WO2018143787A1 - Support de substance physiologiquement active - Google Patents

Support de substance physiologiquement active Download PDF

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Publication number
WO2018143787A1
WO2018143787A1 PCT/KR2018/001617 KR2018001617W WO2018143787A1 WO 2018143787 A1 WO2018143787 A1 WO 2018143787A1 KR 2018001617 W KR2018001617 W KR 2018001617W WO 2018143787 A1 WO2018143787 A1 WO 2018143787A1
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WIPO (PCT)
Prior art keywords
silica particles
porous silica
bioactive
bioactive substance
substance carrier
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PCT/KR2018/001617
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English (en)
Korean (ko)
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원철희
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주식회사 레모넥스
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Priority to SG11201907260PA priority Critical patent/SG11201907260PA/en
Priority to CA3052561A priority patent/CA3052561C/fr
Priority to AU2018216591A priority patent/AU2018216591B2/en
Priority to EP18748562.8A priority patent/EP3578171A4/fr
Application filed by 주식회사 레모넥스 filed Critical 주식회사 레모넥스
Priority to JP2019563995A priority patent/JP6883354B2/ja
Priority to MX2019009271A priority patent/MX2019009271A/es
Priority to CN201880022677.1A priority patent/CN110475546A/zh
Priority to US16/483,830 priority patent/US11129796B2/en
Priority to BR112019016281A priority patent/BR112019016281A2/pt
Priority claimed from KR1020180014842A external-priority patent/KR20180091768A/ko
Publication of WO2018143787A1 publication Critical patent/WO2018143787A1/fr
Priority to PH12019550145A priority patent/PH12019550145A1/en
Priority to US17/399,320 priority patent/US11793757B2/en
Priority to AU2021232725A priority patent/AU2021232725B2/en
Priority to US18/368,097 priority patent/US20240041771A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00—Silicon; Compounds thereof
    • C01B33/113—Silicon oxides; Hydrates thereof
    • C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid

Definitions

  • the present invention relates to a bioactive substance carrier.
  • Drug delivery system refers to a medical technology that can efficiently deliver the required amount of drugs, such as proteins, nucleic acids, or other small molecules by minimizing the side effects and maximizing efficacy and effects of existing drugs.
  • This technology which saves the cost and time required for the development of new drugs, has recently become one of the cutting-edge technologies that create new added value in the pharmaceutical industry, combined with nanotechnology.
  • the company has invested in the development of drug delivery systems along with the development of new drugs, mainly by companies and companies.
  • DDS drug delivery systems
  • Efficient delivery systems are needed for the study of the function of bioactive substances in cells or for intracellular delivery.
  • a universal delivery system capable of delivering a wide range of bioactive substances, a system capable of accommodating and delivering a large amount of drugs, and a system for releasing drugs in a sustained manner is still under development.
  • bioactive substances comprising bioactive substances; And porous silica particles supporting the bioactive material and having a plurality of pores having a diameter of 5 nm to 100 nm.
  • the porous silica particles have a physiologically active substance carrier having t of 24 or more, wherein a ratio of absorbance of Equation 1 is 1/2:
  • a 0 is the absorbance of the porous silica particles measured by placing 5 ml of the 1 mg / ml suspension of the porous silica particles into a cylindrical permeable membrane having pores having a diameter of 50 kDa,
  • the pH of the suspension is 7.4,
  • a t is the absorbance of the porous silica particles measured after t hours have elapsed since the measurement of A 0 ).
  • suspension is at least one bioactive substance carrier selected from the group consisting of PBS (phosphate buffered saline) and SBF (simulated body fluid).
  • PBS phosphate buffered saline
  • SBF simulated body fluid
  • t is a biologically active substance carrier of 24 to 120.
  • porous silica particles are biodegradable bioactive material carrier.
  • the ratio of the absorbance of Equation 1 is 1/5 t is a bioactive material carrier of 70 to 120.
  • the ratio of the absorbance of Equation 1 is 1/20 t is a bioactive material carrier of 130 to 220.
  • porous silica particles are spherical bioactive material carrier.
  • porous silica particles have a mean diameter of 150nm to 1000nm bioactive material carrier.
  • porous silica particles have a BET surface area of 200m 2 / g to 700m 2 / g bioactive material carrier.
  • porous silica particles BET surface area 300m 2 / g to 450m 2 / g bioactive material carrier.
  • porous silica particles have a hydrophilic substituent or a hydrophobic substituent on an outer surface or inside a pore.
  • bioactive material carrier according to 1 above, wherein the bioactive material is poorly soluble and the porous silica particles have a hydrophobic substituent on an outer surface or inside a pore.
  • bioactive material carrier according to 1 above, wherein the bioactive material is poorly soluble, and the porous silica particles have a hydrophobic substituent inside the pores and a hydrophilic substituent on the outer surface.
  • bioactive material carrier according to 1 above, wherein the bioactive material is negatively charged at neutral pH, and the silica particles are positively charged at neutral pH at the outer surface or the inside of the pore.
  • bioactive material carrier according to 1 above, wherein the bioactive material is positively charged at neutral pH, and the silica particles are negatively charged at neutral pH at the outer surface or inside the pore.
  • bioactive substances And spherical porous silica particles carrying the physiologically active substance and having a particle diameter of 150 nm to 500 nm and a plurality of pores having a diameter of 7 nm to 30 nm.
  • porous silica particles are physiologically active substance carrier having t of 24 to 120, where the ratio of absorbance of Equation 1 is 1/2:
  • a 0 is the absorbance of the porous silica particles measured by placing 5 ml of the 1 mg / ml suspension of the porous silica particles into a cylindrical permeable membrane having pores having a diameter of 50 kDa,
  • the suspension is PBS or SBF, pH is 7.4,
  • a t is the absorbance of the porous silica particles measured after t hours have elapsed since the measurement of A 0 ).
  • bioactive material carrier according to the above 22, wherein the bioactive material is poorly soluble and the porous silica particles have a hydrophobic substituent on an outer surface or inside a pore.
  • bioactive material carrier according to the above 22, wherein the bioactive material is poorly soluble and the porous silica particles have a hydrophobic substituent inside the pores and a hydrophilic substituent on the outer surface.
  • bioactive material carrier according to the above 22, wherein the bioactive material is negatively charged at neutral pH, and the silica particles are positively charged at neutral pH at the outer surface or inside the pore.
  • a method of preparing a bioactive substance carrier comprising contacting porous silica particles with a bioactive substance in a solvent.
  • a method of delivering a physiologically active substance comprising parenterally administering the drug carrier of any one of 1 to 27 above to an individual.
  • parenteral administration is intraorbital, intraocular, infusion, intraarterial, intraarticular, intracardiac, dermal, intramuscular, intraperitoneal, intrapulmonary, intramedullary, intrasternal, vertebral, intrauterine , Intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal or intranasal administration.
  • porous silica particles carrying a bioactive substance may be slowly degraded in vivo to deliver the drug in a sustained manner.
  • the porous silica particles carrying the bioactive substance are completely decomposed in vivo, thereby completely delivering the supported bioactive substance to the living body.
  • the bioactive substance carrier of the present invention can be parenterally administered.
  • the bioactive substance carrier of the present invention can deliver various drugs in a sustained release.
  • FIG. 1 is a micrograph of porous silica particles according to an embodiment of the present invention.
  • FIG. 2 is a micrograph of porous silica particles according to an embodiment of the present invention.
  • Figure 3 is a micrograph of the small pore particles during the manufacturing process of the porous silica particles according to an embodiment of the present invention.
  • Figure 4 is a micrograph of the small pore particles according to an embodiment of the present invention.
  • Figure 5 is a micrograph of the pore diameter of the porous silica particles according to an embodiment of the present invention.
  • DDV Delivery Vehicle
  • the number in parenthesis means the diameter of the particle
  • the number of subscripts means the pore diameter.
  • DDV 200 10 refers to a particle of an embodiment having a particle diameter of 200 nm and a pore diameter of 10 nm.
  • Figure 6 is a micrograph to confirm the biodegradability of the porous silica particles according to an embodiment of the present invention.
  • FIG. 7 is a tube having a cylindrical permeable membrane according to one example.
  • FIG. 11 is a result of decreasing absorbance for each pH of the environment over time of porous silica particles according to one embodiment of the present invention.
  • 13 to 17 is a degree of release over time of the bioactive material supported on the porous silica particles according to an embodiment of the present invention.
  • 18 is a tube for confirming the release of a bioactive material according to one example.
  • 19 to 25 are the degree of release over time of the bioactive material supported on the porous silica particles according to an embodiment of the present invention.
  • FIG. 26 is a photograph of a Cas9 protein supported on porous silica particles according to an embodiment of the present invention and transferred into cells.
  • FIG. 26 is a photograph of a Cas9 protein supported on porous silica particles according to an embodiment of the present invention and transferred into cells.
  • FIG. 27 is a micrograph showing the release of siRNA in mice by supporting siRNA on porous silica particles according to an embodiment of the present invention.
  • Bioactive substance carrier of the present invention is a bioactive substance; And porous silica particles supporting the bioactive material and having a plurality of pores having a diameter of 5 nm to 100 nm.
  • a bioactive substance is a bioactive substance / biofunction modulator that is supported on porous silica particles and can be delivered to an individual and exhibit activity.
  • the bioactive substance has direct or indirect, therapeutic, physiological and / or pharmacological effects on human or animal organisms. It can be a therapeutically active agent that can provide.
  • the therapeutically active agent may be, for example, a general medicine, drug, prodrug or target group, or a drug or prodrug comprising the target group.
  • Therapeutic active agents include, for example, cardiovascular drugs, in particular antihypertensive agents (eg calcium channel blockers, or calcium antagonists) and antiarrhythmic agents; Congestive heart failure drugs; Muscle contractors; Vasodilators; ACE inhibitors; diuretic; Deoxidation dehydratase inhibitors; Cardiac glycosides; Phosphodiesterase inhibitors; Blockers; ⁇ blockers; Sodium channel blockers; Potassium channel blockers; ⁇ -adrenergic agonists; Platelet inhibitors; Angiotensin II antagonists; Anticoagulants; Thrombolytics; Bleeding drugs; Anemia treatments; Thrombin inhibitors; Antiparasitic agents; Antibacterial agents; Anti-inflammatory agents, in particular nonsteroidal anti-inflammatory agents (NSAIDs), more particularly COX-2 inhibitors; Steroidal anti-inflammatory agents; Prophylactic anti-inflammatory agents; Anti-glaucoma; Mast cell stabilizer; Acid aids; Drugs affecting the respiratory system; Allergic rhinit
  • the therapeutically active agent is for example erythropoietine (EPO).
  • Cytokines such as thrombopoietine, interleukin (including IL-1 to IL-17), insulin, insulin-like growth factors (including IGF-1 and IGF-2), epidermal growth factors factor (EGF)), transforming growth factor (including TGF-alpha and TGF-beta), human growth hormone, transferrine, low density lipoprotein, high density lipoprotein (high density) lipoprotein, leptine, VEGF, PDGF, ciliary neurotrophic factor, prolactine, adrenocorticotropic hormone (ACTH), calcitonine, human chorionic gonadotropin (chrorionic gonadotropin), cortisol, estradiol, follicle stimulating hormone (FSH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH) ), Progesterone one), testosterone (testosterone), toxins including lysine (ricine) and the like
  • the therapeutically active agent can be selected from the group of drugs for the treatment of oncological diseases and cellular or tissue alterations.
  • Suitable therapeutic agents include alkyl sulfonates, for example busulfan, improsulfan, piposulfane, benzodepa, carboquone, metredepa.
