Biomedical subjects

R Panchagnula

Publications and source records attributed to R Panchagnula.

At least 19 recordsLinked to original sources

PubMed2006

High-throughput evaluation of non-swellable controlled release matrix tablets.

Drug release from controlled-release (CR) matrix tablets involves the permeation and diffusion of water through the system. In this study, a new methodology is proposed for the measurement of water permeation and simultaneous drug release from the inert, non-swellable CR matrix tablet of diltiazem (DLT) and a correlation is made between these two processes. Cylindrical matrices were readily prepared by direct compression of pellets obtained by extrusion-spheronization. Water transport was studied using tritiated water (HTO) as a permeant in a Franz-diffusion cell and simultaneously drug release was measured. Further, dissolution was performed on USP XXI/XXII dissolution apparatus I using demineralized water. Matrices showed a steady water-uptake up to 6 h and the steady state for HTO permeation lasting from 6-h to 24-h Flux of water permeated and flux of drug released correlated well. Thus, HTO permeation through the matrix tablet and the proposed methodology can be used as a tool and/or surrogate marker for evaluation of controlled release matrix tablets. This methodology can be coined as "high-throughput" in terms of amount of labor and resources required in comparison to that of dissolution.

Delayed-Action Preparations↗

PubMed2006

Plasma pooling to expedite bioequivalence estimation of rifampicin in fixed dose combinations.

Rifampicin has been found to be one of the most important antitubercular drugs; however, variable bioavailability of rifampicin in some fixed dose combinations (FDCs) as well as separate formulations has been reported in the literature. This resulted in proper evaluation of FDCs with standard protocol for bioequivalence trials. Earlier, plasma pooling as a rapid method for bioequivalence assessment of rifampicin in FDCs was proposed from our laboratory. Results obtained after pooled plasma sample analysis were compared with those from the individual plasma sample analysis. Case studies from our laboratories further validate and support the use of plasma pooling method as a faster and cost effective tool for bioequivalence assessment of rifampicin in FDCs, which will be useful in order to speed up the registration and approval of good quality FDCs.

Administration, Oral↗

PubMed2006

Dissolution testing of marketed rifampicin containing fixed dose combination formulations using a new discriminative media: a post marketing retrospective study.

Currently recommended compendial dissolution methods for quality control of orally administered solid dosage forms of rifampicin containing formulations are not found to be able to forecast the in vivo performance. A recently proposed dissolution method of 0.01 N HCl at 50 rpm using paddle apparatus for screening was found to be more appropriate and able to predict the in vivo performance of those formulations. The objective of this investigation was to validate the new method of dissolution testing for solid dosage forms of rifampicin containing formulations using a basket apparatus and to compare it with the frequently recommended pharmacopeial method. In the present study the newly proposed dissolution condition (0.01 N HCl) was validated using six formulations of two, three and four drug combinations from two different manufacturers by basket method and compared with the widely recommended compendial medium. In this investigation, the appropriateness of the proposed methodology was confirmed by the dissolution results of the two FDC formulations (a two-drug and a four-drug combinations) that had previously passed the bioequivalence tests. It was found that the recommended dissolution medium of 0.01 N HCl can be used for screening of rifampicin containing formulations using both paddle and basket dissolution apparatus at 50 rpm and 100 rpm, respectively.

Antitubercular Agents↗

PubMed2005

Determination of rifampicin bioequivalence in a three-drug FDC by WHO and indian protocols: effect of sampling schedule and size.

SETTING: To promote the quality assurance of fixed-dose combination (FDC) formulations, the World Health Organization (WHO) has prepared a convenient simplified protocol for the determination of rifampicin (RMP) bioequivalence. During the development of this protocol, it was proved that sampling time up to 8 h can determine the rate and extent of RMP absorption. However, this protocol utilises 20 volunteers in contrast to other local regulatory requirements of a minimum of 12 volunteers. The different sample sizes utilised in these protocols may affect the sensitivity of the bioequivalence outcome. OBJECTIVE: To determine the effect of sampling size and schedule on RMP bioequivalence when two different protocols are used. DESIGN: A bioequivalence trial was conducted with a study design of 20 volunteers and 24 h sampling time, which fulfils the requirements of both the WHO and Indian regulatory protocols. Pharmacokinetic and statistical analysis was done by stepwise reduction in sample size and schedule. RESULT: Bioequivalence limits of RMP were unaffected by a reduced sample size of 12 volunteers and 8 h sampling time. CONCLUSION: Minimising sample size after validation for borderline and poor quality FDC formulations can further reduce the cost of conducting bioequivalence trials.

