Formulation development of novel dispersible fixed dose combination (FDC) of lamivudine, nevirapine and zidovudine for pediatric use
Background: Till 2006, ART for children was complicated and inconvenient as it involved administration of large volume of syrupsr or usage of adult FDC tablets by breaking, compromising on dosage accuracy. Introduction of Lamivudine-Stavudine-Nevirapine based dispersible FDC for children brought a convenient, reliable and a cost effective solution. But there was still need for more safe and efficacious first-line combinations. Consequently Ranbaxy decided to develop dispersible Lamivudine-Zidovudine-Nevirapine based FDC for children.
Methods: To develop the same, the three actives were formulated into FDC Tablets for Oral Suspension (TFOS) - designed to disintegrate quickly into smooth uniform suspension in a small volume of liquid media like water/juices.
The strength of active ingredients, based on NIH treatment guidelines was selected to provide flexibility of dosing.
To enhance Accuracy of dosing, break line was introduced and to enhance Adherence and palatability, flavoring agents preferred by children were incorporated.
TFOS contains the active ingredients in admixture with non-toxic pharmaceutically acceptable excipients like inert diluents, granulating, lubricating and disintegrating agents, belonging to “GRAS” Category.
During prototype development TFOS was subjected to various tests like dispersion time, uniformity of dispersion, taste, dissolution, potency, divisibility test, impurity profile and pharmacokinetic / comparative bioavailability test against individual reference liquid products.
Results: TFOS designed was:
1. Dispersing into a smooth suspension in 5 ml of water within 2 minutes;
2. Showing stability under accelerated conditions;
3. Similar in-vitro dissolution profile as that of three reference liquid products;
4. Complying to divisibility test;
5. Palatable and acceptable Lemon flavor;
6. Having comparable pharmacokinetic parameters to individual reference liquid formulation under fasting condition (N=18. (Refer Table 1)).
| Cmax | AUCt | AUCinf | |
| Lamivudine | 115.35 | 105.40 | 107.08 |
| Nevirapine | 110.76 | 102.93 | 101.39 |
| Zidovudine | 104.00 | 105.08 | 105.20 |
Conclusions: All studied parameters of TFOS showed satisfactory results and supported product feasibility for pediatric Lamivudine-Nevirapine-Zidovudine FDC.
Comparative bioavailability study for the same was successfully completed and product was filed for prequalification with WHO in Nov-07.
R.S. Raghuvanshi1, A. Jaiswal1, A. Chhabra2
1Ranbaxy Research Laboratories, Product Development and Research, Gurgaon, India, 2Ranbaxy Laboratories Ltd, ARV Business, Gurgaon, India