxide and silicon oxide, that form amorphous layers, the coating materials are largely crystalline in their nature.
  • a mixed oxide coating as described herein may be made by making a mixed oxide coating as described herein.
  • a mixed oxide coating as described herein that is predominantly, but not entirely, comprised of zinc oxide, we have been able to coat active ingredients with coatings that appear to be essentially amorphous, or a composite between crystalline and amorphous material and/or in which ingress of injection vehicles such as water may be reduced.
  • the presence of the aforementioned perceived interfaces may be reduced, or avoided altogether, by employing the mixed oxide aspect of the invention, in either a heterogeneous manner (in which the other oxide is 'filling in' gaps formed by the interfaces), or in a homogeneous manner (in which a true composite of mixed oxide materials is formed during deposition, in a manner where the interfaces are potentially avoided in the first place).
  • the gas phase deposition reactor chamber used may optionally, and/or preferably, be a stationary gas phase deposition reactor chamber.
  • 'stationary' in the context of gas phase deposition reactor chambers, will be understood to mean that the reactor chamber remains stationary while in use to perform a gas phase deposition technique, excluding negligible movements and/or vibrations such as those caused by associated machinery for example.
  • a so-called 'stop-flow' process may be employed.
  • the first precursor may be allowed to contact the cores in the reactor chamber for a pre-determined period of time (which may be considered as a 'soaking' time).
  • a pre-determined period of time there is preferably a substantial absence of pumping that may result in flow of gases and/or a substantial absence of mechanical agitation of the cores.
  • the employment of the stop-flow process may increase coating uniformity by allowing each gas to diffuse conformally in high aspect-ratio substrates, such as powders.
  • the benefits may be even more pronounced when using precursors with slow reactivity as more time is given for the precursor to react on the surface. This may be evident especially when depositing mixed oxide coatings according to the invention.
  • a zinc-containing precursor such as diethylzinc (DEZ)
  • DEZ diethylzinc
  • TMA trimethylaluminum
  • a 'multi-pulse' technique may also be employed to feed the first precursor, the second precursor or both precursors to the reactor chamber.
  • the respective precursor may be fed into the reactor chamber as a plurality of 'sub-pulses', each lasting a short period of time such as 1 second up to about a minute (depending on the size and the nature of the gas phase deposition reactor), rather than as one continuous pulse.
  • the precursor may be allowed to contact the cores in the reactor chamber for the pre-determined period of time, for example from about 1 to 500 seconds, about 2 to 250 seconds, about 3 to 100 seconds, about 4 to 50 seconds, or about 5 to 10 seconds, for example 9 seconds, after each sub-pulse.
  • this time could be extended up to several minutes (e.g. up to about 30 minutes).
  • the introduction of a sub-pulse followed by a period of soaking time may be repeated a pre-determined number of times, such as between about 5 to 1000 times, about 10 to 250 times, or about 20 to 50 times in a single step.
  • more than one separate layers of coating material are applied (that is 'separately applied') to the solid cores comprising the biologically active agent sequentially.
  • the cores may be coated with one or more separate, discrete layers, at least one of which may comprise at least one separate coating comprising zinc oxide.
  • more than one separate, discrete layer, coating or shell are applied (that is 'separately applied') to the solid cores comprising biologically-active agent sequentially. It is further preferred that all, or most, of said separate layers, coatings or shells comprise zinc oxide.
  • a further embodiment that may be mentioned in accordance with the invention is one in which at least the outermost layer preferably comprises zinc oxide.
  • each layer may be formed by more than one (e.g. a plurality or a set of) ALD cycles as described herein, each cycle producing a monolayer of, for example metal (e.g.
  • 'gas-phase deposition (e.g. ALD) cycles' may be repeated several times to provide a 'gas-phase deposition (e.g. ALD) set' of cycles, which may consist of e.g.
  • the coated core may be subjected to some form of deagglomeration process, which is followed by a further set of cycles to provide discrete layers of coating material(s).
  • This process may be repeated as many times as is desired and, accordingly, the number of discrete layers of coating material(s) produced by sets of cycles that is in a final coating corresponds to the number of these intermittent deagglomeration steps with the option of a final mechanical deagglomeration being conducted prior to the application of a final layer (set of cycles) of coating material.
  • the particles of the formulation may have between 1 and about 100 discrete layers of mixture of oxides (and, if appropriate, of other coating materials as described hereinafter), for example between 2 and about 50 discrete layers, such as between 3 and about 10 discrete layers, for example between 3 and 6 discrete layers.
  • 'disaggregation' and 'deagglomeration' are used interchangeably when referring to the coated particles, and disaggregating coated particles aggregates is preferably done by way of a mechanical sieving technique.
  • Coated cores may be subjected to the aforementioned deagglomeration process internally, without being removed from said apparatus by way of a continuous process.
  • Such a process will involve forcing solid product mass formed by coating said cores through a sieve that is located within the reactor, and is configured to deagglomerate any particle aggregates upon forcing of the coated cores by means of a forcing means applied within said reactor, prior to being subjected to a second and/or a further coating. This process is continued for as many times as is required and/or appropriate prior to the application of the final coating as described herein.
  • coated cores may be removed from the coating apparatus, such as the ALD reactor, and thereafter subjected to an external deagglomeration step, for example as described in international patent application WO 2014/187995.
  • Such an external deagglomeration step may comprise agitation, such as sonication in the wet or dry state, or preferably may comprise subjecting the resultant solid product mass that has been discharged from the reactor to sieving, e.g. by forcing it through a sieve or mesh in order to deagglomerate the particles, for example as described hereinafter, prior to placing the particles back into the coating apparatus for the next coating step. Again, this process may be continued for as many times as is required and/or appropriate prior to the application of the final coating.
  • deagglomeration may alternatively be effected (additionally and/or instead of the abovementioned processes) by way of subjecting the coated particles in the wet or dry state to one or more of nozzle aerosol generation, milling, grinding, stirring, high sheer mixing and/or homogenization. If the step(s) of deagglomeration is/are carried out on particles in the wet state, the deagglomerated particles should be dried (as hereinbefore described in relation to cores) prior to the next coating step.
  • the deagglomeration step(s) comprise one or more sieving step(s), which may comprise jet sieving, manual sieving, vibratory sieve shaking, horizontal sieve shaking, tap sieving, or (preferably) sonic sifting as described hereinafter, or a like process, including any combination of these sieving steps.
  • sieving step(s) may comprise jet sieving, manual sieving, vibratory sieve shaking, horizontal sieve shaking, tap sieving, or (preferably) sonic sifting as described hereinafter, or a like process, including any combination of these sieving steps.
  • suitable sonic sifters include Advantech Manufacturing, Endecott and Tsutsui.
  • Vibrational sieving techniques may involve a means of vibrationally forcing the solid product mass formed by coating said cores through a sieve that is located internally or (preferably) externally to (i.e. outside of) the reactor, and is configured to deagglomerate any particle aggregates upon said vibrational forcing of the coated cores, prior to being subjected to a second and/or a further layer of coating material. This process is repeated as many times as is required and/or appropriate prior to the application of a final layer of coating material.
  • Vibrational forcing means comprises a vibration motor which is coupled to a sieve.
  • the vibration motor is configured to vibrate and/or gyrate when an electrical power is supplied to it.
  • the vibration motor may be a piezoelectric vibration motor comprising a piezoelectric material which changes shape when an electric field is applied, as a consequence of the converse piezoelectric effect. The changes in shape of the piezoelectric material cause acoustic or ultrasonic vibrations of the piezoelectric vibration motor.
  • the vibration motor may alternatively be an eccentric rotating mass (ERM) vibration motor comprising a mass which is rotated when electrical power is supplied to the motor.
  • the mass is eccentric from the axis of rotation, causing the motor to be unbalanced and vibrate and/or gyrate due to the rotation of the mass.
  • the ERM vibration motor may comprise a plurality of masses positioned at different locations relative to the motor.
  • the ERM vibration motor may comprise a top mass and a bottom mass each positioned at opposite ends of the motor.
  • the vibration motor is coupled to the sieve in a manner in which vibrations and/or gyrations of the motor when electrical power is supplied to it are transferred to the sieve.
  • the sieve and the vibration motor may be suspended from a mount (such as a frame positionable on a floor, for example) via a suspension means such that the sieve and motor are free to vibrate relative to the mount without the vibrations being substantially transferred to or dampened by the mount.
  • the suspension means may comprise one or more springs or bellows (i.e. air cushion or equivalent cushioning means) that couple the sieve and/or motor to the mount.
  • Manufacturers of vibratory sieves or sifters suitable for carrying out such a process include for instance Russell Finex, SWECO, Filtra Vibracion, VibraScreener, Gough Engineering and Farley Greene.
  • the vibrational sieving technique further comprises controlling a vibration probe coupled to the sieve.
  • the vibration probe may be controlled to cause the sieve to vibrate at a separate frequency to the frequency of vibrations caused by the vibration motor.
  • the vibration probe causes the sieve to vibrate at a higher frequency than the vibrations caused by the vibration motor and, more preferably, the frequency is within the ultrasonic range. Providing additional vibrations to the sieve by means of the vibration probe reduces the occurrence of clogging in the sieve, reduces the likelihood of the sieve being overloaded and decreases the amount of time needed to clean the mesh of the sieve.
  • the aforesaid vibrational sieving technique comprises sieving coated particles with a throughput of at least 1 g/minute. More preferably, the vibrational sieving technique comprises sieving coated particles with a throughput of 4 g/minute or more.
  • the vibrational sieving technique may more preferably comprise sieving coated particles with a throughput of up to 1 kg/minute or even higher.
  • any one of the above-stated throughputs represents a significant improvement over the use of known mechanical sieving, or sifting, techniques. For example, we found that sonic sifting involved sifting in periods of 15 minutes with a 15-minute cooling time in-between, which is necessary for preserving the apparatus. To sift 20 g of coated particles required 9 sets of 15 minutes of active sifting time, i.e. a total time (including the cooling) of 255 minutes. By comparison, by using the aforementioned vibrational sieving technique, 20 g of coated particles may be sieved continuously in, at most, 20 minutes, or more preferably in just 5 minutes, or less.
  • the sieve mesh size may be determined so that the ratio of the size of the sieved or sonic sifted particles to the sieve mesh size is about 1 : >1, preferably about 1:2, and optionally about 1:4.
  • the mesh size may range from about 20 pm to about 100 pm, preferably from about 20 pm to about 60 pm.
  • Appropriate sieve meshes may include perforated plates, microplates, grid, diamond, threads, polymers or wires (woven wire sieves) but are preferably formed from metals, such as stainless steel.