Absorption↗

PubMed2005

Plasma pooling: utility in expediting bioequivalence assessment of rifampicin-containing fixed-dose combinations.

To improve the rapidity of the registration process of rifampicin (RMP) containing fixed-dose combination (FDC) formulations, a plasma pooling methodology was used to increase the throughput of bioanalysis of plasma samples from bioequivalence trials of FDCs. Plasma samples of a biostudy were analysed for RMP using traditional analysis methods as well as a plasma pooling method (volunteer and time pooling). Both methods produced similar results, with less than 15% variability in both volunteer and time pooling. The plasma pooling method for bioanalysis was validated. Further studies are required to identify and reduce the percentage variability.

Antibiotics, Antitubercular↗

PubMed2005

Establishment of a reference formulation for bioequivalence assessment of rifampicin-containing FDCs: an essential step towards improving tuberculosis treatment.

SETTING: Selection of a reference product for bioequivalence studies of rifampicin (RMP) in prequalifying fixed-dose combinations (FDC) for worldwide distribution through the WHO is critical. OBJECTIVE: To investigate the feasibility of establishing FDC formulations as reference products for bioequivalence studies of RMP in prequalification programmes. DESIGN: A biostudy was conducted as an open, two-period randomised cross-over trial. Two three-drug FDCs containing RMP, isoniazid and ethambutol hydrochloride were administered to a group of 22 volunteers with a wash-out period of 1 week. Plasma samples were collected and analysed for the concentration of RMP and desacetyl-RMP, a major active metabolite of RMP, up to 24 h. Pharmacokinetic parameters of RMP were calculated: Cmax, AUC0-24, Tmax, kel and absorption efficiencies. RESULTS: No significant difference was observed between the administered formulations with respect to the major pharmacokinetic parameters Cmax, Tmax and AUC0-24 when evaluated by parametric (two-way ANOVA) and non-parametric (Hauschke's analysis) statistical analysis. The concentration of RMP falls within the reported acceptable therapeutic range. CONCLUSION: FDCs can be developed as a reference product for bioequivalence studies.

Antibiotics, Antitubercular↗

PubMed2005

Quality control of anti-tuberculosis FDC formulations in the global market: part II-accelerated stability studies.

OBJECTIVE: To determine the quality and performance of rifampicin (RMP) containing fixed-dose combination (FDC) formulations of anti-tuberculosis drugs sourced from the international market with respect to physical, chemical and dissolution properties after storage at accelerated stability conditions (40 degrees C/75% relative humidity) and to identify appropriate storage specifications. METHODS: Formulations across different companies and combinations were subjected to 6-month accelerated stability testing in packaging conditions recommended by the manufacturer. Various pharmacopeial and nonpharmacopeial tests for tablets were performed for 3- and 6-month samples. RESULTS: All the formulations were found to be stable, where extent of dissolution was within +/- 10% of that of the initial value, and all formulations passed the pharmacopeial limits for assay and content uniformity of 90-110% and +/- 15% of average drug content, respectively. CONCLUSIONS: Good quality RMP-containing FDCs that remain stable after 6-month accelerated stability testing are available in the marketplace.

Antibiotics, Antitubercular↗

PubMed2005

Minimum sample size and sampling time requirements for assessment of rifampicin bioequivalence from FDC formulations.

SETTING: The WHO- and IUATLD-recommended protocol for rifampicin (RMP) bioequivalence utilises 20-22 volunteers and 8 h, whereas the requirement of other regulatory authorities is 12 volunteers with a 24 h sampling schedule. Differing sampling size and time requirements may change the outcome of RMP bioequivalence. OBJECTIVE: To determine the minimal sample size and time required to assess RMP bioequivalence from FDC formulations. DESIGN: Bioequivalence studies were conducted that fulfilled the criteria of the WHO and Indian regulatory protocols. From earlier studies, retrospective pharmacokinetic evaluation, power of the test and bioequivalence limits were also calculated using 8-22 volunteers and sampling points of 8-24 h. Pharmacokinetic and statistical evaluations from three representative studies showing low, moderate and high intra-subject variability are given to determine minimum requirements for RMP bioequivalence. RESULT: It was found that a sampling schedule up to 8 h was sufficient to compare the absorption process of RMP. There was no influence of reduced sample size on bioequivalence estimates of RMP that showed low or moderate variability. However, in a study showing higher variation, a sample size of 14-16 subjects was found to be optimal. CONCLUSION: It is possible to reduce the sample size requirement for determination of RMP bioequivalence using the WHO protocol.

