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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 9  |  Issue : 3  |  Page : 208-215  

Development and optimization of dispersible tablet of Bacopa monnieri with improved functionality for memory enhancement


1 Department of Pharmaceutics, Anand Pharmacy College, Anand, Gujarat, India
2 Department of Formulation Development, Pharmanza Herbals Pvt. Ltd., Anand, Gujarat, India
3 Department of Pharmaceutics, Parul Institute of Pharmacy, Vadodara, Gujarat, India

Date of Web Publication14-Sep-2017

Correspondence Address:
Vaishali Tejas Thakkar
Department of Pharmaceutics, Anand Pharmacy College, Near Town Hall, Anand - 388 001, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpbs.JPBS_8_17

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   Abstract 

Introduction: The Bacopa monnieri is traditional Ayurvedic medicine, and reported for memory-enhancing effects. The Bacoside is poorly soluble, bitter in taste and responsible for the memory enhancement action. Memory enhancer is commonly prescribed for children or elder people. Objective: Poor solubility, patient compliance and bitterness were a major driving force to develop taste masked β-cyclodextrin complex and dispersible tablets. Materials and Methods: The inclusion complex of Bacopa monnieri and β-cyclodextrin was prepared in different molar ratios of Bacopa monnieri by Co-precipitation method. Phase solubility study was conducted to evaluate the effect of β-cyclodextrin on aqueous solubility of Bacoside A. The characterization was determined by Fourier transformation infrared spectroscopy (FTIR),Differential scanning calorimetry (DSC) and X-ray diffraction study (XRD).Crospovidone and croscarmallose sodium were used as super disintigrant.The 32 full factorial design was adopted to investigate the influence of two superdisintegrants on the wetting time and disntegration time of the tablets. Conclusion: The result revels that molar ratio (1:4) of inclusion complex enhance 3-fold solubility. Full factorial design was successfully employed for the optimization of dispersible tablet of B. monnieri . The short-term accelerated stability study confirmed that high stability of B. monnieri in inclusion complex.

Keywords: Bacopa monnieri, dispersible tablet, memory enhancer, β-cyclodextrin


How to cite this article:
Thakkar VT, Deshmukh A, Hingorani L, Juneja P, Baldaniya L, Patel A, Pandya T, Gohel M. Development and optimization of dispersible tablet of Bacopa monnieri with improved functionality for memory enhancement. J Pharm Bioall Sci 2017;9:208-15

How to cite this URL:
Thakkar VT, Deshmukh A, Hingorani L, Juneja P, Baldaniya L, Patel A, Pandya T, Gohel M. Development and optimization of dispersible tablet of Bacopa monnieri with improved functionality for memory enhancement. J Pharm Bioall Sci [serial online] 2017 [cited 2020 Mar 29];9:208-15. Available from: http://www.jpbsonline.org/text.asp?2017/9/3/208/214690


   Introduction Top


In the current years, focus is given to the needs of the patients while developing a formulation. Children shall be provided with medicines that are designed according to their needs. Children with the age of more than 12 years can swallow a solid oral dosage form (SODF) of reasonable size. A large percentage of the children within the age group of 6–12 years find it difficult to swallow SODF. The formulators are left with two options. A liquid dosage form can be developed for such patients. However, the issue of stability and large volume to be administered must be handled. The second option is to formulate dispersible tablets, which takes care of the two issues of stability and large volume to be administered. In the present investigation, decision was taken to develop dispersible tablets of commonly used herbal medicine, i.e., Bacopa monnieri. The common name for the herbal plant is Brahmi.[1]

