Modulation of release from dry powder formulations

• US 20050003003A1
• Filed: 04/28/2003
• Published: 01/06/2005
• Est. Priority Date: 08/25/1999
• Status: Abandoned Application

• Current Assignee: Civitas Therapeutics, Inc. (Acorda Therapeutics Incorporated)
• Original Assignee: Advanced Inhalation Research, Inc. (Alkermes Incorporated)
• Inventors: Deaver, Daniel R., Basu, Sujit K., Caponetti, Giovanni, Elbert, Katharina J., Hrkach, Jeffrey S., Lipp, Michael M.
• Application Number:
  US10/425,194
• Publication Number:
  US 20050003003A1
• Time in Patent Office: Days
• US Class Current: 424/469
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• 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 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61P 11/06 Antiasthmatics

Abstract

Particles which include a bioactive agent are prepared to have a desired matrix transition temperature. Delivery of the particles via the pulmonary system results in modulation of drug release from the particles. Sustained release and/or sustained pharmacologic action of the drug can be obtained by forming particles which include a combination of phospholipids that are miscible in one another and have a high matrix transition temperature.

Claims

1. Particles for modulation of drug release comprising:

(a) a bioactive agent; and

(b) a combination of phospholipids at least two of said phospholipids being miscible in one another, said particles having a matrix transition temperature corresponding to a targeted release rate of the biologically active agent from the particles and a tap density of less than about 0.4 g/cm³.

2. The particles of claim 1 wherein at least two of said phospholipids are highly or perfectly miscible in one another.

3. The particles of claim 1 wherein the particles have a tap density less than about 0.1 g/cm³.

4. The particles of claim 1 wherein the particles have a mean geometric diameter of between about 5 microns and about 30 microns.

5. The particles of claim 4 wherein the particles have a mean geometric diameter of between about 10 microns and 30 microns.

6. The particles of claim 1 wherein the particles have an aerodynamic diameter of between about 1 micron and about 5 microns.

7. The particles of claim 6 wherein the particles have an aerodynamic diameter of between about 1 micron and 3 microns.

8. The particles of claim 6 wherein the particles have an aerodynamic diameter of between about 3 microns and 5 microns.

9. The particles of claim 1 further comprising a compound selected from the group consisting of polysaccharides, sugars, amino acids, polymers, proteins, lipids, surfactants, cholesterol, fatty acids, fatty acid esters and any combination thereof.

10. The particles of claim 1 wherein the bioactive agent is present in the particles in an amount of at least 0.1% weight.

11. The particles of claim 1 wherein the bioactive agent is albuterol sulfate or estrone sulfate.

12. The particles of claim 1 wherein the bioactive agent is a protein or peptide.

13. The particles of claim 1 wherein the bioactive agent is hydrophilic.

14. The particles of claim 1 wherein the bioactive agent is hydrophobic.

15. The particles of claim 1 wherein the combination of phospholipids is present in the particles in an amount of between about 1 and about 99 weight %.

16. The particles of claim 1 wherein the transition temperature is higher than a subject'"'"'s physiological temperature.

17. A method comprising delivering via the pulmonary system of a patient in need of treatment, prophylaxis or diagnosis an effective amount of the particles of claim 1.

18. A method for delivery via the pulmonary system comprising administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of particles having a selected release rate of a bioactive agent, said particles comprising:

(a) the bioactive agent; and

(b) a combination of phospholipids, at least two of said phospholipids being miscible in one another;

wherein the particles have a matrix transition temperature corresponding to a targeted release rate of the therapeutic, prophylactic or diagnostic agent from the particles and a tap density of less than about 0.4 g/cm³.

19. The method of claim 18 wherein at least two of said phospholipids are highly or perfectly miscible in one another.

20. The method of claim 18 wherein the particles have a tap density less than about 0.1 g/cm³.

21. The method of claim 18 wherein the particles have a mean geometric diameter of between about 5 microns and about 30 microns.

22. The method of claim 18 wherein the particles have a mean geometric diameter of between about 10 microns and 30 microns.

23. The method of claim 18 wherein the particles have an aerodynamic diameter of between about 1 and 5 microns.

24. The method of claim 23 wherein the particles have an aerodynamic diameter of between about 1 micron and about 3 microns.

25. The method of claim 23 wherein the particles have an aerodynamic diameter of between about 3 microns and about 5 microns.

26. The method of claim 18 wherein delivery is primarily to the deep lung.

27. The method of claim 18 wherein delivery is primarily to the central airways.

28. The method of claim 18 wherein delivery is primarily to the small airways.

29. The method of claim 18 wherein delivery is primarily to the upper airways.

30. The method of claim 18 wherein the particles further comprise a compound selected from the group consisting of polysaccharides, sugars, amino acids, polymers, lipids, surfactants, cholesterol, fatty acids, fatty acid esters proteins, peptides cyclodextrins, surfactants and and any combination thereof.

31. The method of claim 18 wherein the bioactive agent is present in the particles in an amount of at least 0.1 weight %.

32. The method of claim 18 wherein the bioactive agent is selected from the group consisting of albuterol sulfate or estrone sulfate.

33. The method of claim 18 wherein the bioactive agent is a protein or peptide.

34. The method of claim 18 wherein the bioactive agent is hydrophilic.

35. The method of claim 18 wherein the bioactive agent is hydrophobic.

36. The method of claim 18 wherein the phospholipid or the combination of phospholipids is present in the particles in an amount of between about 1 and about 99 weight %.

37. The method of claim 18 wherein the transition temperature is higher than a subject'"'"'s physiological temperature.

38. The method of claim 18 wherein administration is via a dry powder inhaler.

39. A method for delivery via the pulmonary system particles having a release rate from the particles of a therapeutic, prophylactic or diagnostic agent comprising:

administering to the respiratory system of a patient in need of treatment, prophylaxis or diagnosis an effective amount of particles comprising;

(a) the therapeutic, prophylactic or diagnostic agent, or combinations thereof; and

(b) a combination of phospholipids, at least two of said phospholipids being miscible in one another and said combination of phospholipids resulting in a matrix transition temperature such that the particles have the release rate;

wherein the particles have a tap density less than about 0.4 g/cm³.

40. A method for increasing a release time of a therapeutic, prophylactic or diagnostic agent comprising administering to a patient in need of treatment, prophylaxis or diagnosis an effective amount of particles comprising:

(a) a therapeutic, prophylactic or diagnostic agent; and

(b) a combination of phospholipids, at least two of said phospholipids being miscible in one another;

wherein the particles have a matrix transition temperature higher than the physiological temperature of the patient and a tap density of less than about 0.4 g/cm³.

41. Particles for modulation of drug release having a tap density of less than about 0.4 g/Cm³ comprising:

(a) a therapeutic, prophylactic or diagnostic agent; and

(b) a combination of phospholipids, at least two of said phospholipids being miscible in one another and said combination of phospholipids having a transition temperature higher than the body temperature of a human or veterinary subject.