FORMULATION AND EVALUATION OF ORAL ANTI-DIABETIC IN-SITU GEL SYSTEM OF PIOGLITAZONEHTML Full Text
FORMULATION AND EVALUATION OF ORAL ANTI-DIABETIC IN-SITU GEL SYSTEM OF PIOGLITAZONE
Padmasri * and R. Nagaraju
Department of Pharmaceutical Technology, Sri Venkateswara College of Pharmacy, Etherla, Srikakulam, Andhra Pradesh, India.
ABSTRACT: Pioglitazone is an oral anti-diabetic agent used in treating class – II diabetes mellitus. T1/2of pioglitazone was 3-6 hrs and is eliminated rapidly. Hence sustained release is needed to prolong its duration of action and to increase its oral bioavailability. The main aim of the study was formulation and evaluation of an in-situ gel system of Pioglitazone to increase its bioavailability as a convenient dosage form. Method of Ion-sensitive in-situ gelation was used in this study. Total 15 formulations were prepared with Guar gum, Xanthan gum, and Carbopol-934 in various combinations and assessed for physical appearance, pH, viscosity, in-vitro gelling capacity, drug content, and in-vitro drug release. FTIR, DSC for Pioglitazone, excipients used, and optimized formulation were conducted. In-vivo drug kinetic studies were conducted for optimized formulation. Formulations showed an optimum viscosity allowing ease of administration and swallowing. All formulations have shown pH between 6.9-7.3, floating lag time was 2-3sec and floated for >12 hrs. The x-ray image studies are also confirming the same thing. In- vitro drug release studies reporting that F15 showing drug release of 99.52% over a 12 hrs period. FTIR studies revealed no interaction between drugs and excipients used. The results of In-vivo kinetic studies are approving the better performance of the optimized formulation. In conclusion, the optimized formulation F15 showed maximum drug retardation for above 12 h. Hence it is concluding that the main objective of the study to increase its bioavailability as a convenient dosage form in the treatment of diabetes mellitus had been achieved.
Keywords: Pioglitazone, Diabetes mellitus, In-situ gels, Sodium alginate, Guar gum, Xanthan gum, Carbopol-934
INTRODUCTION: Controlled drug delivery system (CDDS) currently forefront position in drug delivery compare to the developed systems; it consists of various technical approaches to help in individual care.
The strategy of this system having bountiful favorable circumstances than existing conventional types, it involves improved efficiency, diminished toxic effect, and improved consumer conformity in addition ease.
In controlled drug delivery system, systemically or locally, the drug delivers at a predetermined rate for a predefined period. The oral controlled release system entails drug delivery at knowable and consistent kinetics used for predetermined time intervals throughout the gastrointestinal (GI) tract 1.
A perfect and progressed oral drug delivery method is that which precisely regulates velocity, time, in addition, to be the site of the arrival of medicament independently of regular physiological factors like pH and digestive conditions of the gastrointestinal tract, peristaltic movement and circadian cadence 2. The healing capability of a remedy depends on the bioavailability of the drug. The solubility is an essential precondition to attain preferred drug concentration in the systemic bloodstream, absorption, and response. Drug oral administration is the easiest and uncomplicated path of medication as it offers great patient compliance, comfort, precise dosing, and improved stability.
In-situ gel framing polymer systems have gained importance among NDDS novel drug delivery systems in modern days because of their benefits, such as sustained and delayed drug activity, better patient compliance and diminished dosage drug frequency in contrast with regular conventional delivery system 3, 4.
Pioglitazone is an oral anti-diabetic agent, which is used in treating of class – II diabetes mellitus. Biological half-life of pioglitazone was a maximum 3-6 h and is eliminated rapidly 5, 6. Hence sustained-release formulations are needed for pioglitazone to prolong its duration of action and to increase its oral bioavailability. Practically insoluble in water and alkaline buffer solutions majorly absorbed from the stomach so suitable for gastro retentive formulation development.
The main aim of the study was formulation and evaluation of an in-situ gel system of Pioglitazone using different release rate controlling polymers to increase its bioavailability as a convenient dosage form in the treatment of diabetes mellitus.
