Bioavailability Study of Developed S-SMEDDS Formulation for Nicardipine Hydrochloride in Rats

 

Rajesh L. Dumpala1*, Akruti Khodakiya1, Nishant A Oza1, Nehal J. Shah2,

Snigdha Das Mandal3, M. Lakshmi Prasuna4, Rakesh kumar Parmar5

1Dept of Pharmaceutical Science, RDIC - C. U. Shah University, Wadhwan, Gujarat, India.

2Dept of Pharmaceutical Chemistry and Quality Assurance - IPCPRC, Dharmaj, Gujarat, India.

3Faculty of Pharmacy, Parul Institute of Pharmacy and Research,

Faculty of Pharmacy, Parul University, P.O Limda, Vadodra, Gujarat, India.

4Dept of Pharmaceutical Analysis and Quality Assurance,

Sumandeep Vidyapeeth Deemed to be University, Piparia, Vadodara, Gujarat, India.

5Dept of Pharmaceutics, Sardar Patel College of Pharmacy, At post – Bakrol, Anand, Gujarat, India.

*Corresponding Author E-mail: rdumpala64@gmail.com

 

ABSTRACT:

Aim of the current research work to conduct bio availability of Nicardipine Hydrochloride S-SMEDDS in rats, compare with pure drug and Marketed Formulation. Study is conducted by using Wistar rats. 3-Groups were divided into Set-A Pure Drug, Set B: Marketed formulation, Set C: Optimized formulation, Total 18 healthy rats were selected, 6 in each group with weight of 300±50g Rats were labeled by numbers. Blood samples were collected from Tail vein method at pre-determined time intervals then blood samples were analyzed by validated HPLC method. S-SMEDDS exhibit cmax at 1429.58±107.40ng/mL, tmax at 0.75Hr, AUC(0-t) at 3042.05±333.35 ng. min/ml and t1/2 at 3.49±0.016 hr. AUC and maximum plasma concentration of the S-SMEDDS is higher than pure Nicardipine Hydrochloride drug and marketed formulation it indicates S-SMEDDS produce more bioavailability than Nicardipine Hydrochloride powder.

 

KEYWORDS: Rats, Bioavailability, Nicardipine Hydrochloride, S-SMEDDS.

 

 


INTRODUCTION:

Nicardipine Hydrochloride (NHCl) is used in the treatment of hypertension It is calcium channel blocking agent1,2. Nicardipine Hydrochloride have low bio availability due to its low aqueous solubility. In the present research work we are using SMEDDS and liquid solid compact technique to enhance solubility of Nicardipine Hydrochloride3,4.

 

To carry out this research work Capmul MCM C8EP is used as oil, Labrasol as Surfacant, PEG 400 as Co-Surfacant, Neusilin US2 as Carrier, For Coating agent Aerosil 200, For Super disintegrant Crosscarmellose sodium, MCC as Diluent, Mg stearate as Lubricant, Currently most used method for the drug is their conversion into SMEDDS. In comparison to other formulation, SMEDDS are very thermodynamically stable formulations5,6.

 

MATERIAL AND METHODS:

Drug procured from ZIM Lab, From Abitech Capmul MCM C8 EP was procured, From Gattefose (France) Labrasol, From Astron Chemicals PEG 400, Neusilin US2 was procured from Gangawal chemical Ltd, From Astron Chemicals Aerosil-200, From Seva fine Croscarmellose sodium was procured, Mg stearate was procured from  Loba Chemie, All these listed materials were procured as a souvenir sample and Analytical grades solvents and excipients were used.

