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nanoparticle and microparticle generation with super or near critical carbon dioxide

Nanoparticle and Microparticle Generation with Super- or Near-critical Carbon Dioxide

E.T.S.Huang, H. Y. Chang, D. Alargov, S.P.Cape, 
L. Rinner, J. A. Villa, B. P. Quinn and R. E. SieversCenter for Pharmaceutical Biotechnology, 
Dept. of Chemistry and Biochemistry, and CIRES, 
214 UCB, University of Colorado, Boulder, CO
and AKTIV-DRY,
655 Northstar Ct., Boulder, CO 80301

room temperature stable enzymes antibodies and pharmaceuticals
ROOM-TEMPERATURE-STABLE ENZYMES, ANTIBODIES, AND PHARMACEUTICALS

Strategy: Stabilize and dry powders near room temperature by SF processing

  • Nanoparticle and Microparticle Synthesis and Coating
  • Inhalable Antibiotics
  • Inhalable Antielastase Protein Enzyme for Emphysema and Cystic Fibrosis
    • Micronize dry powder alpha-1-antitrypsin for delivery into alveoli

  • Stabilization and Dehydration of Monoclonal Antibodies

    • Stabilize with sugars; dry and store without freezing or refrigeration

    • Avoid aggregation and create rapidly redissolved microparticles
the principle of a new can bd process carbon dioxide assisted nebulization with a bubble dryer
The Principle of a New CAN-BD Process: (Carbon Dioxide Assisted Nebulization with a Bubble Dryer®)
  • In CAN-BD a solution or suspension in acetone,alcohol, or water is mixed intimately with CO2 at 100 bar to form an emulsion.

  • The emulsion is rapidly expanded to atmospheric pressure through flow restrictor to generate aerosols of microbubbles and microdroplets.
  • The aerosol plume is dried at 1 to 60 。C as it mixes with nitrogen or air in the drying chamber.

  • Dry fine powders are collected.
slide7
Particles of antibiotics generated from aqueous solutions

0.5% solution in H2O

Avg. particle size = 0.97


95% <= 1.60 µm

0.5% solution in H2O

Avg. particle size = 1.05


95% <= 1.82 µm

solvents for can bd
SOLVENTS FOR CAN-BD®
  • Water
  • Carbon Dioxide
  • Methanol
  • Ethanol
  • Acetone
  • Acetonitrile
  • Ethyl acetate
  • Methylene chloride (only when required)
  • Mixtures of solvents
slide9
Size distribution of particles of Dipalmitoylphosphatidylcholine (DPPC) from a solution in ethanol, dried in the Bubble Dryer®
slide10
SEM of particles generated from a 2% aqueous solution of lactose + 2% solution of palmitic acid in ethanol with CO2 in a CROSS

SEM of particles generated from a 10% aqueous solution of lactose with CO2 in a TEE

SELECTIVE LEACHING

OF HETEROGENOUS

PARTICLES

Particles suspended in EtOH, stirred for

0.5 hr, and filtered Avg. aerodynamic

diam.=1.03µm

slide11
2% Betamethasone in ETOH +


2% Lactose in H2O + CO2 in a CROSS

Particles suspended in ETOH,


stirred for 0.5 hr, and filtered

Avg. Particle size = 1.16 µm,

95% <= 1.96 µm

Particles suspended in H2O,

stirred for 0.5 hr, and filtered

two fluid particle formation tee
Two Fluid ParticleFormation (Tee)

SEM of particles generated from aハ10% aqueous solution of NaCl withハCO2

Three Fluid Particle

Formation (Cross)

SEM/TEM of particles generated from a 10% aqueous solution of

NaCl + 0.5% solution

of PLGA in acetone

with CO2

slide13

Two Fluid Particle

Formation (Tee)

Three Fluid Particle

Formation (Cross)