Antibiotics, Antitubercular↗

PubMed2005

Co-treatment with grapefruit juice inhibits while chronic administration activates intestinal P-glycoprotein-mediated drug efflux.

P-Glycoprotein (P-gp) mediated efflux is recognized as a significant biochemical barrier affecting oral absorption for a number of drugs. Various conflicting reports have been published regarding the effects of grapefruit juice (GFJ) on P-gp-mediated drug efflux, in which GFJ has been shown both to inhibit and activate it. Hence, the present study adopted a two-way approach, involving both co-treatment and chronic administration. Bi-directional transport of paclitaxel (PCL) was carried out in the absence and presence of GFJ extract, in rat everted ileum sac. Further, the effect of chronic administration of GFJ to rats was characterized by permeability studies with indinavir (INDI). Co-treatment of GFJ extract at 100% concentration reduced the asymmetric transport of PCL (efflux ratio = 20.8) by increasing absorptive (A --> B) transport by 921% and reducing secretory (B --> A) transport by 41%. Further, GFJ showed a concentration dependent effect on PCL permeability. Imipramine, a passive permeability marker with absorptive permeability of 15.33 +/- 4.26 x 10(-6) cm/s showed no asymmetric transport and also no significant (P < 0.05) change in permeability in the presence of GFJ. Chronic administration of GFJ resulted in a significant decrease in absorptive transport of indinavir, which was even greater than that produced by rifampicin pretreatment. No change in permeability of propranolol, a passive permeability marker, was observed. Further, the decrease in absorptive transport of INDI was reversed by the P-gp inhibitor verapamil. In conclusion, GFJ extract inhibited P-gp-mediated efflux in co-treatment, whereas chronic administration led to increased levels of P-gp expression, thus having a profound effect on intestinal absorption and GFJ-drug interactions in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Fixed dose combinations for tuberculosis: Lessons learned from clinical, formulation and regulatory perspective.

Worldwide, tuberculosis (TB) remains one of the most important communicable diseases in terms of morbidity and mortality. Its control requires multi-drug therapy for at least six months, which could lead to patient non-compliance, failure of therapy and ultimately resulting in the emergence of drug resistance. Fixed dose combinations (FDCs) in TB therapy reduce the number of tablets to be consumed and thereby increase patient compliance with recommended treatment regimens. Thus, FDCs play a significant role in preventing the emergence of drug resistance and successful treatment. However, the quality of FDCs with respect to variable bioavailability and their registration requirements are major hurdles to their implementation in national TB control programs. It is anticipated that a large global market for FDCs will encourage large-scale production and increased competition, which in turn will result in FDCs at affordable prices. The Global Drug Facility (GDF), established by the World Health Organization (WHO), aims to ensure universal uninterrupted access to quality TB drugs for implementation of directly observed treatment short-course (DOTS) in resource-poor countries. In this program, four FDCs were accepted as the drugs of first choice because of their obvious advantages in controlling TB. This demands the necessity of addressing quality and registration requirements of FDCs systematically. In light of this current knowledge on anti-TB FDCs, their dosage, combinations, available clinical studies and the experiences with TB therapy has been discussed in this article, which should serve as lessons for selection of appropriate FDCs for other diseases such as malaria and AIDS.

Antitubercular Agents↗

PubMed2004

Quality control of anti-tuberculosis fixed-dose combination formulations in the global market: an in vitro study.

OBJECTIVE: To determine the quality, and especially the dissolution properties of rifampicin, of fixed-dose combination (FDC) formulations of anti-tuberculosis agents manufactured by major market holders in the anti-tuberculosis sector and supplied for use in national tuberculosis control programmes. METHODS: Dissolution studies were performed for four formulations supplied by four different manufacturers in four dissolution media (0.1N and 0.01N HCl, phosphate buffer [PB] and 20% vegetable oil in PB), at four different agitation rates using USP apparatus II. The formulations were subjected to 4-week accelerated stability studies (40 degrees C / 75% RH) and evaluated for physical, chemical and dissolution stability. RESULTS: The formulations tested complied with pharmacopeial quality control (QC) tests. The extent of rifampicin release was independent of dissolution medium; however, a slight decrease in the dissolution rate was observed in two products. More than 75% of drug was released in 45 min at all agitation intensities except 30 rpm, and 20% oil in the medium reflected fed state. Formulations were stable in the packaging conditions recommended by the manufacturer for at least 4 weeks. CONCLUSIONS: The formulations tested passed the QC tests and were found to be stable. A decrease in the rate, although not the extent, of dissolution necessitated multiple point dissolution in gastric and intestinal pH conditions to ensure consistency in in vivo bioavailability.