  • a stainless steel mesh within the vibrational sieving technique is as gentle to the particle coatings as using a softer polymer sieve as part of a mechanical sieving technique such as sonic sifting.
  • a known problem with sieving powders is the potentially dangerous generation of static electricity.
  • a steel mesh has the advantage of removing static electricity from the powder while that is not the case with a polymeric mesh, which has to be used in a sonic sifter.
  • the mesh size of known sonic sifters is limited to about 100 pm since the soundwaves travel through the mesh rather than vibrating it. That limitation does not exist using for vibrational sieving techniques as there is no reliance on soundwaves to generate vibrations in the sieve. Therefore, the vibrational sieving technique described herein allows larger particles to be sieved than if alternative mechanical sieving techniques were used.
  • the process for making coated cores of formulations of the invention comprises discharging the coated particles from the gas phase deposition reactor prior to subjecting the coated particles to agitation, followed by reintroducing the deagglomerated, coated particles into the gas phase deposition reactor prior to applying a further layer of at least one coating material to the reintroduced particles.
  • the thickness of the layers between interfaces correspond directly to the number of cycles in each series that are carried out within the ALD reactor, and between individual external agitation steps.
  • particle aggregates are preferably broken up by a forcing means that forces them through a sieve, thus separating the aggregates into individual particles or aggregates of a desired and predetermined size (and thereby achieving deagglomeration).
  • a forcing means that forces them through a sieve
  • the individual primary particle size is so small (i.e. ⁇ 1 pm) that achieving 'full' deagglomeration (i.e. where aggregates are broken down into individual particles) is not possible.
  • deagglomeration is achieved by breaking down larger aggregates into smaller aggregates of secondary particles of a desired size, as dictated by the size of the sieve mesh.
  • the smaller aggregates are then coated by the gas phase technique to form fully coated 'particles' in the form of small aggregate particles.
  • 'particles' when referring to the particles that have been deagglomerated and coated in the context of the invention, refers to both individual (primary) particles and aggregate (secondary) particles of a desired size.
  • the desired particle size (whether that be of individual particles or aggregates of a desired size) is maintained and, moreover, continued application of the gas phase coating mechanism to the particles after such deagglomeration via the sieving means that a complete coating is formed on the particle, thus forming fully coated particles (individual or aggregates of a desired size).
  • the above-described repeated coating and deagglomeration process may be carried out at least 1, preferably 2, more preferably 3, such as 4, including 5, more particularly 6, e.g. 7 times, and no more than about 100 times, for example no more than about 50 times, such as no more than about 40 times, including no more than about 30 times, such as between 2 and 20 times, e.g. between 3 and 15 times, such as 10 times, e.g. 9 or 8 times, more preferably 6 or 7 times, and particularly 4 or 5 times.
  • At least one sieving step is carried out and further that that step preferably comprises a vibrational sieving step as described above. It is further preferred that at least the final sieving step comprises a vibrational sieving step being conducted prior to the application of a final layer (set of cycles) of coating material. However, it is further preferred that more than one (including each) of the sieving steps comprise vibrational sieving techniques, steps or processes as described herein.
  • the total thickness of the coating (meaning all the separate layers/coatings/shells) will on average be in the region of between about 0.25 nm and about 10 pm, preferably about 0.5 nm and about 2 pm.
  • each individual layer/coating/shell will on average be in the region of about 0.1 nm (including about 0.5 nm, for example about 0.75 nm, such as about 1 nm).
  • each individual layer/coating/shell will depend on the size of the core (to begin with), and thereafter the size of the core with the coatings that have previously been applied, and may be on average about 1 hundredth of the mean diameter (i.e. the weight-, number-, or volume-based mean diameter) of that core, or core with previously-applied coatings.
  • the total coating thickness should be on average between about 1 nm and about 5 nm; for particles with a mean diameter that is between about 1 pm and about 20 pm, the coating thickness should be on average between about 1 nm and about 10 nm; for particles with a mean diameter that is between about 20 pm and about 700 pm, the coating thickness should be on average between about 1 nm and about 100 nm.
  • coated cores of the formulation of the invention have preferred weight-, number-, or volume-based mean diameters that are preferably between about 50 nm (e.g. about 100 nm, such as about 250 nm) and about 30 pm, for example between about 500 nm and about 100 pm, more particularly between about 1 pm (such as about 5 pm, including about 7 pm or about 9 pm) and up to about 50 pm, such as about 25 pm, e.g. about 20 pm.
  • the coating typically completely surrounds, encloses and/or encapsulates said solid cores comprising active ingredient(s).
  • active ingredient(s) typically completely surrounds, encloses and/or encapsulates said solid cores comprising active ingredient(s).
  • particles as hereinbefore disclosed wherein said coating surrounding, enclosing and/or encapsulating said core covers at least about 50%, such as at least about 65%, including at least about 75%, such as at least about 80%, more particularly at least about 90%, such as at least about 91%, such as at least about 92%, such as at least about 93%, such as at least about 94%, such as at least about 95%, such as at least about 96%, such as at least about 97%, such as at least about 98%, such as at least about 99%, such as approximately, or about, 100%, of the surface of the solid core, such that the coating essentially completely surrounds, encloses and/or encapsulates said core.
  • the term 'essentially completely coating completely surrounds, encloses and/or encapsulates said core' means a covering of at least about 98%, or at least about 99%, of the surface of the solid core.
  • processes described herein may result in the deagglomerated coated particles with the essential absence of said cracks through which active ingredient can be released in an uncontrolled way.
  • particles as hereinbefore disclosed wherein at least about 90% of the particles do not exhibit cracks in the coating surrounding, enclosing and/or encapsulating said core.
  • the layers of coating material may, taken together, be of an essentially uniform thickness over the surface area of the particles.
  • essentially uniform' thickness we mean that the degree of variation in the thickness of the coating of at least about 10%, such as about 25%, e.g. about 50%, of the coated particles that are present in a formulation of the invention, as measured by TEM, is no more than about ⁇ 20%, including ⁇ 50% of the average thickness.
  • coatings that are employed in formulations of the invention comprise zinc oxide
  • other coating materials which may be pharmaceutically-acceptable and essentially non-toxic coating materials may also be applied in addition, either between separate coatings comprising zinc oxide (e.g. in-between separate deagglomeration steps) and/or whilst a coating (which may comprise zinc oxide) is being applied.
  • Such materials may comprise multiple layers or composites of zinc oxide and one or more different inorganic or organic materials, to modify the properties of the layer(s).
  • Different coating materials such as pharmaceutically-acceptable and essentially nontoxic coating materials may also be applied in addition, either between separate coatings as described herein (e.g. in-between separate deagglomeration steps) and/or whilst a particular coating is being applied.
  • Such materials may comprise multiple layers or composites of said mixed oxide and one or more different inorganic or organic materials, to modify the properties of the layer(s).
  • the plurality of coated particles in accordance with the invention are essentially free of the aforementioned cracks in the applied coatings, through which active ingredient is potentially exposed (to, for example, the elements), two further, optional steps may be applied to the plurality of coated particles prior to subjecting it to further pharmaceutical formulation processing.
  • the first optional step may comprise, subsequent to the final deagglomeration step as hereinbefore described, application of a final overcoating layer, the thickness of which outer 'overcoating' layer/coating, or 'sealing shell' (which terms are used herein interchangeably), must be thinner than the previously-applied separate layers/coatings/shells (or 'subshells').
  • the thickness may therefore be on average no more than a factor of about 0.7 (e.g. about 0.6) of the thickness of the widest previously-applied subshell.
  • the thickness may be on average no more than a factor of about 0.7 (e.g. about 0.6) of the thickness of the last subshell that is applied, and/or may be on average no more than a factor of about 0.7 (e.g. about 0.6) of the average thickness of all of the previously-applied subshells.
  • the thickness may be on average in the region of about 0.3 nm to about 10 nm, for particles up to about 20 pm. For larger particles, the thickness may be on average no more than about 1/1000 of the coated particles' weight-, number-, or volume-based mean diameter.
  • sealing shell The role of such as sealing shell is to provide a 'sealing' overcoating layer on the particles, covering over those cracks, so giving rise to particles that are not only completely covered by that sealing shell, but also covered in a manner that enables the particles to be deagglomerated readily (e.g. using a non-aggressive technique, such as vortexing) in a manner that does not destroy the subshells that have been formed underneath, prior to, and/or during, pharmaceutical formulation.
  • the sealing shell does not comprise zinc oxide.
  • the sealing shell may on the other hand comprise silicon dioxide or, more preferably, aluminium oxide.
  • the second optional step may comprise ensuring that the few remaining particles with broken and/or cracked shells/coatings are subjected to a treatment in which all particles are suspended in a solvent in which the biologically active agent is soluble (e.g. with a solubility of at least about 0.1 mg/mL), but the least soluble material in the coating (which may comprise zinc oxide) is insoluble (e.g. with a solubility of no more than about 0.1 pg/mL), followed by separating solid matter particles from solvent by, for example, centrifugation, sedimentation, flocculation and/or filtration, resulting in mainly intact particles being left.
  • a solvent in which the biologically active agent is soluble
  • the least soluble material in the coating which may comprise zinc oxide
  • the above-mentioned optional step provides a means of potentially reducing further the likelihood of a (possibly) undesirable initial peak (burst) in plasma concentration of active ingredient, as discussed hereinbefore.
  • coated particles may be dried using one or more of the techniques that are described hereinbefore for drying cores. Drying may take place in the absence, or in the presence, of one or more pharmaceutically-acceptable excipients (e.g. a sugar or a sugar alcohol).
  • one or more pharmaceutically-acceptable excipients e.g. a sugar or a sugar alcohol.
  • 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 patients.
  • a solvent e.g. water, with or without the presence of one or more pharmaceutically acceptable excipients as defined herein
  • cores and/or partially coated particles Prior to applying the first layer of coating material or between successive coatings, cores and/or partially coated particles may be subjected to one or more alternative and/or preparatory surface treatments.
  • one or more intermediary layers comprising different materials i.e. other than the inorganic material(s)
  • An intermediary layer may, for example, comprise one or more surfactants, with a view to reducing agglomeration of particles to be coated and to provide a hydrophilic surface suitable for subsequent coatings.
  • Suitable surfactants in this regard include well known non-ionic, anionic, cationic or zwitterionic surfactants, such as the Tween series, e.g. Tween 80.
  • cores may be subjected to a preparatory surface treatment if the active ingredient that is employed as part of (or as) that core is susceptible to reaction with one or more precursor compounds that may be present in the gas phase during the coating (e.g. the ALD) process.
  • 'intermediary' layers/surface treatments of this nature may alternatively be achieved by way of a liquid phase non-coating technique, followed by a lyophilisation, spray drying or other drying method, to provide particles with surface layers to which coating materials may be subsequently applied.