  • Alkylating agents such as arizidine, such as uredepa; Ethyleneimine such as altretamine, triethylene melamine, triethylene phosphoramide, triethylene thiophosphoramide, trimethylolmelamine and Methylmelamine; Chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydro So-called nitrogen mustards such as chloride (mechlorethaminoxide hydrochloride), melphalan, nomobichin, phenesterine, prednimustine, trofosfamide, uracil mustard nitrogen mustard; Nitroso urea compounds such as carmustine, chlorozotocin, potenmustine, lomustine, nimustine, and ranimustine compound); dacarbazine, mannomustine, mitobranitol, mitoractol; Pipobroman;
  • Therapeutic actives include alaccinomycin, actinomycin, anthracycin, anthraceycin, azaserrin, bleomycin, cuctinomycin, carubicin, carubicin, Carzinophilin, chromomycin, ductinomycin, daunorbicin, 6-diazo-5-oxon-1-norycin (6-diazo-5-oxn- 1-norieucin, doxorubicin, epirubicin, mitomycin, mycophenolsaure, mogalumycin, olivomycin, peplomycin, peplomycin, Plicamycin, porfiromycin, poromycin, puromycin, streptonigrin, streptozocin, tubercidine, ubenimex, ubenimex, genostatin (zinostatin), zorubicin, aminoglycoside or It may be selected from Lien (polyene) or macrolide antibiotics (macrolid-antibiotics), and
  • Therapeutic actives include endostatin, angiostatin, interferon, platelet factor 4 (PF4), thrombospondin, transforming growth factor beta, metal Roperotinase-1.
  • Tissue inhibitor of the metalloproteinases -1, -2, and -3 TNP-470, marimastat, neovastat ( neovastat), BMS-275291, COL-3, AG3340, thalidomide, squalamin, combrestastatin, SU5416, SU6668, IFN- [alpha], EMD121974, CAI, IL-12 And radio-sensitizer drugs such as IM-862, steroidal or nonsteroidal anti-inflammatory drugs, or agents relating to angiogenesis, and combinations and / or derivatives thereof. have.
  • the therapeutically active agent may be selected from the group comprising nucleic acids, wherein the term nucleic acid is wherein at least two nucleotides are covalently linked to each other, for example to provide gene therapeutic or antisense effects. Oligonucleotides that are present.
  • the nucleic acid preferably comprises phosphodiester bonds and also includes analogs with different backbones. Analogs include, for example, phosphoramide phosphorothioate, phosphorodithioate, O-methylphosphoroamidit-compound, and peptide-nucleic acid backbones. (peptide-nukleic acid-backbone) and skeletons thereof, and the like.
  • nucleic acids having one or more carbocyclic sugars may be suitable as nucleic acids for use in the present invention.
  • any combination of naturally occurring nucleic acids and nucleic acid analogs or mixtures of nucleic acids and analogs may be used.
  • Therapeutic active agents are for example, everolimus, tacrolimus, sirolimus, mycophenololate-mofetil, rapamycin, paclitaxel ), Anti-mobility such as actinomycine D, angiopeptin, batimastate, estradiol, VEGF, statin and the like and derivatives and analogs thereof -migratory, anti-proliferative or immuno-suppresive, anti-inflammatory or re-endotheliating agents.
  • Anti-mobility such as actinomycine D, angiopeptin, batimastate, estradiol, VEGF, statin and the like and derivatives and analogs thereof -migratory, anti-proliferative or immuno-suppresive, anti-inflammatory or re-endotheliating agents.
  • Therapeutic active agents include opioid receptor agonists and antagonists, compounds exhibiting agonist / antagonistic activity and compounds exhibiting partial action, such as morphine, depomorphine, etropin, diacetyl morphine, hydromorphine, oxymorphone, levorpa Knoll, methadone, levomethadyl, meperidine, fentanyl, serpentanyl, alfentanil, codeine, hydrocodone, oxycodone, thebaine, desormorphine, nicomorphine, dipropanoylmorphine, benzylmorphine, ethylmorphine, pettidine , Methadone, tramadol, dextrosepropoxyphene; Naloxone and naltrexone; Buprenorphine, nalbuphine, butorpanol, pentazocin and ethyl ketocyclylacin.
  • opioid receptor agonists and antagonists compounds exhibiting agonist / antagonistic activity and compounds exhibiting partial action,
  • Therapeutic active agents and combinations thereof include heparin, synthetic heparin analogs (eg fondaparinux), hirudin, antithrombin III, drotrecogin alpha; Alteplase, plasmin, lysokinase, factor VIIa, prourokinase, urokinase, anistreplase, streptokinase fibrinolytics such as streptokinase; Platelet aggregation inhibitors such as acetylsalicylic acid (aspirine), ticlopidine, clopidogrel, abciximab, dextran and the like; Alclometasone, amcinonide, augmented betamethasone, beclomethasone, betamethasone, budesonide, cordesonide, clobetasol ( clobetasol, clocortolone, desonide, desoximetasone, dexamethasone, sexamethas
  • Partial adrenoceptor agonists such as dihydroergotamine
  • Fibronectin polylysine, ethylene vinyl acetate, TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM-CSF, IGF-a, IL-1, IL-8, IL- 6, inflammatory cytokine such as growth hormone
  • adhesive substances such as cyanoacrylate, beryllium, and silica
  • growth factors such as erythropoetin, corticotropin, gonadotropin, somatotropin, thyrotrophin, desmopressin, and ter Terlipressin, cytosine (pxytocin), cetrorelix, corticorelin, corticorelin, leuprorelin, triptorelin, gonadorelin, ganadorelin hormones such as (ganirelix), buserelin,
  • BMPs such as zoledronic acid, clodronic acid, etidronic acid, alendronic acid, and tiludronic acid, disodium fluoro Bone morphogenetic proteins (BMPs), which are fluorides such as phosphite and sodium fluoride; Calcitonin, dihydrotachystyrol; Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibrobast growth factor (FGFs), transforming growth factor (b) -b (TGFs-b)), transforming growth factors-a (TGFs-a), erythropoietin (EPO), insulin-like growth factor-I IGF-I)), insulin-like growth factor-II (IGF-II), interleukin-1 (IL-1), interleukin-2 (IL 2)), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis, zoledronic acid, clodronic acid, eti
  • Therapeutic active agents are, for example, alprazolam, amoxapine, betazepam, bromazepam, clolazepine, clovazam, clotiazepam, diazepam, lorazepam, flunitrazepam, flulazepam, lomezepam, Medazepam, nitrazepam, oxazepam, temazepam, maprotilin, myanserine, noritilline, risperidone, sertraline, trazodone, baloperidol, trimipramine malate fluoxetine, ondansetron, midazolam, chlor Promazine, haloperidol, triazolam, clozapine, fluoropromazine, flufenazine decanoate, fluanison, perfenazine, pimozide, prochlorperazine, sulfide, thiolidazine, parox
  • Therapeutic active agents are for example opioid receptor agonists and antagonists, compounds exhibiting mixed action / antagonist activity and compounds exhibiting partial action, such as morphine, depomorphine, etropin, diacetyl morphine, hydromorphine, oxymorphone , Levofanol, methadone, levomethadyl, meperidine, fentanyl, serpentanyl, alfentanil, codeine, hydrocodone, oxycodone, thebaine, desormorphine, nicomorphine, dipropanoylmorphine, benzylmorphine, ethylmorphine , Petidine, methadone, tramadol, dextrosepropoxyphene; Naloxone and naltrexone; Buprenorphine, nalbuphine, butorpanol, pentazocin and ethyl ketocyclylacin.
  • morphine depomorphine, etropin
  • diacetyl morphine hydromorphine
  • the therapeutically active agent can be, for example, tricyclic compounds including azothiopine, amitriptyline, pamotidine, promethazine, paroxatin, oxcabazapine and merthazapine.
  • Therapeutic active agents include, for example, antiacetic agents, including acetohexamide, chlorpropamide, glybenclide, glyclazide, glyphide, metformin, tolazamide, glyberid, glymepyride and tolbutamide It may be diabetes.
  • antiacetic agents including acetohexamide, chlorpropamide, glybenclide, glyclazide, glyphide, metformin, tolazamide, glyberid, glymepyride and tolbutamide It may be diabetes.
  • Therapeutic active agents are, for example, beclamid, carbamazepine, gafapentin, tiagabine, vigabatrin, topiramate, clonazepam, etotoin, metoin, methsimid, methylphenobabitone, ox Carbazepine, paramethadione, phenacemide, phenobarbitone, phenyloin, fenximide, primidone, sultiamine, phenytoin sodium, nitrocryptoin monohydrate, gabapentin, lamotrigine, zonisamide, ethoximide And valproic acid.
  • Therapeutic active agents include, for example, zolpidem tartrate, amylobarbitone, barbitone, butobabitone, pentobarbitone, brotizolam, carbromal, chlordiazepoxide, chlormethiazole, ethinamate, Hypnotics / sedatives and / or muscle relaxants, including meprobamate, metaquaalum, cyclobenzaprene, cyclobenzaprene, tizanidine, bacclifen, butalbital, zodiaclone, atraccurium, tubocurin and phenobarbital Can be.
  • Therapeutic active agents are, for example, amphotericin, butoconazole nitrate, clotrimazole, echonazol nitrate, fluconazole, flucitocin, griseoflubin, itraconazole, ketoconazole, myconazole, natamycin, nystatin, Sulfonazole nitrate, terconazole, thioconazole and undecenoic acid; Benzidazole, Clioquinol, Decoquinate, Diiodohydroxyquinoline, Diloxanide furoate, Dinitolamide, Furzolidone, Metronidazole, Nimorazol, Nitrofurazone, Ornidazole, Terbinafine, Clotritri Antifungal, antiprotozoal or antiparasitic agents, including mazol, chloroquine, mefloquine, itraconazole, pyrimethamine, prazicuantel, quinacrine, mebendazo
  • Therapeutic active agents are, for example, antidepressants that can be used, for example, candesartan, hydralazine, clonidine, triamterin, felodipine, cappibrozil, fenofibrate, nifedical, prazosin, mecamylamine, doxazosin, dobutamine, and cilexetil Hypertension or heart treatment.
  • antidepressants for example, candesartan, hydralazine, clonidine, triamterin, felodipine, cappibrozil, fenofibrate, nifedical, prazosin, mecamylamine, doxazosin, dobutamine, and cilexetil Hypertension or heart treatment.
  • the therapeutically active agent may be, for example, an antimigraine agent comprising dihydroergotamine mesylate, ergotamine tartrate, methisurged malate, pizotifen malate and sumatrippan succinate.
  • the therapeutically active agent can be an antimuscarinic agent, including, for example, atropine, benzhexol, biferdene, etopropazine, hydroxyamine, mefenzolate bromide, oxybutynin, oxyphencyclimine and trophamide have.
  • Therapeutic active agents are, for example, aminoglutetimides, amsacrine, azathioprine, busulfan, chlorambucil, cyclosporin, dacarbazine, estramastine, etoposide, romastin, melphalan, mercaptopurine Antineoplastic agents (or immunosuppressive agents), including, metoclexate, mitomycin, mitotans, mitoxanthrone, procarbazine, tamoxifen citrate, testosteroltone, tacrolimus, mercaptopurine and sirolimus Can be.
  • Therapeutic active agents are for example bromocriptine mesylate, levodopa, tolcapone, lopinitrol, bromocriptine, hypoglycemic agents such as sulfonylurea biguanides, alpha-glucosidase inhibitors, Anti-Parkinson's agents, including thiazolidinediones, cabergoline, carbidopa and lisuride malate.
