Recent Options for Phase 1 Formulation Development and Clinical Trial Material Supply - Pharmaceutical Technology

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Recent Options for Phase 1 Formulation Development and Clinical Trial Material Supply
To meet the demands of early-stage development, contract research organizations can evaluate various dosage-form options. The author examines various methods of capsule filling, including binary blends.


Pharmaceutical Technology


Liquid in a capsule


Figure 2
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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