  • Outer surfaces of particles of formulations of the invention may also be derivatized or functionalized, e.g. by attachment of one or more chemical compounds or moieties to the outer surfaces of the final layer of coating material, e.g. with a compound or moiety that enhances the targeted delivery of the particles within a patient to whom the nanoparticles are administered.
  • a compound may be an organic molecule (such as PEG) polymer, an antibody or antibody fragment, or a receptor-binding protein or peptide, etc.
  • the moiety may be an anchoring group such as a moiety comprising a silane function (see, for example, Herrera et al., J. Mater. Chem., 18, 3650 (2008) and US 8,097,742).
  • Another compound, e.g. a desired targeting compound may be attached to such an anchoring group by way of covalent bonding, or non-covalent bonding, including hydrogen bonding, or van der Waals bonding, or a combination thereof.
  • anchoring groups may provide a versatile tool for targeted delivery to specific sites in the body.
  • the use of compounds such as PEG may cause particles to circulate for a longer duration in the blood stream, ensuring that they do not become accumulated in the liver or the spleen (the natural mechanism by which the body eliminates particles, which may prevent delivery to diseased tissue).
  • Formulations of the invention can for example be used in medicine, diagnostics, and/or in veterinary practice.
  • Pharmaceutical (or veterinary) formulations of the invention may include particles of different types, for example particles comprising different functionalization (as described hereinbefore), particles of different sizes, and/or different thicknesses of the layers of coating materials, or a combination thereof.
  • particles with different coating thicknesses and/or different core sizes the drug release following administration to patient may be controlled (e.g. varied or extended) over a specific time period.
  • Formulations of the invention may be administered systemically, for example by infusion, intravenously or intraarterially (including by intravascular or other perivascular devices/dosage forms (e.g. stents)), intraosseously, intracerebrally, intracerebroventricularly, intrasynovially, intrasternally, intrathecally, intralesionally, intracranially, intratumorally, cutaneously, intracutaneously, transdermally or, most preferably by injection, for example intramuscularly or, preferably, subcutaneously, in the form of a pharmaceutically- (or veterinarily) acceptable dosage form.
  • infusion intravenously or intraarterially (including by intravascular or other perivascular devices/dosage forms (e.g. stents)), intraosseously, intracerebrally, intracerebroventricularly, intrasynovially, intrasternally, intrathecally, intralesionally, intracranially, intratumorally, cutaneously, intracutaneously, trans
  • the preparation of formulation of the invention comprises incorporation of coated particles as described herein into an appropriate pharmaceutically-acceptable (by which we include physiologically-acceptable) aqueous carrier system as defined herein, and may be achieved with due regard to the intended route of administration and standard pharmaceutical practice.
  • appropriate excipients including physiologically-acceptable injectable, e.g. physiologically-acceptable, intramuscularly- injectable or, more preferably, physiologically-acceptable, subcutaneously-injectable sources of counter-ions and buffers as mentioned herein
  • physiologically-acceptable injectable e.g. physiologically-acceptable, intramuscularly- injectable or, more preferably, physiologically-acceptable, subcutaneously-injectable sources of counter-ions and buffers as mentioned herein
  • Such pharmaceutically-acceptable carriers may also impart an immediate, or a modified, release of active agent from the particles of the formulations of the invention.
  • formulations of the invention may be in the form of sterile injectable and/or infusible dosage forms, for example, sterile aqueous or oleaginous suspensions of formulations of the invention.
  • Sterile aqueous suspensions of the particles of the formulation of the invention may be formulated according to techniques known in the art.
  • the aqueous media should contain at least about 50% water, but may also comprise other aqueous excipients, such as Ringer's solution, and may also include polar co-solvents (e.g. ethanol, glycerol, propylene glycol, 1,3-butanediol, polyethylene glycols of various molecular weights and tetraglycol); viscosity-increasing, or thickening, agents (e.g.
  • sorbitan esters sodium lauryl sulfate; monoglycerides, polyoxyethylene esters, polyoxyethylene alkyl ethers, polyoxylglycerides and, preferably, Tweens (Polysorbates), such as Tween 80 and Tween 20).
  • Preferred ingredients include isotonicity-modifying agents (e.g. sodium lactate, dextrose and, especially, sodium chloride); as well as other ingredients, such as mannitol, croscarmellose sodium and hyaluronic acid.
  • Formulations of the invention may further be formulated in the form of injectable suspension of coated particles with a size distribution that is both even and capable of forming (or re-forming following an appropriate degree of agitation) a stable suspension within the injection liquid (i.e. without settling), such that it may be injected through a needle.
  • formulations of the invention may comprise an aqueous medium that comprises inactive ingredients that may prevent premature 'caking' (i.e. forming a solid or semi-solid, non-dispersible residue), or gelling (e.g.
  • hydrogel formation within the formulation, by which we mean that the formulation is viscous enough to prevent sedimentation, leading to suspensions that are not 'homogeneous' and thus the risk of under or overdosing of active ingredient, or at the minimum that it is possible to redisperse the formulation to form a sufficiently homogenous dispersal prior to administering it.
  • Formulations of the invention comprise thermogel-forming agents (also referred to herein as thermogelling agents, thermogel-forming excipients and/or thermogelling excipients, which terms may be used interchangeably), which means that the compositions/formulations themselves, which include such agents/excipients have thermogelling properties.
  • thermogelling agents also referred to herein as thermogelling agents, thermogel-forming excipients and/or thermogelling excipients, which terms may be used interchangeably
  • Excipients that are 'thermogelling' or 'thermogel-forming' will be well known to those skilled in the art to include excipients that impart properties on a composition that result in it being of a generally liquid viscosity at room (ambient) temperature (e.g. between about 18°C and about 25°C), for example in a vessel, such as a syringe, prior to injection through a catheter or a needle, but capable of forming a gel at higher (e.g. bodily) temperatures (e.g. within the range of about 35°C (such as about 37°C) to about 40°C).
  • ambient temperature e.g. between about 18°C and about 25°C
  • a vessel such as a syringe
  • higher temperatures e.g. within the range of about 35°C (such as about 37°C) to about 40°C.
  • thermogelling agent/formulations of the invention may transition between liquid and gel within the interval of about 30°C (or about 31°C or about 32°C) to about 38°C (or about 40°C or about 39°C).
  • the transition temperature between liquid and gel may refer either to the transition temperature of the thermogelling agent and/or that of the formulation. Preferably, the transition temperature will refer to that of the formulation.
  • the transition of the thermogelling agent/formulation between liquid and gel takes place around mammal (e.g. human and/or animal) body temperature (e.g. between about 30°C and about 40°C).
  • mammal e.g. human and/or animal
  • body temperature e.g. between about 30°C and about 40°C.
  • thermogelling agent and/or (preferably) the formulation between liquid and gel may take place at a temperature that is within a range that ensures such that gelling occurs after the formulation is injected into subcutaneous tissue.
  • thermogelling agents and/or formulations of the invention may have a modulus of elasticity (G') at room temperature (e.g. between about 20°C and about 25°C), as may be measured in vitro e.g. by way of a standard rheometry technique, of below about 5 Pa, more preferably below about 3 Pa, particularly below about 1 Pa, more particularly below about 0.5 Pa, and even down to between about 0.001 to about 0.1 Pa.
  • G' modulus of elasticity
  • room temperature e.g. between about 20°C and about 25°C
  • a standard rheometry technique of below about 5 Pa, more preferably below about 3 Pa, particularly below about 1 Pa, more particularly below about 0.5 Pa, and even down to between about 0.001 to about 0.1 Pa.
  • body temperature e.g. between about 37°C or about 36°C and about 40°C
  • formulations of the invention exhibit a modulus of elasticity (also known for solids as Young's modulus) when measured e.g. by
  • Modulus of elasticity (e.g. elastic modulus) as disclosed herein may be measured, for instance, using a Kinexus Pro Rheometer from Netzsch.
  • the modulus of elasticity may be measured on a sample of thermogelling agent/formulation (e.g. from about 0.5 to about 5 mL) using oscillatory rheometry with a parallel plate measuring geometry (e.g. with a plate diameter of from about 10 to about 60 mm and/or plate gap of from about 0.1 to about 1 mm) programmed to perform a temperature sweep. Measurements may be carried out at a frequency of from about 0.01 to about 10 rad/s, a deformation amplitude of about 0.1 to about 10% and a heating rate of from about 0.1°C/min to about 5°C/min.
  • formulations of the invention through standard cannulas or injection devices such as needles, as described hereinafter (for example with an inner diameter between about 0.5 mm and about 2 mm (e.g. about 1 mm) at room temperature.
  • thermogelling properties will be well known to those skilled in the art and may include, for example, amphiphilic polymers with both hydrophilic parts and hydrophobic parts that have the ability to form a three-dimensional crosslinked network and preserve a large amount of water which can undergo a sol-gel transition as temperature increases.
  • thermogelling excipients include surface-active block copolymers, including: triblock copolymers of poly(ethylene glycol)-b-poly(d,l-lactide-co-glycolide)-b- poly(ethylene glycol) (PEG- PLGA-PEG), triblock copolymers of PLGA-PEG-PLGA, polycaprolactone (PCL) polymers, triblock copolymers of PEG-PCL-PEG, triblock copolymers of PCL-PEG-PCL, copolymers of methoxy poly(ethylene glycol) polycaprolactone (mPEG-PCL), copolymers of chitosan and p-glycerolphosphate (GP), chitosan derivatives such as chitosan-g-PEG copolymer, hydroxybutyl chitosan, chitosan-poly vinyl alcohol (PVA), elastin-like polypeptides (ELP) containing a pen
  • These copolymers are generally referred to in the art as 'poloxamers' (also commercially known as Pluronics®, Synperonics® and Lutrol®).
  • Poloxomers that may be mentioned include those that are known to those skilled in the art as P105, P188, P122, P123, P124, P182, P183, P184, P188, P212, P215, P217, P234, P235, P237, P238, P288, P333, P335, P338, and P402.
  • Non-ionic triblock copolymers of this nature may be provided with different molecular weights, and on occasion as mixtures of such different poloxamers (i.e. a mixture of poloxamers with a higher and a lower molecular weight poloxamer).
  • thermo-responsive gelation characteristics including cellulose and derivates thereof, such as, for example, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl/hydroxyethyl cellulose (see, for example, Bonetti et al, Tissue Engineering, 27, 486 (2020) and Husnaini Zainal et al, Journal of Materials Research and Technology, 10, 935 (2021)).
