Propellant-based nanoparticulate dry powder aerosols and method of making

• US 8,124,057 B2
• Filed: 01/26/2009
• Issued: 02/28/2012
• Est. Priority Date: 11/12/1998
• Status: Expired due to Fees

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: Bosch, H. William, Ostrander, Kevin D., Cooper, Eugene R.
• Primary Examiner(s): ALSTRUM ACEVEDO, JAMES HENRY
• Application Number:
  US12/320,431
• Publication Number:
  US 20090181100A1
• Time in Patent Office: 1,128 Days
• Field of Search: 424/45
• US Class Current: 424/45
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

There invention discloses aqueous dispersions of nanoparticulate aerosol formulations, dry powder nanoparticulate aerosol formulation, propellant-based aerosol formulations, methods of using the formulations in aerosol delivery devices, and methods of making such formulations. The nanoparticles of the aqueous dispersions or dry powder formulations comprise insoluble drug particles having a surface modifier on the surface thereof.

Claims

1. A method for making a propellant-based dry powder composition, comprising:

(a) obtaining dry powder of a nanoparticulate drug composition; and

then

(b) dispersing the dry powder in at least one propellant,

wherein the nanoparticulate drug composition;

(i) comprises a poorly soluble drug, (ii) has an effective average particle size of less than 1000 nm or equal to about 1000 nm, and (iii) has a surface modifier adsorbed on the surface of the drug particles, and

wherein step (a) comprises;

(i) forming an aqueous nanoparticulate dispersion of the drug and surface modifier; and

(ii) spray-drying or freeze-drying the nanoparticulate dispersion to form a dry powder of spherically shaped aggregates of the nanoparticulate drug and surface modifier, wherein the aggregates have a diameter of less than 100 microns or equal to about 100 microns.

2. The method of claim 1, further comprising adding a diluent to the nanoparticulate dispersion prior to spray-drying.

3. The method of claim 2, wherein the diluent is lactose or mannitol.

4. The method of claim 1, further comprising adding a diluent to the nanoparticulate dispersion prior to freeze-drying.

5. The method of claim 4, wherein the diluent is lactose or mannitol.

6. The method of claim 1, wherein the propellant is selected from the group consisting of a chlorinated propellant, a non-chlorinated propellant, a hydrofluorinated alkane, and a halogenated hydrocarbon propellant having a low boiling point.

7. The method of claim 1, wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, a drug for treating cystic-fibrosis, a drug for treating asthma, a drug for treating emphysema, a drug for treating respiratory distress syndrome, a drug for treating chronic bronchitis, a drug for treating chronic obstructive pulmonary disease, a drug for treating organ-transplant rejection a drug for treating tuberculosis and other infections of the lung, a drug for treating fungal infection, a drug for treating respiratory illness caused by acquired immune deficiency syndrome, an oncology drug, an anti-emetic, a cardiovascular agent, beclomethasone dipropionate, naproxen, triamcinolone acetonide, budesonide, and an anti-emetic.

8. The method of claim 1, wherein the surface modifier is selected from the group consisting of a nonionic surfactant and an ionic surfactant.

9. The method of claim 1, wherein the surface modifier is selected from the group consisting of tyloxapol, cetyl pyridinium chloride, gelatin, casein, lecithin, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid esters;

polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers, poloxamines, a charged phospholipid, dioctylsulfosuccinate (DOSS), dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether, sulfonate, a mixture of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), C₁₈H₃₇CH₂(CON(CH₃)—

CH₂(CHOH)₄(CH₂0H)₂, decanoyl-N-methylglucamide, n-decyl β

-D-glucopyranoside, n-decyl β

-D-maltopyranoside, n-dodecyl β

-D-glucopyranoside, n-dodecyl β

-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β

-D-glucopyranoside, n-heptyl β

-D-thioglucoside, n-hexyl β

-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl β

-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β

-D-glucopyranoside, octyl β

-D-thioglucopyranoside.