 

Preparation of Nicardipine Hydrochloride S-SMEDDS:

20mg of Nicardipine Hydrochloride is solubilised in Capmul MCM C8EP, Labrasol and  PEG 400 on the basis of solubility study, this  Liquid medicament Converted into Solid-SMEDDS by using Neusilin US2, Aerosil 200, Crosscarmellose sodium,Microcrystalline  cellulose and Magnesium stearate it produced dried powder, the prepared S-SMEDDS were evaluated by different evaluation parmeters7,8 such as Angle of slide, Differential scanning calorimetry, XRD,TEM, SEM, Zeta-potential, Particle size, Flow characteristic, Comparison of % drug release, In vivo pharmacokinetic study, Accelerated stability studies and the results are elaborated From this blend we are taken dose according dose calculation for rat9,10

 

Dose calculation for rat:-Animal dose calculations were based on BSA as per the following formula:

The dose of NHCl for rat was calculated from following formula based of weight of rat in mg/kg11,12

 

HED (Human Equivalent Dose) for rat =

                        Animal Dose × (Animal Km/Human Km)

Human equivalent dose (mg/Kg) =

                                                  20mg/60kg = 0.33mg/Kg

0.33 = Animal Dose * (6/37) =

                                            0.33 = Animal Dose *0.162

Animal Dose = 2.037mg/kg =

                                    For Rat weighing approx. 300gm

Animal dose = 0.611mg, Considering maximum daily dose of NHCl 20mg (0.33mg/kg),

 

The calculated dose for rat was found to be 0.611mg

 

Details of Animals used for Pharmacokinetic Study:

For in vivo Pharmacokinetic study, Wistar rats of either sex having weight 300±50g were used. Temperature and relative humidity for housing was animals were kept at 25±2°C and 70±2°C with natural light and dark conditions13,14,15 Animals were feed with marketable pellet chow and provided water add libitum. The animal experiments was done as per the guidelines of the (CPCSEA), New Delhi, IAEC approved protocol No 984/2020-12 of this study at Vadodara from Parul Institute of Pharmacy and Research, Limda. Bioavailability of Pure Drug, Optimized formulation, Marketed formulation (Cardene) was compared, 18 rats (300±50g) were fasted for 24 h (with free access to the tap water) being randomly assigned into three groups with 6 rats in each group. 15ml of stock solution of API, Marketed formulation and Optimized S-SMEDDS were prepared and orally administered to these rats in the dose of 2.037mg/kg.

 

Blood samples (0.2ml) were withdrawn from tail vein blood collection at specified times intervals. The blood samples were collected into heparinized microcentrifuge tubes. Plasma was separated immediately by centrifuging the blood samples at 10,000rpm for 10 min at 4°C (4-8). Plasma sample is transferred to 2ml of test tube then 10mcg/ml of di ethyl stelbesterol was added and centrifuged then supernatant was removed. 200µL of Acetonitrile was added and mix well then centrifuge for 5 min for separation of phases then evaporate at room temperature. Then again 200µL of mobile phase was added then 20µL solution is injected to HPLC16,17,18.

 

Pharmacokinetic analysis:

Plasma samples obtained from the rats were analysed by developed RP-HPLC method Non-compartmental pharmacokinetic analysis was performed using kinetica software. With the trapezoidal rule Cmax, Tmax, AUC (0-t), t1/2. 19,20 All data for pharmacokinetic analysis are reported as Mean±SD.

 

Preparation of Stock Solutions:

Primary stock solution (100µg/mL) of NHCl prepared by dissolving accurately weighed 10mg of NHCl to 100mL of acetonitrile (ACN). Further dilutions were done using ACN: water (50:50) to get the secondary stock solution of 10000ng/mL.

 

Preparation of Calibration Curve of NHCl :

Secondary stock solution thus obtained was spiked with 200µL rat plasma to obtain solutions of 25, 50, 100, 250, 500, 750, 1000, 1500, 2000 and 2500ng/mL concentration of NHCl.

 

Bioanalysis of NHCl by RP-HPLC Method in Rat Plasma:

The chromatographic separation was achieved on a C18 reverse phase column (Waters, 100mm long and 4.6mm internal diameter, particle size 5µm, Spherisorb ODS, Ireland) equipped with a guard column of same packing material21,22,23 The mobile phase consisted of Acetonitrile and water (pH adjusted to 3.5 with o-phosphoric acid) in a ratio of 50:50. The HPLC system was operated at a flow rate of 1mL/min in the isocratic mode and 236 nm was used as a detection wavelength

 

BIOANALYTICAL METHOD VALIDATION:

Bioanalytical method was validated as per USFDA guidelines and ICH guidelines24,25,26

 

Linearity:

Linearity of developed method was established in the range of 20-2500ng/mL (25, 50, 100, 250, 500, 750, 1000, 1500, 2000 and 2500ng/mL) of NHCl. All the measurements were done in triplicates. Least square regression analysis of the obtained area of NHCl vs. concentration curve was carried out. The linearity was confirmed by correlation coefficient.