Brahmi is extensively used to for memory enhancement and to enhance learning by the students. It has ability to enhance cognitive function. Study on brahmi has been conducted in children [2] and also in alzheimer's patient.[3]B. monnieri contains various alkaloids such as brahmin, herpestine, saponins, monierin, and hersaponin.[4],[5],[6] The key active herbal principle is reported to be Bacoside A, which is poorly water soluble [7] and bitter in taste. B. monnieri has poor bioavailability due to poor aqueous solubility; hence, solubility enhancement is quite necessary to enhance the oral bioavailability of B. monnieri, and meanwhile, it also helps to decrease the dose and dose-related side effect of drug.[8] Solubility enhancement can be achieved by a variety of means. Supersaturated solid formulations such as cyclodextrin (CD) inclusion complex, solid dispersion, and self-emulsifying drug delivery system are widely examined by researchers.[9] As taste masking was also to be achieved in the formulation of B. monnieri, CD inclusion complexation technique [10] was chosen in the present work to achieve the dual goals of solubility enhancement and taste masking. The method can be easily adopted at industry since scale up can be done. Super disintegrant can be used to facilitate the preparation of dispersion just before use by the patients. The regulators currently demand the use of a scientific approach in the formulation development work.[11] Full factorial design was adopted in the present work to examine the influence of two super disintegrates. To examine the reason of solubility enhancement of B. monnieri extract, analytical tools such as infra-red (IR) and X-ray diffraction (XRD) were used. Finally, the optimized formulation was evaluated for routine tableting properties such as crushing strength and friability.


   Materials and Methods Top


B. Monnieri extract Bacognize was obtained as gift from Pharmanza Herbal Pvt. Ltd. (Dharmaj, Gujarat, India). It contained 16% of bacosides, analyzed by USP method high-performance liquid chromatography method, as per data obtained from supplier. β-CD was procured from SD fine Chem Pvt. Ltd., (Vadodara, Gujarat, India). Crospovidone, croscarmellose sodium, Avicel PH 101, and mannitol were purchased from Astron Chemicals Pvt. Ltd., (Ahmedabad, Gujarat, India). Aerosil, Mg-stearate, talc, mannitol, and PVP-K30 were procured from Astron Chemicals Pvt. Ltd., (Ahmedabad, Gujarat, India).

Phase solubility study

Phase solubility study was conducted according to the method described by Higuchi and Connor.[12] An excess amount of bacopa extract was placed into 25-ml glass flasks containing different concentrations of beta CD (1%, 2%, 3%, and 4% w/v) in 20 ml water. All the flasks were stoppered to avoid solvent loss. The content was shaken for 24 h in orbital shaking incubator at 100 rpm at 37°C. After 72 h, supernatant was withdrawn and filtered through Whatmann filter paper and analyzed using a ultraviolet (UV) – visible spectrophotometer at 260 nm.[13] The solubility measurements were performed in triplicate.

Preparation of inclusion complex and solid dispersion of bacosides by coprecipitation method

Inclusion complex were prepared with bacosides: β-CD in 1:1, 1:2, 1:3, 1:4, and 1:5 molar ratios by coprecipitation method.[14] Accurately weighed quantity of β-CD was dissolved in ethanol using magnetic stirrer (REMI, 1MLH, Ahmedabad, India). Subsequently, weighed quantity of bacoside was mixed. Distilled water was added to the ethanolic mixture and stirred for 30 min. The complex was collected by filtration, dried in an oven at 55°C for 6 h, and then passed through sieve #100. The samples were stored in a screw-capped glass vial until use.

Characterization of inclusion complex of Bacoside A

Solid-state study and characterization were performed for bacosides, β-CD in inclusion complex of selected batch.

Infra-red spectrometry

IR spectrometry was conducted using an Fourier transformation IR (FTIR) spectroscopy spectrophotometer (Spectrum GX-FT-IR, Perkin Elmer, USA). The spectrum was recorded in the range of 4000-400 cm −1. The procedure consisted of dispersing the samples in potassium bromide and gently ground, thus avoiding solid transition possibly inducing by extended grinding. The spectrum was scanned at a resolution of 0.15 cm −1 and scan speed 20 scan/s.[15] The IR spectra of Bacopa and the excipients (β-CD) and its inclusion complex were recorded on FTIR spectrophotometer to detect the existence of interaction between the drug and excipients.

Differential scanning calorimetry

Differential scanning calorimeter (DSC-PYRIS-1, Phillips, Netherlands) was performed to assess the thermal behavior of the samples. The experiments were performed in dry nitrogen atmosphere. The samples were heated at a rate of 10°C min −1 from ambient temperature to the melting point. The calorimeter measuring range was 1 μW–750 mW with 11% accuracy. Empty aluminum pan was used as a reference.

