Pharmacokinetic-pharmacodynamic (PK-PD) modeling has emerged as a major tool in clinical pharmacology to optimize drug use by designing rational dosage forms and dosage regimes. Quantitative representation of the dose-concentration-response relationship should provide information for the prediction of the level of response to a certain level of drug dose. This paper describes the experimental details of the preformulation study, tablet manufacture, optimization, and bioanalytical methods for the estimation of dexibuprofen in human plasma. The hydrophilic matrix was prepared with xanthen gum with additives Avicel PH 102. The effect of the concentration of the polymer and different filler, on the
Dexibuprofen, S(+)-ibuprofen, is a pharmacologically active form and is more potent than ibuprofen, which has equal quantities of R(−)- and S(+)-enantiomers [
Mathematical models can be considered as the simplifications of a phenomenon described in terms of an algebraic or differential equation. In the case of PK-PD modeling, it is expected to not only describe, but also predict distinct situations, such as scaling between preclinical to clinical trials, multiple dosing schemes, or different routes of administration [
Because of the multiple factors intervening in a PK-PD study, it then appears adequate to divide the modeling project into the following two basic blocks such as concerning the clinical or experimental design by itself and the data analysis. Diverse models have been suggested to describe the PK-PD relationship depending upon the nature of drug administration scheme (single doses, multiple doses, long-term infusions, etc.) and the time dependency of PD parameters. Thus, when the system is kinetically at steady state, the concentrations of the active moiety at the active site are constant (after long-term infusions or multiple doses); relatively simple models are needed to characterize the PK-PD relationship. Otherwise, after single doses (nonsteady-state condition) and when time variant PD parameters are present, more complex models are needed to account for phenomena involved in the PK-PD relationship. Approaches such as disequilibrium between biophase and plasma compartment [
The development and validation of a PK/PD is based on the ability of the fraction of the drug absorbed versus the fraction of the drug-dissolved relationship of various formulations. For the estimation of the drugs present in the biological fluids, HPLC method [
Acetonitrile, methanol, orthophosphoric acid, sodium acetate, perchloric acid, and triethylamine were supplied by Qualigens Fine Chemicals and S.D. Fine Chemicals. Water (HPLC grade) was obtained from Milli-Q system. All the reagents and chemicals used were of HPLC or analytical grade.
Working standards of dexibuprofen was purchased from Noven Life Sciences (Hyderabad, India) HPMC (Methocel - K100-CR, apparent viscosity, 2% in water at 20°C is 80,000–12000 cP); xanthen and starch 1500 were gift samples from Colorcon Asia Pvt Ltd (Goa, India). Polyvinyl pyrrolidine (PVP-K-30) was a gift sample from Anshul Agencies (Mumbai, India). Aerosil was purchased from Degussa India Pvt Ltd (Mumbai, India).
This chapter describes the experimental details of the preformulation study, tablet manufacture, bio availability study design and data handling, optimization and validation of the bio analytical methods for the estimation of dexibuprofen in human plasma samples, preparation of standard and sample solutions, development of
Preformulation in the broadest sense encompasses all the activities and studies that are required to convert an active pharmacological substance into a suitable dosage form. It can be defined as an investigation of the physical and chemical properties of a drug substance alone and also when combined with the excipients. In the present study, therefore, the evaluation of granulations, development of
Dexibuprofen SR tablets were prepared by the wet granulation method. All the composition, with the exception of magnesium stearate and aerosol, were thoroughly mixed in a tumbling mixer for 5 min and wetted in a mortar with isopropyl alcohol. The wet mass was sieved (16 mesh) and granules were dried at 40°C for 16 h. The dried granules were sieved (22 mesh) and these granules were lubricated with a mixture of magnesium stearate and aerosil (2 : 1). The dexibuprofen tablets were prepared using an electrically operated punching machine. Compression was performed after granulation process with a single punch press applying a compression force of a 9 KN (preliminary work) or 12 KN (experimental design), equipped with a 12 mm flat-faced punch. For the preliminary work, batches of 100 tablets were prepared. Each batch of experimental design consisted of 100 tablets (drug content in the tablet was 300 mg). Three batches were prepared for each formulation and the compositions of different batches of dexibuprofen SR tablets are given in Table
Formulation prepared by wet granulation method (F1–F10) for dexibuprofen.