 

Precision and Accuracy:

Precision and accuracy were determined using triplicate analysis (n=9) of samples at three concentrations. The Precision analysis was performed on same day and on third consecutive days. SD and %RSD were calculated for the results obtained 27

 

Extraction Recovery:

Extraction recovery was analysed by comparing mean peak areas of six extracted low quality control (LQC) samples to mean peak areas of six un-extracted reference solutions.

 

Selectivity:

Selectivity for the method was analysed to confirm the ability of method to discriminate NHCl in presence of other components in sample matrix and to quantify it.28,29 The selectivity was determined by injecting six blank rat plasma samples extracted with the same method as that of the sample.

RESULT AND DISCUSSION:

Table 1: Parameter of Solid SMEDDS

Evaluation of  S-SMEDDS

Flow characteristic of solid SMEDDS

Parameters

Results

Parameters

Results

Globule size

98.165 nm

Angle of repose

24.10° ± 0.140°

PDI

0.236

Bulk density

0.317 ± 0.004 gm/ml

Zeta potential

-28.5

Tapped density

0.370 ± 0.014 gm/ml

% Transmittance

99.40 ± 0.2 %

Carr’s index

14.21 ± 4.12 %

Cloud point

72.70 ± 0.79°C

Hausner’s ratio

1.16  ± 0.060

Emulsification time

33.13 ± 1.22 sec

 

Drug content (%)

99.45 ± 0.14


 

Particle size and Zeta-potential

    

FIG 1. A.Globule size distribution of S-SMEDDS

B. Zeta-potential of S-SMEDDS

 


Table 2 : Comparison of % drug release of solid-SMEDDS (tablet) of optimized batch with marketed product (Cardene).

Time

Optimized batch

Marketed product

5 min

35.82 ± 0.33

9.00 ± 0.01

10 min

67.69 ± 0.32

17.46 ± 0.46

15 min

90.82 ± 0.26

26.37 ± 0.16

20 min

97.25± 0.70

35.41± 0.22

25 min

98.18± 0.93

38.80± 0.25

30 min

99.54  ± 0.37

50.41  ± 0.42

 

As shown in Table 2 optimized batch solid SMEDDS of Nicardipine  Hydrochloride showed a drug release of 99.54±0.37% in 30 min while marketed product showed around drug release of 50.61±0.112% in 30 min.

 

 

Fig 2. Drug release study of optimized batch and marketed product

In vivo study: Optimization of Chromatographic Conditions :

The chromatographic conditions for the separation of NHCl in rat plasma were optimized and it is summarized in Table 3.

 

Table 3. Optimized Chromatographic Conditions for Estimation of NHCl in Rat Plasma

Equipment

Hitachi L-2400 equipped with pump L-2130

Mobile phase

Acetonitrile: water(50:50) (pH adjusted to3.5with o-phosphoric acid)

Column

C18 (150X4.6mm,3.5 µ)

Column temperature

Ambient

Injection volume

20 µL

Flow rate

1 mL/min

Wavelength

236 nm

Retention time of  NHCl

4.73min

Diluent

Acetonitrile: water(50:50)

 

Bioanalytical Method Validation for Estimation of NHCl in Rat Plasma:

Developed bioanalytical method for estimation of NHCl in rat plasma was validated as per USFDA guidelines ICH guidelines.

 

 

a)Linearity:

The calibration curve of NHCl in rat plasma (Fig. 3) was constructed using ten point calibration standards within the concentration range of 25-2500ng/mL. The calibration curve was obtained by plotting peak area vs concentration and fitted to y = mx+c. The calibration curve showing linearity is depicted in Fig.3.The slope for the calibration plot was found to be 207.5 and intercept was 298.8. Correlation coefficient was found to be 0.999 which is above 0.98 limits for bioanalytical method.