X-ray diffraction

Vacuum grease was applied onto a glass slide to stick the sample. The samples, namely, pure untreated B. monnieri and inclusion complex of B. monnieri and β-CD were spread on the glass slide in approximately 0.5 mm thickness. The slide was then placed vertically at 0° angle in the X-ray diffractometer. The results were recorded over a range of 0–900 limits using the Cu-target X-ray tube and Xe filled detector. The operating conditions were voltage 40 kV; current 20 mA; scanning unit per min temperature of acquisition: room temperature; detector: scintillation counter detector; sample holder: nonrotating holder.

Preparation of dispersible tablet of β-cyclodextrin complex of Bacoside A by direct compression method

Trial formulations were prepared using different ratios of the croscarmellose sodium, crospovidone and PVP K30 with the fixed quantity of Aerosil, magnesium sterate, and talc. Avicel PH 101 was added to adjust the total weight of tablet to 250 mg. The ingredients were sieved through 80# and weighed accurately. [Table 1] shows composition of tablets. B. monnieri was mixed with required quantity of superdisingrants, mannitol, and binder for 5 min. The blend was lubricated with 1% magnesium stearate and 2% talc. The blends were compressed on 16 station rotary tablet press (Cadmach, Ahmedabad, Gujarat, India) using 9 mm flat-face round punches. The batch size was 500 tablets.
Table 1: Factor and combination chosen as per experimental design and translation

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Optimization of formulation parameters

Experimental design

A 32 full factorial design was selected for optimization of the concentration of crospovidone and concentration of croscarmellose sodium to achieve low wetting time (Y1) and disintegration time (Y2). Eleven trials including two center point batches were conducted for this design [Table 1] and [Table 2].
Table 2: Optimal regression equation for each response variable

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Optimization data analysis and validation of optimization model

The responses wetting time (Y1) and disintegration time (Y2) of all formulations were analyzed by Design-Expert® software (Version 9, Stat-Ease, Inc., Minneapolis, MN). Models were evolved (equations 1 and 2). The best fitting mathematical model was selected based on the comparisons of several statistical parameters including the coefficient of variation, the multiple correlation coefficient (R2), adjusted multiple correlation coefficient (adjusted R2), and the predicted residual sum of square (PRESS). PRESS indicates how well the model fits the data, and for the chosen model, it should be small relative to the other models under consideration.[16]

Linear model:

Y = β0+ β1X1+ β2X2(Equation 1)

Quadratic model:

Y = β0+ β1X2+ β2X2+ β12X1X2+ β4X12+ β5X22(Equation 2)

Where, β0 is the intercept representing the arithmetic average of all quantitative outcomes of the 11 runs; βi are the coefficients computed from the observed experimental values of Y; and X1 and X2 are the coded levels of the independent variable(s) (IVs). The terms X1X 2 and X12 represent the interaction and quadratic terms, respectively. Statistical validity of the polynomials was established on the basis of analysis of variance (ANOVA). Subsequently, the feasibility and grid searches were performed to locate the composition of optimum formulations. In addition, two-dimensional contour plots were constructed using Design Expert software shown in [Figure 5].

Evaluation of dispersible tablets

All formulations were evaluated for precompression parameters such as angle of response, bulk density, tapped density, percentage compressibility, and Hausner's ratio.

Postcompression evaluation parameter of dispersible tablet

Weight variation

The test was performed as per Indian pharmacopoeia. Twenty tablets were selected from each formulation, weighed individually and the average tablet weight and % variation of weight was calculated.

Friability

Six tablets were weighed and placed in the Roche friabilator test apparatus (Electrolab Pvt. Ltd., Mumbai, Maharashtra, India), the tablets were exposed to rolling and repeated shocks, resulting from free falls within the apparatus. After 100 evolutions, the tablets were dedusted and weighed again. The friability was determined as the percentage loss in weight of the tablets. The friability (F) was given by the formula:

F = (1 − W0/W) × 100

Where, W0 was the weight of the tablets before the test and W was the weight of the tablet after the test.

Hardness

Hardness was measured using the Monsanto hardness tester (Electrolab Pvt. Ltd., Mumbai, Maharashtra, India). The observations were recorded in triplicate.

In vitro disintegration study

Along with the conventional test for tablets described in Indian pharmacopoeia, a modified method was also used to check the disintegration time. About 6–8 ml of phosphate buffer with pH 6.8 was taken in 10 ml of measuring cylinder. Tablet was placed in the cylinder and the time needed for complete dispersion of tablet was recorded.