Antibiotics, Antitubercular↗

PubMed2004

In vitro analysis of rifampicin and its effect on quality control tests of rifampicin containing dosage forms.

The chemical stability of rifampicin both in solid state and various media has widely been investigated. While rifampicin is appreciably stable in solid-state, its decomposition rate is very high in acidic as well as in alkaline medium and a variety of decomposition products were identified. The literature reports on highly variable rifampicin decomposition in acidic medium. Hence, the objective of this investigation was to study possible reasons responsible for this variability. For this purpose, filter validation and correlation between rifampicin and its degradation products were developed to account for the loss of rifampicin in acidic media. For analysis of rifampicin with or without the presence of isoniazid, a simple and accurate method was developed using high performance chromatography recommended in FDC monographs of the United States Pharmacopoeia. Using the equations developed in this investigation, the amount of rifampicin degraded in the acidic media was calculated from the area under curve of the degradation products. Further, it was proved that in a dissolution study, the colorimetric method of analysis recommended in the United States Pharmacopoeia provides accurate results regarding rifampicin release. Filter type, time of injection as well as interpretation of data are important factors that affect analysis results of rifampicin in in vitro studies and quality control.

Antibiotics, Antitubercular↗

PubMed2004

In vitro evaluation of fixed dose combination tablets of anti-tuberculosis drugs after real time storage at ambient conditions.

Rifampicin exhibits variable bioavailability from solid oral dosage forms and this problem is more apparent when it is formulated as fixed dose combination (FDC) in presence of other first-line anti-tuberculosis drugs. To determine the cause of variable bioavailability, the aging effect on physical and chemical performance of rifampicin from FDC formulations after real time storage at the ambient conditions was investigated. For this purpose, six FDC formulations from different manufacturers were stored at ambient conditions (20-35 degrees C, with no control of humidity) in the final packing for a period of 16-38 months and its in vitro quality control tests for rifampicin were compared with the initial performance of these tablets. None of the formulations have shown significant weight gain/loss and the assay values were within the pharmacopeial limits when evaluated by a stability indicating method. Further storage had no effect on physical performance of FDC tablets as indicated by unaltered dissolution profiles. Formulation reevaluation after real time storage at the ambient conditions for 16-38 months indicated that rifampicin containing FDC formulations are stable throughout its shelf life and instability is not a cause of variable bioavailability.

Antitubercular Agents↗

PubMed2003

Combination strategies to enhance transdermal permeation of zidovudine (AZT).

The objective of this study was to evaluate the effect of simultaneous application of two penetration enhancers of different chemical classes or a chemical penetration enhancer and current application on permeation of zidovudine (AZT) across rat skin. Ex vivo permeation of AZT using combinations of cineole or menthol in vehicle with either oleic acid/linolenic acid or 0.5 mA/cm2 anodal current application for 6 h was studied. Penetration enhancers were significantly different in enhancing the permeability of AZT across rat skin and are in the decreasing order of activity: linolenic acid > menthol > oleic acid > cineole > vehicle. The combination of cineole and oleic acid synergistically enhanced transdermal flux of AZT in addition to reducing lag time. However, this was not observed for combinations of menthol with oleic or linolenic acid. On the other hand, the simultaneous application of current with menthol and cineole significantly increased cumulative amounts of AZT permeating during the course of current application and reduced the lag time but failed to further increase steady state flux of AZT. These results suggest that a combination of two penetration enhancers of different classes or the simultaneous use of iontophoresis and a penetration enhancer may be advantageous to achieve permeation enhancement with low risk of skin damage.

Administration, Cutaneous↗

PubMed2002

LC determination of cephalosporins in in vitro rat intestinal sac absorption model.