  • additives such as sucrose, fructose, glycerol, sorbitol, pectin, alginate, hyaluronic acid, gellan gum, xanthan gum and/or polyethylene glycol; or salts comprising anions, whose influence on the gelling tendency generally follows the Hofmeister series; and/or surface active agents, such as e.g., sodium dodecyl sulphate (see, for example, Joshi, Materials, 4, 1861 (2011).
  • additives such as sucrose, fructose, glycerol, sorbitol, pectin, alginate, hyaluronic acid, gellan gum, xanthan gum and/or polyethylene glycol
  • salts comprising anions whose influence on the gelling tendency generally follows the Hofmeister series
  • surface active agents such as e.g., sodium dodecyl sulphate (see, for example, Joshi, Materials, 4, 1861 (2011).
  • thermogelling excipients that are included in formulations of the invention exhibit thermoreversible properties, which means that the rheological characteristics are capable of increasing and decreasing with repeated warming and cooling cycles. This is important given that formulations of the invention may need to be sterilized prior to use, which sterilization may be physical and comprise irradiation and/or heat.
  • thermogels may further depend on the homogeneity of the suspension of coated particles in aqueous carrier comprising the thermogelling excipient.
  • thermogelling excipients may lead to non-homogenous suspensions due to the formation of, for example, foams.
  • the increased amount of air in the form of bubbles in the suspension may result in less efficient thermogel formation following administration.
  • thermogel-forming excipients that are present in the formulation are typically in the range of between about 5% and about 50% by weight of the composition/formulation, preferably from about 10% to about 30% by weight, such as between about 15% and about 35% (or about 25%) by weight.
  • the pharmaceutically-acceptable aqueous carrier system of a formulation of the invention, in which the coated particles are suspended may further comprise:
  • an injectable (e.g. intramuscularly- and/or subcutaneously-injectable) compound that is capable of reacting with zinc and, in doing so, reduces (e.g. essentially prevents) the reaction of zinc with water to form zinc hydroxide.
  • a compound may, for example, comprise a compound that, when dissolved in the aqueous carrier, provides a source of counter-ions that are capable of forming a compound (e.g. a salt) with zinc that is, for example, essentially insoluble in said aqueous media (at any given temperature, pressure and pH); and
  • an injectable e.g. intramuscularly- and/or subcutaneously-injectable buffer system that either:
  • a source of counter-ions that are capable of forming a compound (e.g. a salt) with zinc that is more soluble in said aqueous media than zinc hydroxide (at any given temperature, pressure and pH).
  • a compound e.g. a salt
  • zinc hydroxide at any given temperature, pressure and pH.
  • viscous agglomerates and/or hydrogels may be formed, which have a tendency to clog needles when attempting to inject formulations e.g. subcutaneously or intramuscularly.
  • a compound that competes with with water to react with zinc is thus capable of reacting with zinc and, in doing so, reduced and/or substantially prevents (e.g. prevents up to about 75% of, such about 80% of, including up to about 90% of, such as about 95% of, and even up to about 99% of) the reaction of zinc with water to form zinc hydroxide.
  • Such a compound may for example provide a source of counter-ions to the aqueous carrier system that, when included (e.g. dissolved) in the latter, may form compounds (e.g. salts) with zinc that serve to prevent the above-mentioned reaction of free zinc with water.
  • Such counter-ions may achieve this by, for example, complexing with zinc in some way, and/or by being essentially insoluble in water and/or precipitating out of aqueous solution, which competing reactions may occur at or near the surfaces of coated particles. Whatever the mechanism involved, in competing with water to react with zinc, further reaction of zinc with water (and therefore gelling) is reduced and/or prevented.
  • aqueous media such as pure water
  • compounds (e.g. salts) of zinc that are sparingly soluble in such media, such as those with a solubility that is less than about 33.3 mg/mL, such as less than about 25 mg/mL, including less than about 20 mg/mL, particularly less than about 10 mg/mL, such as less than about 5 mg/mL, down to less than about 1 mg/mL and including less than about 0.1 mg/mL, at atmospheric pressure (e.g. about 1 bar), room temperature (e.g. about 21°C) and neutral pHs (e.g. pH values between about 5 and about 9, such as about 6 and about 8.5, such as between about 7 and about 8 (e.g. about 7.4).
  • solubility that is less than about 33.3 mg/mL, such as less than about 25 mg/mL, including less than about 20 mg/mL, particularly less than about 10 mg/mL, such as less than about 5 mg/mL, down to less than about 1 mg/mL
  • solubility of the relevant compound (e.g. salt) of zinc in aqueous media is less (e.g. at least about 10% less, such as at least about 5% less) than that of zinc hydroxide (Zn(OH)z) at any given temperature, pressure and pH.
  • Appropriate counter-ions that possess the aforementioned properties in this respect include aspartate, tartrate, maleate, fumarate, malate, benzoate and, preferably, phosphate counter-ions.
  • Appropriate sources of such counter-ions include materials that are capable of forming aspartate-, tartrate-, maleate-, fumarate-, malate-, benzoate- and/or phosphate-based buffers, such as: aspartic acid, aspartate salts (e.g. sodium aspartate) and hydrates thereof, and mixtures of these components; tartaric acid, tartrate salts (sodium tartrate) and hydrates thereof (e.g.
  • maleic acid maleate salts (e.g. sodium maleate) and hydrates thereof, and mixtures of these components
  • fumaric acid, fumarate salts e.g. monosodium fumarate
  • malic acid malate salts and hydrates thereof, and mixtures of these components
  • benzoic acid benzoate salts (e.g. sodium benzoate) and hydrates thereof, and mixtures of these components
  • phosphate buffers such as phosphoric acid, disodium hydrogen phosphate dihydrate, sodium acid phosphate, sodium dihydrogen phosphate monohydrate, and combinations thereof).
  • Alternative sources of phosphate counter-ions include salts such as sodium phosphate, potassium phosphate and calcium phosphate. Sources may also include sources of organophosphates (e.g. glycerol phosphate, sodium glycerophosphate and potassium glycerophosphate), as well as pyrophosphates and polyphosphates.
  • Alternative sources of tartrate counter-ions include potassium tartrate, diethyl tartrate and disodium tartrate.
  • Alternative sources of benzoate counter-ions include sodium benzoate, benzyl benzoate, denatonium benzoate and potassium benzoate.
  • Appropriate concentrations of phosphate counter-ions in the aqueous medium are in the range of about 1 mM, such as about 2 mM up to about 50 mM, including about 40 mM, such as about 3 mM up to about 35 mM, e.g. between about 4 mM (e.g. about 5 mM) and about 30 mM (such as about 25 mM, including about 20 mM, about 15 mM and about 10 mM).
  • the recommended upper concentration limit for phosphate buffer in e.g. subcutaneously injectable compositions is 10 mM; see Usach et al, Adv. Then, 36, 2986 (2019).
  • the above-mentioned sources of counter-ions capable of forming a zinc compound may prevent the gelling issue mentioned herein, we have unexpectedly found that this may result in a change in the pH of the resultant formulation (particularly over time, e.g. during storage). This is thought to arise from the reaction of the above-mentioned counter-ion(s) (e.g. phosphate ions) with zinc depleting the buffering capacity of the relevant sources of counter-ions (e.g. buffer(s)).
  • the above-mentioned counter-ion(s) e.g. phosphate ions
  • a physiologically- acceptable injectable e.g. intramuscularly- or subcutaneously-injectable
  • a physiologically- acceptable injectable e.g. intramuscularly- or subcutaneously-injectable
  • a physiologically- acceptable injectable e.g. intramuscularly- or subcutaneously-injectable buffer system that either:
  • • comprises a source of counter-ions that are capable of forming a salt with zinc that is more soluble in aqueous media than zinc hydroxide (Zn(OH)z), or, more preferably
  • Buffers that comprise a source of counter-ions that are capable of forming a salt with zinc that is more soluble in aqueous media than zinc hydroxide include citrate buffers (e.g. citric acid, trisodium citrate dihydrate and combinations thereof), acetate buffers (e.g. acetic acid, sodium acetate and combinations thereof), lactate buffers (e.g. lactic acid, magnesium lactate and combinations thereof), gluconate buffers (e.g. gluconic acid, sodium gluconate and combinations thereof), glutamate buffers (e.g. glutamic acid, monosodium glutamate and combinations thereof), succinate buffers (e.g.
  • citrate buffers e.g. citric acid, trisodium citrate dihydrate and combinations thereof
  • acetate buffers e.g. acetic acid, sodium acetate and combinations thereof
  • lactate buffers e.g. lactic acid, magnesium lactate and combinations thereof
  • gluconate buffers e.g.
  • succinic acid, sodium succinate and combinations thereof a -ketoglutarate buffers (a- ketoglutararic acid, a -ketoglutarate salts and combinations thereof), ascorbate buffers (e.g. ascorbic acid, sodium ascorbate and combinations thereof), bicarbonate buffers (e.g . carbonic acid, sodium bicarbonate and combinations thereof), ammonium buffers (e.g. ammonium chloride, ammonium hydroxide and combinations thereof), glycine buffers (e.g. glycine, sodium glycinate and combinations thereof) or combinations of any of the above.
  • a -ketoglutarate buffers a- ketoglutararic acid, a -ketoglutarate salts and combinations thereof
  • ascorbate buffers e.g. ascorbic acid, sodium ascorbate and combinations thereof
  • bicarbonate buffers e.g . carbonic acid, sodium bicarbonate and combinations thereof
  • ammonium buffers e.g.
  • Buffers that are essentially incapable of forming a salt with zinc include histidine, diethanolamine (e.g. diethanolamine, magnesium chloride hexahydrate and combinations thereof) or, most preferably, tromethamine ('Tris' or 'Trizma'), buffers.
  • diethanolamine e.g. diethanolamine, magnesium chloride hexahydrate and combinations thereof
  • tromethamine 'Tris' or 'Trizma'
  • All of the aforementioned buffers may be employed, alone or in combination with along with standard inorganic acids and bases, such as hydrochloric acid and sodium hydroxide, which may be used in order to adjust pH.
  • Preferred pH values for formulations of the invention may be in the pH range of about pH 3 and about pH 10, such as about pH 4 and about pH 9, including about pH 5 and about pH 8.
  • pH buffers e.g. tromethamine buffers
  • concentrations of such buffers are in the range of about 0.1 mM (such as about 5 mM, including about 10 mM) up to about 200 mM, such as about 25 mM up to about 175 mM, for example between about 50 mM and about 150 mM, including between about 75 mM and about 125 mM (e.g. about 100 mM).
  • Formulations may thus be stored under normal storage conditions, and maintain their physical and/or chemical integrity.
  • the phrase 'maintaining physical and chemical integrity' essentially means chemical stability and physical stability.