  • the therapeutically active agent may be an antithyroid agent, including, for example, carbazole and propithiouracil.
  • the therapeutically active agent can be, for example, a cardiac muscle contractor including amlinone, milnonone, digitoxine, enoxymon, lanatoside C and medigoxin.
  • the therapeutically active agent can be hypolipidemia or hyperlipidemia, including, for example, fenofibrate, clofibrate, probucol, egestimib and tocetrapib.
  • the therapeutically active agent can be an anti-inflammatory agent, including, for example, meoxycham, triamcinolone, chromoline, nedocromyl, hydroxychloroquine, montelukast, giluton, zapyrucast and meloxycamp.
  • an anti-inflammatory agent including, for example, meoxycham, triamcinolone, chromoline, nedocromyl, hydroxychloroquine, montelukast, giluton, zapyrucast and meloxycamp.
  • Therapeutic active agents are, for example, pesofenadin, chloral hydrate, hydroxyzine, promethazine, cetyrazine, cimetidine, cclizin, meclizin, dimenhydrinate, loratabin, nizatabin and It may be an antihistamine including promethazine.
  • the therapeutically active agent may be an anti-ulcer agent including, for example, omeprazole, lansoprazole, pantoprazole and ranitidine.
  • the therapeutically active agent may be a diuretic including, for example, hydrochlorothiazide, amylolide, acetazolamide, furosemide, and torsemide.
  • the therapeutically active agent is, for example, a second occurrence, such as retinol, retinal, tretanoin (retinoic acid, retin-A), isotretinoin and alitretinoin, a second occurring retinoid, etretinate and its metabolite acitretin.
  • the therapeutically active agent can be, for example, statins including atorvastatin, fluvastatin, lovastatin, nystatin, roschvastatin, pravastatin, olistat and simvastatin and / or derivatives thereof.
  • the therapeutically active agent may be, for example, a stimulant including amphetamine, phentermine, tyramine, eiffelrin, metaramimin, phenylephrine, dexamphetamine, dexfenfluramine, fenfluramine, nicotine, caffeine and marginol.
  • a stimulant including amphetamine, phentermine, tyramine, eiffelrin, metaramimin, phenylephrine, dexamphetamine, dexfenfluramine, fenfluramine, nicotine, caffeine and marginol.
  • the therapeutically active agent may be a vasodilator including, for example, carvedilol, terazosin, pentolamin and menthol.
  • the therapeutically active agent can be, for example, an anti-alzheimer's agent including levetiracetam, levetiracetam and donepezil.
  • the therapeutically active agent may be, for example, an ACE inhibitor including benzapril, enalapril, ramipril, fosinopril sodium, ricinopril, minoxidil, isosorbide, lamprill and quinapril.
  • an ACE inhibitor including benzapril, enalapril, ramipril, fosinopril sodium, ricinopril, minoxidil, isosorbide, lamprill and quinapril.
  • the therapeutically active agent may be, for example, a beta adrenergic receptor antagonist, including atenolol, timolol, pindolol, pronanol hydrochloride, bisprolol, esmolol, metoprolol succinate, metoprolol and metoprolol tartrate.
  • a beta adrenergic receptor antagonist including atenolol, timolol, pindolol, pronanol hydrochloride, bisprolol, esmolol, metoprolol succinate, metoprolol and metoprolol tartrate.
  • the therapeutically active agent may be, for example, angiotensin II antagonist, including rozatan.
  • the therapeutically active agent may be a platelet inhibitor, including, for example, Absiksimab, clopidrogel, tyropiban and aspirin.
  • Therapeutic active agents are, for example, tramadol, tramadol hydrochloride, allopurinol, calcitriol, cilostazol, soltalol, urasodiol bromperidol, dropperidol, flufenticsol decanoate, albuterol, albuterol Alcohols or phenols including sulfate, carisoprodol, clobetasol, rofinirol, labetalol and metocarbamol.
  • the therapeutically active agent can be, for example, ketones or esters including amioderon, fluticasone, spironolactone, prednisone, triazonedon, desoxymethasone, methyl prednisone, benzonatate nabumethone and buspyrone .
  • the therapeutically active agent may be an antiemetic agent, including, for example, metoclopramide.
  • the therapeutically active agent may be, for example, an eye treatment comprising dorzolamide, brimonidine, olopatadine, cyclopenttolate, pilocarpine and ecothioate.
  • the therapeutically active agent may be an anticoagulant or antithrombotic agent, including, for example, warfarin, enoxaparin and repyrudine.
  • the therapeutically active agent may be, for example, a gout treatment comprising probenesin and sulfinpyrazone.
  • the therapeutically active agent may be, for example, a COPD or asthma treatment comprising ypratropium.
  • the therapeutically active agent can be, for example, a treatment for osteoporosis, including raloxifene, pamidronate and risedronate.
  • the therapeutically active agent can be, for example, a cosmetic peptide comprising acetyl hexapeptide-3, acetyl hexapeptide-8, acetyl octapeptide and l-carnosine.
  • Therapeutic active agents include, for example, vaccines comprising toxoids (inactivated toxic compounds); Proteins, protein subunits and polypeptides; Polynucleotides such as DNA and RNA; Conjugates; Vaccines comprising saponins, virosomes, murine and organic adjuvants such as jostaxax.
  • toxoids inactivated toxic compounds
  • Proteins, protein subunits and polypeptides Polynucleotides such as DNA and RNA
  • Conjugates such as DNA and RNA
  • Vaccines comprising saponins, virosomes, murine and organic adjuvants such as jostaxax.
  • Therapeutic active agents include, for example, coenzyme Q10 (or ubiquinone), ubiquinol or resveratrol; carotenoids such as ⁇ , ⁇ or ⁇ -carotene, lycopene, lutein, zeaxanthin and astaxanthin; Phytonutrients such as lycopene, lutein and cyaxanthin; Omega-3 fatty acids, including linoleic acid, conjugated linoleic acid, docosahexaenoic acid (DHA) and ericosapentaenoic acid (EPA) and their glycerol-esters; Vitamin D (D2, D3 and derivatives thereof), vitamin E ( ⁇ , ⁇ , ⁇ , ⁇ -tocopherol, or ⁇ , ⁇ , ⁇ , ⁇ -tocotrienol), vitamin A (retinol, retinal, retinoic acid and derivatives) Fat soluble vitamins including vitamin K (K1, K2, K3 and
  • Silica particles according to the present invention is a particle of silica (SiO 2 ) material, and has a particle size of nano size.
  • Silica nanoparticles according to the present invention is a porous particle, having nano-sized pores.
  • Porous silica particles according to the present invention may carry a bioactive material on its surface and / or pores.
  • Porous silica particles according to the present invention is a biodegradable particle, it is possible to release the bioactive material as it is biodegraded in the body when administered to the body carrying a bioactive material.
  • porous silica particles are biodegraded, the bioactive material is released, and the porous silica particles according to the present invention may be slowly decomposed in the body so that the supported bioactive material may have sustained release.
  • t which becomes the ratio of the absorbance of following formula (1) 1/2 is 24 or more.
  • a 0 is the absorbance of the porous silica particles measured by placing 5 ml of the 1 mg / ml suspension of the porous silica particles into a cylindrical permeable membrane having pores having a diameter of 50 kDa,
  • the pH of the suspension is 7.4,
  • a t is the absorbance of the porous silica particles measured after t hours have elapsed since the measurement of A 0 ).
  • Equation 1 means that the rate at which the porous silica particles are degraded in an environment similar to the body.
  • Absorbance A 0 , A t in Equation 1 may be measured by putting porous silica particles and a suspension in a cylindrical permeable membrane and putting the same suspension outside the permeable membrane, as illustrated in FIG. 7.
  • the porous silica particles of the present invention are biodegradable, and can be slowly decomposed in suspension, 50 kDa in diameter corresponds to about 5 nm, and biodegradable porous silica particles can pass through a permeable membrane of 50 kDa in diameter, and a cylindrical permeable membrane is 60 rpm horizontal. Under stirring, the suspension can be mixed evenly and the degraded porous silica particles can come out of the permeable membrane.
  • the absorbance in Equation 1 may be measured, for example, in an environment in which the suspension outside the permeable membrane is replaced with a new suspension.
  • the suspension may be one that is constantly replaced, one that may be replaced every period, and the period may be periodic or irregular. For example, within the range of 1 hour to 1 week, 1 hour interval, 2 hours interval, 3 hours interval, 6 hours interval, 12 hours interval, 24 hours interval, 2 days interval, 3 days interval, 4 days interval, 7 It may be replaced at day intervals, but is not limited thereto.
  • the ratio of the absorbance to 1/2 means that after t hours the absorbance is half of the initial absorbance, which means that approximately half of the porous silica particles are decomposed.
  • the suspension may be a buffer solution, for example, at least one selected from the group consisting of phosphate buffered saline (PBS) and simulated body fluid (SBF), and more specifically, PBS.
  • PBS phosphate buffered saline
  • SBF simulated body fluid
  • T in which the ratio of absorbance of Equation 1 according to the present invention is 1/2 is 24 or more, for example, t may be 24 to 120, for example, within the range of 24 to 96, 24 to 72, 30 to 70, 40 to 70, 50 to 65 and the like, but is not limited thereto.
  • the porous silica particles according to the present invention may be, for example, 70 to 140, where t is the ratio of absorbance of Equation 1 to 1/5, for example, 80 to 140, 80 to 120, and 80 to 80 within the above range. 110, 70 to 140, 70 to 120, 70 to 110 and the like, but is not limited thereto.
  • the porous silica particles according to the present invention may be, for example, 130 to 220 in which the ratio of the absorbance of Equation 1 is 1/20, for example, 130 to 200, 140 to 200, 140 to 140 within the above range. 180, 150 to 180, and the like, but is not limited thereto.
  • the porous silica particles according to the present invention may have a measured absorbance of 0.01 or less, for example, 250 or more, for example, 300 or more, 350 or more, 400 or more, 500 or more, 1000 or more, and the upper limit thereof is 2000. It may be, but is not limited thereto.
  • the ratio of the absorbance of Formula 1 and t have a high positive correlation, for example, the Pearson correlation coefficient may be 0.8 or more, for example, 0.9 or more and 0.95 or more. have.
  • T in Equation 1 means how fast the porous silica particles decompose in an environment similar to the body, for example, the surface area, particle diameter, pore diameter, surface and / or inside the pores of the porous silica particles. It can be controlled by controlling the substituent, the degree of compactness of the surface, and the like.
  • the surface area of the particles can be increased to reduce t, or the surface area can be reduced to increase t.
  • the surface area can be adjusted by adjusting the diameter of the particles and the diameter of the pores.
  • t can be increased by reducing the direct exposure of porous silica particles to the environment (such as solvents).
  • the surface may be made more densely at the time of preparation of the particles to increase t.
  • Porous silica particles according to the present invention may be, for example, spherical particles, but is not limited thereto.
  • Porous silica particles according to the present invention may have an average diameter of, for example, 150nm to 1000nm, for example within the above range, for example 150nm to 800nm, 150nm to 500nm, 150nm to 400nm, 150nm to 300nm, 150nm to 200nm It may be, but is not limited thereto.
  • the porous silica particles according to the present invention may have an average pore diameter of, for example, 1 nm to 100 nm, for example, within the above range, for example, 5 nm to 100 nm, 7 nm to 100 nm, 7 nm to 50 nm, 10 nm to 50 nm, 10 nm to It may be 30nm, 7nm to 30nm, but is not limited thereto. Having a large diameter as described above can carry a large amount of bioactive material, it is possible to carry a large size of the bioactive material.