SEM of particles generated from a 10% aqueous solution of NaCl with CO2

SEM of particles generated from a 10% aqueous solution of NaCl + 3% suspension of silica nanoparticles with CO2

aerodynamic size distribution of betamethasone 17 21 dipropionate from ethanol
Aerodynamic Size Distribution of Betamethasone 17,21-dipropionate from Ethanol
  • Base Conditions:
  • 1200 psi
  • 3 wt %
  • CO2 to Ethanol mass flow ratio = 14.5
  • Results:
  • Mean Diam. = 0.81 µm
  • 95% < 1.34 µm
effect of pressure and flow ratio on particle size
Effect of Pressure and Flow Ratio on Particle Size

1200 psig, 3% conc. -- 14.5

1200 psig, 0.2% conc. -- 15

700 psig, 3% conc. -- 0.5

300 psig, 3% conc. -- 0.007

coating particles
COATINGPARTICLES

SEM of particles generated by CAN-BD from a solution containing 2% ovalbumin + 2% trehalose (uncoated)

SEM of particles coated

with 0.5% PLGA

SEM of particles coated with 1% PLGA

slide17

NaCl particles generated by

CAN-BD

PLA-coated NaCl particles

generated by CAN-BD

slide18
Size distribution (by Aerosizer) and SEM of alpha-1-antitrypsin micronized by CAN-BD from an aqueous solution (2.8% AAT, 4.6% trehalose in 0.1M sodium phosphate, 0.1% Tween 20, pH 7.0). Dried at 40 。C.
  • Mean diameter = 2.2 オm; with 95% under 5.3 オm・Moisture content = 7.5% H2O (initial), 1.8% H2O (after storage in vacuum desiccator)
  • Activity retained after processing = 98% ア 2%
  • Completely redissolves in a few minutes with gentle swirling

Stephen P. Cape, Ph.D.

slide19

REPRESENTATIVE SOLUTES THAT HAVE BEEN MICRONIZED BY A LAB-SCALE CAN-BD UNIT

Antibodies:

Enzymes:

Antibiotics:

Water-soluble

drugs:

Alcohol-soluble

drugs:

Sugars:

Polymers:

anti-CD4, IVIG, anti-human lambda light chain

alpha-1-antitrypsin, trypsinogen, lysozyme, lactate

dehydrogenase

ciprofloxcin, moxifloxacin, tobramycin sulfate, amoxycillin,

doxycycline

albuterol sulfate, cromolyn sodium

naproxen, budesonide, betamethsone, amphotericin B,

cyclosporin, DPPC

lactose, sucrose, trehalose, mannitol

PLA, PLGA, PEG

slide20
The CAN-BD process is based on the methods invented and developed by Sievers, Carpenter, and coworkers, licensed exclusively to AKTIV-DRY®
  • Sievers, R.E. and Karst, U. US Patent 5639441 (1997)

  • Sievers, R.E. and Karst, U. US Patent 6095134 (2000)

  • Sievers, R.E., Sellers, S.P. and Carpenter, J.F., WO 00/75281-A2 (2001); national phase entered in US, UK, Japan, Australia, China, Italy, Spain, Germany, France, Switzerland, etc. US Patent has been allowed.

  • Sievers, R.E., European Patent 0677332 B1, Feb. 27, 2002; registered in UK, Germany, France, Switzerland.

  • Other patent applications have been filed that are divisionals of the CAN-BD patent filed April 8, 1994, and the European application.
conclusions
Conclusions
  • A nebulization, and drying and coating method (CAN-BD) has been presented that can manufacture dry powders of proteins, enzymes, antibodies,and other drugs without detectable degradation.

  • Both solutions and suspensions can be processed.

  • Coating and drying requires only seconds at near- ambient conditions of temperature and pressure.

  • Water and many organic solvents yield nanoparticles and microparticles.

  • Fluid ratios and solute concentrations determine size.

  • Multiple constituents can be incorporated in three fluids in a low volume cross to make heterogenous and homogenous nanoparticles and microparticles