  • any formulation of the invention may be stored (with or without appropriate pharmaceutical packaging), under normal storage conditions, with an insignificant degree of chemical (including stereochemical) degradation or decomposition of any biologically active agent and/or inert excipient, and/or the aforementioned changes in pH.
  • any formulation of the invention may be stored (with or without appropriate pharmaceutical packaging), under normal storage conditions, with an insignificant degree of physical transformation, such as sedimentation as described above, or changes in the nature and/or integrity of the coated particles, for example in the coating itself or the active ingredient (including dissolution, solvatisation, solid state phase transition, etc.).
  • Examples of 'normal storage conditions' for formulations of the invention include temperatures of between about -50°C and about +80°C (preferably between about -25°C and about +75°C, such as about 50°C), and/or pressures of between about 0.1 and about 2 bars (preferably atmospheric pressure), and/or exposure to about 460 lux of UV/visible light, and/or relative humidities of between about 5 and about 95% (preferably about 10 to about 40%), for prolonged periods (i.e. greater than or equal to about twelve, such as about six months).
  • formulations of the invention may 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, as appropriate.
  • the skilled person will appreciate that the above-mentioned upper and lower limits for temperature and pressure represent 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).
  • Formulations of the invention may comprise between about 1% to about 99%, such as between about 10% (such as about 20%, e.g. about 50%) to about 90% by weight of the coated particles with the remainder made up by carrier system and/or other pharmaceutically-acceptable excipients.
  • Formulations of the invention may be in the form of a liquid, which is administrable via a surgical administration apparatus, e.g. a needle, a catheter or the like, to form a depot formulation.
  • a surgical administration apparatus e.g. a needle, a catheter or the like
  • Formulations of the invention and dosage forms comprising them may thus be formulated with conventional pharmaceutical additives and/or excipients used in the art for the preparation of pharmaceutical formulations, and thereafter incorporated into various kinds of pharmaceutical preparations and/or dosage forms using standard techniques (see, for example, 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 edition, 2013), and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference. According to a further aspect of the invention there is provided a process for the preparation of
  • the formulations of the invention may be presented in the form of sterile injectable and/or infusible dosage forms administrable via a surgical administration apparatus (e.g. a syringe with a needle for injection, a catheter or the like), to form a depot formulation.
  • a surgical administration apparatus e.g. a syringe with a needle for injection, a catheter or the like
  • formulations of the invention can be stored prior to being loaded into a suitable injectable and/or infusible dosing means (e.g. a syringe with a needle for injection), or may even be prepared immediately prior to loading into such a dosing means.
  • a suitable injectable and/or infusible dosing means e.g. a syringe with a needle for injection
  • Sterile injectable and/or infusible dosage forms may thus comprise a receptacle or a reservoir in communication with an injection or infusion means into which a formulation of the invention may be pre-loaded, or may be loaded at a point prior to use, or may comprise one or more reservoirs, within which coated particles of the formulation of the invention and the aqueous carrier system are housed separately, and in which admixing occurs prior to and/or during injection or infusion.
  • kit of parts comprising:
  • a carrier system of the formulation of the invention as well as a kit of parts comprising coated particles of the formulation of the invention along with instructions to the end user to admix those particles with a carrier system according to the invention.
  • a pre-loaded injectable and/or infusible dosage form as described herein above, but modified by comprising at least two chambers, within one of which chamber is located the coated particles of the formulation of the invention and within the other of which is located the aqueous carrier system of the formulation of the invention, wherein admixing, giving rise to a suspension or otherwise, occurs prior to and/or during injection or infusion.
  • Formulations of the invention may typically be injected in volumes in the range of about 0.05 mL to about 20 mL, more preferably between about 0.25 mL and about 5 mL, depending on the active ingredient and the preferred drug release profile. Injection procedures may comprise:
  • the needle may be kept static for a moment, awaiting the solidification of the depot, to ensure that the injected depot is positioned correctly.
  • an injectable and/or infusible dosage form comprising a formulation of the invention, wherein said formulation is contained within a reservoir that is connected to, and/or is associated with, an injection or infusion means (e.g. a syringe with a needle for injection, a catheter or the like).
  • an injection or infusion means e.g. a syringe with a needle for injection, a catheter or the like.
  • Formulations of the invention comprising biologically active agents may be used in human or animal medicine. Formulations of the invention are particularly useful in any indication in which the relevant biologically active agent is either approved for use in, or otherwise known to be useful in.
  • Formulations of the invention are indicated in the therapeutic, palliative, and/or diagnostic treatment, as well as the prophylactic treatment (by which we include preventing and/or abrogating deterioration and/or worsening of a condition) of any relevant condition.
  • formulations of the invention have the advantage that the need for coadministration thereof along with an antiinflammatory agent that is suitable for injection is reduced, it is not excluded that appropriate antiinflammatory agents may be employed in this respect.
  • acetic acid derivatives and related substances indomethacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpiramide, oxametacin, proglumetacin, ketorolac, aceclofenac and bufexamac
  • oxicams such as piroxicam, tenoxicam, droxicam, lornoxicam and meloxicam
  • propionic acid derivatives such as ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen
  • Preferred antiinflammatory agents include non-steroidal anti-inflammatory drugs, such as diclofenac, ketoprofen, meloxicam, aceclofenac, flurbiprofen, parecoxib, ketorolac, indomethacin or pharmaceutically acceptable salts thereof.
  • Subjects may receive (or may already be receiving) one or more of the aforementioned co-therapeutic and/or antiinflammatory agents, separate to a formulation of the invention, by which we mean receiving a prescribed dose of one or more of those other therapeutic agents, prior to, in addition to, and/or following, treatment with a formulation of the invention.
  • the active ingredients may be administered together in the same formulation, or administered separately (simultaneously or sequentially) in different formulations (hereinafter referred to as 'combination products').
  • Such combination products provide for the administration of biologically active agent in conjunction with the antiinflammatory agent, and may thus be presented either as separate formulations, wherein at least one of those formulations is a formulation of the invention, and at least one comprises the antiinflammatory agent in a separate formulation, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including biologically active agent and the antiinflammatory agent).
  • an antiinflammatory agent may be co-presented with biologically active agent at an appropriate dose in one or more of the cores that form part of a formulation of the invention as hereinbefore described, or may be formulated using the same or a similar process for coating to that described hereinbefore for the biologically active agent, which may allow for the release of the other antiinflammatory agent over the same, or over a different timescale.
  • a pharmaceutical formulation of the invention that further comprises an antiinflammatory agent
  • the antiinflammatory agent may be included by:
  • the antiinflammatory agent may be presented in a formulation of the invention in any form in which it is separate to the biologically active agent-containing cores. This may be achieved by, for example, dissolving or suspending that antiinflammatory agent directly in the aqueous medium of a formulation of the invention, or by presenting it in a form in which its release can, like the biologically active agent, also be controlled following injection.
  • the latter option may be achieved by, for example, providing the antiinflammatory agent in the form of additional particles suspended in the aqueous carrier system of formulation of the invention, which additional particles have a weight-, number-, or volume-based mean diameter that is between amount 10 nm and about 700 pm, and comprise cores comprising the biologically active agent, which cores are coated, at least in part, by one or more coating materials as hereinbefore described (which formulation is hereinafter referred to as a 'combination suspension').
  • composition (B) a pharmaceutical formulation, comprising an antiinflammatory agent, which Components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.
  • Component (B) of a kit of parts as presented above may be different in terms its chemical composition and/or physical form from Component (A) (i.e. a formulation of the invention), it may also be in a form that is essentially the same or at least similar to a formulation of the invention, that is in the form of a plurality of particles suspended in an (e.g. aqueous) carrier system, which particles: (a) have a weight-, number-, or volume-based mean diameter that is between amount 10 nm and about 700 m; and
  • (b) comprise solid cores comprising that other therapeutic agent, which cores are coated, at least in part, by one or more coatings of (e.g. inorganic) material.
  • the coated cores comprising the antiinflammatory agent may be different in terms of their chemical composition(s) and/or physical form(s), it is preferred that the coating of inorganic material that is employed is the same or similar to that employed in coated cores of the formulations of the invention, which means that the antiinflammatory agent is coated by one or more inorganic coatings as hereinbefore described, for example one or more inorganic coating materials comprising zinc oxide, and more particularly inorganic coatings comprising a mixture of:
  • the atomic ratio ( ( i) : (ii)) is at least about 1 : 1 and up to and including about 6: 1.
  • a method of making a kit of parts as defined above comprises bringing Component (A), as defined above, into association with a Component (B), as defined above, thus rendering the two components suitable for administration in conjunction with each other.
  • Components (A) and (B) of the kit of parts may be:
  • kit of parts as hereinbefore defined in which Components (A) and (B) are packaged and presented together as separate components of a combination pack, for use in conjunction with each other in combination treatment, as well as a kit of parts comprising:
  • kits of parts described herein may comprise more than one formulation including an appropriate quantity/dose of biologically active agent, and/or more than one formulation including an appropriate quantity/dose of the antiinflammatory agent, in order to provide for repeat dosing as hereinbefore described.
  • kits of parts as described herein by 'administration in conjunction with', we include that Components (A) and (B) of the kit are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition.
  • the term 'in conjunction with' includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration of the other component.
  • the terms 'administered simultaneously' and 'administered at the same time as' include that individual doses of biologically active agent and antiinflammatory agent are administered within 48 hours (e.g. 24 hours) of each other.
  • a physician may initially administer a formulation of the invention alone to treat a patient, and then find that that person exhibits an inflammatory response (which may be caused by the active ingredient per se and/or by any other component of the formulation). The physician may then administer one or more of:
  • antiinflammatory agents mentioned above may be employed in combination products according to the invention in the form of a (e.g. pharmaceutically-acceptable) salt, including any such salts that are known in the art and described for the drugs in question to in the medical literature, such as Martindale - The Complete Drug Reference, 38 th Edition, Pharmaceutical Press, London (2014) and the documents referred to therein (the relevant disclosures in all of which documents are hereby incorporated by reference).
  • a (e.g. pharmaceutically-acceptable) salt including any such salts that are known in the art and described for the drugs in question to in the medical literature, such as Martindale - The Complete Drug Reference, 38 th Edition, Pharmaceutical Press, London (2014) and the documents referred to therein (the relevant disclosures in all of which documents are hereby incorporated by reference).
  • the amount of the antiinflammatory agent that may be employed in combination products according to the invention must be sufficient so exert its pharmacological effect.
  • Doses of such antiinflammatory agents that may be administered to a patient should thus be sufficient to affect a therapeutic response over a reasonable and/or relevant timeframe.
  • One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by not only the nature of the other active ingredient, but also inter alia the pharmacological properties of the formulation, the route of administration, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease, as well as genetic differences between patients.