  • the porous silica particles according to the present invention may have a BET surface area of, for example, 200 m 2 / g to 700 m 2 / g.
  • a BET surface area of, for example, 200 m 2 / g to 700m 2 / g.
  • 200m 2 / g to 650m 2 / g 250m 2 / g to 650m 2 / g
  • 300m 2 / g to 700m 2 / g 300m 2 / g to 650m 2 / g
  • 300m 2 / g to 600m 2 / g 300m 2 / g to 550m 2 / g
  • Silica nanoparticles according to the present invention may have a volume per g, for example, 0.7 ml to 2.2 ml.
  • a volume per g for example, 0.7 ml to 2.2 ml.
  • Silica nanoparticles according to the present invention may have a volume per g, for example, 0.7 ml to 2.2 ml.
  • 0.7ml to 2.0ml 0.8ml to 2.2ml, 0,8ml to 2.0ml, 0.9ml to 2.0ml, 1.0ml to 2.0ml and the like, but is not limited thereto. If the volume per gram is too small, the rate of decomposition may be too high, and excessively large particles may be difficult to manufacture or may not have an intact shape.
  • Porous silica particles according to the present invention may have hydrophilic substituents and / or hydrophobic substituents on the outer surface and / or inside the pores.
  • hydrophilic substituents may exist on both the surface and inside of the pores, or only hydrophobic substituents may exist, hydrophilic substituents may exist on the surface or inside of the pores, hydrophobic substituents may exist on the surface, hydrophilic substituents on the surface, and hydrophobic substituents inside the pores. It may be present and vice versa.
  • the release of the bioactive material supported on the porous silica particles is mainly performed by the decomposition of the nanoparticles, and the interaction of the porous silica particles with respect to the bioactive material release environment is controlled by the control of the substituents.
  • the rate of degradation may be controlled to control the release rate of the bioactive material.
  • the bioactive material may be diffused and released from the nanoparticles, and the binding force of the bioactive material to the nanoparticles may be controlled by controlling the substituents. Active substance release can be controlled.
  • hydrophobic substituents are present inside the pores to enhance binding to poorly soluble (hydrophobic) bioactive substances, and the surface of the particles may be treated with hydrophilic substituents in view of ease of use and formulation.
  • Hydrophilic substituents are, for example, hydroxyl groups, carboxy groups, amino groups, carbonyl groups, sulfhydryl groups, phosphate groups, thiol groups, ammonium groups, ester groups, imide groups, thiimide groups, keto groups, ether groups, indene groups, sulfonyl groups, polyethylene Glycol groups and the like
  • the hydrophobic substituent is, for example, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C30 cycloalkyl group, substituted or unsubstituted C6 to C30 aryl group, substituted Or an unsubstituted C2 to C30 heteroaryl group, a halogen group, a C1 to C30 ester group, a halogen-containing group, or the like.
  • the porous silica particles according to the present invention may be one in which the outer surface and / or the inside of the pores are positively and / or negatively charged.
  • both the surface and the inside of the pore may be positively charged, or may be negatively charged, only the surface or the inside of the pore may be positively charged, or may be negatively charged, the surface may be positively charged, and the interior of the pore may be negatively charged. The reverse is also possible.
  • the charging may be, for example, by the presence of a cationic substituent or an anionic substituent.
  • the cationic substituent may be, for example, an amino group or other nitrogen-containing group as the basic group, and the anionic substituent may be, for example, a carboxy group (-COOH), sulfonic acid group (-SO 3 H), thiol group (- SH) and the like, but is not limited thereto.
  • the interaction of the porous silica particles with respect to the physiologically active substance releasing environment is controlled by the charging of the substituent so that the decomposition rate of the nanoparticles can be controlled to regulate the physiologically active substance release rate, and also, the physiological activity
  • the material may be diffused from the nanoparticles and released, and the binding force of the bioactive material to the nanoparticles may be controlled by controlling the substituents, thereby controlling the release of the bioactive material.
  • porous silica particles according to the present invention may be carried on the surface and / or the pores in addition to the support of the bioactive material, the transfer of the bioactive material to the target cell, the support of the material for other purposes, or other additional substituents.
  • Substituents for such may be present, and may further include antibodies, ligands, cell permeable peptides, or aptamers bound thereto.
  • Substituents, charges, binders and the like within the aforementioned surfaces and / or pores may be added, for example, by surface modification.
  • Surface modification can be carried out, for example, by reacting a compound having a substituent to be introduced with the particles, which may be, for example, an alkoxysilane having a C1 to C10 alkoxy group, but is not limited thereto.
  • the alkoxysilane has one or more alkoxy groups, and may have, for example, 1 to 3, and there may be a substituent to be introduced into a site where the alkoxy group is not bonded or a substituent substituted therewith.
  • the porous silica particles of the present invention may be prepared through a small pore particle preparation and a pore expansion process, and may be manufactured through a calcination process, a surface modification process, and the like, as necessary. If both the calcination and surface modification process has gone through may be surface modified after calcination.
  • the small pore particles may be, for example, particles having an average pore diameter of 1 nm to 5 nm.
  • Small pore particles can be obtained by adding a surfactant and a silica precursor to a solvent, stirring and homogenizing.
  • the solvent may be water and / or an organic solvent
  • the organic solvent may be, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Acetone, methyl isobutyl ketone, ⁇ -butyrolactone, 1,3-dimethyl-imidazolidinone, methyl ethyl ketone, cyclohexanone, cyclopentanone, 4-hydroxy-4-methyl-2-pentanone, etc.
  • ethers such as 1,4-dioxane (particularly cyclic ethers)
  • Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachlor
  • Ketones Carbon-based aromatics such as benzene, toluene, xylene and tetramethylbenzene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; Ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, ethylene glycol monobutyl ether, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether Glycol ethers (cellosolve) such as dipropylene glycol diethyl ether and triethylene glycol monoethyl ether; Dimethylacetamide (DMAc), N, N-diethylacetamide,
  • the ratio may be, for example, water and an organic solvent in a volume ratio of 1: 0.7 to 1.5, for example, 1: 1: 0.8 to 1.3, but is not limited thereto.
  • the surfactant may be, for example, cetyltrimethylammonium bromide (CTAB), hexadecyltrimethylammonium bromide (TMABr), hexadecyltrimethylpyridinium chloride (TMPrCl), tetramethylammonium chloride (TMACl), and the like, and specifically, CTAB may be used.
  • CTAB cetyltrimethylammonium bromide
  • TMABr hexadecyltrimethylammonium bromide
  • TMPrCl hexadecyltrimethylpyridinium chloride
  • TMACl tetramethylammonium chloride
  • the surfactant may be added in an amount of, for example, 1 g to 10 g, for example, 1 g to 8 g, 2 g to 8 g, 3 g to 8 g, etc., per liter of solvent, but is not limited thereto.
  • the silica precursor may be added after stirring with the addition of a surfactant to the solvent.
  • the silica precursor may be, for example, tetramethyl orthosilicate (TMOS), but is not limited thereto.
  • the stirring may be performed, for example, for 10 minutes to 30 minutes, but is not limited thereto.
  • the silica precursor may be added, for example, 0.5 ml to 5 ml per liter of solvent, for example, 0.5 ml to 4 ml, 0.5 ml to 3 ml, 0.5 ml to 2 ml, 1 ml to 2 ml, etc. within the above range, but is not limited thereto. It is not.
  • sodium hydroxide may be further used as a catalyst, which may be added with stirring after adding the surfactant to the solvent and before adding the silica precursor.
  • Sodium hydroxide may be, for example, 0.5 ml to 8 ml per liter of solvent, for example, 0.5 ml to 5 ml, 0.5 ml to 4 ml, 1 ml to 4 ml, 1 ml to 3 ml, 2 ml to 3 ml, etc., based on 1 M aqueous sodium hydroxide solution.
  • the present invention is not limited thereto.
  • the solution can be reacted with stirring.
  • the stirring may be performed for example, for 2 hours to 15 hours, for example, within the above range, for example, 3 hours to 15 hours, 4 hours to 15 hours, 4 hours to 13 hours, 5 hours to 12 hours, 6 hours to 12 hours. , 6 hours to 10 hours, but is not limited thereto. If the stirring time (reaction time) is too short, nucleation may be insufficient.
  • the solution may be aged. Aging may be performed for example, for 8 hours to 24 hours, for example, within the range of 8 hours to 20 hours, 8 hours to 18 hours, 8 hours to 16 hours, 8 hours to 14 hours, 10 hours to 16 hours. , 10 hours to 14 hours, but is not limited thereto.
  • reaction product may be washed and dried to obtain porous silica particles.
  • separation of unreacted material may be preceded before washing.
  • Separation of the unreacted material can be carried out by separating the supernatant, for example by centrifugation.
  • Centrifugation can be carried out, for example, at 6,000 to 10,000 rpm, the time being for example 3 to 60 minutes, for example 3 to 30 minutes, 3 to 30 minutes, 5 minutes to within the above range. It may be performed in 30 minutes, but is not limited thereto.
  • the washing may be performed with water and / or an organic solvent, and in particular, since the substances that can be dissolved for each solvent may be different, water and an organic solvent may be used once or several times, and water or an organic solvent may be used only once or several times.
  • the number of times may be, for example, two or more, ten or less, for example, three or more and ten or less, four or more and eight or less, four or more and six or less.
  • the organic solvent is, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Acetone, methyl isobutyl ketone, ⁇ -butyrolactone, 1,3-dimethyl-imidazolidinone, methyl ethyl ketone, cyclohexanone, cyclopentanone, 4-hydroxy-4-methyl-2-pentanone, etc.
  • ethers such as 1,4-dioxane (particularly cyclic ethers)
  • Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloro
  • Ketones Carbon-based aromatics such as benzene, toluene, xylene and tetramethylbenzene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; Ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, ethylene glycol monobutyl ether, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether Glycol ethers (cellosolve) such as dipropylene glycol diethyl ether and triethylene glycol monoethyl ether; Dimethylacetamide (DMAc), N, N-diethylacetamide,
  • Washing may be carried out under centrifugation, for example at 6,000 to 10,000 rpm, the time being for example 3 to 60 minutes, for example 3 to 30 minutes, 3 minutes within this range. To 30 minutes, 5 minutes to 30 minutes, etc., but is not limited thereto.
  • Washing may be performed by filtering out particles with a filter without centrifugation.
  • the filter may have pores less than or equal to the diameter of the porous silica particles. If the reaction solution is filtered through such a filter, only particles remain on the filter, and water and / or an organic solvent can be poured over the filter and washed.
  • water and an organic solvent When washing, water and an organic solvent may be used one or several times, and may be washed once or several times with water or an organic solvent alone.
  • the number of times may be, for example, two or more, ten or less, for example, three or more and ten or less, four or more and eight or less, four or more and six or less.
  • Drying may be performed, for example, at 20 ° C. to 100 ° C., but is not limited thereto, and may be performed in a vacuum state.
  • Pore expansion can be performed using pore expanding agents.
  • the pore swelling agent may be trimethylbenzene, triethylbenzene, tripropylbenzene, tributylbenzene, tripentylbenzene, trihexylbenzene, toluene, benzene, and the like, and specifically, trimethylbenzene may be used, but is not limited thereto. It doesn't happen.
  • the pore swelling agent may use, for example, N, N-dimethylhexadecylamine (N, N-dimethylhexadecylamine, DMHA), but is not limited thereto.
