Pharmaceutical applications

Enhance bioavailability of poorly soluble drugs (BCS class II/IV)

A new drug with pH dependent, poor solubility (<10 μg/mL) at intestinal pH, and low-medium permeability. This results in poor drug bioavailability and precipitation in intestinal fluids.

With the cryospraying technology it was possible to:

  • Formulate the drug as solid dispersion into amphiphilic, lipid-based microspheres to improve its dissolution profile.
  • Develop a solid micronized system with self-emulsifying properties, with drug loading up to 40% w/w.
  • Improve bioavailability (more than doubled AUC vs formulated bulk drug) after oral administration in beagle dogs.

Dissolution profiles of microparticles formulations based on cryospraying technology vs. drug in aqueous suspension. FeSSIF, sink conditions.

Drug plasma concentrations after oral administration to Beagle dogs.

Controlled release of highly soluble, BCS Class I drugs

Metoclopramide is a highly soluble, highly absorbable drug (BCS Class I), used to treat GI disorders, and as antiemetic in chemotherapy treatments. Very bitter taste. It is usually administered 3 to 4 times a day.
Controlled release formulations would maintain constant drug concentration in plasma, reduce drug dosing frequency while prolonging the antiemetic effect.
Applying cryospraying technology, it is possible to:

  • Formulate microspheres in excipient blends which can solubilize the drug and modulate its release
  • Encapsulate drug in lipidic matrix microspheres, forming a physical barrier between the drug and the taste receptors on the tongue
  • Modulate metoclopramide release by modifying the excipients composition without significantly changing the processing conditions

Metoclopramide (MCP) dissolution profile in PBS at PH 6.8, from different microspheres formulations based on cryospraying technology. Drug release rate can be modified by adjusting the excipients ratios and introducing minimal adjustments of process conditions. L. Segale et al., CRS Newsletter, 25, 3, (2008), pp.16-17.

Controlled release microspheres maintain their matrix structure during drug release process

Electron Microscopy (SEM) images of MCP-CeCo50 microparticles before drug release test in PBS pH 6.8.

SEM images of MCP-CeCo50 microparticles collected after drug release test in PBS pH 6.8.

Modify PK profile and improve bioavailability of Celecoxib

Celecoxib is BCS Class II: Poor drug solubility leads to scarce and erratic drug bioavailability. As other COX-2i, its cardiovascular toxicity limits its wider therapeutic application.

Applying cryospraying, amphiphilic microspheres were designed whereby:

  • Celecoxib is converted to the amorphous form within a lipid self-emulsifying matrix
  • Drug release is controlled by microspheres excipients composition
  • Particles can dissolve in GI tract and create a favourable environment for COX-2i dissolution and absorption
This project was partially funded by MINECO

Microparticles facilitate celecoxib solubilization and maintain drug dissolved in supersaturated conditions (pH 5.5 buffer).

In collaboration with:

Drug release from microparticles produced by cryospraying technology vs. Celebrex®. USP II Paddle; sink conditions, buffer pH 6.8, 0.75% SLS.

In collaboration with:

In-vivo study in Male Wistar rats (n=8), particles suspended in water, oral gavage 5 mg/Kg dose. A 40% increase in bioavailability vs. marketed product was observed

In collaboration with:

Pediatric formulations of a protein complex for oral delivery

Clinical Needs

  • Marketed product not suitable for pediatric use
  • High daily dose
  • Excipients selection limited by maximum daily intake

Objectives

  • High drug load, micronized solid formulation for pediatric use
  • Target different age groups (with same formulation)
  • Maintain biological activity and drug release rate target in GI tract

Different particles sizes for different products

  • Small: «sprinkle», dispersible in juices, yogurts, milk
  • Larger: suitable for further processing
  • CO2 couples congealing and atomizing effect
  • Use of liquid CO2 produces small particles (D90 < 120 μm)
  • Bioactivity higher than 95%
  • Drug load up to 40%
  • N2 effect limited to congealing
  • Use of liquid N2 produces large particles (D50 > 300-400 μm)
  • Bioactivity higher than 95%
  • Drug load up to 60%
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