  • formulations of the invention may be continuous or intermittent (e.g. by bolus injection), dosages of such other active ingredients may also be determined by the timing and frequency of administration.
  • any particular additional antiinflammatory agent which will be most suitable for an individual patient
  • doses of the relevant antiinflammatory agents mentioned above include those that are known in the art and described for the drugs in question to in the medical literature, such as Martindale - The Complete Drug Reference, 38 th Edition, Pharmaceutical Press, London (2014) and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference.
  • formulations of the invention may also, highly advantageously, control the dissolution rate of core materials (such as biologically active agents) and affect the pharmacokinetic profile by reducing any burst effect as hereinbefore defined (e.g. a concentration maximum shortly after administration), and/or by reducing Cmax in a plasma concentration-time profile.
  • core materials such as biologically active agents
  • Formulations of the invention may thus also provide a release and/or pharmacokinetic profile that increases the length of release of core materials (such as biologically active agents) from the formulation, and, biologically active agents, affect their pharmacokinetic profiles by reducing any burst effect as hereinbefore defined (e.g. a concentration maximum shortly after administration), and/or by reducing Cmax in a plasma concentration-time profile).
  • core materials such as biologically active agents
  • the formulation of the invention also has the advantage that by controlling the release of active ingredient at a steady rate over a prolonged period of time, a lower daily exposure to biologically active agent is provided, which is expected to reduce unwanted side effects.
  • formulations and processes described herein may also have the advantage that, in the treatment of relevant conditions, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it may have other useful pharmacological properties over, any similar treatments known in the prior art.
  • Figure 1 shows the released liraglutide as a function of time in an in vitro experiment, with and without a thermogelling excipient
  • Figure 2 shows swelling size upon injection of a suspension with and without a thermogelling excipient in an in vivo minipig experiment
  • Figure 3 shows plasma concentrations of liraglutide as a function of time in an in vivo rat experiment, with (dots) and without (squares) the presence of a thermogelling excipient
  • Figure 4 shows plasma concentrations of liraglutide as a function of time in an in vivo rat experiment, with (Groups 2 and 3) and without (Group 1) the presence of a thermogelling excipient
  • Figure 5 shows plasma concentrations of liraglutide as a function of time in an in vivo rat experiment, with (Group 5) and without (Group 4) the presence of a thermogelling excipient.
  • Samples of microparticles of indomethacin were prepared by jet-milling.
  • Powders were loaded to an ALD reactor (Picosun, SUNALETM R-200 Standard, Espoo, Finland) where 24 ALD cycles were performed at a reactor temperature of 50°C, with stop-flow cycles as follows: 20 doses of precursors with a 1 second pulse time each, 30 second soak and 45 second purge.
  • the coating sequence was three ALD cycles, employing diethyl zinc and water as precursors, followed by one cycle of trimethylaluminium and water, repeated five times.
  • the first layer was between about 4 and about 8 nm in thickness (as estimated from the number of ALD cycles).
  • the powder was removed from the reactor and deagglomerated by means of forcing the powder through a polymeric sieve with a 20 pm mesh size using a sonic sifter.
  • the resultant deagglomerated powder was re-loaded into the ALD reactor and further 24 ALD cycles were performed as before, forming a second layer of mixed oxide at the aforementioned ratio, followed by extraction from the reactor and deagglomeration by means of sonic sifting as above, followed by reloading to form a third layer, deagglomeration and then reloading to form a final, fourth layer.
  • the drug load i.e. w/w% of indomethacin in the powder
  • the formed mixed oxide layer had an atomic ratio of zinc:aluminium of 3: 1.
  • Coated indomethacin microparticles were suspended in five different vehicles at an indomethacin concentration of about 200 mg/mL. A balance was tared with a 2 mL glass vial without a rubber stopper and about 243 mg of powder was weighed into the vial along with about 842 pL vehicle.
  • the vehicles were as described in Table 1 below (with the suspension number being designated as Vehicle 'No.').
  • PNIPAM as used herein is poly(N-isopropyl acrylamide) NHS ester end functionalised, average Mn 5,000, CsHioNC CCeHiiNCOnH from Sigma, product code 900188.
  • vehicles comprising any of the two polymers PLGA-PEG- PLGA or PNIPAM may form gels in suspension comprising the coated particles described herein.
  • Vehicles comprising PNIPAM form stable gels at all tested concentrations.
  • Vehicles comprising PLGA-PEG-PLGA may form stable gels, when the polymer concentration is sufficiently high.
  • Syringeability (ability of an injectable therapeutic to pass easily through a hypodermic needle on transfer from a vial prior to an injection), and injectability (a formulation's performance during injection), are key product-performance parameters of any parenteral dosage form.
  • the two parameters are of particular significance for specialized dosage forms such as suspensions.
  • Powders of lactose were loaded to an ALD reactor (Picosun, SUNALETM R-200 Standard, Espoo, Finland) where 48 ALD cycles were performed at a reactor temperature of 50°C, with stop-flow cycles as follows: 20 doses of precursors with a 1 second pulse time each, 30 second soak and 45 second purge.
  • the coating sequence was three ALD cycles employing diethyl zinc and water as precursors, followed by one cycle of trimethylaluminium and water, repeated eleven times.
  • the first layer was between about 4 and about 8 nm in thickness (as estimated from the number of ALD cycles).
  • the powder was removed from the reactor and deagglomerated by means of forcing the powder through a polymeric sieve with a 20 pm mesh size using a sonic sifter.
  • the resultant deagglomerated powder was re-loaded into the ALD reactor and further 48 ALD cycles were performed as before, forming a second layer of mixed oxide at the aforementioned ratio, followed by extraction from the reactor and deagglomeration by means of sonic sifting as above.
  • the particle size distribution after coating was as follows: Dio 2.1 pm; Dso 7.6 pm; D90 23.4 pm.
  • the formed mixed oxide layer had an atomic ratio of zinc:aluminium which is 3: 1.
  • Coated lactose microparticles were suspended in two different vehicles as well as a control at a powder sample concentration of about 200 mg/mL. A balance was tared with a glass vial and about 200 mg of powder was weighed into the vial along with 1 mL vehicle.
  • the vehicles were as follows:
  • Control 2 % Na-CMC in 10 mM PB + 25 mM Trizma + 0.8% NaCI.
  • the suspensions were found to be easily transferable to the syringe.
  • the sample containing the vehicle (A) appeared foamy, but air bubbles in the syringe were easily avoided.
  • the sample containing the vehicle (B) air bubbles were unavoidable to get transferred to the syringe.
  • the control sample (C) did not form any bubbles.
  • the injection force for coated lactose suspended in 25% PLGA-PEG-PLGA has been shown to be lower than that of a control suspension.
  • thermoformed gels comprising coated liraglutide microparticles.
  • the dissolution media is a solution consisting of about 6 g/L PIPES and about 1.3 g/L NaOH dissolved in water to reach a pH of 7.2.
  • the dissolution test was performed at 37°C in a forced convection incubator.
  • coated liraglutide microparticles and suspensions comprising said microparticles is described below.
  • Powders of liraglutide microparticles were loaded to an ALD reactor (Picosun, SUNALETM R-200 Standard, Espoo, Finland) where 40-43 ALD cycles were performed at a reactor temperature of 30°C, with stop-flow cycles as follows: 20 doses of precursors with a 1 second pulse time each, 30 second soak and 45 second purge.
  • the coating sequence was three ALD cycles employing diethyl zinc and water as precursors, followed by one cycle of trimethylaluminium and water, repeated nine times. Additionally, the first and the final cycle include three cycles of trimethylaluminium and water.
  • the first layer was between about 4 and about 8 nm in thickness (as estimated from the number of ALD cycles).
  • the powder was removed from the reactor and deagglomerated by means of forcing the powder through a polymeric sieve with a 20 pm mesh size using a sonic sifter.
  • the resultant deagglomerated powder was re-loaded into the ALD reactor and further 24 ALD cycles were performed as before, forming a second layer of mixed oxide at the aforementioned ratio, followed by extraction from the reactor and deagglomeration by means of sonic sifting as above, followed by reloading to form a third, fourth, fifth and sixth layer through the same steps.
  • the drug load i.e. w/w% of liraglutide in the powder
  • the formed mixed oxide layer has an atomic ratio of zinc:aluminium which is 5: 1.
  • Coated liraglutide microparticles were suspended in five different vehicles at a coated liraglutide particle concentration of about 100 mg/mL (about 50 mg/mL liraglutide concentration). A balance was tared with a 2 mL glass vial without a rubber stopper and about 42 mg of powder was weighed into the vial, as set out in Table 5 below.
  • A 1 wt% poloxamer 188 in 20 mM PIPES (1 g poloxamer 188 / 100 mL 20 mM PIPES).
  • B 16 wt% PLGA-PEG-PLGA (LA:GA 95: 5) in 10 mM PB + 25 mM Trizma + 0.8% NaCI (160 mg/mL PLGA-PEG-PLGA, 1.3 mg/mL Na 2 HPO 4 ⁇ 2 H 2 O, 0.4 mg/mL NaH 2 PO 4 ⁇ 2H 2 O, 3.3 mg/mL Trizma HCI, 0.5 mg/mL Trizma base, 8 mg/mL NaCI).
  • diluent A 400 pL of the suspensions were transferred; for diluent A, the suspension was transferred to a glass bottle, while diluents B-E were placed in an aluminium cap within a glass bottle that was pre-heated to 37°C.
  • Table 8 Table 9 The dissolution results for the coated liraglutide particles are also shown as a function of time in Figure 1.
  • thermogel-forming excipients are too high to allow for direct comparison between different concentrations of thermogel-forming excipients or different thermogel-forming excipients (PNIPAM vs PLGA-PEG-PLGA). Comparison can however be made between dissolution profiles from the control vehicle compared to those containing thermogel-forming excipients. Percentage released active ingredient was higher for the control sample than for those containing thermogel-forming excipients. Thereby, results of this study indicate that gels formed in situ decrease initial release of coated liraglutide.
  • Gelation tendency is determined on a scale from 0 to 2. The higher the number, the more gelation has occurred. If the suspension has not gelled, it receives the number 0, while a sample that has gelled and can hold its weight upon flipping the vial for 1 minute receives the number 2. An intermediate gelation, such as higher viscosity or partial gelation is given a number 1.
  • vehicles comprising any of the two polymers PLGA-PEG- PLGA or PNIPAM may form gels.
  • Vehicles comprising PNIPAM form gels at all tested concentrations, however, stable gels are not formed at PNIPAM concentrations of 20% or below.
  • Vehicles comprising PLGA-PEG-PLGA form gels at all tested concentration, but a stable gel is only seen in the sample with a polymer concentration of 25%.
