Analysis of generic antiretroviral formulations manufactured in India.

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Dear FORUM,

Any one has got acces to the following paper? Is so please post it

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Geetha Ramachandran; Elke S Perloff; L von Moltke; Soumya

Swaminathan; A Wanke; J Greenblatt

Analysis of generic antiretroviral formulations manufactured in

India. AIDS. July2004, Volume 18, Issue 10. CORRESPONDENCE PP. 1482-

1484.

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Joe

AIDS Treatment

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AIDS: Volume 18(10) 2 July 2004 pp 1482-1484

Analysis of generic antiretroviral formulations manufactured in India

Ramachandran, Geethaa; Perloff, Elke Sb; von Moltke, Lb; Swaminathan,

Soumyaa; Wanke, Ab; Greenblatt, Jb

aTuberculosis Research Center (Indian Council of Medical Research), Chennai,

India; and bTufts University School of Medicine, Boston, MA, USA.

Sponsorship: This work was supported by the Fogarty AIDS International Training

and Research Program 5D437W000237, Lifespan/Tufts/Brown Center

for AIDS Research.

Received: 17 December 2003; revised: 23 December 2003; accepted: 27 January

2004.

Highly active antiretroviral therapy has significantly modified the natural

history of HIV infection, decreasing mortality and the incidence

of opportunistic infections [1]. However, 90% of infected individuals worldwide

do not have access to these drugs [2], because their cost is too

high for the developing countries that are most affected by the AIDS epidemic.

India is a major producer of generic antiretroviral drugs that are widely used

in developing countries because they are less expensive than those produced

elsewhere. There have, however, been reports of generic

medications, including antiretroviral agents, which contain little or no active

ingredients [3,4]. It is therefore important that generic

antiretroviral medications be analysed for drug content. Data describing the

integrity of these drugs are not publicly available except for a

report by Penzak et al. [5] on nevirapine.

We analysed the content of six commonly used nucleoside and non-nucleoside

reverse transcriptase inhibitors alone and in combination, from three Indian

sources (Aurobindo Pharma, Ranbaxy and Cipla) and compared the

values with proprietary medications manufactured in the United States.

The antiretroviral drugs tested were efavirenz (600 mg), nevirapine (200 mg),

zidovudine (300 mg), didanosine (250 mg), stavudine (30 mg), lamivudine (150 mg)

and a combination pill containing nevirapine, stavudine and lamivudine

in the same dosages. They were physician's samples given by the drug companies

for patient use during July-August 2003. The date of manufacture of the drugs

was from December 2001 and June 2003 and expiration dates were from December

2003 and April 2006.

Six tablets/capsules of each drug were processed and analysed in duplicate by

high-performance liquid chromatography (HPLC). The entire tablet/contents

of the capsule were crushed into a fine powder and dissolved in methanol.

Appropriate dilutions of the drug solutions were made in methanol and the

methanolic solutions were injected into a Waters HPLC (Milford, MA, USA) with a

Waters 300 mm ¥ 3.9 mm micro Bondapak reverse phase C18 column. The syrup

solutions containing the antiretroviral drugs were suitably diluted in

methanol and injected into the HPLC.

The methods used to estimate the drugs in the tablet/capsule/syrup were modified

from those reported for estimating drug concentrations in

blood [6,7]. All drugs, except efavirenz, were monitored using an ultraviolet

detector set at 260 nm using a flow rate of 1.5 ml/min and maintaining the

column at room temperature. In the case of efavirenz, the ultraviolet detector

was set at 245 nm, the flow rate was adjusted to 2.4 ml/min and the column

maintained at 40°C. The mobile phase consisted of a mixture of potassium

phosphate solution, acetonitrile and methanol in varying proportions for the

different drugs.

A range of calibration standards containing known concentrations of the drugs

were prepared in methanol and run simultaneously. Calibration standards of

zidovudine and didanosine were prepared using pure powder obtained from the

Sigma Chemical Company (St Louis, MO, USA). In the case of the others, drugs

manufactured in the USA were used. These drugs were obtained from the

local pharmacies.

The concentration of the active ingredient in each tablet/capsule was calculated

from the height of the peak that was obtained on the

chromatogram and compared with that obtained for the corresponding standard

solutions of known drug concentration. Appropriate dilution factors

were employed to calculate the drug content in tablets/capsules/syrup.

In all, 12 chromatographic analyses were performed for each individual

medication. All drug assays were undertaken after coding them.

The mean drug content of all the preparations is given in Table 1. They compared

well with the proprietary formulations and the variability

(coefficient of variation) ranged from 0.01 to 8.3%. All the formulations

werwere within the 5% range of the stated contents compared with the

proprietary drugs, except for stavudine and lamivudine, which were slightly

higher but within the 10% range.

Table 1. Antiretroviral drug content from different sources.CV, Coefficient of

variation.

This report adds to the published data on the content of antiretroviral drugs

manufactured outside the USA. Penzak et al. [5] analysed nevirapine from six

international sources representing four countries and three manufacturers, and

reported an average nevirapine content of 99% in tested preparations compared

with labeled amounts.

In the present study, analyses of specific antiretroviral medications supplied

by Aurobindo Pharma, Ranbaxy and Cipla from India indicate that the amount of

active drug is very similar to those medications manufactured in the USA.

Although these data are encouraging given the widespread use of such products in

the developing world, further studies are required to evaluate

whether these results are applicable consistently to randomly selected lots of

the drugs. Studies documenting bioequivalence between generic and

proprietary antiretroviral medications and bioavailability in different

populations are also necessary. This information will enable

healthcare providers and governmental agencies to choose the antiretroviral

formulations most likely to provide HIV-infected patients in the developing

world with the greatest possibility of clinical benefits.

Acknowledgements

The authors acknowledge the Fogarty AIDS International Training and Research

Program, Lifespan/Tufts/Brown Center for AIDS Research for funding this project.

They also thank Aurobindo Pharma, Ranbaxy and Cipla for granting eprmission to

carry out drug analysis of their products.

They are grateful to Dr Mayer, Program Director, Fogarty AITRP and Dr

P.R. Narayanan, Director, Tuberculosis Research Center for their encouragement

and support. The secretarial assistance provided by Mr B. Doraiswamy is

acknowledged.

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© 2004 Lippincott & Wilkins, Inc.

___________________________

Contributed by:

Koen Van Rompay, D.V.M., Ph.D.

Associate Research Virologist

California National Primate Research Center

University of California

County Road 98 & Hutchison

, CA 95616

USA

Phone: +(530)-752-5281

Fax: +(530)-754-4411

E-mail: kkvanrompay@...

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