 

FIG 3. Calibration curve of NHCl in rat plasma

 

b)Precision and Accuracy:

The precision and accuracy of all samples, LQC, MQC and HQC samples were measured (n=9). The precision for inter-day (0.58 to 0.531 %RSD) and  intraday (0.018 to 0.377%RSD).The results obtained were found to be in the acceptable limit. The data thus obtained demonstrates that method is accurate and precise for the quantification of NHCl from rat plasma.

 

c) Extraction Recovery:

The extraction recovery was performed to evaluate extraction procedure used to extract NHCl from rat plasma in the developed bioanalytical method. The overall mean recovery of NHCl was found to be 99.12± 1.98%. Extraction recovery of IS was found to be 86.56± 1.23%, indicating that the extraction procedure employed is suitable for measurement of NHCl from blank plasma.

 

d) Selectivity:

To assess selectivity of the method, six blank rat plasmas were injected and chromatograms were obtained. From the chromatogram, it was evident that at the retention time of NHCl no interference from the endogenous substance was seen. The NHCl was well separated from the plasma proteins using the developed chromatographic conditions with retention time of 4.73 min. Representative chromatograms of plasma, NHCl and that of NHCl and di ethyl stilbesterol depicted in Fig 4. (a), (b), (C) respectively.


 

 

Figure 4. (a) Representative chromatogram of blank plasma, (b) HPLC spectra of Nicardipine Hydrochloride, (C) HPLC spectra of Nicardipine Hydrochloride and di ethyl stilbesterol

 

The developed method could analyse 49.52 ng/mL so it was selected as LLOQ. The results of selectivity conclude that the developed method is accurate and precise.

 

 

 

The results of bioanalytical method validation along with acceptance criteria are summarized in Table 4.

 

Table 4. Summary of results for Bioanalytical method validation for NHCl in rat plasma

Parameter

Observed Results

Acceptance Criteria

Calibration range (Coefficient determination)

25-2500 ng/mL r2≥0.999

Slope (207.5)

Intercept (298.8)

 

> 0.98 with consistency

System suitability

%CV (Area ratio) ≤ 1.33

%CV (RT-analyte) ≤ 0.852

%CV (RT-IS) ≤ 0.765

%CV ≤ 2.0 for area ratio and Rt of analyte

Sensitivity

%CV = 8.35

Mean % nominal Conc= 92.99

%CV≤ 20.0 Mean % nominal

conc should be 80-120%

Accuracy

(N=9)

Levels

%RSD

%Recovery

 

± 15 % deviation in RSD

LQC

1.65

99.20 -102.4

HQC

0.58

99.67 -100.83

MQC

0.40

99.81 -100.58

Precision

 (N=9)

Levels (Intraday)

%RSD

 

 

± 15 % deviation in RSD

LQC

0.377

HQC

0.018

MQC

0.055

Levels (Interday)

%RSD

LQC

0.531

HQC

0.231

MQC

0.058

 

Table 5 A. Average Plasma Concentration after oral administration of  Pure NHCl, NHCl MKT, and NHCl S-SMEDDS rats

S. No

Time (hour)

Plasma Concentration in ng/mL (Mean ± SD )

Pure Drug

NHCl Marketed Tablet

NHCl S-SMEDDS

1.

0.25

268.63±20.18

515.05±38.69

1001.52 ±75.24

2.

0.5

337.32±25.34

746.42±56.07

1147.05±86.17

3.

0.75

420.87±31.62

863.97±64.91

1429.58±107.40

4.

1

175.45±13.18

314.39±23.62

468.44±35.19

5.

2

159.77±12.0

235.00±17.65

390.70±29.35

6.

4

154.55±11.61

209.20±15.72

274.04±20.59

7.

6

143.95±10.81

162.81±12.23

187.08±14.05

8.

8

102.30±7.69

70.02±5.26

100.10±7.52

9.

