Modulation of release from dry powder formulations
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.
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/cm 3 .
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/cm 3 .
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/cm 3 .
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/cm 3 .
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/cm 3 .
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/cm 3 .
41 . Particles for modulation of drug release having a tap density of less than about 0.4 g/Cm 3 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.