Advantages of ETI Phospholipid Gels in Drug Delivery

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Encore Therapeutics Inc. (ETI) proprietary Phospholipid Gel (PL Gel) is a unique formulation designed to delivery drugs intradermally or intramuscularly for prolonged action (i.e. a depot formulation). The PL Gel is a non-liposomal preparation comprising mainly phospholipids along with other injectable ingredients. All components are biocompatible and biodegradable and are selected from the GRAS (Generally Regarded as Safe) list or have been used in other injectable products approved by the FDA. PL Gel does not contain any new or unproven raw materials

The PL Gel is capable of delivering a high load (10-20%) and sustained release drug profile (3-7 days) for hydrophilic or lipophilic drugs. This unique formulation is robust with low risk of initial drug burst release. ETI believes that this high-load and 3-7 day duration depot system represents a great opportunity to improve therapeutic benefits and patient compliance for many injectable drugs.

In addition to the GRAS composition of this product, wide- application potential, high drug- load capabilities and reliable drug release characteristics, PL Gel is also straightforward to manufacture with the raw materials commercially available.

In many aspects, PL Gel performs better other biodegradable depot formulations used in drug delivery. The other depot formulations available can be categorized into four classes:

• Class 1: Polymer-based Microspheres- Microspheres prepared with biodegradable polymers such as PLGA or PLA may provide longer action (>1 month) than the PL gel but suffer from other significant disadvantages including: (1) a very limited drug loading, (2) complex fabrication process, especially for water-soluble drugs, and (3) limited application to ONLY extremely potent drugs such as hormones.

• Class 2: Vegetable-oil Based Solutions: The oil solution approach requires the drug to have high solubility in oil and is thus applicable ONLY to highly lipophilic drugs such as steroids. In fact, most drugs do not have sufficient solubility in oil and are not suitable for sustained release kinetics in the oil formulation.

• Class 3: Organic Solvent-base Gels- Organic solvent such as n-methyl pyrrolidone has been used to dissolve the biodegradable PLGA or PLA and the active drug to form an injectable gel. Upon injection, the solvent diffuses into the surrounding tissue causing the polymer to precipitate and entrap the drug to form a depot. This approach requires harsh solvents, works only for lipophylic drugs and is usually produces a dramatic initial release (burst) of active drug.

• Class 4: Liposomal Formulations- Liposomes are difficult to make and have limited shelf life or require a sub-ambient temperature for storage. Due to its particle size and fragile nature which preclude the use of common sterilization methods such as filtration, irradiation or autoclave, a liposome for depot application is usually made under aseptic conditions which may add sufficient complicity and cost to the manufacturing process. In addition, a liposomal depot provides ONLY a limited duration of action for about 12 hours.

In summary, the ETI PL Gel depot technology provides the following advantages:
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1. Long-action for 3-7 days
2. GRAS components with Based safe and compendial injectable materials
3. High drug loading (up to 10-20%)
4. Low risk of burst release
5. Ease of manufacturing
6. Wide application