Lipid Based SMEDDS Formulation of Ibuprofen and Phenylephrine for Softgels
Posted on January 16,2017
By Martin Piest1, Suparna Gupta, Ad Bernaerts
Patheon Softgels B.V., De Posthoornstraat 7, 5048AS, Tilburg, Netherlands
A lipid based formulation was developed for a combination product that contained Ibuprofen (IBU, 200 mg) and Phenylephrine (PE, 5 mg) as active ingredients. A high throughput and lean solubility screen was designed for excipient selection. Pseudo-ternary phase diagrams were developed to identify softgel compatible SEDDS/SMEDDS region.
Formulations were characterized for thermodynamic stability, aqueous dispersion, API recovery and droplet size assessment to select lead formulation for IVIVC studies.
Recent increase in number of BCS Class II APIs has necessitated the development of self-emulsifying drug delivery (SEDDS) and self micro-emulsifying drug delivery (SMEDDS) as an oral strategy for bioavailability enhancement. Development of unique solubility-enhancing formulation poses challenges such as:
• Rapid and parallel development for lean API consumption
• Robust in-vitro characterization
• Data interpretation for in vitro – in vivo correlation
The goal of this study was to develop robust methods following a systematic formulation approach to deliver solutions for key pharmaceutical challenges:
• Improve bioavailability of APIs
• Reduce food effect on pharmacokinetics
• Demonstrate utility of Softgels as a drug delivery system
Current formulation design focused on delivering novel solutions to unique molecules by optimizing methods for lead SEDDS/SMEDDS selection. Lastly, for an in vitro – in vivo correlation the lead formulations will undergo analysis for drug concentration in SGF / FaSSIF / FeSSIF, lipolysis and fill-shell compatibility.
EFFICIENT AND LEAN SOLUBILITY SCREENING
At the early stage of drug development often times API availability is limited because of lack of synthetic process development and API usage over multiple preclinical studies. Therefore a lean and fast solubility screen was developed using best-in-class technology. This screen was focused on reducing cycle times and API consumption by incorporating following features in the design of experiment:
• 96-well format for rapid and parallel screening
• Accurate and time efficient solid dispending
• Lean approach for low API consumption
• Smart design to reduce HPLC analysis
• Potential for automation
VISUAL SOLUBILITY IN 15 EXCIPIENTS
A solubility screening protocol was developed in a 96-well format using a thermally controlled shaker with adaptability for 96-well plates and vials. An accurate solid powder dispenser was utilized for efficient multiple dispensing across 96-well plate.
This visual solubility screening was designed to evaluate two concentrations of the APIs in low volumes of excipients to minimize number of samples for HPLC analysis at a later stage.
Table 1. Solubility screening of Ibuprofen (IBU) and Phenylephrine HCl (PE) across 15 excipients
PSEUDO-TERNARY PHASE DIAGRAM
Pseudo-ternary phase diagrams were developed using two concentrations (3% and 6% w/w) of cosolvent propylene glycol and varying concentration of oil and surfactant (0% to 100% w/w).
Figure 1. Pseudo-ternary phase diagrams showing the Self- Emulsifying region
LEAD FORMULATION COMPOSITION
Lead vehicle composition were selected by varying concentration of Capryol 90 and Labrasol with increasing amounts of Vitamin E TGPS. Propylene glycol was added to dissolve Phenylephrine HCl.
Compositions of investigated lead formulations are shown in Table 2.
Table 2. Vehicle composition
Equilibrium solubility of ibuprofen was determined for each lead candidate formulations by UHPLC. Results in Figure 2 show that equilibrium was achieved within 2-4 hours already and no significant differences between the different lead formulations were observed.
Figure 2. Equilibrium solubility of Ibuprofen in lead candidate Lipid Formulations
From the resulting equilibration solubility of ~30% it was decided to continue with 25% ibuprofen in the formulation, being approximately 80% of the saturation solubility.
Table 3. Composition of lipid formulations in theoretical values as mg per capsule
For reference purposes also three PEG-based controls were formulated:
• Control #1: 200 mg/cap Ibuprofen in 461 mg/cap total using PEG400 and KOH (aq.).
• Control #2: 200 mg/cap Ibuprofen and 10 mg/cap Phenylephrine HCl in 471 mg/cap total using PEG400 and KOH (aq.).
• Control #3: 200 mg/cap Ibuprofen and 10 mg/cap Phenylephrine and 12 mg/cap Vitamin E TGPS in 483 mg/cap total using PEG400 and KOH (aq.).
AQUEOUS DISPERSION IN SGF
Samples were diluted: 2 g in 400 ml simulated gastric fluid (USP) using a USP Paddle dissolution apparatus at 37 ⁰C, 100 RPM for >30 minutes. Both the lead formulations (Table 3) and the control formulations were assessed by Dynamic Light Scattering.
Figure 3. Aqueous Dispersion in Simulated Gastric Fluid for the five lead candidate Lipid Formulations (Table 3). Top: front view. Bottom: top view of LF1, LF2, LF3, LF4, and LF5 respectively.