  • Pore expansion can be carried out, for example, by mixing porous silica particles in a solvent with a pore swelling agent and heating to react.
  • the solvent may be, for example, water and / or an organic solvent
  • the organic solvent may be, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Ketones such as acetone, methyl isobutyl ketone and cyclohexanone; Carbon-based aromatics such as benzene, toluene and xylene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; Or the like
  • the porous silica particles are, for example, 10 g to 200 g per liter of solvent, for example, 10 g to 150 g, 10 g to 100 g, 30 g to 100 g, 40 g to 100 g, 50 g to 100 g, 50 g to 80 g, 60 g to 80 g, etc., within the above range. It may be added in a ratio, but is not limited thereto.
  • the porous silica particles may be evenly dispersed in a solvent, for example, the porous silica particles may be added to the solvent and ultrasonically dispersed.
  • the second solvent may be added after the porous silica particles are dispersed in the first solvent.
  • the pore swelling agent is, for example, 10 to 200 parts by volume, 100 to 150 parts by volume, 10 to 100 parts by volume, 10 to 80 parts by volume, 30 to 80 parts by volume, 30 to 70 parts by volume based on 100 parts by volume of solvent. It may be added in a ratio such as volume parts, but is not limited thereto.
  • the reaction can be carried out, for example, at 120 ° C to 180 ° C.
  • 120 ° C to 170 °C, 120 °C to 160 °C, 120 °C to 150 °C, 130 °C to 180 °C, 130 °C to 170 °C, 130 °C to 160 °C, 130 °C to 150 °C It may be performed, but is not limited thereto.
  • the reaction can be carried out, for example, for 24 hours to 96 hours.
  • 24 hours to 96 hours for example, within the range of 30 hours to 96 hours, 30 hours to 96 hours, 30 hours to 80 hours, 30 hours to 72 hours, 24 hours to 80 hours, 24 hours to 72 hours, 36 hours to 96 hours, 36 36 hours to 80 hours, 36 hours to 72 hours, 36 hours to 66 hours, 36 hours to 60 hours, 48 hours to 96 hours, 48 hours to 88 hours, 48 hours to 80 hours, 48 hours to 72 hours, etc. It is not limited to this.
  • the time and temperature can be adjusted within the ranges exemplified above so that the reaction can be carried out sufficiently without excess. For example, when the reaction temperature is lowered, the reaction time may be increased, or when the reaction temperature is lowered, the reaction time may be shortened. If the reaction is not sufficient, the expansion of the pores may not be sufficient, and if the reaction proceeds excessively, the particles may collapse due to the expansion of the pores.
  • the reaction can be carried out, for example, by gradually raising the temperature. Specifically, it may be carried out by gradually increasing the temperature at a rate of 0.5 °C / min to 15 °C / min from the room temperature to the temperature, for example, 1 °C / min to 15 °C / min, 3 °C / min within the above range To 15 ° C./minute, 3 ° C./minute to 12 ° C./minute, 3 ° C./minute to 10 ° C./minute, and the like, but are not limited thereto.
  • the reaction liquid can be cooled slowly, for example, it can be cooled by gradually reducing the temperature. Specifically, it may be carried out by gradually decreasing the temperature at a rate of 0.5 °C / min to 20 °C / min from the temperature to room temperature, for example, from 1 °C / min to 20 °C / min, 3 °C / min to within the above range 20 ° C./minute, 3 ° C./minute to 12 ° C./minute, 3 ° C./minute to 10 ° C./minute, and the like, but is not limited thereto.
  • reaction product After cooling, the reaction product can be washed and dried to obtain porous silica particles with expanded pores.
  • separation of unreacted material may be preceded before washing.
  • Separation of the unreacted material can be carried out by separating the supernatant, for example by centrifugation.
  • Centrifugation can be carried out, for example, at 6,000 to 10,000 rpm, the time being for example 3 to 60 minutes, for example 3 to 30 minutes, 3 to 30 minutes, 5 minutes to within the above range. It may be performed in 30 minutes, but is not limited thereto.
  • the washing may be performed with water and / or an organic solvent, and in particular, since the substances that can be dissolved for each solvent may be different, water and an organic solvent may be used once or several times, and water or an organic solvent may be used only once or several times.
  • the number of times may be, for example, two or more times, ten times or less, for example, three times, four times, five times, six times, seven times, eight times, and the like.
  • the organic solvent is, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Ketones such as acetone, methyl isobutyl ketone and cyclohexanone; Carbon-based aromatics such as benzene, toluene and xylene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; Or the like, and specifically, alcohol, more specifically ethanol, may be used, but is not limited
  • Washing may be carried out under centrifugation, for example at 6,000 to 10,000 rpm, the time being for example 3 to 60 minutes, for example 3 to 30 minutes, 3 minutes within this range. To 30 minutes, 5 minutes to 30 minutes, etc., but is not limited thereto.
  • Washing may be performed by filtering out particles with a filter without centrifugation.
  • the filter may have pores less than or equal to the diameter of the porous silica particles. If the reaction solution is filtered through such a filter, only particles remain on the filter, and water and / or an organic solvent can be poured over the filter and washed.
  • water and an organic solvent When washing, water and an organic solvent may be used one or several times, and may be washed once or several times with water or an organic solvent alone.
  • the number of times may be, for example, two or more, ten or less, for example, three or more and ten or less, four or more and eight or less, four or more and six or less.
  • Drying may be performed, for example, at 20 ° C. to 100 ° C., but is not limited thereto, and may be performed in a vacuum state.
  • the particles obtained can then be calcined.
  • Calcination is a process of heating the particles to have a more dense structure on the surface and the inside, and removing the organic substances filling the pores, for example, 3 to 8 hours at 400 °C to 700 °C, specifically 500 to 600 It may be performed at 4 °C to 5 hours, but is not limited thereto.
  • porous silica particles may be surface modified.
  • Surface modification can be performed inside the surface and / or pores.
  • the particle surface and the inside of the pore may be surface-modified identically or may be surface-modified differently.
  • Surface modification can cause the particles to charge or to have hydrophilic and / or hydrophobic properties.
  • Surface modification can be carried out, for example, by reacting a compound having substituents such as hydrophilic, hydrophobic, cationic, anionic and the like to be introduced with the particles, and the compound can be, for example, an alkoxysilane having a C1 to C10 alkoxy group.
  • the alkoxysilane has one or more alkoxy groups, and may have, for example, 1 to 3, and there may be a substituent to be introduced into a site where the alkoxy group is not bonded or a substituent substituted therewith.
  • the alkoxysilane reacts with the porous silicon particles, a covalent bond is formed between the silicon atom and the oxygen atom so that the alkoxysilane can be bonded to the surface and / or inside the pores of the porous silicon particle, and the alkoxysilane has a substituent to be introduced.
  • the substituents may be introduced into the surface and / or the pores of the porous silicon particles.
  • the reaction may be carried out by reacting porous silica particles dispersed in a solvent with an alkoxysilane.
  • the solvent may be water and / or an organic solvent
  • the organic solvent may be, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Acetone, methyl isobutyl ketone, ⁇ -butyrolactone, 1,3-dimethyl-imidazolidinone, methyl ethyl ketone, cyclohexanone, cyclopentanone, 4-hydroxy-4-methyl-2-pentanone, etc.
  • ethers such as 1,4-dioxane (particularly cyclic ethers)
  • Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachlor
  • Ketones Carbon-based aromatics such as benzene, toluene, xylene and tetramethylbenzene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; Ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, ethylene glycol monobutyl ether, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether Glycol ethers (cellosolve) such as dipropylene glycol diethyl ether and triethylene glycol monoethyl ether; Dimethylacetamide (DMAc), N, N-diethylacetamide,
  • Charging to a positive charge can be carried out by reacting with an alkoxysilane having a basic group such as a nitrogen-containing group such as an amino group or an aminoalkyl group.
  • an alkoxysilane having a basic group such as a nitrogen-containing group such as an amino group or an aminoalkyl group.
  • Charging to the negative charge can be carried out by reacting with an alkoxysilane having an acidic group such as a carboxyl group, a sulfonic acid group, a thiol group, and the like.
  • an alkoxysilane having an acidic group such as a carboxyl group, a sulfonic acid group, a thiol group, and the like.
  • 3-Mercaptopropyl) trimethoxysilane may be used, but is not limited thereto.
  • Hydrophilic properties include hydrophilic groups such as hydroxy groups, carboxy groups, amino groups, carbonyl groups, sulfhydryl groups, phosphate groups, thiol groups, ammonium groups, ester groups, imide groups, thiimide groups, keto groups, ether groups, indene groups, sulfonyl groups And an alkoxysilane having a polyethylene glycol group or the like.
  • Hydrophobic properties include hydrophobic substituents such as substituted or unsubstituted C1 to C30 alkyl groups, substituted or unsubstituted C3 to C30 cycloalkyl groups, substituted or unsubstituted C6 to C30 aryl groups, substituted or unsubstituted C2 It can be made to react with the alkoxysilane which has a heteroaryl group of C30-C30, a halogen group, an ester group of C1-C30, a halogen containing group, etc.
  • Trimethoxy (octadecyl) silane, Trimethoxy-n-octylsilane, Trimethoxy (propyl) silane, Isobutyl (trimethoxy) silane, Trimethoxy (7-octen-1-yl) silane, Trimethoxy (3,3,3-trifluoropropyl) Silane, Trimethoxy (2-phenylethyl) silane, Vinyltrimethoxysilane, Cyanomethyl, 3- (trimethoxysilyl) propyl] trithiocarbonate, (3-Bromopropyl) trimethoxysilane, etc. may be used, but is not limited thereto.
  • hydrophobic substituents are present inside the pores to enhance the bonding ability with poorly water-soluble (hydrophobic) bioactive substances through surface modification, and the surface of the particles has hydrophilic substituents in terms of ease of use and formulation. May be treated, and a substituent may be present on the surface to bind other substances.
  • Surface modification may also be carried out in combination. For example, two or more surface modifications may be performed on the outer surface or inside the pores. As a specific example, it is possible to change the positively charged particles to have different surface properties by binding a compound containing a carboxyl group to an amide bond with silica particles into which amino groups are introduced, but are not limited thereto.
  • the reaction of the porous silica particles with alkoxysilanes can be carried out, for example, under heating.
  • the heating is performed at 80 ° C to 180 ° C, for example, at 80 ° C to 160 ° C, 80 ° C to 150 ° C, 100 ° C to 160 ° C, 100 ° C to 150 ° C, 110 ° C to 150 ° C, and the like within the above range. It may be, but is not limited thereto.
  • the reaction of the porous silica particles with the alkoxysilane is for example 4 to 20 hours, for example 4 to 18 hours, 4 to 16 hours, 6 to 18 hours, 6 to 16 hours, 8 hours to 18 hours, 8 hours to 16 hours, 8 hours to 14 hours, 10 hours to 14 hours, etc., but is not limited thereto.
  • the reaction temperature, time, and the amount of the compound used for surface modification may be selected according to the degree of surface modification, and the porous silica particles may be changed depending on the hydrophilicity, hydrophobicity, and charge of the bioactive material.
  • the degree of hydrophilicity, hydrophobicity, and charge By controlling the degree of hydrophilicity, hydrophobicity, and charge, the rate of release of the bioactive substance can be controlled. For example, if the bioactive material has a strong negative charge at neutral pH, the reaction temperature can be increased or the reaction time can be increased, and the compound throughput can be increased, so that the porous silica particles have a strong positive charge.
  • the present invention is not limited thereto.