12

49.08±3.69

49.39±3.71

60.20±4.52

10.

16.

44.73±3.36

44.24±3.32

49.39±3.71

 


TABLE 5 B. Pharmacokinetic parameters after oral absorption of Pure NHCl, NHCl MKT, and NHCl S-SMEDDS

Pharmacokinetic parameters

Pure Drug

NHCl Marketed Tablet

NHCl

S-SMEDDS

tmax (h)

0.75

0.75

0.75

Cmax (ng/mL)

420.87±31.62

863.97±64.91

1429.58±107.40

AUC(0-t)(ng.h. mL-1)

1789.33±225.09

2157.83±239.85

3042.05±333.35

t1/2 (h)

5.22±0.61

4.33±0.074

3.49±0.016

 

 

FIGURE 5 Pharmacokinetic Plasma Drug Concentration profile for NHCl, NHCl MKT and NHCl S-SMEDDS

 

DISCUSSION:

As per the result obtained from earlier studies involving NHCl, it was observed that solubility and in vitro dissolution of NHCL from S-SMEDDS is significantly increased. In vivo performance of NHCl from S-SMEDDS was performed to study the behaviour and compare them with in vivo behaviour of NHCL pure and marketed Capsules of NHCl. Plasma samples for the pharmacokinetic study of NHCl pure, S-SMEDDS and Marketed formulation were analysed by calibration curve. Average results of analysis of plasma samples obtained from rat is Depicted in Table 5A. The plasma drug concentration profile obtained for all the three is illustrated in Fig.5

 

From the plasma drug concentration profile it is evident that the formulation of NHCl S-SMEDDS shows better oral absorption as compared to the NHCl pure.

 

Data shown as Mean±SD, tmax - The time to reach maximum plasma concentration; Cmax - Plasma peak concentration; AUC-Area under the plasma-concentration–time curve; t1/2- Elimination half-life.

 

From the pharmacokinetic parameters it is observed that AUC(0-t) and Cmax for S-SMEDDS is higher than NHCl pure and marketed formulation indicating that the techniques produces a formulation that is better absorbed.

 

Cmax for S-SMEDDS was highest 1429.58±107.40 showing 3.40 fold increases in Cmax NHCl pure and 1.65 fold increase compared to marketed tablets which is 420.87± 31.62 and 863.97± 64.91 respectively. Similar observations were seen in case of AUC (0-t), whereby S-SMEDDS  showed 1.70 (3042.05± 333.35) fold increase as compared to AUC(0-t) of NHCl pure (1789.33± 225.09). When compared with marketed formulation, S-SMEDDS showed 1.41 fold increase in AUC(0-t). Moreover tmax for S-SMEDDS was found to be similar that of NHCl pure which was observed at 0.75 h. but its concentration was more in comparison to NHCl pure and Marketed formation (Cardene) which indicated increase in vivo absorption of NHCl from S-SMEDDS  The poorly water soluble drug involves dissolution in GI fluid followed by absorption through epithelial membrane  Hence its absorption is limited by solubilisation and dissolution. Study of in vivo pharmacokinetics of the formulations suggests the improvement in bioavailability of NHCl from S- SMEDDS.

 

CONCLUSION:

From the above study it was concluded that, the Optimized formulation of Nicardipine Hydrochloride S-SMEDDS was increases bioavailability with Compared to Pure Drug and marketed formulation of Nicardipine Hydrochloride

 

ACKNOWLEDGMENT:

The Authors acknowledge to Zim Lab for providing  Nicardipine Hydrochloride gift sample and Lipoids, Gattefose, Abitec, BASF, Corel Pharma, and Gangwal Chemicals for the excipients respectively. The authors are grateful to IPCPRC and Parul University for providing necessary facilities and support.

 

CONSENT OF ETHICS:

The animal experiments was done as per the guidelines of the (CPCSEA), New Delhi, IAEC approved protocol of this study at Vadodara from Parul Institute of Pharmacy and Research, Limda.

 

CONFLICT OF INTERESTS:

Authors report no conflict of interest.