Wetting time

The tablets were placed at the center of two layers of absorbent paper fitted into a dish. After the paper was thoroughly wetted with distilled water, excess water was completely drained out of the dish. The time required for the water diffuse from the wetted absorbent paper throughout the entire tablet was then recorded as wetting time using a stopwatch.[17]

In vitro drug dissolution

The dissolution study was conducted in USP paddle apparatus, using phosphate buffer with pH 6.8, as the dissolution medium (300 ml) at 50 rpm and at 37°C ± 0.5°C. Samples were withdrawn at predetermined time and analyzed for the drug content by UV spectrophotometry method.

Accelerated stability studies of optimized batch

The optimized formulation of dispersible tablet of B. monnieri was selected for conducting the stability study. The accelerated stability study was carried out according to ICH guidelines by storing the samples at 40°C ± 2°C and 75% ± 5% RH for 3 months. The tablets were evaluated for hardness, drug content, and dissolution test.


   Results and Discussion Top


Phase solubility study

According to the Higuchi and Connors classification, the diagram [Figure 1]a shows the AN type curve where the solubility of Bacopa constituents increases linearly with β-CD concentration and further deviates negatively at higher β-CD concentrations. The product obtained in coprecipitation method exhibited highest solubility constant, i.e., 505.43 M −1. Phase solubility diagram of B. monnieri with β-CD illustrate the solubility enhancement capability of CD. The phase solubility study show that the molar ratio 1:4 exhibits the highest solubility, and after that, a decline in the solubility was noticed [Figure 1]b.
Figure 1: Phase solubility of inclusion complex a) Phase solubility diagrams of B. monnieri in inclusion complex. b) The phase solubility diagram corresponds to AL-type profiles.

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Characterization of inclusion complex bacoside

IR spectrum obtained for bacosides presented typical molecule bands and peaks: 3379–3087 cm −1 (O–H), 1639 cm −1 (C = O), 1571 cm −1 (C = C), 1371 cm −1 (C–OH), and 1274 cm −1 (C–O–C) [Figure 2]a. IR spectrum of β-CD presented a large band and a peak in the region of 2900–3900 cm −1, a short band between 1600 and 1700 cm −1 and a large band containing distinct peaks in the region of 900–1200 cm −1 [Figure 2]b. IR spectrum obtained for bacosides-β-CD solid was exhibited the overlapped peak [Figure 2]c, except for those in the 3000 cm −1 region and between 850 and 1000 cm −1. The reduction of intensity of bands and peaks, the presence of a new peak in the between 1000 and 1150 cm −1 when compared with bacosides extract suggest an interaction bacosides and β-CD.
Figure 2: Fourier transformation infra-red spectra of (a) Bacopa monnieri extract (b) β-cyclodextrin (c) Bacopa monnieri β-cyclodextrin and inclusion complex

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Differential scanning calorimetry study

The DSC patterns are represented in [Figure 3]. Negligible change in the melting endotherms of the B. monnieri extract and β-CD (1:4) in prepared inclusion complex of B. monnieri extract was noticed. Melting point of inclusion complex was found to be almost same but with a slight reduction, which is not significant. Sharp peaks of B. monnieri extract were observed at temperature 106.6°C, and 225.05°C. There was a noticeable reduction in endothermic peak height and of heat of fusion. This suggest that the physical state of changed from crystalline to amorphous.
Figure 3: Overlay differential scanning calorimeter spectra of Bacopa monnieri extract, βcyclodextrin and inclusion complex

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X-ray diffraction

The XRD study spectra of B. monnieri and inclusion complex of B. monnieri and β-CD are shown in [Figure 4]a and [Figure 4]b. The XRD scan of untreated Bacopa extract showed intense peaks of crystallinity whereas the XRD pattern of inclusion complex exhibited a reduction in both number and intensity of peaks compared to the untreated extract. This may be due to decrease in crystallinity or partial amorphization of the drug.
Figure 4: X-ray diffraction patterns of (a) untreated Bacopa monnieri (b) inclusion complex of Bacopa monnieri and β-cyclodextrin

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Optimization of formulation parameters