  • porous silica particles according to an embodiment of the present invention may be produced by, for example, the preparation of particles of small pores, pore expansion, surface modification, internal pore modification process.
  • the small pore particle preparation and pore expansion process may be based on the above-described process, and the washing and drying process may be performed after the small pore particle production and after the pore expansion process.
  • separation of unreacted material may be preceded before washing.
  • Separation of the unreacted material can be carried out by separating the supernatant, for example by centrifugation.
  • Centrifugation can be carried out, for example, at 6,000 to 10,000 rpm, and the time is, for example, 3 to 60 minutes, specifically, 3 to 30 minutes, 3 to 30 minutes, 5 minutes to within the above range. It may be performed in 30 minutes, but is not limited thereto.
  • the washing after the preparation of the particles of the small pores may be performed by a method / condition within the ranges exemplified above, but is not limited thereto.
  • Washing after pore expansion can be carried out in more relaxed conditions than previously illustrated. For example, washing may be performed within three times, but is not limited thereto.
  • Surface modification and internal pore modification may be by the processes as described above, respectively, the process may be carried out in the order of surface modification and internal pore modification, and the washing process of the particles may be further performed between the two processes. have.
  • the reaction solution such as the surfactant used in the preparation of the particles and the expansion of the pores is filled in the pores so that the inside of the pores is not modified during surface modification. Only the surface can be modified. Then, washing the particles may remove the reaction solution in the pores.
  • Particle washing between surface modification and internal pore reforming can be done with water and / or an organic solvent, and in particular, different solvents can be used to dissolve the water and the organic solvent once or several times.
  • the organic solvent alone may be washed once or several times.
  • the number of times may be, for example, two or more, ten or less, specifically, three or more and ten or less, four or more and eight or less, four or more and six or less.
  • Washing may be carried out under centrifugation, for example at 6,000 to 10,000 rpm, the time being for example 3 to 60 minutes, specifically 3 to 30 minutes, 3 minutes within this range. To 30 minutes, 5 minutes to 30 minutes, etc., but is not limited thereto.
  • Washing may be performed by filtering out particles with a filter without centrifugation.
  • the filter may have pores less than or equal to the diameter of the porous silica particles. If the reaction solution is filtered through such a filter, only particles remain on the filter, and water and / or an organic solvent can be poured over the filter and washed.
  • water and an organic solvent When washing, water and an organic solvent may be used one or several times, and may be washed once or several times with water or an organic solvent alone.
  • the number of times may be, for example, two or more, ten or less, specifically, three or more and ten or less, four or more and eight or less, four or more and six or less.
  • Drying may be performed, for example, at 20 ° C. to 100 ° C., but is not limited thereto, and may be performed in a vacuum state.
  • the bioactive material may be supported on the surface of the porous silica particles and / or inside the pores.
  • Support may be carried out, for example, by mixing porous silica particles and a bioactive material in a solvent.
  • the solvent may be water and / or an organic solvent
  • the organic solvent may be, for example, ethers such as 1,4-dioxane (particularly cyclic ethers); Halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, dichloroethylene, trichloroethylene, perchloroethylene, dichloropropane, amyl chloride and 1,2-dibromoethane; Ketones such as acetone, methyl isobutyl ketone and cyclohexanone; Carbon-based aromatics such as benzene, toluene and xylene; Alkyl amides such as N, N-dimethylformamide, N, N-dibutylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Alcohols such as methanol, ethanol, propanol and butanol; Etc. can be used.
  • PBS phosphate buffered saline solution
  • SBF Simulated Body Fluid
  • Borate-buffered saline Borate-buffered saline
  • Tris-buffered saline may be used as a solvent.
  • the ratio of the porous silica particles and the bioactive material is not particularly limited.
  • the weight ratio is 1: 0.05 to 0.8, for example, 1: 0.05 to 0.7, 1: 0.05 to 0.6, 1: 0.1 to 0.8 within the above range. , 1: 0.1 to 0.6, 1: 0.2 to 0.8, 1: 0.2 to 0.6, and the like.
  • the bioactive material supported on the porous silica particles may be gradually released over an extended time. Such slow release may be continuous or discontinuous, linear or nonlinear, and may vary due to the nature of the porous silica particles and / or their interaction with the bioactive material.
  • the bioactive material supported on the porous silica particles is released as the porous silica particles are biodegraded, and the porous silica particles according to the present invention may be slowly decomposed to release the supported bioactive materials in a sustained manner. This may be controlled by, for example, adjusting the surface area, particle diameter, pore diameter, substituents in the surface and / or pores, degree of compactness of the porous silica particles, and the like, but are not limited thereto.
  • the bioactive material supported on the porous silica particles may be released while being diffused from the porous silica particles, which is affected by the relationship between the porous silica particles, the bioactive material and the bioactive material emitting environment.
  • the release of bioactive substances For example, it can be controlled by strengthening or weakening the binding strength of the porous silica particles with the bioactive material by surface modification.
  • the surface and / or the inside of the pores may have hydrophobic substituents, thereby increasing the bonding strength between the porous silica particles and the bioactive material, Thereby, the bioactive substance can be released in a sustained manner.
  • This may be, for example, the surface-modified porous silica particles with an alkoxysilane having a hydrophobic substituent.
  • “poorly soluble” means to be insoluble (practically insoluble) or only slightly soluble (with respect to water), which means “Pharmaceutical Science” 18 th Edition ( USP, Remington, Mack Publishing Company).
  • the poorly water-soluble bioactive substance may be, for example, water solubility at less than 10 g / L, specifically less than 5 g / L, more specifically less than 1 g / L at 1 atmosphere and 25 ° C., but is not limited thereto.
  • the surface and / or the inside of the pore may have a hydrophilic substituent, thereby increasing the binding force between the porous silica particles and the bioactive material, whereby the bioactive material is sustained. May be released.
  • This may be, for example, the surface-modified porous silica particles with an alkoxysilane having a hydrophilic substituent.
  • the water-soluble bioactive substance may have a water solubility of 10 g / L or more at 1 atmosphere and 25 ° C., but is not limited thereto.
  • the surface of the particle and / or the inside of the pore may be charged with the opposite charge, thereby increasing the binding force between the porous silica particles and the bioactive material, whereby the bioactive material is This can be released slowly.
  • This may be, for example, the surface-modified porous silica particles with an alkoxysilane having an acidic group or a basic group.
  • the surface of the particles and / or the inside of the pores may be negatively charged at the neutral pH, whereby the binding force between the porous silica particles and the bioactive material is increased.
  • bioactives may be released in a sustained manner.
  • the porous silica particles may be surface-modified with an alkoxysilane having an acidic group such as a carboxyl group (-COOH) and a sulfonic acid group (-SO 3 H).
  • the surface of the particles and / or the inside of the pores may be positively charged, thereby increasing the binding force between the porous silica particles and the bioactive material, thereby increasing the bioactive material. This can be released slowly.
  • the porous silica particles may be surface-modified with an alkoxysilane having a basic group such as an amino group or another nitrogen-containing group.
  • the bioactive material may be released for a period of, for example, 7 days to 1 year or more, depending on the type of treatment required, the release environment, and the porous silica particles used.
  • porous silica particles according to the present invention may be 100% decomposed as biodegradable, the bioactive material supported thereon may be released 100%.
  • Bioactive substance carriers of the invention may be formulated for delivery via any route of administration.
  • Route of administration can refer to any route of administration known in the art including, but not limited to, aerosol, nasal, oral, transmucosal, transdermal, parenteral or intestine.
  • porous silica particles according to the present invention are biodegradable and can be 100% decomposed, and thus can be parenterally administered because of excellent stability in the body, and thus can be formulated into preparations for parenteral administration.
  • Parenteral means orbital, intraocular, intravenous, intraarterial, intraarticular, intracardiac, dermal, intramuscular, intraperitoneal, intrapulmonary, spinal cord, intrasternal, intravertebral, intrauterine, intravenous, subarachnoid, It refers to a route of administration generally associated with injection, including subcapsular, subcutaneous, transmucosal, or synapse.
  • the carrier Via the parenteral route, the carrier may be in the form of a solution or suspension, for infusion or for injection or lyophilized form. Via the parenteral route, the carrier may be in the form of a solution or suspension for infusion or for injection.
  • bioactive carriers may be in the form of tablets, gel capsules, sugar coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymer vesicles that allow controlled release. Can be.
  • the carrier is administered by injection, either intravenously or intraperitoneally. Methods for these administrations are known to those skilled in the art.
  • the bioactive substance carrier according to the present invention may also contain any pharmaceutically acceptable carrier.
  • a "pharmaceutically acceptable carrier” is a pharmaceutical composition involved in the transport or transport of a compound of interest from one tissue, organ or part of the body to another tissue, organ or part of the body. It refers to acceptable materials, compositions or vehicles.
  • the carrier may be a liquid or solid filler, diluent, excipient, solvent or encapsulating material or combinations thereof.
  • Each component of the carrier must be “pharmaceutically acceptable", ie compatible with the other ingredients of the formulation. It should also be suitable for use when in contact with any tissue or organ to which it can be contacted, which should not involve the risk of any other complications that are too great than toxic, irritant, allergic reactions, immunogenicity or its therapeutic advantages. do.
  • Bioactive carriers according to the invention can also be encapsulated, purified or prepared in emulsions or syrups for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate the preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohol and water.
  • Solid carriers include starch, lactose, calcium sulfate, dihydrate, white earth, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include sustained release materials such as glyceryl monostearate or glyceryl distearate, alone or in combination with waxes.
  • Bioactive carriers can be milled, mixed, granulated and compressed if necessary for tablet form; Or prepared according to conventional pharmaceutical techniques involving grinding, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or aqueous or non-aqueous suspension.
  • Such liquid formulations may be administered orally directly or filled into soft gelatin capsules.
  • the bioactive substance carrier according to the present invention may be delivered in a therapeutically effective amount.
  • the exact therapeutically effective amount is that amount of the composition that produces the most effective result for therapeutic efficacy in a given subject. This amount includes the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics and bioactivity), the physiological condition of the subject (age, sex, disease type and stage, general physical health, response to a given dosage and type of medicament) ), The nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration, and will depend upon a number of factors. One skilled in the clinical and pharmacological arts will determine the therapeutically effective amount through routine experimentation, for example by monitoring the subject's response to administration of the compound and adjusting the dosage accordingly. For further guidance, see Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).
  • the subject to which the drug delivery agent of the present invention is administered may be a mammal, including a human, specifically a human.
  • the formulation Prior to administration to the subject, the formulation may be added to the formulation.
  • Liquid formulations may be preferred.
  • these formulations may include oils, polymers, vitamins, carbohydrates, amino acids, salts, buffers, albumin, surfactants, extenders or combinations thereof.
  • Carbohydrate formulations include sugars or sugar alcohols such as monosaccharides, disaccharides or polysaccharides or water soluble glucans.
  • Sugars or glucans are fructose, dextrose, lactose, glucose, mannose, sorbose, xylose, maltose, sucrose, dextran, pullulan, dextrin, alpha and beta cyclodextrin, soluble starch, hydroxyethyl starch and Carboxymethylcellulose or mixtures thereof.
  • “Sugar alcohol” is defined as a C4 to C8 hydrocarbon with --OH group and includes galactitol, inositol, mannitol, xylitol, sorbitol, glycerol and arabitol. These sugars or sugar alcohols mentioned above may be used individually or in combination. There is no fixed limit to the amount used if the sugar or sugar alcohol is soluble in the aqueous formulation. In one embodiment, the sugar or sugar alcohol concentration is 1.0 w / v% to 7.0 w / v, more preferably 2.0 to 6.0 w / v%.