 

REFERENCE:

1.   Catarina M. Vieira T. Veiga F et al. Physicochemical characterization and in vitro dissolution behavior of Nicardipine Hydrochloride cyclodextrins inclusion compounds. Eur J Pharm Sci 2002; 15(1):79–88.  doi.org/10.1016/s0928-0987(01)00208-1

2.    Sharma R. Nathiya D. Sharma A et al. Assessment of wound healing activity of roots of Bauhinia variegata Linn by excision and incision model in Albino Rats. Asian Journal of Research in Pharmaceutical Sciences 2015; 5(3): 145-152.doi.org/10.5958/2231-5659.2015.00023.5

3.    David S. Timmins P and Conway B  et al.  Impact of the counter ion on the solubility and physicochemical properties of salts of carboxylic acid drugs. Drug Dev Ind Pharm.2012; 38(1): 93-103.doi.org/10.3109/03639045.2011.592530

4.    Bhandary P. Khan G. Aryal B et al. Non-Compartmental Pharmacokinetics Modelling of Amlodipine In Rats. Int. Res J Pharm. App Sci  2013; 3(5):120-126.

5.    Nitin M. Girish M. Chetan M. Ather J, Krunal S. Krishna Kumar et al. Comparative Influence of Selected Antioxidants with Lansoprazole in Aspirin Induced Ulcer Model in Rats. Research J. Pharm. and Tech. 2011; 4(8):1273-1277.

6.    Graham D. Dow D. Hall D. Alexander O. Mroszczak. Freedman D. et al. The metabolism and pharmacokinetics of Nicardipine Hydrochloride in man. Br. J. Clin. Pharmacol. 1985; 20(1):233-285.doi.org/10.1111/j.1365-2125.1985.tb05141.x

7.    Leandro T. Clarissa C and Teresa D et al. Pharmacokinetic Plasma Profile and Bioavailability Evaluation of Gatifloxacin in Rats. Latin American Journal of Pharmacy.2008; 27(2):270-273.

8.    Rihana Fathima H. Reddy N. et al. Effect of Asoka Bark (Saraca indica) and Custard Apple Pulp (Annona squamosa) on Wound Healing in Female Albino Rats. Research J. Pharm. and Tech. 2011; 4(6): 928-931.

9.    Maurin M. Rowe S. Christopher A. Munir H. et al. Solubilization of Nicardipine Hydrochloride via complexation and salt formation: J Pharm Sci. 1994; 83(10): 1418-1420. doi.org/10.1002/jps.2600831011

10.  Ashok P. Meyyanathan S. Vadivelan R. Jawahar N. et al. Nanosuspensions by Solid Lipid Nanoparticles method for the Formulation and in vitro/in vivo characterization of Nifedipine. Asian J. Res. Pharm. Sci. 2021; 11(1): 1-6.doi.org/10.5958/2231-5659.2021.00001.1

11.  Meiling Q. Peng W. Xin J. Liquid chromatography–mass spectrometry method for the determination of Nicardipine Hydrochloride in human plasma. J Chromatogr B analyt technol biomed life sci. 2006; 830(1): 81–85. doi.org/10.1016/j.jchromb.2005.10.035

12.  Mithun B. Pancholi S. Shelke N. et al. Oral bioavailability enhancement of a poor water-soluble drug by co-surfactant free self-emulsifying drug delivery system (SEDDS). Research J. Pharm. and Tech.2011; 4(10) :1557-1562.

13.  Nanda A. Kalyan G. Mamatha T. et al. Study of Pharmacokinetic And Pharmacodynamic Drug – Drug Interaction Between Rosuvastatin And Glimepiride In Normal Rabbits. world journal of pharmacy and pharmaceuticalsciences.2014; (1):1218-1230. doi.org/10.2147/DDDT.S129586.

14.  Vakhariya R. Talokar S. Salunkhe S. Magdum C. et al. Formulation Development and Optimization of Simvastatin Loaded Solid Lipid Nanoparticles. Asian J. Res. Pharm. Sci. 2017; 7(1): 49-52. doi.org/10.5958/2231-5659.2017.00008.X

15.  Jagtap O. Godse V. Deshpande S. Deodhar M. et al. HPLC Determination Of Satranidazole In Rat Plasma. Asian Journal Of Chemistry.2011; 23(10):4317-4320.

