Technical Development For Multiphase Products

Currently, oral lipid-based formulations delivered in capsule formats are singlephase products with immediate release delivery profiles. However, there are various cases in which a multi-phase, modified-release product would be appropriate, such as: (i) clinical requirements for specific plasma time-course profiles, for the purpose of maximizing therapeutic efficacy or minimizing toxicity, (ii) avoidance of site-specific degradation of drug in the gastrointestinal tract, and (iii) resolution of chemical incompatibility issues for multi-component products. One method for achieving a modified-release profile takes advantage of the flexibility of liquid-filling machines and the combination of semi-solid and liquid excipients to enable the filling of multiple formulations of the same drug into a single capsule. Technically, the filling operation can be performed in a single or in multiple passes through the filling machine and results in a final product possessing multiple, discrete layers with differing release characteristics (Layercap™, Encap Drug Delivery). Selection of appropriately calculated proportions of the individual formulations would enable the manufacture of a _single capsule with a predetermined, specific release profile. This approach has yet to be marketed on a commercial scale.

The issue of chemical incompatibility between different formulation components has been recently addressed by Encap Drug Delivery through the development of the DuoCap™ multiple capsule system for the delivery of multi-phase lipid formulation products. The concept that has been successfully applied to product manufacture, involves specialist liquid-filling techniques executed on custom-designed filling equipment, which allows the insertion of a prefilled, smaller capsule into a larger, liquid-filled capsule. The smaller, inner capsule may contain either a liquid or semi-solid formulation and, according to the formulation or product requirements, either or both capsules may be of gelatin or HPMC composition and can be coated, if necessary.

The DuoCap™ process is graphically outlined in Figure 2. The inner capsule is first manufactured by using conventional liquid-filling and sealing technology, with the final dosage form being processed on a GKF 1500L liquid-fill machine, which has been re-engineered inhouse by Encap Drug Delivery. This machine utilizes a single, empty-capsule feed station to deliver the outer empty capsule shell to the filling station, where it is then filled to the required volume by "pump 1." A second, specially-designed feed station for the prefilled inner capsule replaces the original "pump 2" mechanism and inserts the inner capsule into the prefilled outer capsule body. The system enables the filling of one capsule (size X) into an outer capsule [size (X + 2) or larger] containing a liquid formulation, (e.g., a #0 capsule containing 0.140 mL of formulation could contain an inner #2 capsule containing 0.325 mL of a second formulation). Capsule total capacities for various combinations are shown in Table 7. The outer capsule is then closed and ejected from the machine by the standard mechanism and is available for subsequent sealing. The machine has various electronic controls to monitor inner capsule and empty outer

Figure 2 Unit operations involved in the production of the DuoCap™ multiple capsule dosage form. Custom-designed filling equipment is utilized which allows the insertion of a pre-filled, smaller capsule into a larger, liquid-filled capsule The smaller, inner capsule may contain either a liquid or semi-solid formulation Either or both capsules may be of gelatin or HPMC composition and can be coated, if necessary.

Figure 2 Unit operations involved in the production of the DuoCap™ multiple capsule dosage form. Custom-designed filling equipment is utilized which allows the insertion of a pre-filled, smaller capsule into a larger, liquid-filled capsule The smaller, inner capsule may contain either a liquid or semi-solid formulation Either or both capsules may be of gelatin or HPMC composition and can be coated, if necessary.

Table 7 Capacities of Combination of Inner and Outer Capsules for DuocapTM Format

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