MATERIALS AND METHODS: Pioglitazone was acquired from Brundavan Laboratories private Ltd, Hyderabad, India. All the polymers received were of pharmaceutical grade (Guar gum/ Xanthan gum/ Carbopol-934 are obtained from Sigma-Aldrich, Germany) were used as received. Sodium alginate, Sodium citrate and Calcium carbonate were obtained from S.D Fine chemicals, Mumbai, India. All chemicals and solvents utilized were of HPLC grade. Throughout the study, distilled water was used.
Determination of Absorption Maximum (λmax) of Pioglitazone: Solution of drug were prepared in methanol and scanned in the range of 200 to 400 nm using Elico UV spectrophotometer, in order to determine the absorption maxima for analysis of dissolution samples 7.
Preparation of Calibration Curve of Pioglitazone: 10 mg of pioglitazone was dissolved in the required amount of methanol and made upto10 ml of 0.1N HCl by slight shaking (1000 mcg/ml). 1 ml of this solution was taken and made up to 10 ml with 0.1N HCl, which gives 100 mcg/ ml concentration (second stock solution). From the second stock solution, concentrations of 10, 20, 30, 40, and 50 µg/ml in 0.1N HCl were prepared. The absorbance of diluted solutions was measured at 264 nm, and a standard plot was drawn using the data obtained. The correlation coefficient was calculated 8.
Preparation of Pioglitazone Oral In-situ Gel: Ion-sensitive in-situ gelation method was employed for the preparation of Pioglitazone in-situ gels. In preparation of in-situ gels sodium alginate was used as a gelling agent, Sodium citrate as a sequestering agent, and cross-linking agent was Calcium carbonate apart from polymers like Guar gum/ Xanthan gum/carbopol- 934 were utilized as drug release rate controlling polymer. Different formulations are prepared with various proportions of polymers such as Guar gum, Xanthan gum, and carbopol-934; several trials were performed varying the concentration of individual polymer to distinguish the ideal concentration needed for preparation.
Accurately weighed Pioglitazone was solubilized in 10ml of warm de-ionized water with continuous stirring until a uniform solution was obtained. Diverse concentrations of Guar gum, Xanthan gum, and carbopol- 934 are taken, added 70ml of de-ionized water, and gently stirred and heated to 60°C to obtain a uniform solution. The required quantity of calcium carbonate and sodium citrate were dissolved in 20ml of distilled water Heated to 60oc and added to polymer solution at 60 °C. Then the resultant solution was cooled to 40°C, and added with the drug solution. The chart of formulations is specified in Table 1.
TABLE 1: PREPARATION OF PIOGLITAZONE IN-SITU GEL FORMULATION SYSTEMS
|Sodium Alginate (g)||2||2||2||2||2||2||2||2||2||2||2||2||1.5||1.5||1.5|
|Calcium Carbonate (g)||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5|
|Sodium Citrate (g)||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5||0.5|
|Xanthan GUM (mg)||75||100||125||150||--||--||--||--||--||--||--||--||50||-||50|
|Guar Gum (mg)||--||--||--||--||75||100||125||150||--||--||--||--||50||50|
|Carbopol 934 (mg)||--||--||--||--||--||--||--||--||75||100||125||150||-||50||50|
|Water upto 100ml||Q.S||Q.S||Q.S||Q.S||Q.S||Q.S||Q.S||Q.S||Q.S||Q.S||Q.S||Q.S||Q.S||Q.S||Q.S|
Drug and Excipients Compatibility Study by FTIR Spectroscopy: The compatibility and interaction between drug and excipients utilized in the preparation of in situ gels are assessed by using FTIR-spectrophotometer 8400S 9. IR spectra of pioglitazone and excipients were determined by scanning at a range of 400 to 4000 cm-1.
Differential Scanning Calorimeter (DSC) Studies: The sample's thermal behavior was investigated by using DSC Q100. Accurately weighed, the required amount of samples were taken in aluminum pans then precisely crimped. At the rate of 20°C/min from- 40°C to 300°C, test samples were heated under stable nitrogen cleansing at a rate of 40 ml/min.