Cefotaxime sodium (CX) and Ceftazidime pentahydrate (CZ) are peptidomimetic cephalosporins (CPS) which exist as zwitterionic compounds at physiological pH and because of this reason they are not absorbed appreciably on peroral administration. The permeability of these compounds can be increased transiently by altering membrane characteristics of absorptive epithelium by use of sorption promoters (SPs). In present work a simple validated HPLC method utilizing isocratic mobile phase and having short retention times for CX and CZ is developed which can be used to monitor their concentrations in Kreb's Ringer Bicarbonate (KRB) solution in in vitro intestinal sac absorption model. The same was utilized to determine apparent permeability coefficients and absorption profiles of CPS by modified Wilson-Wiseman method. The CPS were analysed by the reverse phase HPLC method using Shim-pack C18 column. The mobile phase used was of isocratic composition with phosphate buffer (pH 7.0, 3.5 g/l of KH(2)PO(4) dissolved in 0.03 M Na(2)HPO(4).2H(2)O) and methanol in proportion 85:15 for CZ and 70:30 for CX. The flow rate was 1 ml/min and quantitative determinations were carried out at 254 nm at 25 degrees C. The method was found specific because none of the proposed SPs, components of KRB and intestinal sac artefacts interfered with the drug peaks. The drug concentration versus area under peak relationship was found to be linear in concentration range of 0.25-20.0 microg/ml. The recovery studies, intraday variation, interday variation and interanalyst variation were within statistical limits. The limit of detection (LOD) was 95.0 and 100.0 ng/ml for CZ and CX, respectively. The limit of Quantitation (LOQ) was 240.0 and 250.0 ng/ml for CZ and CX, respectively. The proposed method was found to be rapid and selective and hence applied for continuous monitoring of CPS in in vitro intestinal sac absorption studies.

Animals↗

PubMed2002

Bioequivalence assessment of rifampicin, isoniazid and pyrazinamide in a fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol vs. separate formulations.

Depending on the patient category, tuberculosis requires treatment with 3 to 5 drugs which means that patient's compliance to therapy may not be optimal. To increase patient's adherence to treatment schedules, these drugs can be given as single drug preparations or fixed dose combinations (FDCs) of 2 or more drugs in a single formulation. However, an important issue associated with a rifampicin-containing FDC is its quality. Hence, to avoid spurious formulations entering the market, the World Health Organization and the International Union Against Tuberculosis and Lung Disease have recommended FDCs only of proven bioavailability. In this study, the relative bioavailability of rifampicin, isoniazid and pyrazinamide was assessed in a group of 14 healthy male subjects using the FDC tablet containing 4 drugs versus separate formulations at the same dose levels. The study was designed as an open, crossover trial. A total of 9 blood samples were collected over a period of 24 h. The concentration of rifampicin, its main metabolite desacetyl rifampicin, isoniazid and pyrazinamide in plasma were assessed using HPLC analysis. The pharmacokinetic parameters AUC(0-24) and Cmax were subjected to parametric and non-parametric statistical tests at 90% confidence interval. In addition, time to reach peak concentration (tmax), elimination rate constant (Kel) and terminal elimination half-life (t1/2) for each drug were also calculated. It was concluded that the FDC tablet containing 4 drugs is bioequivalent to separate rifampicin, isoniazid and pyrazinamide formulations at the same dose levels.

Analysis of Variance↗

PubMed2001

Insulin therapies - past, present and future.

The discovery of insulin is one of the greatest milestones in medical history. This discovery revolutionized the use of peptides and proteins as therapeutic agents. For more than six decades, insulin from different animal sources was used, until the breakthrough in biotechnology made it possible to produce human insulin in sufficient amounts. The evolution of the biotechnological era gave rise to modified insulins to solve some of the bottlenecks in insulin therapy. Efforts are currently focused towards developing non-invasive insulin delivery systems, and there are several competing technologies in different stages of development. The next few years will see several novel approaches to mimic the endogenous release and kinetics of insulin, and also many improved analogues designed to achieve better control and effective treatment of diabetes.

Journal Article↗

PubMed2001

Transdermal delivery of naloxone: effect of water, propylene glycol, ethanol and their binary combinations on permeation through rat skin.

The effect of the solvent systems water, ethanol (EtOH), propylene glycol (PG) and their binary combinations was studied on the ex vivo permeation profile of the opioid receptor antagonist, naloxone, through rat skin. Fourier transform-infrared (FT-IR) spectroscopic studies were done to investigate the effect of enhancers on the biophysical properties of the stratum corneum (SC), in order to understand the mechanism of permeation enhancement of naloxone by the solvent systems used. The flux of naloxone was found to increase with increasing concentrations of EtOH, upto 66% in water, and PG upto 50% in water. The maximum flux of 32.85 microg cm(-2) h(-1) was found with 33% PG in EtOH. The FT-IR spectra of SC treated with EtOH showed peak broadening at 2920 cm(-1) at all concentrations of EtOH studied indicating that EtOH increases the translational freedom (mobility) of lipid acyl chains. Theoretical blood levels well above the therapeutic concentration of naloxone can be achieved with the solvent system comprising 33% PG in EtOH and hence, provides flexibility in choice of patch size depending on the addiction status of the patient to be treated.

Administration, Cutaneous↗