Liquid in a capsule 
Figure 2
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Liquid in a capsule is a method for not only improving the bioavailability of poorly water-soluble compounds, but also for
enhancing low-melting point and low-dose–high-potency drug candidates. The challenge of this approach is solubilizing the
API in a favorable surfactant, solvent, and cosolvent system. When it comes to solubility, the rule of thumb is "like dissolves
like." Physical mixtures, solid solutions, solid dispersions, or a self-microemulsifying drug-delivery system may be used
(7). The developed system can be filled into appropriately sized capsules and banded (e.g., STI Lab Model capsule bander, Schaefer Technologies, Indianapolis, IN) or filled and sealed (e.g., "CFS 1200" encapsulator, Capsugel, see Figure 2).
Banding capsules using the STI Lab Model can be manual or semiautomatic. The process involves a significant amount of labor
and additional time for drying the capsules. The CFS 1200 machine uses liquid encapsulation microspray sealing technology
LEMS Capsugel http://www.capsugel.com/pdf/Liquids_Formulation_Licaps.pdf|~www.capsugel.com/pdf/Liquids_Formulation_Licaps.pdf to create a robust and an impervious capsule seal (8). The process involves spraying approximately 50 μL of a water–ethanol
microspray solution to penetrate the space surrounding the cap and the body joint of the capsule. The melting point must
be lowered at the sealing area of the capsule. The entire filling and sealing process is quickly completed (0.33 s/capsule)
with warm air (40–60 °C) gently blown across the capsule body and cap-joint surface to form a seal. The CFS 1200 encapsulator, which operates at a speed of 1200 capsules/h, completes early-phase batches in 1–2 days. A high
dose or a poorly soluble compound can be accommodated to a volume range between 0.1 and 1.2 mL in capsule sizes between 000
to 4. Another advantage of the CFS 1200 unit is its ability to fill a liquid between 20 and 70 °C, which makes it suitable
for a semisolid dosage form as well. A semisolid formulation with excipients such as polyethylene glycol ("Carbowax Sentry", The Dow Chemical Company, Midland, MI) or polyoxylglycerides ("Gelucire," Gattefossé, Paramus, NJ) can enhance bioavailability
to attain positive clinical data (9).Capsugel used the "Coni-snap" two-piece hard-gelatin capsule as the basis for its "Licaps" product, which is more suitable
for liquid fills. Licaps is a six-dimple design that protects the filled material from leaking into the zone between the body
and the cap of the capsule. It also has the low oxygen permeability necessary to protect the liquid system from oxidation
(10). Including a placebo in a developmental stability study is recommended to justify any chemical data surprises. The stability
study is worth initiating for both gelatin and hydroxypropyl methylcellulose capsules. The benefits of the developed liquid-in-capsule
process can be well supported for large-scale manufacturing by high-speed commercial equipment such as "IN-CAP 130-01" Dott.
Bonapace, Milan), "MG2 Futura" (Futura, MG America, Fairfield, NJ), and "Liqfil Super Hicapseal" (40 and 100 models, Qualicaps, Whitsett, NC). Binary blends Manufacturing multiple binary blends is another option to expedite formulation development for immediate-release products.
Binary-blend prototypes are combinations of API and an excipient encapsulated with a manual process using encapsulators such
as "Feton" (ChemiPharm, Ramsey, NJ) or "MF30" (Pam Pharmaceuticals and Allied Machinery Company, Kandivli, Mumbai), which
are capable of manufacturing thousands of capsules for early-phase clinical trials. This technique not only serves the goal
of acquiring API, excipient, and capsule compatibility data, but is a short process that can save development time. Assay and impurities methods can be developed and qualified quickly because there is less interference from excipients. With
minimal analytical work, the final product can be at the clinic in 11–12 weeks. When the API enters clinical trials, the clinical
data obtained by using binary blends provide a starting point for the development of a commercially acceptable dosage form
such as a tablet or a capsule.
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