Visual Appearance, Clarity, and pH Measurement: The general appearance, color and odor of formulation were physically observed and recorded, and the pH was determined by using digital pH meter 10.
Drug Content Estimation: Gel equivalent to 10 mg of drug is transferred into a 100 ml volumetric flask and initially dissolved in 20 ml of 50% Methanol. Finally, the volume is fabricated to 100 mL with 50% Methanol. 1 ml of this supernatant is then transferred into a 10ml measuring flask and makes volume to 10ml. Drug concentration was determined by using UV spectrophotometer against a blank solution at wavelength of 264 nm.
In-vitro Floating Time: The in-vitro floating studies were performed by introducing about 10 ml of in-situ gel preparation to 100ml of 0.1N HCl, pH of 1.2 at 37○C. The time taken by the formulation to float was recorded.
In-vitro Gelation Studies: The formulations are subjected to know their in-vitro gelling capacity; accurately 10ml of measured each formulation was taken in a beaker and added 0.1N HCl 100ml, pH of 1.2 followed by gentle agitation. The formed gels were observed and gel formed patterns are recorded.
Viscosity Studies: The viscosity of pioglitazone in-situ gels was measured for solution form and to gel form at 37°C by viscometer Brookfield DV Pro-II, United States. The testing samples are equilibrated in a water thermo-stated jacket for 10 min; measured at 50 rpm with spindle no 65.
In-vitro Release Studies: The in-vitro drug release study was carried in a triplicate using USP II [paddle apparatus method] dissolution apparatus. The medium for dissolution studies was 900 ml of 0.1N hydrochloric acid as dissolution at 37 ºC. The rate of stirring was 50 rpm. The maintained speed to simulate in-vivo existing gentle agitation moreover be sluggish enough to avoid the infringement of gel formulation. At programmed time intermissions, accurately 5ml of the sample was withdrawn, and an equivalent amount of fresh medium replaced at 37°C and the absorbance of the samples was measured at 264 nm using a UV-Visible spectrophotometer.
In-vitro Kinetic Studies: To know the mechanism of drug release, kinetic models are used. In order to study the definite mechanism of drug release from the formulation, drug release data were analyzed by Zero-order, first-order, Korsmeyer/Peppas, and Higuchi square root plot. The obtained data were processed for regression analysis by MS EXCEL statistical function. It is known that the Peppas model is broadly used to affirm whether the release mechanism is Fickian diffusion and non- Fickian diffusion.
The release exponent of the Korsmeyer/ Peppas model ‘n’ value could be used to explain different release mechanisms. The interpretation of the n value was done in the following manner, showed in Table 2.
TABLE 2: DIFFUSION COEFFICIENT AND MECHANISM OF DRUG TRANSPORT
|Release exponent (n)||Drug transport mechanism|
|0.89||case II transport|
|Higher than 0.89||Super case II transport|
X-Ray Imaging Studies for Floating of The Formulation: A protocol was designed for the x-ray studies to know the floating time period of an optimized in-situ gel formulation of Pioglitazone. After getting authorization from Institutional Animal Ethical committee having approval no. 1962/PO/Re/S/17/CPCSEA, the studies were performed using White Newzealand Rabbits. As per protocol, the healthy rabbit weighing 2.5 kg which has housed for a minimum of 72 h early to the study and had free access to water and food. Animals were kept for overnight fasting, and prepared optimized Pioglitazone in-situ gel formulation along with radio-opaque agent BaCl2 at the concentration of 15% w/v to ensure visibility by X-ray was administered orally. Throughout the experiment, the animal was not allowable to eat but have free access to water. X-ray imaging studies were performed at programmed time intervals of 0, 0.5, 1, 2, 4, 6, 8, 10, and 12 h.
