Dabigatran Formulation for Oral Administration – an Evaluation

Abstract

Dabigatran etexilate mesylate is a pro-drug of Dabigatran – a BSC Class II drug used as anti-coagulant in deep vein thrombosis as a direct thrombin inhibitor. Due to increasing solubility in the acidic regime, tartaric acid pellets (TAP) are used as starter beads. A processed formulation is compared with the existing formulation from the innovator Boehringer Ingelheim Pharmaceuticals (Pradaxa, 150 mg). Experimental findings in this note have been first conducted and published by Balaji et al. [1].

Motivation for Dabigatran

The apparent partition coefficient of the neutral form (free base) of Dabigatran etexilate mesylate is log­ P = 3.8, and the dissociation constants are pKa1 = 4.0 ± 0.1 (Benzimidazole moiety) pKa2 = 6.7 ± 0.1 (Carbamic Acid Hexyl Ester moiety). The solubility of the API is a critical factor in pharmaceutical formulations and in case of Dabigatran depends strongly on the pH value. Thereby, the solubility is increasing at lower pH values: In pure water, the solubility of a saturated solution of the API is at 1.8 mg/ml. Additionally with the high intrinsic passive permeability of the API, Dabigatran etexilate mesylate is classified as a BCS class II drug substance according to the Biopharmaceutical Classification System [2-6]. Obviously, an increase of local solubility is strongly requested and fulfilled by the use of Tartaric acid pellets in size from 600 µm to 800 µm.

Materials

Dabigatran etexilate mesylate (CAS number 593282-20-3 is used as active. TAP 500 and TAP 700 are used as functional starter beads. Further excipients are Povidone K-30, Hydroxypropyl cellulose (HPC), PEG 400, Isopropyl alcohol (IPA), Opadry white, Sodium laurilsulfate (SLS), Talc. Acetone and methanol are solvents for spray drying or dissolution tests. Layering and coating of pellets is performed by fluidized bed technology.

Material	Composition (mg/capsule)
Seal Coating
TAP 500	0
TAP 700	152.63
Povidone K-30	7.268
HPC	0
PEG-400	0.363
IPA	50.69
Acetone	50.69
Drug Loading
Seal Coated pellets	160.261
Dabigatran etexilate mesylate	172.95
Povidone K-30	30
HPC	0
PEG-400	1.5
IPA	499.1
Acetone	499.1
Protective Coating
Opadry white	0
Lubrication
SLS	8.289
Talc	2

Table 1: Formulation of the Dabigatran etexilate mesylate IR pellets.

Dabigatran Formulation

Balaji et al. studied different formulations and compared the drug release times, dissolution profiles and physical properties with the innovator product. The innovator product is PRADAXA 150mg, as capsules with a shelf life of 3years, by Boehringer Ingelheim Pharmaceuticals. We will resume information for one optimized formulation, which fits best to the properties of the innovator product. The composition of this formulation is given in Table 1.

The polymers used in the formulation were found to be compatible with the drug, proven by a concordant FT-IR spectrum of Dabigatran etexilate mesylate pure drug and combination with excipients. For characterizing the formulated pellets, bulk density, tapped density, the Hausner’s ratio, and the angle of response have been analyzed. The compressibility index seems to be fair, while the Hausner’s ratio and the angle of response indicate good flowing properties and flowability of the pellets.

Parameter	Value
Processability
Bulk density (g/ml)	0.821 ± 0.062
Tapped density (g/ml)	0.847 ± 0.009
Hausner’s ratio	1.03 ± 0.12
Angle of Repose θ (°)	28 ± 3
Size
# sieve no 14 (% retained)	0
# sieve no 25 (% retained)	43
Bottom plate (% retained)	3
Water
Assay (%)	100.1 ± 0.084
Water by Karl-Fischer (%)	1.8 ± 0.245
IR capsules
Average weight (mg)	453 ± 1.36
Lock length (mm)	19.01 ± 0.11
Disintegration time (min)	6.55 ± 0.014

Table 2: Micromeritic properties of Dabigatran etexilate mesylate IR pellet formulation.

Dissolution profile of Dabigatran formulations

The in-vitro dissolution profiles of the optimized formulation and of the innovator product are shown in Figure 1. Both formulations meet the general requirements of dissolution profiles and show comparable time dependencies. After 10 minutes, more than half of drug is released; after 45 minutes the drug discharge indicated 100%.

Figure 1: Dissolution (in %) versus time (in minutes). Comparative In-vitro dissolution profile of the innovator product (grey) and of the optimized formulation of Dabigatran etexilate mesylate (orange) IR capsules.

Figure 2: Dissolution (in %) versus time (in minutes). Comparative in-vitro dissolution profile of the optimized formulation of Dabigatran etexilate mesylate IR capsules after 1 month, 2 months and 3 months. Stability studies at 40 °C and 75% rH.

Figure 2 presents the comparative in-vitro dissolution profile of the optimized formulation of Dabigatran etexilate mesylate IR capsules after 1 month, 2 months and 3 months. The stability studies are performed at 40 °C and 75% rH. The dissolution profile remains comparable within the first 10 minutes, while at later times, the aged drug substance dissolves slightly slower, reaching a level of approximately 100% dissolution after 45 minutes.

Summary

This case study compares an optimized formulations of Dabigatran etexilate mesylate with the formerly formulation of the innovator. The optimized formulation is based on TAP 700. Smaller pellet sizes have been investigated, as well, but a poor flow and sticking of the smaller pellets is observed. In the specified formulation, Povidone K30 was taken as binder and lubrication was done with SLS and Talc which results in a good flow behavior. In-vitro dissolution is performed before and after stability studies and yields comparable time dependent profiles as the innovator product, with a drug release at 95% to 100% after 45 minutes.

References

[1] K. Balaji, and A.Anusha, EPRA International Journal of Research and Development, 5(12): 248-262 (2020)

[2] Bhandari Neeraj*, Kumar Abhishek, A Review On Immediate Release Drug Delivery System International Research Journal of Pharmaceutical and Applied Sciences (IRJPAS), 4(1):78-87 (2014).

[3] Lachman.L, Lieberman.A, Kinig.J.L, The Theory and Practice of Industrial Pharmacy, 4th edition, Varghese Publishing House, Bombay, 317 (1991).

[4] Survase S, Kumar N., Immediate release drug delivery: Current scenario, Current Research & Information on Pharmaceutical Science, 8:1-8 (2007).

[5] N. Harrison, R. Gordon, MB Fawzi, RU Nesbitt, Evaluation of a high-speed pelletization process and equipment, Drug Delivery, International Journal,11:1523-1541 (1985).

[6] Ravi Teja Pusapati*, T. Venkateswara Rao, Fluidized bed processing: A review Indian Journal of Research in Pharmacy and Biotechnology, ISSN: 2321-5674(Print) ISSN: 2320 – 3471 (2014).