Info

0.190/0.585

0.190/0.335

0.190/0.165

0.190/0.076

Abbreviation: N/A, not applicable.

Abbreviation: N/A, not applicable.

capsule feed and a maximum filling rate of approximately 30 k capsules per hour, which is about half that of the original, single-capsule dual-pump system.

The GKF 1500L capsule filling machine described herein was specifically modified to allow the preparation of dual liquid-filled capsules. However, appropriate modification of the fill-head would readily allow powders or even tablet dosage forms to be combined with a liquid formulation in a single capsule dosage unit. The system is highly versatile, allowing for the preparation of combination dosage forms, with specially-tailored drug-release profiles or for the combination of potentially incompatible components within the same dosage unit, in either coated or uncoated formats.

A practical example of the successful application of the DuoCap™ multiphase, lipid based formulation technology is found in the nutriceutical probiotic product, "Floraguard," launched in 2004 by Biocare U.K., Ltd. and manufactured by Encap Drug Delivery. This product, which is marketed as a dietary supplement, is intended for the restoration of the normal balance of microbial flora within the gut. As such, it finds application in the treatment of diarrhea, which commonly results subsequent to the disturbance of gut flora that frequently follows antibiotic therapy. The main, competing commercial products are simple, freeze-dried granulation formulations of the lactic acid bacteria, Lactobacillus acidophilus, Lactobacillus casei, Enterococcus faecium, and Bifidobacterium bifidum, which must be protected from excessive heat and moisture. Exposure to moisture during manufacture or storage results in early activation of the organisms, which in the absence of nutrients typically encountered in the gut following ingestion, results in the devitalization of the organisms and loss of product potency. In addition, since the beneficial activity of these organisms is targeted to the colon, early activation during passage through the stomach can reduce the viability of those organisms reaching the colon. Finally, the organisms in the granulation formulations are mechanically fragile and relatively unprotected against the effects of heat, thereby necessitating refrigerated storage.

The DuoCap™ probiotic formulation described here addresses all of the deficiencies of the simple granulation formulations by incorporating live, freeze-dried Lactobacillus acidophilus and Bifidobacterium bifidum organisms into a multi-component, oil-filled, and enteric coated capsule formulation. The issue of early activation by environmental moisture is addressed by suspending the freeze-dried organisms in a protective oily vehicle, which is filled into a low-moisture content HPMC inner capsule (4-6% moisture content as opposed to the 13-16% moisture content of hard gelatin capsules). The greater resistance of HPMC capsules to embrittlement and cracking subsequent to extraction of moisture by the hydrophilic freeze-dried fill further adds to the attractiveness of HPMC capsule shells for this product. From a physiological standpoint, early activation of the organisms in the stomach prior to arrival in the colon was addressed by coating the inner capsule with a new, pH-dependent food-grade aqueous-coat system based on shellac (patent pending, Encap Drug Delivery), which met standard phar-macopoeial requirements for enteric-coat performance. The product also required coadministration of a second oily formulation, which was incompatible with the probiotic since it possessed native antimicrobial activity. The final product consisted of a sealed, liquid-filled ("Formulation 2") outer size 00 HPMC capsule into which had been inserted a sealed, enteric-coated, size 1 HPMC capsule containing an oily suspension of the freeze-dried microorganisms ("Formulation 1"). Critical requirements for meeting the label claim pertaining to the viability of the organisms (4 X 109 cfu's/capsule, information provided by courtesy of BioCare Ltd., U.K.) were met using the DuoCap™ drug delivery system, as demonstrated by microbiological monitoring based on plate-counts of lactic acid bacteria (20). Thus, by addressing multiple and complex product stability issues in a single dosage unit, the DuoCap™ technology allowed maintenance of the product label claim over a shelf-life that was both competitive and commercially-attractive. This example clearly demonstrates the versatility of multi-component lipid-based formulations as well as their suitability for large-scale manufacture.

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