1. R6231
DEVELOPMENT, CHARACTERIZATION AND OPTIMIZATION OF NOVEL MULTIFUNCTIONAL FREEZE DRIED EMULSIONS USING EXPERIMENTAL DESIGN.
MARIANNA PAPAMICHAIL, STAVROS N. POLITIS AND DIMITRIOS M. REKKAS
UNIVERSITY OF ATHENS, FACULTY OF PHARMACY, DPT. OF PHARMACEUTICAL TECHNOLOGY, PANEPISTIMIOPOLIS ZOGRAFOU, ATHENS, 15771, GREECE, TEL: +30 2107274023, FAX: +30 2107274027, EMAIL: rekkas@pharm.uoa.gr.
BACKGROUND MATERIALS AND METHODS RESULTS AND DISCUSSION
Emulsions are dispersion systems that typically require the use of primary emulsifiers Materials: The initial emulsions exhibited droplet size distributions, with d(v, 0.9) ranging between 0.74 to 36.52μm, depending on the proportion of their
and preservatives in order to retain their physicochemical and microbiological Extra virgin olive oil (Latzimas, Greece), Hydroxypropylmethylcellulose (HPMC) constituents. For example, figure 2 depicts a trace plot describing the relative effect of each component on d(v, 0.9). Semi synthetic polymers such as
stability. Such materials have been in the focal point of criticism as they are among Methocel® E4M, HPMC Methocel® E6 (Colorcon, UK), Peppermint oil (Munoz HPMCs can effectively act as emulsifiers [7] eliminating the need for use of primary surfactants. In addition, essential oils were found to function
the most frequent reasons for allergic reactions [1]. Freeze dried emulsions have Galvez, Spain), Mastic oil (CMGA, Greece), Desloratadine (Cipla Ltd, India) and synergistically resulting in further reduction of droplet size. The microscopic evaluation of a representative optimal formulation at the lower end of the
been proposed as carriers for specific applications including orally dispersible tablets deionised water were used. droplet range, with d(v, 0.9) below the one micron level is depicted in figure 3 (right), in comparison with emulsions with d(v, 0.9) at the higher end of
(ODTs). Apart from their benefits, these delivery systems exhibit several the distribution (figure3 left). In detail, as the proportion of the polymers and especially the low viscosity HPMC E6 increased, d(v, 0.9) decreased
disadvantages [2, 3], related to their physical stability during lyophillization, as well as Preparation of emulsions and freeze dried forms: (figure 4 top), providing emulsions that were proven stable under stress tests. The same was observed for peppermint oil (figure 4 bottom), while the
with the general limitations of freeze dried ODTs. These mainly include hygroscopicity The polymers were dispersed in water under intense stirring and were left presence of HPMC E4M and mastic oil was proven beneficial for the long term stability of the products. After the reconstitution of the freeze dried
and increased friability, which consequently lead to the use of expensive peel-off overnight in order to provide clear gels free of entrapped air. In a following step, forms, the droplet size distribution for approximately 20% of the formulations was found similar to that of the initial ones, with their d(v, 0.5) ranged
primary packaging and the adoption of complex multi-ingredient formulations and the oil phase was added at room temperature under homogenization, at between 0.7 and 3.0μm. These emulsions were also proven stable at the conditions described above, and were able to withstand intensive stress
production processes. As a result they introduce high risk of incompatibilities and 4.500rpm for 8 minutes, using a Silverson L4R apparatus. such as the four consecutive Freeze-Thaw cycles.
restrictions in their manufacturability. The preparations were freeze-dried (figure 1) for 15 hours at 0.5mbar and -55oC,
Multiple response optimization utilizing the desirability function revealed that this cluster of formulations
Furthermore, dry emulsions have been the basis of solid self-emulsifying drug using a Martin-Christ Alpha 1-2 apparatus (Martin Christ GmbH, Germany).
irrespectively of their loading in olive oil shared two common characteristics i.e. concentration of polymers
delivery systems (SSEDDS) for several years. However, they are characterized by
Experimental Design: close to their upper limit and the presence of at least one essential oil at proportions over 2.5%.
large quantities of primary emulsifiers at the range of 30-60%, which can induce
The formulations were developed using a IV optimal mixture design, with 31 Regarding the disintegration time of the freeze dried forms, values between 10 seconds to 3 minutes were
allergies and irritation, especially in the GI tract [4]. Moreover this amount restricts
experiments. The components and their levels are presented in Table 1. The observed, while Desloratadine loaded formulations released the API quantitatively in less than 3 minutes.
their capacity to incorporate only low dose actives [5].
results were evaluated using Design Expert® V. 8.0.0, Stat-ease Inc, The analysis of the mixture design revealed statistically significant models correlating the above-mentioned
It is thus evident that several technical challenges need to be met, in order to provide
Minneapolis. CQAs with the mixture components.
cost-effective, lean and agile technology platforms for freeze dried emulsions, which
Summarizing the previous findings:
will facilitate realization of products free of the aforementioned deficiencies.