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DXI | HPMC |
Xanthen |
Avicel PH 102 | Magnesium stearate | Aerosil | PVP-k-29/32 | Total (mg/tab) |
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F1 | 300 | 37.5 | — | 130 | 5 | 2.5 | 25 | 500 |
F2 | 300 | 75 | — | 92.5 | 5 | 2.5 | 25 | 500 |
F3 | 300 | 112.5 | — | 55 | 5 | 2.5 | 25 | 500 |
F4 | 300 | 150 | — | 17.5 | 5 | 2.5 | 25 | 500 |
F5 | 300 | — | 112.5 | 55 | 5 | 2.5 | 25 | 500 |
F6 | 300 | — | 37.5 | 130 | 5 | 2.5 | 25 | 500 |
F7 | 300 | — | 75 | 92.5 | 5 | 2.5 | 25 | 500 |
F8 | 300 | — | 150 | 17.5 | 5 | 2.5 | 25 | 500 |
F9 | 300 | — | 50 | 117.5 | 5 | 2.5 | 25 | 500 |
F10 | 300 | — | 12.5 | 160 | 5 | 2.5 | 25 | 500 |
Bioavailability studies of the optimized formulations were carried out in crossover design in healthy human volunteers between the developed formulations and the conventional dosage form. The protocol of the study was submitted to the Institutional Human Ethical Committee and the approval for conducting the same was obtained and a prior consent of the volunteers participated in the study was taken. Randomized, two-treatment, two-period, two-sequence, single-dose, crossover bioavailability studies were carried out in healthy human volunteers between the developed sustained release (SR) formulation and the marketed conventional immediate release (IR) formulation to prove the safety and efficacy of the developed SR formulation. A reproducible analytical technique was developed for the estimation of the drugs in the plasma samples. Various pharmacokinetic parameters such as
A visual analogue scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. For example, the amount of pain that a patient feels ranges across a continuum from none to an extreme amount of pain. From the patient’s perspective, this spectrum appears continuous ±; their pain does not take discrete jumps, as a categorization of none, mild, moderate, and severe would suggest. It was to capture this idea of an underlying continuum that the VAS was devised. Operationally a VAS is usually a horizontal line, 100 mm in length, anchored by word descriptors at each end (see Figure
The patients mark on the line the point that they feel it represents their perception of their current state. The VAS score is determined by measuring in millimetres from the left hand end of the line to the point that the patient marks. There are many other ways in which VAS has been presented, including vertical lines and lines with extra descriptors. Wewers and Lowe [
This section describes the experimental results obtained in the present investigation in the form of tables and figures along with a detailed analysis on the results of preformulation study, tablet manufacture, bioavailability study design, data handling, optimization and validation of the bio analytical methods for theestimationofdexibuprofen in human plasma samples, amount of the selected drugs present in plasma samples,
The physical properties of different batches of developed tablets are given in Table
Release profiles of dexibuprofen from xanthen (polymer) containing formulation (F10).
A single-dose, randomized, complete, two-treatment crossover study was conducted in healthy human subjects for the selected drug formulations. Six volunteers aged between 20 and 30 years were selected. Seven days prior to the commencement of the study, volunteers were subjected to preliminary screening and standard clinical and biochemical investigations.