  • the vehicles of Example 4 were placed at room temperature (RT) after the long term incubation.
  • an Altromin minipig diet (Altromin 9069) from Altromin Spezialfutter GmbH & Co. KG, Im Seelenkamp 20, D-32791 Heil, Germany, was offemred twice daily in an amount of approximately 175 g per animal per meal. Further, domestic quality drinking water was offered ad libitum.
  • Each pig was subjected to two different injections, both of which contained lenalidomide particles that had been coated with a metal oxide in accordance with the invention.
  • Each suspension contained 138 mg/mL coated lenalidomide powder (or 100 mg/mL lenalidomide) and a diluent as specified below:
  • A 2% sodium carboxymethylcellulose (Na-CMC; average Mw 90 000)* in 10 mL
  • CMC was added to the PTS-diluent to raise the viscosity a bit resulting in a more stable suspension.
  • CMC also functions as a thermogelling excipient, however, only at concentrations of at least 10%. Therefore, diluent A does not cause gelling upon injection.
  • the vial was tapped several times to dislodge material from the bottom.
  • the vial was manually shaken for 60 seconds to ensure a uniform suspension.
  • the sample was vortexed if this was considered necessary.
  • the sample vial was inverted 3 times (again) just prior to retracting the sample for each injection, in order to avoid sedimentation of the test material and subsequent deviation from the correct dose.
  • the dose formulations were prepared less than 30 minutes prior to administration.
  • the animals were anaesthetised by an intramuscular injection in the neck (1.0 mL/15 kg body weight) of a mixture of Zoletil 50®Vet., Virbac, France (125 mg tiletamine and 125 mg zolazepam), 20 mg xylazine/mL (6.25 mL), 100 mg ketamine/mL (1.25 mL) and 10 mg butorphanol/mL (2.5 mL).
  • diluent A and diluent B 1 mL of each of the suspensions (hereinafter, diluent A and diluent B), were subcutaneously injected into each minipig on two different locations using a 23G needle.
  • the minipigs were observed for 22 days after which they were killed.
  • the degree of swelling is tabulated (as size in mm) in Table 15 and 16 below on each day starting from Day 1. Two observations were made; one before injection of the suspensions (la), and one after injection of the suspensions (lb). Table 15 shows the results upon administration of coated lenalidomide in diluent A, and Table 16 shows the results upon administration of coated lenalidomide in diluent B.
  • thermogelling excipient B a solution containing a thermogelling excipient
  • Coated particles were prepared in an analogous fashion to that described in Example 3 above, with the exception that the coating process started with ten ALD cycles employing trimethylaluminium and water, whereafter the following coating sequence was completed for 40 cycles: Three ALD cycles employing diethyl zinc and water as precursors, followed by one cycle of trimethylaluminium and water. Upon sieving through a 20 pm mesh, the particles were reloaded to form a second, a third, and a fourth layer through the same steps to reach a final number of 200 cycles.
  • Suspensions of the coated liraglutide were formulated with and without thermogelling excipients, and subcutaneously injected to six male rats; three rats received suspensions comprising a thermogelling excipient (diluent A, see below), and three received a suspension without the thermogelling excipient (diluent B, see below). Each suspension contained 10 mg/mL of liraglutide.
  • Hyonate vet.* 1% hyaluronic acid in 1.86 mM phosphate buffered saline, isotonic, pH 7.4.
  • Hyonate vet is a commercially available product used for intraarticular injection in horses and has no noteworthy safety or tolerability risks associated.
  • Blood samples of approximately 0.2 mL were collected from the jugular vein into K2EDTA tubes at the following timepoints (in hours) after injection: 3, 6, 12, 24, 36, 48, 72, 120, 168, 251, 384, 480, 576 and 672.
  • the rats were humanely sacrificed by CO2 narcosis and death confirmed by cervical dislocation.
  • plasma was generated by centrifugation (1500g, 10 mins, 4°C) and transferred to cryotubes (Eppendorf Protein LoBind Deep Well Plates and LoBind tubes). The resultant plasma was stored in a freezer set to maintain a temperature of -65 °C until the concentration of liraglutide was measured using UPLC-MS.
  • Mean Cmax values and mean plasma exposure for various intervals are presented in Table 17. Mean plasma exposure was determined as the mean of the area under the curve.
  • thermogelling excipient alters the pharmacokinetic properties in a favourable manner, in that the preseence of a thermogelling excipient results in a significant lowering of Cmax compared to a solution without that excipient. Furthermore, the mean plasma exposure is lower when a suspension containing a thermogelling excipient was administered.
  • liraglutide was dissolved in water for injection (WFI) to 5% (w/w) in the spray-drying process.
  • WFI water for injection
  • Batches of 5 g and 30 g were produced in a small- scale spray-drier, PROCEPT SD3, with equipment setting parameters as defined in Tables 18 (setpoint of process parameters) and 19 (range of outcome parameters during the process).
  • the spray-dried liraglutide particles of Batch 1 were first coated with ten layers of pure aluminium oxide by way of the following process: a. A valve on the piping between the pump and the ALD reactor was closed. b. A valve on the trimethylaluminium (TMA) precursor bottle was then opened for 1 second, letting evaporated metal containing precursor fill the ALD reactor for 1 second. c. The valve to the precursor bottle was closed and before opening to the pump again the chamber rested for 30 seconds (soaking time) to ensure the metal containing precursor vapour reacted with the surface of the drug particles. d. The ALD reactor was thereafter pumped for 9 seconds. e. Steps a-d above were repeated 20 times.
  • TMA trimethylaluminium
  • steps (a) to (e) above were essentially repeated, with the exception that water was used as a second reagent to form a discrete aluminium oxide layer on the surfaces of the active ingredient microparticles. This was followed by a further purging pulse using nitrogen in a continuous flow, which was carried out to remove gaseous water and organic gases.
  • step (b) twenty layers of zinc oxide were applied by repeating the above ALD steps using diethylzinc (DEZ), and then water, as precursors, in step (b) above to form a total of twenty zinc oxide layers.
  • DEZ diethylzinc
  • step (b) twenty layers of zinc oxide were applied by repeating the above ALD steps using diethylzinc (DEZ), and then water, as precursors, in step (b) above to form a total of twenty zinc oxide layers.
  • DEZ diethylzinc
  • step (b) a multilayer structure of pure aluminium oxide and zinc oxide with a total of 30 atomic layers (AhOsiZnO), including the ten initial aluminium oxide atomic layers.
  • the powder was then removed from the ALD reactor and deagglomerated using a sonic sifter (Tsutsui Sonic Agitated Sifting Machine SW-20AT) with a 45 pm mesh size sieve.
  • a sonic sifter Tesutsui Sonic Agitated Sifting Machine SW-20AT
  • the resultant deagglomerated powder was re-loaded into the ALD reactor and the same procedure for coating the particles with ten pure aluminium oxide followed by twenty pure zinc oxide layer with a total 30 atomic layers. After the last deagglomeration step the same procedure for coating the particles with seven pure aluminium oxide layers followed by a twenty pure zinc oxide layers and finished by three pure aluminium oxide layers to give a mixed oxide (AhChiZnCLAhOs) layer with a total 30 atomic layers. The deagglomeration and coating steps were repeated four times to create a sample with 5 discrete coatings of pure aluminium oxide and zinc oxide.
  • valve to the precursor bottle was closed and before opening to the pump again the chamber rested for 30 seconds (soaking time) to ensure the metal containing precursor vapour reacted with the surface of the drug particles.
  • the ALD reactor was thereafter pumped for 9 seconds.
  • Steps a-d above were repeated 20 times.
  • steps (a) to (e) above were essentially repeated, with the exception that water was used as a second reagent to form a discrete aluminium oxide layer on the surfaces of the active ingredient microparticles. This was following by a further purging pulse using nitrogen in a continuous flow, which was carried out to remove gaseous water and organic gases.
  • step (b) three layers of zinc oxide were applied by repeating the above ALD steps using diethylzinc (DEZ), and then water, as precursors, in step (b) above to form a total of three zinc oxide layers. That was followed by coating with one layer of aluminium oxide, using the same precursors as mentioned above under (b). This provided a mixed oxide layer with an atomic ratio of 1 :3 (AhChiZnO) of a total of four atomic layers.
  • the powder was then removed from the ALD reactor and deagglomerated using a sonic sifter (Tsutsui Sonic Agitated Sifting Machine SW-20AT) with a 32 pm mesh size sieve.
  • a sonic sifter Tesutsui Sonic Agitated Sifting Machine SW-20AT
  • the resultant deagglomerated powder was re-loaded into the ALD reactor and the same procedure for coating the particles with three pure aluminium oxide followed by a mixed oxide (1:3 A ChiZnO) layer with a total 27 atomic layers.
  • the same procedure for coating the particles with three pure aluminium oxide followed by a mixed oxide (1 :3 AhOsiZnO) with a total 27 atomic layers were repeated three times to create a sample with a priming layer of pure aluminium oxide and 4 discrete coatings of mixed oxide in a 1:3 AhChiZnO atomic ratio.
  • the particle size distribution of the batches was determined by suspending the coated particles in a solution of 1% Span 85 (Sigma-Aldrich, MO, USA) in heptane (Merck, Germany). The distribution, as measured by laser diffraction, was as follows: Dio 7.2 pm; Dso 17.9 pm; D90 36.2 pm for Batch 1 and Dio 3.8 pm; D50 11.2 pm; D90 26.3 pm for Batch 2.
  • the drug load of the batches was determined by etching sample in a solution of 88% water (PanReac, Spain) and 12% (v/v) phosphoric acid (Merck, Germany) to dissolve the coatings, before diluting to 75 pg/mL with 75% (Rathburn, UK) in water + 0.1% trifluoroacetic acid (Merck, Germany) and injection into an HPLC system for quantification (Prominence-I HPLC-UV-DAD, Shimadzu, Japan), with column Kinetex F5, 150x4.6 mm, 150x4.6 mm, 2.6 pm particle size (Phenomenex Ltd., CA, USA); Mobile phase A: 10% acetonitrile in water 0.1% TFA Mobile phase B: 80% acetonitrile in water + 0.1% trifluoroacetic acid; injection volume 2 pL, autosampler temp.
  • the drug load as measured by means of HPLC-UV was 72.6 ⁇ 0.4% for Batch 1 and 80.9 ⁇ 0.2% for Batch 2.
  • the coating integrity of the batches was characterised by suspending coated particles in dimethylsulfoxide (Rathburn, UK) at a concentration of 0.4 mg liraglutide per mL of solvent and rotated on an overhead stirrer for 3 hours. Intermittent samples were taken, centrifuged (EBA 20, Hettich, Germany) for 7 min at 6000 rpm, and the supernatant diluted in Mobile Phase A (as above) before injection into the above HPLC system for quantification. The results after 3 hours show 6.6% liraglutide released for Batch 1 and 5.2% liraglutide released for Batch 2, indicating minimal defects in the coating, so any burst release is expected to be low.