Characterization of emulsions: It is feasible to prepare multipurpose stable emulsions with droplet size below the one micron level without
PURPOSE Droplet size distribution was selected as a response either for the initial the use of primary emulsifiers and by conventional means, at room temperature with the minimum of
emulsions and those derived from the reconstitution of their freeze dried forms. resources. This approach may facilitate the development of natural products through green, low-energy
The purpose of this study was the development, according to the ICHQ8 guideline of For the latter the disintegration time and the release profile of the selected API, processes.
novel, lean, multi-purpose emulsion based products, which are free of primary namely Desloratadine, were also determined and evaluated using USP Specific formulations and their freeze dried counterparts are retaining the original droplet distribution patterns
emulsifiers and preservatives. Such formulations could be used as either cosmetic apparatus II with sinkers, while the quantification was performed using a throughout the stressed conditions applied. Moreover it was found that the use of essential oils promoted their
vehicles or pharmaceutical drug delivery systems such as freeze dried ODTs and validated HPLC method. stability profile, while they provide mild antimicrobial protection [8] and taste enhancement.
SSEDDS, while their production requirements remain within the current The stability of the formulations was also assessed, at normal and accelerated The formulations are lean, as they practically require few excipients for their preparation and agile since they
manufacturing capabilities and regulatory framework of the relevant industries. ICH conditions and after four Freeze-Thaw cycles using the protocol proposed can be used for a number of cosmetic and pharmaceutical applications without compromising safety.
by Palazolo et al [6]. The use of a mixture design in product development, proved a useful tool for acquiring the necessary
ABSTRACT
Development, characterization and optimization of novel Low Component High Droplet size determination was performed using a lazer scattering technique with process knowledge leading to robust formulations.
multifunctional freeze dried emulsions using experimental design.
PURPOSE: Development of novel, agile freeze dried emulsions for a Mastersizer apparatus (Malvern UK) equipped with a 300RF lens, capturing The incorporation of an API for testing the applicability of the technology platform in developing a freeze dried
pharmaceutical and cosmetic use, free of primary emulsifiers and
51.5≤ A: Water ≤99.5 ODT was proven successful, as the final product was not fragile, removed very easily from its blister cavity and
preservatives.
METHODS: The emulsions were prepared using extra virgin olive oil,
sizes in the range of 0.05-890.00μm. The samples were also microscopically
deionized water, hydroxypropylmethylcellulose E4M and E6 as
emulsifiers and essential oils, i.e. mastic and peppermint oil. The
0.0≤ B: olive oil ≤20.0 observed at 1500X magnification (Leica Q 500 IW system, Leica, Cambridge, met the requirements for the disintegration time and dissolution rate.
formulations were developed using a IV optimal mixture design for the six
constituents, with 31 experiments. The polymers were dispersed in water 0.5≤ C: HPMC E4M ≤1.5 UK).
and the oil phase was then added under homogenization, using a Figure 4. Contour plots for d(v, 0.9). CONCLUSIONS
0.0≤ ≤7.0
Silverson L4R apparatus. The emulsions were freeze-dried for 15 hours
at 0.5mbar and -55°C. The Critical Quality Attributes (CQAs) of both the D: HPMC E6
initial emulsions and the freeze dried forms were selected as the
responses of the design. These included the reconstitution and the
0.0≤ E: Mastic Oil (MO) ≤10.0 Using a lean approach and DoE techniques in the QbD framework [9], a novel multifunctional formulation platform has been developed [10]. The
disintegration of the freeze dried emulsions, as well as the droplet size
distribution of the initial and the reconstituted forms. The stability of the proposed agile emulsions and freeze dried products can offer customized solutions with improved safety profile, in the field of pharmaceuticals and
formulations was also assessed, at normal and accelerated ICH
conditions and after four Freeze-Thaw cycles. Finally, selected
0.0≤ F: Peppermint Oil (PO) ≤10.0 cosmetics, while they are in compliance with the current manufacturing trends in these sectors [11].
formulations incorporating Desloratadine were prepared and evaluated
for their dissolutions profiles. A+B+C+D+E+F= 100.0
RESULTS: After reconstitution, the droplet size distribution for
approximately 20% of the formulations was similar to that of the initial BIBLIOGRAPHY
ones, while their d(v, 0.5) ranged between 0.7 and 3.0μm. These
emulsions were also proven stable at the conditions described above.
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Regarding the disintegration time of the freeze dried forms, values
between 10 seconds to 3 minutes were observed and the API was
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SSEDDS, mucoadhesive carriers and practically natural cosmetics.
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agile solutions with improved safety profile, in the field of pharmaceuticals
Figure 1. Freeze Figure 2. Trace plot for d(v, 0.9) Figure 3.Microscopic [5] Tang B., Chenkg G., Gu J.C., Xu C.H., 2008, Development of solid self-emulsifying drug delivery systems: [10] Rekkas D.M., Papamichail M., Politis S., 2012, GR20120100181 patent application.
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