Download Oral Bioavailability

Oral Bioavailability
Dosage Form Solutions
Low aqueous solubility resulting in poor oral
bioavailability of drug candidates is an increasingly
common challenge for the pharmaceutical industry.
An estimated 60% to 70% of compounds in
early development have poor bioavailability due
to low solubility, representing a significant loss in
economic and therapeutic opportunity. Capsugel
Dosage Form Solutions has developed a patented
delivery platform based on spray-dried dispersions
(SDDs), which is available for license.
SDD Functionality and Advantages
Technology Overview
•Enhanced oral bioavailability of poorly
water-soluble compounds by attaining and
sustaining a supersaturated concentration
of drug in the gastrointestinal environment
for biologically relevant time frames
An SDD is a single-phase, amorphous molecular dispersion of a drug in a
polymer matrix. SDDs are prepared by dissolving drug and polymer in an
organic solvent and then spray-drying the solution. The formulation and
process conditions are chosen to quickly evaporate the solvent from the
droplets, allowing insufficient time for phase separation or crystallization.
•A solid, shelf-stable drug form that
avoids crystallization or phase separation
of amorphous drug and is suitable for
delivery using suspensions or traditional
solid dosage forms such as tablets
and capsules
Capsugel Dosage Form Solutions formulates SDDs using a number of
commercially available polymers, including hydroxypropyl methylcellulose
acetate succinate (HPMCAS). Due to the high glass-transition temperature
and low water sorption of HPMCAS, “homogeneous” SDDs made from this
polymer have robust physical stability, allowing long-term storage over a wide
range of conditions without amorphous phase separation or crystallization of
the drug, which could negatively affect performance. These properties also
allow SDDs to have higher drug loadings than solid dispersions manufactured
with more-hydrophilic polymers. For some drugs and some problem
statements, alternate polymers, or polymers and surfactants, are used to
provide optimal performance and acceptable stability.
•A reproducible, controllable, and scalable
manufacturing process that can be used
from discovery to commercial production
•A technology that is broadly applicable to
structurally diverse insoluble compounds
across a wide range of physical properties
[Compound] ( µ g/mL)
70
60
50
SDD (HPMCAS)
Crystalline drug
Spray-dried
PVP dispersion
Amorphous drug
40
30
20
10
0
0
30
60
90
Time (min)
Figure 1. In Vitro Concentration Profiles Over Time
for an HPMCAS SDD, Spray-Dried PVP Dispersion,
Amorphous Drug, and Crystalline Drug in Simulated
Intestinal Fluid (Test Concentration = 100 μg/mL)
The amorphous drug in an SDD is in a high-energy state relative to
crystalline drug. When placed into an aqueous solution, SDDs dissolve to
a drug concentration well above the solubility of the drug’s crystalline form.
Interaction of the drug with the polymer inhibits conversion of the drug to
a lower-energy form. The higher drug concentration provides the driving
force for rapid absorption of the drug. Because of the strong interaction
of HPMCAS with a wide variety of drugs, the performance of these SDD
formulations is often superior to that of other dispersion systems, such as
those based on polyvinyl pyrrolidone (PVP). Figure 1 shows concentrationversus-time profiles for an example HPMCAS SDD, a spray-dried PVP
dispersion, amorphous drug, and crystalline drug.
Performance
SDDs can be prepared from compounds with a broad range
of physicochemical properties, including:
•Aqueous solubilities as low as 0.001 μg/mL
700
Plasma Concentration (ng/mL)
Capsugel Dosage Form Solutions has formulated more than
1,000 compounds as SDDs for in vivo testing. In addition,
more than 80 compounds have been formulated as SDDs
and manufactured at Capsugel Dosage Form Solutions for
advancement to Phase 1 through Phase 3 clinical trials.
600
500
400
200
100
0
0
•Log P values from 1 to more than 8
•Melting points from 0°C to 300°C and greater
•Acidic, basic, or neutral composition
SDD absorption enhancement relative to crystalline drug
ranges from around 2-fold to more than 50-fold. Figure 2
shows clinical results for plasma concentration versus time
for an HPMCAS SDD and crystalline drug.
Stability
SDD (HPMCAS)
Crystalline drug
300
6
12
18
24
Time (hr)
Figure 2. Clinical Pharmacokinetic Profiles for SDD and Crystalline
Drug Dosed to Healthy Volunteers (Dose = 200 mg, Fasted State;
Aqueous Solubility = 1.3 μg/mL; Crystalline Drug Size = 5 μm)
results in low bulk drug requirements for early-stage testing
and rapid turnaround times to support fast-paced projects.
Safety
SDDs with shelf lives of more than 2 years have been consistently
demonstrated. Proven physical-stability models allow reliable
identification of stable formulations from short-term data.
An extensive safety package addressing chronic oral use of
HPMCAS is available in an FDA Type V Drug Master File for
reference when using Capsugel Dosage Form Solutions
SDD technology.
Manufacturability
Progressible Dosage Forms
SDD manufacturing has been reproducibly demonstrated at
scales from milligrams to metric tons, enabling production of
developmental quantities through Phase 3 clinical supplies and
product launch. Process development, technology transfer,
and scale-up are successfully achieved using a comprehensive
set of experimental tools and fundamental models. This
The excellent stability and physical properties of SDDs makes
them well-suited to suspensions and traditional solid dosage
forms such as tablets and capsules. Capsugel Dosage Form
Solutions also has extensive experience in developing and
manufacturing immediate- and controlled-release dosage
forms for SDDs.
About Capsugel Dosage Form Solutions
Capsugel’s Dosage Form Solutions business unit solves customers’ most
pressing product development challenges, including bioavailability
enhancement, modified release, abuse deterrence, biotherapeutic
processing, and inhalation formulation. We utilize an integrated product
development approach ensuring that our clients can rely on one partner
from design to commercial scale production of innovative drug product
intermediates and finished dosage forms. Capsugel Dosage Form Solutions
accelerates and improves product development through an array of
technologies including lipids and liquids, spray-dried dispersions, hotmelt extrusion, and through specialized manufacturing including FDA/
MHRA-accredited finished dosage sites that can handle highly potent,
controlled substance, hormonal and oncology compounds. High quality
science and engineering is core to our offering at each stage of the product
development cycle and has enabled the successful advancement of
hundreds of compounds.
For more information on our oral bioavalability technology contact
us at [email protected], visit capsugel.com, or reach a
Capsugel representative directly at:
Europe, Middle East & Africa: +44 (0) 150 644 8080 | North America: +1 (541) 382-4100
Capsugel will use reasonable efforts to include accurate and up-to-date information on this brochure but makes no warranties or representations of any kind as to its accuracy or completeness. The entire contents of this brochure are subject to
copyright protection. Copyright © 2014 Capsugel Belgium NV. All rights reserved. GMCN 201409018