16.  Dumpala R.L et al. Solubility and dissolution enhancement of Erlotinib by liquisolid compact technique. International Journal of Pharma O2. 2020; 2(4): 0271-0270.

17.  Giri T. Mishra S. Tripathi D. et al. Carriers used for the development of solid dispersion for poorly water-soluble drugs. Research J. Pharm. and Tech. 2011; 4(3):356-366.

18.  Pomponio R, Gotti R. Fiori J. Mura P. Cirri M. Maestrelli F et al. Photostability studies on Nicardipine Hydrochloride cyclodextrin complexes by capillary electrophoresis. J Pharm and Biomed  Anal. 2004; 35(2): 267–275. doi.org/10.1016/S0731-7085(03)00532-6

19.  Karki D. Kulkarni G. Swamy S. Sheeba FR.F et al. Formulation and Evaluation of Mucoadhesive Buccal Tablets of Curcumin and its Bioavailability Study. Research J. Pharm. and Tech 2017, 10(12): 4121-4128. doi.org/10.5958/0974-360X.2017.00750.8

20.  Rupender R. Karambir Singh D. Ilango K. Shaik S et al. Pharmacokinetic Studies of Ambroxol Hydrochloride Microspheres In Rats After Oral Administration. International Journal Of Research In Pharmacy And Chemistry.2012; 2(2):280-288.

21.  Nitin M. Girish M. Chetan M. Ather J. Krunal S. Krishna Kumar et al. Comparative Influence of Selected Antioxidants with Lansoprazole in Aspirin Induced Ulcer Model in Rats. Research J. Pharm. and Tech.2011, 4(8): 1273-1277.

22.  Farina P et al. Pharmacokinetics of Nicardipine in Animals. I. Absorption, Plasma Concentrations, and Excretion After Administration of Nicardipine to Rats, Mice, Rabbits, and Dogs. Journal of Cardiovascular Pharmacology. 1997; 29:S86-S96.

23.  Dumpala RL and Khodakiya A et al. Formulation and statistical optimization of S-SMEDDS of nicardipine hydrochloride by using BBD and PCA design. Int J Pharm Sci & Res 2021. 12(3): 1860-74. doi.org/10.13040/IJPSR.0975-8232.12(3).1860-74

24.  Budhwani A. Shrivastava B. Singhai A. Gupta P et al. Antihyperglycemic activity of ethanolic extract of leaves of Dioscorea japonica in STZ-induced diabetic rats. Research J. Pharm. and Tech.2012, 5(4): 553-557.

25.  Wagner  J. G. and Nelson  E et al. Kinetic analysis of blood levels and urinary excretion in the absorptive phase after single doses of drug. Journal of Pharmaceutical Sciences. 1964; 53(11): 1392-1403.doi.org/10.1002/jps.2600531126.

26.  Dalvi PB. Ingale PR. et al. An Approach for Enhancement of Solubility. World Journal of Pharmacy and Pharmaceutical sciences. 2014; 3(12): 434-446.

27.  Patel BU. Modi DC. Shah PD et al. A Review International Journal of Advances in Pharmaceutics. 2017; 6(7): 110-113.

28.  Patel AR.  Vavia PR et al. Preparation and in vivo evaluation of SMEDDS (self-microemulsifying drug delivery system) containing fenofibrate. AAPS J. 2007; 9:E 344–52.doi.org/10.1208/aapsj0903041.

29.  Shah U, Patel K et al. Effects of Strychnos potatorum Linn. seeds on Triton WR 1339 Induced Hyperlipidemia in Rats. Research J. Pharm. and Tech. 2012, 5(7): 901-904.

 

 

 

 

Received on 24.03.2021           Modified on 16.06.2021

Accepted on 05.08.2021         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(6):2525-2530.

DOI: 10.52711/0974-360X.2022.00422