Gelatin-free Softgels: Development and Optimization of Polysaccharide Capsule ShellSystems Suitable for the Encapsulation of Semi-solid Fill Formulations

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INTRODUCTION
Purpose
To develop polysaccharide-based capsule shell formulations in combination with elevated temperature filling processes, suitable for the encapsulation of semi-solid fill formulations.

Background
Gelatin has been the natural polymer, of choice, for many years, for the encapsulation of pharmaceutical fill formulations. Its success as a shell-forming polymer is attested by the wide range and number of soft capsule (softgel) products that have been, and continue to be, manufactured worldwide. Gelatin essentially is a water soluble protein that is derived from the insoluble protein collagen. Although gelatin has many desirable properties as an encapsulating medium, its use does involve some drawbacks.
Pharmaceutical fill formulations that exist in solid-like or semi solid form at room temperature and melt at temperatures greater than 40°C pose a challenge for the softgel formulator. These types of formulations typically do not lend themselves readily to encapsulation using conventional gelatin-based encapsulating films, since the latter typically have a sealing limit of approximately 40°-43°C.
The significant interest in the potential of semi-solid systems for the development of extended release, pulsatile release, and abuse-deterrent products has prompted researchers to develop alternative encapsulating systems. At Catalent Pharma Solutions, research is in progress to develop and optimize “high melting point” polysaccharide based (OptiShell™) encapsulating films. In the last 5-8 years our research has indicated that these films are more amenable to high temperature processing.
This poster presents the results obtained from recent studies where the OptiShell™ technology has been used for the “hot fill” encapsulation of semi-solid formulations.

MATERIALS
Formulatory Excipients

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METHODS
Shell-forming, natural, polymers were selected from native and modified starches, in combination with iota-carrageenan. Plasticizers were selected from glycerol and sorbitol-based polyols.
Capsule fill excipients were selected from 1) hydrophilic and 2) lipophilic ingredients, with a focus on those ingredients that are of interest for 1) SMEDDS formulations and 2) ER formulations. The selected ingredients exist as semi solids or in solid-like form at room temperature but become mobile liquids when warmed to temperatures in the range 45°-65°C (Table 1).
Optimum processing conditions for the fill formulations were based on rheological profiling; the dependency of viscosity on temperature was determined. Viscosity was measured using a Haake RheoStress 6000 rheometer equipped with a parallel plate measuring system. Viscosity was determined using a test frequency of 1.0 Hz. The samples were examined over the range 30°-70°C. Temperature control was achieved using a Peltier plate. The effect of temperature on viscosity was determined using a ‘ramp’ of 2.5°C min-1.
Encapsulation and “hot filling” trials were conducted using a rotary-die encapsulation machine equipped with 1) state-of-the-art film extruders and 2) a capsule filling system equipped with advanced thermal processing capabilities.
Softgels were prepared from the polysaccharide-based shell compositions in accordance with the formulations and processes described in US patents:
6,582,727
6,340,473

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EXPERIMENTAL AND RESULTS
Capsule Shell Development

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Rheological profiles

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Encapsulation trials and compositional investigations
Encapsulation trials of the excipients were conducted utilizing OptiShell™ encapsulating films in conjunction with a ‘hot-filling’ process. The most suitable capsule shell compositions were found to comprise:
• Modified starch: iota-carrageenan in the ratio, 2.8-3.4:1
• Sorbitol-based plasticizers
• Plasticizer:shell polymer ratio, 0.75-0.9:1
Rheological profiling and processing studies showed that the optimum encapsulating temperature was in the range 50°-65°C. At these temperatures the fill material is fluid-like; viscosities range between 2,000 and 6,000 mPa. s.
Soft capsules were successfully produced using the polysaccharide shell compositions in conjunction with a “hot fill” process.

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CONCLUSION
Semi-solid fill formulations can be successfully encapsulated using novel, polysaccharide-based shell compositions in conjunction with elevated temperature filling and capsule sealing processes.

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