Pulmonary delivery particles comprising an active agent

• US 9,554,993 B2
• Filed: 05/05/2010
• Issued: 01/31/2017
• Est. Priority Date: 09/29/1997
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Tarara, Thomas E., Weers, Jeffrey G., Kabalnov, Alexey, Schutt, Ernest G., Dellamary, Luis A.
• Primary Examiner(s): Berrios, Jennifer A
• Application Number:
  US12/774,540
• Publication Number:
  US 20100272823A1
• Time in Patent Office: 2,463 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• 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 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• 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 11/10 Expectorants
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 23/00 Anaesthetics
• 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 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: Y10S 977/904 : for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/906 : Drug delivery
• CPC Class Codes: Y10S 977/926 : Topical chemical, e.g. cosmetic or sunscreen

Abstract

A pulmonary delivery medicament comprises a plurality of particulates, the particulates comprising a structural matrix and a water insoluble and/or crystalline active agent. The particulates have a geometric diameter of 0.5 to 50 μm. The water insoluble active agent can be a fungicide, antibiotic, budesonide. A method of making the medicament comprises forming a liquid feedstock, and forming a feedstock suspension by suspending in the liquid feedstock, the active agent and an excipient capable of forming a structural matrix, such as a phospholipid. The feedstock suspension is spray dried to produce the particulates.

Claims

1. An inhaleable powder composition comprising a plurality of particulate microstructures, the particulate microstructures comprising:

(a) a structural matrix comprising phospholipid, wherein the particulate microstructures comprise greater than 10% phospholipid;

(b) an active agent, wherein the particulate microstructures comprise greater than 50% active agent and wherein the active agent comprises an antibiotic;

(c) residual amounts of a blowing agent, wherein the blowing agent comprises a fluorinated compound having a boiling point greater than 80°

C., and wherein the residual amounts are 5% w/w or less; and

(d) a mean aerodynamic diameter of less than 5 microns and a mean geometric diameter of less than 5 microns.

2. The inhaleable powder composition of claim 1 wherein the particulate microstructure comprises 1% w/w or less of blowing agent.

3. The inhaleable powder composition of claim 1 wherein the particulate microstructure comprises 3% w/w or less of blowing agent.

4. The inhaleable powder composition of claim 1 wherein the blowing agent comprises perfluorooctylbromide.

5. The inhaleable powder composition of claim 1 wherein the microstructures comprise a bulk density of less than 0.5 g/cm³.

6. The inhaleable powder composition of claim 1 wherein the microstructures have a mean porosity of 0.5-80%.

7. The inhaleable powder composition of claim 1 wherein the phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, dibehenoylphosphatidylcholine, diarachidoylphosphatidylcholine and combinations thereof.

8. The inhaleable powder composition of claim 1 wherein the structural matrix further comprises calcium.

9. The inhaleable powder composition of claim 1 wherein the powder has a fine particle fraction of from 30-70% by weight.

10. The inhaleable powder composition of claim 7 wherein the structural matrix further comprises calcium.

11. The inhaleable powder composition of claim 1 wherein the antibiotic comprises an aminoglycoside.

12. The inhaleable powder composition of claim 11 wherein the aminoglycoside comprises gentamicin.

13. The inhaleable powder composition of claim 1 wherein the blowing agent has a boiling point greater than 100°

C.

14. An inhaleable powder composition comprising a plurality of particulate microstructures, the particulate microstructures comprising:

(a) a structural matrix comprising phospholipid, wherein the particulate microstructures comprise greater than 10% phospholipid;

(b) an active agent, wherein the particulate microstructures comprise greater than 50% active agent and wherein the active agent comprises an antibiotic;

(c) residual amounts of a blowing agent, wherein the blowing agent comprises a fluorinated compound having a boiling point greater than 80°

C., and wherein the residual amounts are 5% w/w or less;

(d) residual amounts of a moisture, wherein the residual amounts are less than 6% w/w and wherein the moisture comprises water; and

(e) a mean aerodynamic diameter of less than 5 microns.

15. The inhaleable powder composition of claim 14 wherein the residual amount of moisture is less than 3% w/w.

16. The inhaleable powder composition of claim 14 wherein the blowing agent has a boiling point greater than 100°

C. and a mean geometric diameter of less than 5 microns.

17. The inhaleable powder composition of claim 14 wherein the phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, dibehenoylphosphatidylcholine, diarachidoylphosphatidylcholine and combinations thereof.

18. The inhaleable powder composition of claim 14 wherein the antibiotic comprises an aminoglycoside.