AQUEOUS DISPERSION IN SGF
An aqueous dispersion in SGF clearly demonstrated that whereas the lipid-based formulation formed a fine emulsion, the PEG-based control formulations immediately crashed out of solution.
Figure 4. Aqueous dispersion in Simulated Gastric Fluid for the three control formulations (Table 4). Top: front view. Bottom: close up of the precipitated formulation.
RECOVERY OF IBU IN SGF BY UHPLC
Duplicate samples were taken after the aqueous dispersion study and centrifuged at 4000 rpm at 37°C for 5 minutes. Supernatant was assayed for Ibuprofen content by UHPLC after dilution with sample solvent followed by filtration using a PTFE filter with 0.45 μM pore size. The PEG-based formulations showed negligible recovery of ca 3-4%, whereas the lipid formulations high in Capryol 90 showed highest recovery of ca 50-70%. The results are shown in Figure 5.
Figure 5. Solubility of Ibuprofen in SGF for the five lead candidate Lipid Formulations and the three control formulations.
Lipid digestion was performed following the protocol from the Lipid Formulation Classification System Consortium as described in the paper from Williams .
In short 1 g lipid formulation is digested by pancreatin at pH 6.5 using a Metrohm Titrando to perform a pH-stat titration. During the titration the coarse emulsion is forming a micro- to nano-emulsion when the digested lipids are converted into free fatty acids that form mixed micelles with phosphatidylcholine. The turbid mixture becomes a opalescent transparent liquid as can be observed in Figure 6.
Figure 6. Digestion of lipid formulation LF1 after 0, 15, and 60 minutes, respectively.
Samples were collected after 0, 15, 30, 45, and 60 minutes, respectively. After adding the enzyme inhibitor to stop the digestion, samples are centrifuged at 14,000 rpm for 30 minutes at 37°C. Next, supernatant is collected for analysis by UHPLC and the 60 minute sample is analyzed by DLS.
RECOVERY OF IBU BY UHPLC
Duplicate samples were taken from the digestion test and assayed for Ibuprofen content by UHPLC after dilution with sample solvent followed by filtration using a PTFE filter with 0.45 μM pore size. The results shown in Figure 7 demonstrate that the lipid formulations and the PEG-based control readily yielded >90% recovery, not showing significant differences.
Figure 7. Ibuprofen recovery profiles during lipid digestion for LF1, LF2, LF3, LF4, LF5, and the PEG control#1, respectively.
DROPLET SIZE MEASUREMENT BY DLS
Mean droplet size was assessed by Dynamic Light Scattering using a Malvern Nanosizer apparatus. From the results in Figure 8 it is immediately clear that thelipid formulations LF1-LF4 are capable of forming nanosized emulsions with droplet size of 120 +/- 70 nm. For LF5 and the control formulation the signal was very low, which is interpreted as absence of nano-sized droplets.
Figure 8. Top: Average droplet size and PDI width in nm for the lipid formulations and non-lipid control.* Not accurate due to low signal. Bottom: derived count rate in kcps (signal representing number of micelles) for LF1, LF2, LF3, LF4, LF5, and Control#1, respectively.
In vial stability
Lipid Formulations LF1, LF2, LF3, LF4, and LF5 as well as the three control formulations were put on stability in the stability unit at 25°C/60%RH and at 40°C/75%RH. Preliminary results are shown in Figure 9 for the ibuprofen assay at 40°C/75%RH for the first three weeks. The preliminary results indicate some degradation takes place and no significant differences are observed between the lipid formulation and the PEG control formulations. Study is ongoing.
Figure 9. Ibuprofen assay for the five lead candidate Lipid Formulations and the three control formulations stored at 40°C/75%RH.
A lean and high throughput solubility screen resulted in lipid based formulations with varying ratios Capryol 90, Labrasol, Propylene Glycol, and Vitamin E TGPS. After establishing the Self-Emulsifying properties for these prototype formulations upon aqueous dilution, the formulation design space was established. The Self- Micro-Emulsifying properties were later confirmed again by Dynamic Light Scattering upon dilution with SGF and after lipid digestion, see Figure 8. It was found that nano-sized micelles were formed and best results were obtained for LF1 and LF3 high in Capryol 90. Contrary to the PEG-based formulations, lipid-based formulations (LF1 and LF3) showed promising IBU recovery upon aqueous dilution, also in acidic SGF.
Next step is to encapsulate lead formulations into Softgels and place them on stability to assess API degradation upon storage.
1. Williams et al. Journal of Pharmaceutical Sciences, (2012), 101. 3360 – 3380
2. Gattefossé bioavailability enhancement formulation guidelines
3. Colin W. Pouton, European Journal of Pharmaceutical Sciences, (2000), 11, S93 – S98
4. Wei Guo Dai et al. Advanced Drug Delivery Reviews, (2008), 60, 657 – 672
Olympia Hofman, Marjolein van Baest, Katerina Rousou for analytical support.
Gattefosse Inc. for providing excipient samples and technical consultation.
For more information please visit http://www.patheon.com/en-us