  • Suspensions of the coated microparticles of liraglutide of Example 9 were prepared by adding an appropriate volume of 25% PLGA-PEG-PLGA (LA:GA ratio 15: 1, PLGA Mw: 1,700 Da, PEG Mw: 1,500 Da), 10 mM sodium phosphate, 20 mM tromethamine, water and sodium hydroxide to reach a pH of 7.2-7.6 to the test item vials to achieve a concentration of liraglutide corresponding to 10 mg/mL.
  • the vial was then tapped at least 10 times to dislodge any material which might have settled to the bottom of the test vial.
  • the formulation was then vortexed for ca. 60 seconds to ensure a uniform suspension.
  • thermogelling excipient (Vehicle A, as described in detail below) were administered to Groups 2, 3 and 5, while suspensions without the thermogelling excipient (Vehicle B) were administered to Groups 1 and 4:
  • Vehicle A 25% PLGA-PEG-PLGA, referred to as PPP (LA:GA ratio 15: 1, PLGA Mw: 1,700 Da, PEG Mw: 1,500 Da) + 10 mM sodium phosphate + 20 mM tromethamine + water (and NaOH to reach a pH of 7.2-7.6)
  • Vehicle B Hyonate vet. (1% hyaluronic acid in 1.86 mM phosphate buffered saline, isotonic, pH 7.4).
  • Blood samples (ca. 0.2 mL) were collected from the jugular vein into K2EDTA (dipotassium ethylenediaminetetraacetic acid) tubes at the following time-points for Groups 1 to 3: 1, 3, 6, 12, 24, 48, 72, 120, 168, 251, 384, 480, 576 and 672 hours post-dose, and at the following time-points for Group 4: 1, 2, 3, 6, 9, 12, 24 and 48 hours post subcutaneous dose. Actual sampling times were recorded. As soon as practically possible following blood sampling, plasma was separated by centrifugation (1500 g for 10 min at 4°C), which was stored at -80°C until analysis was conducted.
  • K2EDTA dipotassium ethylenediaminetetraacetic acid
  • Plasma concentration of liraglutide was determined with LC-MS/MS. Study samples were prepared by pipetting 35 pL of rat plasma into a 96 well plate, adding 75 pL of an internal standard working solution using an EVO-2 liquid handling robot (Tecan, Austria). The 96 well plates were then shaken for 15 minutes and centrifuged. All samples were then injected on a UPLC-MS/MS system (Waters, MA, USA). Separation was obtained with an ACQUITY UPLC Protein BEH C4 Column, 300 A, 1.7 pm, 2.1 mm x 50 mm (Waters, MA, USA) at 60°C using 0.3% formic acid in water as mobile phase A and acetonitrile as mobile phase B.
  • PK pharmacokinetic
  • NCA noncompartmental analysis
  • C max and tmax were derived from the observed plasma concentration data.
  • AUC was assessed by integration of the plasma concentration vs time curve using linear interpolation for increasing plasma levels and logarithmic interpolation for decreasing plasma levels (Linear Up Log Down method).
  • AUCiast measurable plasma concentration
  • ti/2,z was calculated by In2 / lambdaz.
  • 'Cmax/D' is the maximum concentration normalised to 1 mg/kg expressed in ng/mL/mg/kg body weight of the rat
  • • 'AUCiast/D' is the area under blood concentration vs. time curve up to the last detectable concentration normalised to 1 mg/kg expressed in ng*h/mL/mg/kg body weight of the rat
  • • 'AUCoo/D' is the area under concentration vs. time curve up to infinite time normalized to 1 mg/kg expressed in ng*h/mL/mg/kg body weight of the rat
  • Groups 1 and 4 had higher initial drug release compared with the formulations comprising thermogel excipients in Groups 2, 3 and 5.
  • thermogel-forming excipients are suitable for delivery of coated active ingredients.
  • Suspensions comprising the coated active ingredient and PNIPAM (20-25%) or PLGA-PEG-PLGA (25%) were found to be syringeable and injectable at ambient conditions, and are able to form a gel at 34°C.
  • thermoreversible gels • The neat vehicles formed thermoreversible gels, with heating at 121°C and subsequent cooling not serving to destroy the gelation function.
  • thermogel-forming excipients decrease initial release of coated active ingredients.
  • thermogel-forming excipients induces significantly less swelling upon subcutaneous injection compared to a solution not containing thermogelforming excipients.
  • thermogel-forming excipients significantly reduced the level of 'burst' (as manifest by a lower Cmax upon subcutaneous injection compared to a solution not containing thermogel-forming excipients).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dispersion Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une formulation comprenant : (a) une pluralité de particules ayant un diamètre moyen en poids, en nombre ou en volume qui est compris entre environ 10 nm et environ 700 µm, lesquelles particules comprenant des noyaux solides enrobés d'au moins un matériau d'enrobage ; (b) un système de véhicule aqueux pharmaceutiquement acceptable, dans lequel lesdites particules enrobées sont en suspension ; et (c) lequel système de véhicule aqueux comprend un agent thermogélifiant. Lesdits noyaux solides comprennent de préférence un ou plusieurs agents biologiquement actifs et lesdites particules enrobées sont de préférence synthétisées au moyen d'une technique d'enrobage en phase gazeuse, telle qu'un dépôt de couche atomique. La formulation permet d'obtenir des suspensions aqueuses injectables stables à des pH physiologiquement acceptables, laquelle est susceptible de former un gel in situ après injection, ce qui diminue la libération initiale des agents biologiquement actifs.
PCT/EP2024/066678 2023-06-15 2024-06-14 Nouvelles compositions pharmaceutiques injectables à effet retard Pending WO2024256696A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB2308932.9 2023-06-15
GB202308932 2023-06-15

Publications (1)

Publication Number Publication Date
WO2024256696A1 true WO2024256696A1 (fr) 2024-12-19

Family

ID=87570938

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/066678 Pending WO2024256696A1 (fr) 2023-06-15 2024-06-14 Nouvelles compositions pharmaceutiques injectables à effet retard

Country Status (1)

Country Link
WO (1) WO2024256696A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001045742A1 (fr) * 1999-12-22 2001-06-28 Samyang Corporation Composition liquide d'un copolymere bloc biodegradable destinee a un systeme d'administration de medicaments et procede de fabrication correspondant
US8097742B2 (en) 2005-01-20 2012-01-17 Agency For Science, Technology And Research Water-soluble, surface-functionalized nanoparticle for bioconjugation via universal silane coupling
WO2014187995A1 (fr) 2013-05-24 2014-11-27 Candix Ab Nanoparticule solide à revêtement inorganique
WO2020033903A1 (fr) * 2018-08-10 2020-02-13 Ephemeral Solutions, Inc. Particules contenant des agents colorants et procédés pour les utiliser
WO2022258988A1 (fr) * 2021-06-10 2022-12-15 Nanexa Ab Nouvelle composition comprenant un médicament immunomodulateur
WO2022258987A1 (fr) * 2021-06-10 2022-12-15 Nanexa Ab Nouvelles formulations comprenant de l'azacitidine
WO2023105227A1 (fr) 2021-12-08 2023-06-15 Nanexa Ab Nouvelle formulation de combinaison injectable

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001045742A1 (fr) * 1999-12-22 2001-06-28 Samyang Corporation Composition liquide d'un copolymere bloc biodegradable destinee a un systeme d'administration de medicaments et procede de fabrication correspondant
US8097742B2 (en) 2005-01-20 2012-01-17 Agency For Science, Technology And Research Water-soluble, surface-functionalized nanoparticle for bioconjugation via universal silane coupling
WO2014187995A1 (fr) 2013-05-24 2014-11-27 Candix Ab Nanoparticule solide à revêtement inorganique
WO2020033903A1 (fr) * 2018-08-10 2020-02-13 Ephemeral Solutions, Inc. Particules contenant des agents colorants et procédés pour les utiliser
WO2022258988A1 (fr) * 2021-06-10 2022-12-15 Nanexa Ab Nouvelle composition comprenant un médicament immunomodulateur
WO2022258987A1 (fr) * 2021-06-10 2022-12-15 Nanexa Ab Nouvelles formulations comprenant de l'azacitidine
WO2023105227A1 (fr) 2021-12-08 2023-06-15 Nanexa Ab Nouvelle formulation de combinaison injectable

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Aulton's Pharmaceutics: The Design and Manufacture of Medicines", 2013, ELSEVIER
"Remington: The Science and Practice of Pharmacy", 2006, UNIVERSITY OF THE SCIENCES IN PHILADELPHIA
BONETTI ET AL., TISSUE ENGINEERING, vol. 27, 2020, pages 486
HELLRUP ET AL., INT. J. PHARM., vol. 529, 2017, pages 116
HERRERA ET AL., J. MATER. CHEM., vol. 18, 2008, pages 3650
HUSNAINI ZAINAL ET AL., JOURNAL OF MATERIALS RESEARCH AND TECHNOLOGY, vol. 10, 2021, pages 935
LACHMANLEAFEBIGER ET AL.: "The Theory and Practice of Industrial Pharmacy", 1986
MARTINDALE: "The Complete Drug Reference", 2014, PHARMACEUTICAL PRESS
USACH ET AL., ADV. THER., vol. 36, 2019, pages 2986
ZHANG ET AL., NANOMANUF. METROL., 2022, Retrieved from the Internet <URL:https://doi.org/10.1007/s41871-022-00136-8>

Similar Documents

Publication Publication Date Title
US20250041208A1 (en) New injectable combination formulation
US20230157968A1 (en) Injectable oil-based pharmaceutical composition
US20230009472A1 (en) New composition
US20230020272A1 (en) New process for the manufacture of pharmaceutical compositions
US20250312275A1 (en) Gas phase deposition technique for preparation of pharmaceutical compositions
WO2024256696A1 (fr) Nouvelles compositions pharmaceutiques injectables à effet retard
CN121013708A (zh) 包含胰高血糖素样肽-1受体激动剂的新型药物组合物
WO2024127018A1 (fr) Nouvelle suspension injectable de particules enrobées
US20250073219A1 (en) New composition comprising immunomodulatory drug
US20240261228A1 (en) New process
WO2022223821A1 (fr) Particules de silicium pour la libération d&#39;hydrogène
GB2594083A (en) New composition
CN118647367A (zh) 新颖可注射组合制剂
US20240277624A1 (en) New formulations comprising biologic active drugs

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24735545

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE