# US 10,864,171 B2 · Solid nanoparticle with inorganic coating

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- Number: US 10,864,171 B2
- Document ID: US10864171B2
- Status: Granted
- Kind: B2
- Application number: 16/654,648
- Filed: 2019-10-16
- Published: 2020-04-09
- Granted: 2020-12-15
- Earliest claimed: 2013-05-24
- Assignees: Nanexa AB
- Applicants: Nanexa AB
- Inventors: Jan-Otto Carlsson; Anders Johansson; Marten Rooth
- Web page: https://patentgrep.com/patent/US10864171B2

## CPC

- A61K 9/5192: {Processes}
- A61K 9/143: {with inorganic compounds}
- A61K 9/145: {with organic compounds}
- A61K 9/5073: {having two or more different coatings optionally including drug-containing subcoatings}
- A61K 9/5115: {Inorganic compounds}
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/4422: 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
- C23C 16/403: {of aluminium, magnesium or beryllium}
- C23C 16/405: {of refractory metals or yttrium}
- C23C 16/4417: {Methods specially adapted for coating powder}
- C23C 16/442: using fluidised bed process
- C23C 16/45555: {applied in non-semiconductor technology}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C23C: COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL (making metal-coated products by extrusion B21C23/22; covering with metal by connecting pre-existing layers to articles, see the relevant places, e.g. B21D39/00, B23K; metallising of glass C03C; metallising mortars, concrete, artificial stone, ceramics or natural stone C04B41/00; enamelling of, or applying a vitreous layer to, metals C23D; treating metal surfaces or coating of metals by electrolysis or electrophoresis C25D; single-crystal film growth C30B; by metallising textiles D06M11/83; decorating textiles by locally metallising D06Q1/04)

## Abstract

A nanoparticle having a solid core comprising a biologically active substance, said core being enclosed by an inorganic coating, a method for preparing the nanoparticle, and the use of the nanoparticle in therapy. A kit comprising the nanoparticle and a pharmaceutical composition comprising the nanoparticle.

## Claims

### Claim 1

A method of preparing a controlled or delayed release pharmaceutical composition comprising:
i. a plurality of coated particles of a size that is from 0.1 μm to 50 μm, said coated particles having a solid core comprising a buffering agent, said solid core being enclosed by one or more metal oxide materials; and
ii. a pharmaceutically acceptable carrier,
the method comprising the sequential steps of:
(1) applying an initial coating of at least one metal oxide to said solid cores in an atomic layer deposition reactor;
(2) discharging the coated particles from the reactor and subjecting the coated particles to agitation to disaggregate particle aggregates formed during step (1);
(3) reintroducing the disaggregated, coated particles from step (2) into an atomic layer deposition reactor and applying a further coating of at least one metal oxide to the reintroduced particles;
(4) optionally repeating steps (2) and (3) one or more times to increase total thickness of the one or more metal oxide materials that enclose said solid core; and
(5) admixing said coated particles obtained from step (3) or step (4) with said pharmaceutically acceptable carrier to form said pharmaceutical composition.

### Claim 2 (depends on 1)

The method of claim 1, wherein steps (2) and (3) are repeated at least once.

### Claim 3 (depends on 1)

The method of claim 1, wherein steps (2) and (3) are repeated at least twice.

### Claim 4 (depends on 1)

The method of claim 1, wherein steps (2) and (3) are repeated three times.

### Claim 5 (depends on 1)

The method of claim 1, wherein steps (2) and (3) are repeated up to nine times.

### Claim 6 (depends on 1)

The method of claim 1, wherein the one or more metal oxide materials comprise aluminium oxide, titanium dioxide, iron oxide, gallium oxide, magnesium oxide, zinc oxide, niobium oxide, hafnium oxide, tantalum oxide, lanthanum oxide, zirconium dioxide, and/or silicon dioxide.

### Claim 7 (depends on 1)

The method of claim 1, wherein the one or more metal oxide materials comprise aluminium oxide, titanium dioxide and/or zinc oxide.

### Claim 8 (depends on 1)

The method of claim 1, wherein the solid core consists essentially of the buffering agent.

### Claim 9 (depends on 1)

The method of claim 1, wherein the buffering agent in the solid core is either in admixture with one or more other substances selected from excipients and other biologically active ingredients, or is free from said other substances.

### Claim 10 (depends on 9)

The method of claim 9, wherein the biologically active ingredient is selected from the group consisting of an analgesic, an anesthetic, an anti-inflammatory agent, an anthelmintic, an anti-arrhythmic agent, an antiasthma agent, an antibiotic, an anticancer agent, an anticoagulant, an antidepressant, an antidiabetic agent, an antiepileptic, an antihistamine, an antitussive, an antihypertensive agent, an antimuscarinic agent, an antimycobacterial agent, an antineoplastic agent, an antioxidant agent, an antipyretic, an immunosuppressant, an immunostimulant, an antithyroid agent, an antiviral agent, an anxiolytic sedative, a hypnotic, a neuroleptic, an astringent, a bacteriostatic agent, a beta-adrenoceptor blocking agent, a blood product, a blood substitute, a bronchodilator, a cardiac inotropic agent, a chemotherapeutic, a contrast media, a corticosteroid, a cough suppressant, an expectorant, a mucolytic, a diuretic, a dopaminergic, an antiparkinsonian agent, a free radical scavenging agent, a growth factor, a haemostatic, an immunological agent, a lipid regulating agent, a muscle relaxant, a protein, a peptide, a polypeptide, a parasympathomimetic, a parathyroid calcitonin, a biphosphonate, a prostaglandin, a radio-pharmaceutical, a hormone, a sex hormone, an anti-allergic agent, an appetite stimulant, an anoretic, a steroid, a sympathomimetic, a thyroid agent, a vaccine, a vasodilator and a xanthine.

### Claim 11 (depends on 9)

The method of claim 9, wherein the biologically active ingredient is selected from the group consisting of alprazolam, amiodarone, amlodipine, astemizole, atenolol, azathioprine, azelatine, beclomethasone, budesonide, buprenorphine, butalbital, carbamazepine, carbidopa, cefotaxime, cephalexin, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clonazepam, clozapine, cyclosporin, diazepam, diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine, doxazosin, enalapril, estradiol, etodolac, etoposide, famotidine, felodipine, fentanyl citrate, fexofenadine, finasteride, fluconazole, flunisolide, flurbiprofen, fluvoxamine, furosemide, glipizide, gliburide, ibuprofen, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen, lamotrigine, lansoprazole, loperamide, loratadine, lorazepam, lovastatin, medroxyprogesterone, mefenamic acid, methylprednisolone, midazolam, mometasone, nabumetone, naproxen, nicergoline, nifedipine, norfloxacin, omeprazole, paclitaxel, phenyloin, piroxicam, quinapril, ramipril, risperidone, sertraline, simvastatin, sulindac, terbinafine, terfenadine, triamcinolone, valproic acid, zolpidem and pharmaceutically acceptable salts of any of these agents.

### Claim 12 (depends on 1)

The method of claim 1, wherein the total thickness of all the metal oxide coatings is from 0.1 nm to 500 nm.

### Claim 13 (depends on 1)

The method of claim 1, wherein the total thickness of all the metal oxide coatings is from 0.1 nm to 100 nm.

### Claim 14 (depends on 1)

The method of claim 1, wherein the total thickness of all the metal oxide coatings is from 0.1 nm to 50 nm.

### Claim 15

A controlled or delayed release pharmaceutical composition comprising:
i. a plurality of coated particles of a size that is from 0.1 μm to 50 μm, said coated particles having a solid core comprising a buffering agent, said solid core being enclosed by one or more metal oxide materials to enable a therapeutically effective controlled or delayed release of the buffering agent from the coated particles in said pharmaceutical composition; and
ii. a pharmaceutically acceptable carrier,
the pharmaceutical composition being prepared according to a process comprising the sequential steps of:
(1) applying a coating of at least one metal oxide to said solid cores in an atomic layer deposition reactor;
(2) discharging the coated particles from the reactor and subjecting the coated particles to agitation to disaggregate particle aggregates formed during step (1);
(3) reintroducing the disaggregated, coated particles from step (2) into an atomic layer deposition reactor and applying a further coating of at least one metal oxide to the reintroduced particles;
(4) optionally repeating steps (2) and (3) one or more times to increase total thickness of the one or more metal oxide materials that enclose said solid core; and
(5) admixing said coated particles obtained from step (3) or step (4) with said pharmaceutically acceptable carrier to form said pharmaceutical composition;
wherein the controlled or delayed release of the buffering agent from the coated particles is provided by the process steps (1) to (3) and (4), if performed.

### Claim 16 (depends on 15)

The pharmaceutical composition of claim 15, wherein the pharmaceutically acceptable carrier is in the form of a solid.

### Claim 17 (depends on 15)

The pharmaceutical composition of claim 15, wherein steps (2) and (3) are repeated at least once.

### Claim 18 (depends on 15)

The pharmaceutical composition of claim 15, wherein steps (2) and (3) are repeated at least twice.

### Claim 19 (depends on 15)

The pharmaceutical composition of claim 15, wherein steps (2) and (3) are repeated three times.

### Claim 20 (depends on 15)

The pharmaceutical composition of claim 15, wherein steps (2) and (3) are repeated up to nine times.

### Claim 21 (depends on 15)

The pharmaceutical composition of claim 15, wherein the one or more metal oxide materials comprise aluminium oxide, titanium dioxide, iron oxide, gallium oxide, magnesium oxide, zinc oxide, niobium oxide, hafnium oxide, tantalum oxide, lanthanum oxide, zirconium dioxide, and/or silicon dioxide.

### Claim 22 (depends on 15)

The pharmaceutical composition of claim 15, wherein the one or more metal oxide materials comprise aluminium oxide, titanium dioxide and/or zinc oxide.

### Claim 23 (depends on 15)

The pharmaceutical composition of claim 15, wherein the solid core consists essentially of the buffering agent.

### Claim 24 (depends on 15)

The pharmaceutical composition of claim 15, wherein the buffering agent in the solid core is either in admixture with one or more other substances selected from excipients and other biologically active ingredients, or is free from said other substances.

### Claim 25 (depends on 24)

The pharmaceutical composition of claim 24, wherein the biologically active ingredient is selected from the group consisting of an analgesic, an anesthetic, an anti-inflammatory agent, an anthelmintic, an anti-arrhythmic agent, an antiasthma agent, an antibiotic, an anticancer agent, an anticoagulant, an antidepressant, an antidiabetic agent, an antiepileptic, an antihistamine, an antitussive, an antihypertensive agent, an antimuscarinic agent, an antimycobacterial agent, an antineoplastic agent, an antioxidant agent, an antipyretic, an immunosuppressant, an immunostimulant, an antithyroid agent, an antiviral agent, an anxiolytic sedative, a hypnotic, a neuroleptic, an astringent, a bacteriostatic agent, a beta-adrenoceptor blocking agent, a blood product, a blood substitute, a bronchodilator, a cardiac inotropic agent, a chemotherapeutic, a contrast media, a corticosteroid, a cough suppressant, an expectorant, a mucolytic, a diuretic, a dopaminergic, an antiparkinsonian agent, a free radical scavenging agent, a growth factor, a haemostatic, an immunological agent, a lipid regulating agent, a muscle relaxant, a protein, a peptide, a polypeptide, a parasympathomimetic, a parathyroid calcitonin, a biphosphonate, a prostaglandin, a radio-pharmaceutical, a hormone, a sex hormone, an anti-allergic agent, an appetite stimulant, an anoretic, a steroid, a sympathomimetic, a thyroid agent, a vaccine, a vasodilator and a xanthine.

### Claim 26 (depends on 24)

The pharmaceutical composition of claim 24, wherein the biologically active ingredient is selected from the group consisting of alprazolam, amiodarone, amlodipine, astemizole, atenolol, azathioprine, azelatine, beclomethasone, budesonide, buprenorphine, butalbital, carbamazepine, carbidopa, cefotaxime, cephalexin, cholestyramine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clonazepam, clozapine, cyclosporin, diazepam, diclofenac sodium, digoxin, dipyridamole, divalproex, dobutamine, doxazosin, enalapril, estradiol, etodolac, etoposide, famotidine, felodipine, fentanyl citrate, fexofenadine, finasteride, fluconazole, flunisolide, flurbiprofen, fluvoxamine, furosemide, glipizide, gliburide, ibuprofen, isosorbide dinitrate, isotretinoin, isradipine, itraconazole, ketoconazole, ketoprofen, lamotrigine, lansoprazole, loperamide, loratadine, lorazepam, lovastatin, medroxyprogesterone, mefenamic acid, methylprednisolone, midazolam, mometasone, nabumetone, naproxen, nicergoline, nifedipine, norfloxacin, omeprazole, paclitaxel, phenyloin, piroxicam, quinapril, ramipril, risperidone, sertraline, simvastatin, sulindac, terbinafine, terfenadine, triamcinolone, valproic acid, zolpidem and pharmaceutically acceptable salts of any of these agents.

### Claim 27 (depends on 15)

The pharmaceutical composition of claim 15, wherein the total thickness of all the metal oxide coatings is from 0.1 nm to 500 nm.

### Claim 28 (depends on 15)

The pharmaceutical composition of claim 15, wherein the total thickness of all the metal oxide coatings is from 0.1 nm to 100 nm.

### Claim 29 (depends on 15)

The pharmaceutical composition of claim 15, wherein the total thickness of all the metal oxide coatings is from 0.1 nm to 50 nm.