Experimental design

Full factorial design (32) was explored to systematically investigate the influence of super disintegrants on disingration and wetting time. Design Expert software (version 9) was batches for optimization of formulation. The design was chosen since it is suitable for investigating the quadratic response surfaces. Best-fitted polynomial equation involving the main effects and interaction terms were selected based on correlation coefficient (R2) and the PRESS. As presented in [Table 3], the quadratic model was selected as a suitable statistical model, it had the smallest value of PRESS. PRESS is a measure of the fit of the models to the points in the design. The smaller PRESS value is the indication of best model fits to the given data points.
Table 3: Analysis of variance analysis of Y1 (wetting time) and Y2 (disintegration time) of the tablets

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For estimation of significance of model, ANOVA was determined as per the provision of design expert using 5% significance level. A model is considered statistically significant if P < 0.05. The significant coefficients (P < 0.05) are represented in boldface letters in [Table 3].{Table 3}

Contour plots and response surface analysis

2-D contour plots and 3-D response surface plots are presented in [Figure 5]. For both the response, when the IVs X1 and X2 where increased from low to high (i.e., from 2.5 to 5 mg), the response Y1 and Y2 decreased. This behavior may be due to superior performance of the disintegrants. The contour plots also indicate non-linear relationship between IV and DV.
Figure 5: a) Contour plot for response Y1, b) Response surface plot for Y1, c) Contour plot for response Y2, d) Response surface plot for Y2

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Validation of model

To verify the evolved models, two formulations were prepared. [Table 5] shows the results for both the responses. The predicted and observed values of responses were quite close to each other. This proves the predictive ability of the equations within the design space.
Table 5: Stability studies of optimized batch

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Evaluation of dispersible tablet

The hardness of all formulations was measured in kg/cm 2. Hardness of all the formulation batches were found in the range of 2.2 to 3.4 kg/cm 2. The value of friability were found to be less than 1%. The results of friability indicate that the tablets were mechanically stable and could handle the rigors of transportation and handling. Further tablets were subjected for the evaluation of disintegration time for all eleven formulations varied from 25 to 60 sec. The disintegration time is 25 sec which is from F2 due to it contains the 5% of crocarmellose sodium and crospovidone.

In vitro drug release study

In vitro drug release (pH 6.8) study showed that the drug release within the standard limit (more than 60% within 50 min) as shown in [Figure 6]. Batch F1 containing the crospovidone (2.5%) showed the less drug release than the other batches. As the concentration of croscarmellose sodium increases the drug release increases. However, after 15 min batch F3, F4, F5, and F6 showed lesser drug release compared to Batch F7, F8, F9, F10, F11, and F12. Batch F7, F8, F9, F10, and F11 contain mixture of crospovidone and croscarmellose sodium. The batch F10 showed that mixture of 5% crospovidone and 5% croscarmellose sodium respectively, showed higher dissolution rate. So batch F2 was considered optimized batch as it showed 20 s disintegration time and higher drug release rate 97% within 30 min.
Figure 6: In vitro drug release study

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Accelerated stability studies of optimized batch

The results of short-term stability studies carried out according to ICH guidelines indicate that optimized batch showed no change in disintegration time as well as wetting time as shown in [Table 5]. In addition, drug content showed negligible effect after 3 months.


   Conclusion Top


From the present investigation, it can be concluded that dispersible tablets of B. monnieri can be successfully prepared by direct compression method. The inclusion complex using β-CD with 1:4 molar ratio of B. monnieri: β-CD exhibits 3-fold solubility enhancement. FTIR spectra and DSC studies revealed that there was no interaction between drug and polymer. 32 full factorial design was used to optimize concentration of super disintegrant. The dispersible tablet formulated with 5% crospovidone and 5% croscarmellose sodium showed less disintegration time and wetting time. Batch F2 showed least disintegration and wetting time. Drug content, disintegration time, and wetting time did not change in stability study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

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Giramkar S, Kulkarni O, Jagtap S, Kuvalekar A, Mukherjee S, Jagtap R, et al. Anticonvulsant potential of commonly practiced formulations of brahmi (Bacopa monnieri Linn.) in Wistar rats. J Pharm Res 2013;9:787-91.  Back to cited text no. 1
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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