After overnight fasting, the volunteers were given code numbers and allocated to the treatment in accordance with the randomized code. The order of treatment administration was randomized in two sequences (AB and BA) in blocks of two. In each dosing session, volunteers received reference product A (immediate release formulations) and Test B (sustained release formulations). A wash-out period of seven days was allowed between dose administrations. Blood samples (4 mL) were collected at 0 (before drug administration), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 18.0, and 24.0 h after dosing. The samples were centrifuged and plasma was separated. There were no serious adverse effects observed during the entire study (Table
Mean pharmacokinetic profile (
Drug name |
|
|
AUC0– |
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|
AUC0–∞ |
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IR | 13.812 |
2.25 |
45.591 |
2.188 |
0.318 |
47.621 |
| ||||||
SR | 14.178 |
5.00 |
117.843 |
4.772 |
0.145 |
122.620 |
aImmediate release (IR) tablets.
bSustained release (SR) tablets.
†Significantly higher than IR tablets.
‡Significantly lower than IR tablets.
Mean plasma concentration-time profile of dexibuprofen from developed sustained release tablets (test) and marketed immediate release tablet (reference).
Pharmacokinetic parameters such as peak plasma concentration (
The pharmacokinetic parameters of two different drug formulations of dexibuprofen was compared statistically by one-way ANOVA (analysis of variance) using SPSS version 16.0.
The results indicated by the pain scale [
Pain response versus plasma concentration of dexibuprofen (test product).
Time points |
Pain response | Plasma concentration |
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0 | 1.1 | 0.5 | 2.3 | 1.4 | 2.4 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
2 | 5.1 | 3.5 | 5.4 | 4.4 | 5.7 | 4.1 | 7.1254 | 7.5624 | 5.2039 | 8.1283 | 6.9584 | 7.9892 |
4 | 9.3 | 8.6 | 9.4 | 9.1 | 9.7 | 9.8 | 13.5241 | 10.0548 | 12.5264 | 11.9856 | 9.5321 | 12.6354 |
6 | 9.9 | 9.6 | 9.8 | 9.9 | 9.1032 | 12.1627 | 9.9287 | 9.9012 | 12.9658 | 8.7541 |
Pain response versus plasma concentration of dexibuprofen (reference product).
Time points (h) | Pain response | Plasma concentration (mcg/mL) | ||||||||||
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0 | 0.7 | 0.6 | 1.7 | 1.6 | 2.1 | 1.3 | 0 | 0 | 0 | 0 | 0 | 0 |
2 | 4.3 | 2.9 | 4.3 | 3.7 | 4.6 | 3.7 | 5.9826 | 6.3614 | 4.6985 | 7.4978 | 7.3956 | 5.3869 |
4 | 8.9 | 7.5 | 6.9 | 7.4 | 8.5 | 6.4 | 12.4958 | 11.3057 | 12.0498 | 10.2584 | 12.0394 | 13.0695 |
6 | 9.2 | 8.5 | 8.7 | 9 | 9.3 | 8.9 | 8.9375 | 9.5473 | 8.9573 | 8.5893 | 9.2738 | 9.4752 |
Mean pain response (reference and test product).
Mean plasma concentration (reference and test product).
Mean pain response and plasma concentration (reference and test product).
Based on these observations, it is concluded that the formulated matrix tablets containing dexibuprofen are capable of exhibiting sustained release properties, stable and feasible for industrial scale production. Thus they are capable of reducing the dose intake, minimize the blood level oscillations, dose-related adverse effects and cost, and ultimately improve the patient compliance in the therapeutic management of pain and hypertension. It is also concluded that the present PK/PD studies have demonstrated that pain and blood pressure management were found to be effective in developed SR formulations of dexibuprofen as compared with marketed immediate release formulations. Further studies involving their suitability for long-time application, shelf life determination, bioavailability, and clinical investigations in large populations may, however, be necessary to further establish its potential and therapeutic efficacy.
The author is thankful to the Indian Council of Medical Research (ICMR), New Delhi, for providing financial assistance of this project (File no. 45/47/2007/PHA/BMS). He thanks Dr. S. N. Meyyanathan, Department of Pharmaceutical Analysis and Dr. B. Suresh, Vice Chancellor, J.S.S. University, Mysore, for his encouragement and the facilities extended to him for carrying out this Work.