  • Amino acid formulations include the sympathetic (L) forms of carnitine, arginine and betaine; However, other amino acids may be added.
  • the polymer as a formulation comprises polyvinylpyrrolidone (PVP) having an average molecular weight of 2,000 to 3,000, or polyethylene glycol (PEG) having an average molecular weight of 3,000 to 5,000.
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • a buffer in the composition it is also desirable to use a buffer in the composition to minimize pH change in solution prior to lyophilization or after reconstitution.
  • physiological buffers can be used, including but not limited to citrate, phosphate, succinate and glutamate buffers or mixtures thereof.
  • concentration is 0.01-0.3 moles.
  • Surfactants that can be added to the formulation are shown in European Patents 270,799 and 268,110.
  • the carriers can be chemically modified, for example, by covalent conjugation to the polymer to increase their circulating half-life.
  • Preferred polymers and methods for attaching them to peptides are described in US Pat. No. 4,766,106; 4,179,337; No. 4,495,285; And 4,609,546, all of which are incorporated by reference in their entirety.
  • Preferred polymers are polyoxyethylated polyols and polyethylene glycols (PEG).
  • PEG is soluble in water at room temperature, and in some embodiments, the average molecular weight is 500-40,000, 2000-20,000, or 3,000-12,000.
  • PEG has at least one hydroxy group, such as a terminal hydroxy group. The hydroxyl group can be activated to react with the free amino group on the inhibitor.
  • the type and amount of reactor can be varied to achieve the covalently conjugated PEG / antibody of the present invention.
  • Water soluble polyoxyethylated polyols are also useful in the present invention. They include polyoxyethylated sorbitol, polyoxyethylated glucose, polyoxyethylated glycerol (POG) and the like. POG is preferred. One reason is that the glycerol backbones of polyoxyethylated glycerol are mono-, di-, triglycerides of the same backbone of natural origin, for example in animals and humans. Thus, this branch is not necessarily regarded as a foreign agent in the body. POG is in the same molecular weight range as PEG. The structure for POG is described in Knauf et al., 1988, J. Bio. Chem. 263: 15064-15070, a discussion of POG / IL C 2 conjugates is found in US Pat. No. 4,766,106, both of which are incorporated herein by reference in their entirety.
  • the liquid bioactive carrier After the liquid bioactive carrier is prepared, it can be lyophilized to prevent degradation and preserve sterility. Methods of lyophilizing liquid compositions are known to those skilled in the art.
  • the carrier may be reconstituted with a sterile diluent (eg, Ringer's solution, distilled water, or sterile saline) which may include additional components.
  • a sterile diluent eg, Ringer's solution, distilled water, or sterile saline
  • the carrier Upon reconstitution, the carrier is administered to the subject using the methods known to those skilled in the art.
  • the bioactive substance carrier of the present invention includes a drug and porous silica particles, and the present invention provides the use of the porous silica particles described above in preparing a bioactive substance carrier.
  • the porous silica particles according to the present invention are biodegradable and can be slowly decomposed in vivo, and can release the supported bioactive substances in a sustained manner, and thus can be used in the preparation of sustained-release bioactive substance carriers. Can be.
  • the detailed physical properties, specifications, surface modifications, and the like may be within the ranges exemplified above, and may be manufactured by the methods / conditions within the ranges exemplified above.
  • reaction solution was then centrifuged at 8000 rpm for 10 minutes at 25 ° C. to remove the supernatant, centrifuged at 8000 rpm for 10 minutes at 25 ° C. and washed five times with alternating ethanol and distilled water.
  • the reaction was carried out starting at 25 ° C. and warming up at a rate of 10 ° C./min, then slowly cooling at a rate of 1-10 ° C./min in the autoclave.
  • the cooled reaction solution was centrifuged at 8000 rpm for 10 minutes at 25 ° C to remove the supernatant, and centrifuged at 8000 rpm for 10 minutes at 25 ° C, and washed five times with alternating ethanol and distilled water.
  • the porous silica particles prepared in 2) were put in a glass vial, heated at 550 ° C. for 5 hours, and cooled slowly to room temperature after completion of the reaction to prepare particles.
  • Porous silica particles were prepared in the same manner as in 1. (1), except that the reaction conditions at the time of pore expansion were changed to 140 ° C. and 72 hours.
  • Porous silica particles were prepared in the same manner as in Example 1. (1), except that a 5-fold large container was used and each material was used in a 5-fold volume.
  • Porous silica particles were prepared in the same manner as in (1), except that 920 ml of distilled water and 850 ml of methanol were used to prepare the small pore particles.
  • Porous silica particles were prepared in the same manner as in (1), except that 800 ml of distilled water, 1010 ml of methanol, and 10.6 g of CTAB were used to prepare the small pore particles.
  • Porous silica particles were prepared in the same manner as in (1), except that 620 ml of distilled water, 1380 ml of methanol, and 7.88 g of CTAB were used to prepare the small pore particles.
  • Porous silica particles were prepared in the same manner as in (1), except that 2.5 mL of TMB was used for pore expansion.
  • Porous silica particles were prepared in the same manner as in (1), except that 4.5 mL of TMB was used for pore expansion.
  • Porous silica particles were prepared in the same manner as in (1), except that 11 mL of TMB was used for pore expansion.
  • Porous silica particles were prepared in the same manner as in (1), except that 12.5 mL of TMB was used for pore expansion.
  • Example (1) Small pore particles were prepared in the same manner as in 1).
  • Example (1) 2 In the same manner as in Example (1) 2), the small pore particles were reacted with TMB, cooled and centrifuged to remove the supernatant. Thereafter, centrifuged under the same conditions as in Example (1) 2), washed three times with alternating ethanol and distilled water, and then dried under the same conditions as in Example (1) 2) to form porous silica particles (pore diameter 10) 15 nm, particle diameter 200 nm).
  • reaction solution of the previous step remains inside the pore, so that the inside of the pore is not modified.
  • the cooled reaction solution was centrifuged at 8000 rpm for 10 minutes to remove the supernatant, centrifuged at 8000 rpm for 10 minutes at 25 ° C, and washed five times with alternating ethanol and distilled water.
  • Example 1 The porous silica particles of (4) were reacted with (3-Aminopropyl) triethoxysilane (APTES) to charge with a positive charge.
  • APTES (3-Aminopropyl) triethoxysilane
  • porous silica particles were dispersed in a 10 mL toluene in a 100 mL round bottom flask with a bath sonicator. Then 1 mL of APTES was added and stirred at 400 rpm and stirred at 130 ° C. for 12 hours.
  • Example 1 The porous silica particles of (1) were charged with positive charge by reacting with (3-Aminopropyl) triethoxysilane (APTES), except that 0.4 ml of APTES was added and the reaction time was 3 hours. 2. (1) It was modified similarly to the method of 1).
  • APTES (3-Aminopropyl) triethoxysilane
  • Example 1 The porous silica particles of (9) were charged with positive charge by reacting with (3-Aminopropyl) triethoxysilane (APTES), and the other methods were modified in the same manner as in 2. (1) 1). .
  • APTES (3-Aminopropyl) triethoxysilane
  • Example 1 The porous silica particles of (10) were charged with positive charge by reacting with (3-Aminopropyl) triethoxysilane (APTES), and were modified in the same manner as in 2. (1) 1).
  • APTES (3-Aminopropyl) triethoxysilane
  • the porous silica particles of (1) were reacted with Trimethoxy (propyl) silane to introduce propyl groups on the surface and inside of the pores, except that 0.35ml of Trimethoxy (propyl) silane was added instead of APTES and reacted for 12 hours. Modification was carried out in the same manner as 2. (1).
  • porous silica particles of (1) were reacted with Trimethoxy-n-octylsilane to introduce propyl groups on the surface and inside of pores, except that 0.5ml of Trimethoxy-n-octylsilane was added instead of APTES and reacted for 12 hours. Modification was carried out in the same manner as 2. (1).
  • porous silica particles of (1) were reacted with succinic anhydride and charged negatively,
  • DMSO dimethyl sulfoxide
  • 80 mg of succinic anhydride was added instead of APTES, and the mixture was stirred at room temperature for 24 hours.
  • Example 1 Doxorubicin was loaded into the porous silica particles of (1).
  • porous silica particle powder 5 mg was mixed under distilled water, and then allowed to stand at room temperature for 1 hour.
  • Negatively charged Example 2 (3) 5 mg of the porous silica particle powder of 1) was dispersed in 1 mL of 1 ⁇ PBS, 2 mg of irinotecan was added and dispersed for 15 minutes, and then allowed to stand at room temperature for 1 hour.
  • Sorafenib sorafenib
  • porous silica particle powder and 2 mg of sorafenib were mixed in 1 ml of deionized water / ethanol in a 5: 5 mixing ratio (volume ratio), and then incubated at room temperature for 1 hour. Then washed three times with 1 ml of deionized water.
  • Example 2 (1) 1 ml of retinoic acid solution (50 mM ethanol) was added to 100 ⁇ g of the porous silica particle powder of 1 and left to stand at room temperature for 4 hours, followed by washing three times with 1 ml of ethanol.
  • the particles of Example 1. (11) 5) 1 were used as the porous silica particles.
  • the p53 peptide used mimics a portion of the p53 protein sequence involved in apoptosis.
  • the mimicked sequence relates to the sequence of the hydrophobic secondary helix structure where the p53 protein binds to the hMDM2 protein.
  • the p53 peptide acts as an antagonist of the hMDM2 protein.
  • the amino acid sequence of the p53 peptide (Cal. m.w. 2596.78, found by MALDI-TOF 2597.92) is shown in Formula 1 (N terminus-> C terminus).
  • X is a non-natural amino acid with an azide functional group introduced, 2-amino-5-azido-pentanoic acid
  • Y is a non-natural amino acid with an alkyne functional group introduced, and the side chain of D-Lys ) Introduced 4-pentynoic acid
  • X and Y are linked together to form a triazole functional group via an azide-alkyne cycloaddition, or click reaction;
  • p53 peptide 1.3 mg (500 nmole) of p53 peptide was dissolved in 100 ⁇ l of DMSO, and 5 mL of an aqueous solution of 5 mg of porous silica particle powder was mixed in a 15 mL conical tube, followed by incubation at room temperature for 12 hours.
  • Porous silica particles loaded with p53 peptide were purified by centrifugation (9289 rcf, 8500 rpm, 20 minutes, 15 mL conical tube) and washing with water three times.
  • GFP Green Fluorescence Protein
  • Example 2 (1) 10 ⁇ g of porous silica particles of 2) and 50 pmol of siRNA were mixed under 1 ⁇ PBS conditions and allowed to be loaded at room temperature for 30 minutes.
  • a 6.7k base pair of plasmid DNA (SEQ ID NO: 5) prepared to express GFP with pcDNA3.3 backbone was produced from bacteria and used after purification.
  • Example 2 (1) 10 ⁇ g of porous silica particles of 3) and 0.25 ⁇ g of plasmid DNA were mixed under 1 ⁇ PBS and loaded at room temperature for 30 minutes.
  • Example 2 (1) 2) 3 12.5 ⁇ g of porous silica particles and 0.25 ⁇ g of linear DNA were mixed under 1 ⁇ PBS conditions and loaded at room temperature for 30 minutes.
  • Example 1 The microporous particles of the particles of (1) to (3) and the prepared porous silica particles were observed under a microscope to determine whether the small pore particles were formed uniformly or the pores were sufficiently expanded to form the porous silica particles uniformly. It was confirmed whether or not (Figs. 1 to 4).
