1. Fenofibrate USP (Micronized, control)
Solubilization of Fenofibrate, a Poorly Soluble BCS Class II Active
Presenting Author: Girish Venkatachalaiah, PhD,
Co-Authors: Praveen Saligram, PhD, Swetha
SPI Pharma
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Conclusion(s)
Co-processing of fenofibrate via a proprietary granulation process resulted in the formulation of an acceptable tablet dosage form as evidenced by the assay, content uniformity, dissolution, and bio-equivalency test results. The formation of fused structure of drug, soluble and insoluble excipient combinations by co-processing as shown in the figure helps in increasing the surface area thereby increasing the rate of solution with increased absorption.
The rat PK studies revealed that both co-processed formulation (Test) and Tricor (Reference) had higher bio-availability than the control – fenofibrate USP (Micronized). It further showed that the co-processed formulation (Test) had similar pharmacokinetic attributes as that of Tricor (Reference) which is a marketed nanocrystal formulation of fenofibrate. Economical co-processing techniques of drug with soluble and insoluble excipients employed in this study can be likely alternatives to obtain acceptable solubility enhancement of BCS Class II molecules with enhanced bioavailability.
The results from this study clearly demonstrate the potential to improve the solubility of BCS Class II molecules and enhance their bioavailability by using a customized combination of excipients, chosen based on the specific properties of the API, in a cost- effective co-granulation process.
PURPOSE
Actives administered orally as swallow tablets are intended to exert a systemic effect following their dissolution in the GI tract and subsequent absorption. Before actives can effectively pass through the GI wall they must be in a soluble state. Actives which are BCS Class II therefore have the rate of solution (dissolution) in the GI fluids as a rate limiting factor affecting their absorption – impacting pharmacokinetic aspects of Tmax, Cmax and AUC. In this study an attempt was made to increase the rate of solution of a model BCS Class II active, fenofibrate (lipid regulating agent) by co-processing with a customized, proprietary combination of excipients (Co-processed fenofibrate). Rat pharmacokinetic (PK) modelling was carried out in comparison to a marketed fenofibrate formulation (Tricor by nanocrystal technology) from Abbott Laboratories to assess bio-equivalency.
Objective(s)
To increase the rate of solution of a BCS Class II active, fenofibrate, by co-processing with proprietary combination of excipients, including soluble and insoluble processing aids and to formulate into a tablet dosage form.
To demonstrate its pharmacokinetic behavior using rat pharmacokinetic (PK) modelling in comparison to marketed product (Tricor) and Fenofibrate USP active.
Physical mixture
(Active and excipients)
Fused mixture after co-processing (Active and excipients)
Porous structure of drug after co-processing and selective washing away of excipients(SPI Technology)
Method(s)
Fenofibrate USP (Micronized) from IPCA Laboratories and a proprietary combination of tableting excipients, including soluble and insoluble processing aids, were granulated using a proprietary, co-granulation process. The co-processing step was optimized using design of experiments (DOE).
The dried, co-processed fenofibrate was blended with additional tableting excipients and compressed into tablets using an instrumented rotary press (Pacific Smart Press, SRC-10i) fitted with mm round, FFBE punches.
The compressed tablets were evaluated for drug content (assay), content uniformity, related substances using in-house HPLC (Waters, Alliance®) analytical methods and dissolution rate was measured in 1000 mL of 25 mmol SLS (Sodium lauryl sulfate) in water at 50 rpm, USP Apparatus II (Electrolab dissolution tester, TDT-08L). In-vitro dissolution profile comparisons were done using appropriate discriminatory dissolution media before dosing in to the animals. This was done in comparison with nanocrystal technology and unmodified API as the references.
The animal pharmacokinetic studies were performed in three way parallel design with co-processed formulation (Test), reference (Tricor) tablets and pure fenofibrate active (Control). The powdered tablets from both formulations and pure fenofibrate (micronized) were filled into empty mini gelatin capsules (size 9), male Sprague Dawley rats were dosed using Torpac® oral gavage needles. After a single oral dose administration, the blood samples were collected from each rat at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours post dose. Blood samples were centrifuged to collect plasma for bioanalysis. The plasma samples were analyzed for quantification of fenofibric acid (active metabolite of fenofibrate) using a fit for the purpose HPLC (Shimadzu, UFLC system) method with a lower limit of quantification of 200 ng/mL. The pharmacokinetic parameters for fenofibric acid were calculated using the non-compartmental analysis tool of the Phoenix 64 software.
The area under the concentration time curve (AUC) was calculated by linear trapezoidal rule. The peak plasma concentration (Cmax) and time for the peak plasma concentration (Tmax) were observed values. The plasma concentrations and pharmacokinetic parameters were reported.
Result(s)
Co-processed fenofibrate tablets had a total assay of 98.6% with a content uniformity acceptance value (AV) of 5.3. The drug content in the tablets varied from 98.6% to 105.6% with a mean value of 101%. Dissolution release of 85% (Q) was achieved within 15 minutes in release media. The assay of Tricor tablets, the reference product, was 97.2% and the dissolution release was 90% in 15 minutes. The in-vitro discriminatory dissolution data was as given in Figure 1.
The similarity factor (F2) was 55 showing the similarity of the profiles of co-processed tablets and reference tablets.
The rat PK plot with concentration of fenofibric acid in y-axis and time in x-axis was as given in Figure 2.
The summary of rat PK data was presented in the Table 1.
Rat PK studies showed that co-processed tablets (Test) had a Cmax of 18.2 µg/mL and an AUC0-∞ of 124 µg.h/mL while Tricor (Reference) had a Cmax of 21.5 µg/mL and an AUC0-∞ of 135 µg.h/mL. The relative bio-availability (Frel) in comparison to control fenofibrate USP (Micronized), were found to be 138% and 150% for Test and Reference formulations respectively. The two-sample t-Test for the observed differences in Cmax and AUC0-∞ between the co-processed and reference formulations were statistically insignificant (α 0.05) with a P(T<=t) two-tail values of 0.35 and 0.43 correspondingly.
The tablet formula was
Sl. No.
Ingredients
mg/unit
%w/w 1
Co-processed fenofibrate
716.0
71.6 2
Silicon dioxide
9.0
0.9 3
Mannogem® EZ
230.0
23.0 4
Crospovidone
25.0
2.5 5
Lubripharm®
20.0
2.0
Total
1000.0
100.0
The tablet manufacturing process was as follows
Dispensing
Step 1. Sifting Co-processed fenofibrate sifted along with other tabletting excipients
Blending
Step 2. Compression Blend compressed using rotary compression machine for 1000 mg target tablet weight
Step 3. Packing Packed the tablets in HDPE bottles with suitable labelling
PK Parameter
Co-processed tablets
(SPI Technology)
Reference
(Tricor)
Fenofibrate USP (Micronized, control)
Cmax (mcg/mL)
18.2
(CV % - 21)
21.5
(CV % - 36)
14.6
(CV % - 27)
AUC (mcg.h/mL)
124
135
(CV % - 11) 90
(CV % )
Relative BA – Frel (%)
138
150 -
Fenofibrate Solubility enhancement
Fenofibrate rat PK data
Figure 1
Figure 2
Table 1
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