  • FIG. 1 is a photograph of the porous silica particles of 1.
  • Figure 2 is a photograph of the porous silica particles of 1. (2) it can be seen that evenly formed spherical porous silica particles with sufficiently expanded pores,
  • Figure 3 is a photograph of the small pore particles of 1. (1)
  • Figure 4 is a comparison photograph of the small pore particles of 1. (1) and 1. (3), confirming that the spherical small pore particles are evenly generated. Can be.
  • the surface area and pore volume of the small pore particles of Example 1. (1) and the porous silica particles of Examples 1. (1), (7), (8) and (10) were calculated.
  • the surface area was calculated by the Brunauer-Emmett-Teller (BET) method, and the pore size distribution was calculated by the Barrett-Joyner-Halenda (BJH) method.
  • porous silica particles are biodegraded and nearly decomposed after 360 hours.
  • a 0 is the absorbance of the porous silica particles measured by placing 5 ml of the 1 mg / ml suspension of the porous silica particles into a cylindrical permeable membrane having pores having a diameter of 50 kDa,
  • a t is the absorbance of the porous silica particles measured after t hours have elapsed since the measurement of A 0 ).
  • porous silica particle powder was dissolved in 5 ml of SBF (pH 7.4). Thereafter, 5 ml of the porous silica particle solution was placed in a permeable membrane having pores having a diameter of 50 kDa shown in FIG. 7. 15 ml of SBF was added to the outer membrane, and the SBF of the outer membrane was changed every 12 hours. The decomposition of the porous silica particles was performed at 37 ° C. with 60 rpm horizontal stirring.
  • Example 1 The absorbance of the porous silica particles of (1), (5) and (6) was measured according to Equation 1, and the results are shown in FIG. 9 (using SBF as a suspension and a solvent).
  • Example 1 The absorbance of the porous silica particles of (1) and (9), and the microporous porous silica particles of Example 1. (1) as a control was measured according to Equation 1, and the results are shown in FIG. (SBF was used as the suspension and the solvent).
  • porous silica particles of the example have a significantly larger t than the control.
  • t which is a ratio of absorbance 1/2
  • t which has a ratio of absorbance 1/2 of a positively charged particle, was 24 or more.
  • porous silica particles loaded with doxorubicin 0.1 mg were dispersed in PBS.
  • the solution is maintained in a dynamic condition of horizontal stirring at 37 ° C. at 200 rpm.
  • doxorubicin is loaded with a relatively weak binding force with the particle surface, it can be seen that because of the high solubility of doxorubicin is released in relatively fast release, the physiologically active substance was released continuously over 70 hours have.
  • porous silica particles loaded with irinotecan 1 mg were dispersed in 1 mL of human plasma.
  • the solution is maintained in a dynamic condition of horizontal stirring at 37 ° C. at 200 rpm.
  • the results are shown in FIG. 14.
  • sorafenib a poorly soluble bioactive substance, is released very slowly by interaction with porous silica particles having a hydrophobic substituent.
  • retinoic acid having a negative charge is released very slowly by interaction with the positively charged porous silica particles, and is almost 100% released in about 10 days.
  • 5 mg of p53 peptide loaded particles were added to 5 mL of 1x PBS containing 10% FBS, or 5 mL of 1x PBS and rotated at 37 ° C. at 20 rpm to maintain a dynamic environment.
  • the p53 peptide is loaded with the binding force through the hydrophobic effect (hydrophobic effect) inside the porous silica particles can be seen that the release in the PBS solution.
  • a protein such as FBS (fetal bovine serum)
  • FBS fetal bovine serum
  • the p53 peptide can be dissolved in the solution while binding to the hydrophobic segment of the FBS protein and released out of the porous silica particles. have.
  • FBS fetal bovine serum
  • Release solvents were recovered at 0.5, 1, 2, 4, 8, 12, 24 hours elapsed time before 24 hours, thereafter at 24 hour intervals, 0.5 ml of released solvent was recovered for fluorescence measurements and SBF was added.
  • the siRNA 50% release time is about 48 hours.
  • Porous silica particles loaded with Plasmid DNA (1 ⁇ g of psdmid DNA, 50 ⁇ g of porous silica particles) were resuspended in PBS (pH 7.4, 37 ° C.), and a permeable membrane having a pore diameter of 20 kDa (the same tube as the tube of FIG. 18). Put in.
  • the release solvent was recovered at the time of 0.5, 1, 2, 4, 8, 12, 24 hours before 24 hours, thereafter, at 24 hours intervals, 0.5 ml of the release solvent was recovered for the Hoechst-binding assay. Equivalent amount of PBS was added.
  • the release time of 50% of the plasmid DNA is about 24 hours.
  • Porous silica particles loaded with linear DNA (3 ⁇ g linear DNA, 100 ⁇ g porous silica particles) were resuspended in PBS (pH 7.4, 37 ° C.) and a permeable membrane having a pore diameter of 20 kDa (the same tube as the tube of FIG. 18). Put in.
  • the release solvent was recovered at the time of 0.5, 1, 2, 3, 4, 6, 12, and 24 hours before 24 hours, and thereafter, at 24 hours, 0.5 ml of the release solvent was collected for the Hoechst-binding assay. Recovered and added an equal amount of PBS.
  • the release time of 50% of linear DNA is about 24 hours.
  • BSA is released in both SBF and PBS in a sustained manner, and is almost 100% released over 250 hours.
  • IgG is released slowly in both SBF and PBS, and is almost 100% released over 250 hours.
  • RNase A Release of RNase A was carried out at 37 ° C. with 60 rpm horizontal stirring.
  • RNaseA is released in both SBF and PBS in a sustained manner and is almost 100% released over 250 hours.
  • porous silica particles were treated in a serum-free medium in a slide glass on which 50,000 NIH 3T3 cells, known as mouse fibroblasts, were laid and incubated at 5% CO 2 at 37 ° C.
  • the medium was removed, washed with 1 ⁇ PBS solution, and incubated with 4% paraformaldehyde for 15 minutes to fix cells.
  • His tag antibody (Santa Cruz, sc-8036) was incubated for 16 hours.
  • Alexa Fluor 488-linked anti mouse secondary antibody (Abcam, ab150113) was incubated for 2 hours.
  • the slide glass was treated with DAPI (dye staining cell nuclei) to stain the nuclei of cells. Since the distribution of protein in the cell was confirmed using a fluorescence microscope, the results are shown in FIG.
  • DAPI is a reagent for staining the nucleus, which is shown in blue in the fluorescence microscope image, and shows the location of the cell nucleus.
  • Alexa Fluor 488 is a fluorescent dye labeled with Cas9 protein, which appears green in the fluorescence microscopy image and shows the location of the intracellular Cas9 protein.
  • the fluorescence microscopy image confirmed whether the Cas 9 protein was introduced into the cell by the silica particles and the position of the nucleus.
  • Cas9 protein introduced into the cell is mainly observed in the cytoplasmic part 3 hours after the introduction, it can be seen that observed in the nucleus after 24 hours. Since the used silica particle itself is almost impossible to enter into the cell nucleus, it can be seen that the Cas9 protein is released from the silica particle after 24 hours in the cell and enters the nucleus known as an intracellular organelle, where the Cas9 protein is accumulated.
  • mice To verify the possible role of the carrier in the siRNA delivery studies at the animal level, the degree of tumor suppression according to the release of bioactive substances in mice (mouse) was confirmed.
  • Balb / c nude males (5 weeks old) were purchased from Orient Bio, Inc., and 3 million HeLa cells (cervical cancer cells) were dispersed in sterile 1x PBS to grow subcutaneous Xenograft tumors in mice, 70 mm When solidified tumors of three sizes were identified, PBS, FITC-porous silica particles (porous silica particles of Example 2.
  • the FITC label was prepared by dispersing 50 mg of silica particles in 1 mL dimethyl sulfoxide (DMSO) and adding 25 ⁇ g (10 ⁇ l) of FITC-NHS (N-hydroxycuccinimide) solution (2.5 mg / mL) and blocking the light with aluminum foil. After reacting for 18 hours at room temperature, the reaction product was purified by centrifugation (8500 rpm, 10 minutes), and the supernatant was discarded. The supernatant was collected and dispersed evenly in ethanol, and this was repeated 3-4 times with ethanol-distilled water. Purification was performed until no FITC color was seen.
  • DMSO dimethyl sulfoxide
  • the control is PBS alone administration
  • cy5-siRNA is cy5-siRNA administration alone
  • FITC-DDV is FITC-only porous silica particles alone
  • the complex is cy5-siRNA loaded and FITC-labeled porous silica particles are administered.
  • the siRNA delivered to the body by loading the particles have a longer duration of activity and stay longer at the injected site, showing strong fluorescence even after 48 hours.

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Abstract

La présente invention concerne un support de substance physiologiquement active, comprenant : une substance physiologiquement active; et des particules de silice poreuse supportant la substance physiologiquement active et ayant une pluralité de pores ayant un diamètre de 5 à 100 nm, les particules de silice poreuse ayant des propriétés physiques particulières, pouvant administrer divers médicaments en une quantité supportée de manière durable, et pouvant être administrées par voie parentérale.
PCT/KR2018/001617 2017-02-06 2018-02-06 Support de substance physiologiquement active WO2018143787A1 (fr)

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MX2019009271A MX2019009271A (es) 2017-02-06 2018-02-06 Portador de sustancia fisiologicamente activa.
AU2018216591A AU2018216591B2 (en) 2017-02-06 2018-02-06 Physiologically active substance carrier
EP18748562.8A EP3578171A4 (fr) 2017-02-06 2018-02-06 Support de substance physiologiquement active
US16/483,830 US11129796B2 (en) 2017-02-06 2018-02-06 Physiologically active substance carrier
JP2019563995A JP6883354B2 (ja) 2017-02-06 2018-02-06 生理活性物質送達体
CA3052561A CA3052561C (fr) 2017-02-06 2018-02-06 Support de substance physiologiquement active
CN201880022677.1A CN110475546A (zh) 2017-02-06 2018-02-06 生理活性物质载体
SG11201907260PA SG11201907260PA (en) 2017-02-06 2018-02-06 Physiologically active substance carrier
BR112019016281A BR112019016281A2 (pt) 2017-02-06 2018-02-06 veículo de substância fisiologicamente ativa
PH12019550145A PH12019550145A1 (en) 2017-02-06 2019-08-05 Physiologically active substance carrier
US17/399,320 US11793757B2 (en) 2017-02-06 2021-08-11 Physiologically active substance carrier
AU2021232725A AU2021232725B2 (en) 2017-02-06 2021-09-15 Physiologically active substance carrier
US18/368,097 US20240041771A1 (en) 2017-02-06 2023-09-14 Physiologically active substance carrier

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US201762455148P 2017-02-06 2017-02-06
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KR1020180014842A KR20180091768A (ko) 2017-02-06 2018-02-06 생리활성물질 전달체
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US11530132B2 (en) * 2017-09-05 2022-12-20 Lemonex Inc. Composition comprising porous silica particles carrying a cell fate modulating factor
JP2021531321A (ja) * 2018-07-31 2021-11-18 レモネックス インコーポレイテッドLemonex Inc. 傷治療用の医薬組成物
EP3845218A4 (fr) * 2018-07-31 2022-05-04 Lemonex Inc. Préparation pharmaceutique de cicatrisation de plaies
JP7140431B2 (ja) 2018-07-31 2022-09-21 レモネックス インコーポレイテッド 傷治療用の医薬組成物

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