In-vivo Pharmacokinetic Studies for the Optimized Formulation: Measurement of pharmacokinetic parameters of the treatments confirmed to guidelines of Institutional Animal Ethical committee having Approval No. 1962/PO/ Re/S/17/CPCSEA. Each group consists of three white albino rats. Pure drug suspension and the optimized formulation were administered orally to the rabbits by oral feeding tube, and the dose was followed considering the literature review. Animals weighing 180-200 g were divided into three groups of 3 each. Groups were named as Blank, Pure drug and optimized formulation. Animals were maintained under standard laboratory conditions at 24 ± 2°C, relative humidity 50 ± 15%, and maintained under normal photoperiod (12 h dark / 12 h light cycles) throughout the experiment.
Blood samples were collected in K2 EDTA coated blood collection tubes from marginal ear vein as per the standard protocol. The sampling time intervals were 0.0, 0.5, 1.0, 2.0, 4.0, 6.0, 12.0, and 24 h, respectively, for each animal of all the groups. The blood samples were collected, centrifuged at 4000 rpm, and the plasma was separated. Plasma samples were stored at -20°C until analysis. Samples are examined for medicine concentrations by HPLC, and PK parameters were studied. The PK parameters such as t1/2, Tmax, Cmax, AUC0-t are estimated for the formulation and compared to that of API.
RESULTS AND DISCUSSION:
Determination of Absorption Maximum (Λmax) Of Pioglitazone: UV spectrum of pioglitazone: UV-Scan Spectrum Performed at Range 200.00 to 350.00 nm showed maximum absorbance at 270nm wave-length are shown in figure no1. The calibration curve of pioglitazone by plotting concentration against absorbance results in a straight line, and Better peak response and less placebo interference were observed at 264 nm. Therefore, wavelength of 264 nm, as shown in Fig. 2 was preferred to estimate the drug.
FIG. 1: PIOGLITAZONE ABSORPTION CURVE (ΛMAX: 264 nm)
FIG. 2: CALIBRATION CURVE OF PIOGLITAZONE WITH REGRESSION VALUE
FTIR and DSC Studies: The IR spectrum of pioglitazone pure, excipients of optimized formulation, and pioglitazone optimized formulation illustrated that peak characteristics of pioglitazone are not-altered and with no changes in their spot, by this means representing no chemical drug interaction among drug and excipients. IR spectral studies confirmed the compatibility of pioglitazone with polymers utilized for in-situ gel preparations. The major peaks are obtained almost at the same wavenumbers belonging to drug functional groups. On the other hand, in the physical mixtures, additional peaks were obtained due to the attendance of impurities; however, there is no influence on the drug peaks. The observation of spectral studies indicates no significant change in the peaks of the drug-polymer mixture. Therefore, no specific interaction among drugs and polymers was observed, outcomes of IR studies were given in Fig. 3. The DSC studies of pioglitazone indicate that the obtained sample was a hydrate form result was shown in Fig. 3.
FIG. 3: THE IR SPECTRUMS OF THE PIOGLITAZONE, EXCIPIENTS OF OPTIMIZED FORMULATION AND DSC OF THE PIOGLITAZONE
Physical Appearance, pH and Response of Gelation: The pH measurement is essential for oral preparations; or else, it leads to annoyance to the gullet. All prepared formulations pH was found in the range of 6.9-7.3 and physical appearance of formulations as shown in Table 3.
TABLE 3: EVALUATION PARAMETERS (GEL APPEARANCE, pH, GELATION RESPONSE, %DRUG CONTENT, VISCOSITY, FLOATING LAG TIME IN SEC AND FLOATING DURATION IN HRS) OF IN-SITU GEL FORMULATIONS OF PIOGLITAZONE
|% Drug content||Floating:
|F1||Pourable and pleasing||6.9||+++||94.21||2sec||>12 hrs||312± 31||1456|
|F2||Pourable and pleasing||7.1||+++||94.73||3sec||>12 hrs||325± 26||1478± 23|
|F3||Pourable and pleasing||7.1||+++||95.78||2sec||>12 hrs||348± 16||1512± 26|
|F4||Pourable and pleasing||7.0||+++||94.94||2sec||>12 hrs||356± 68||1536± 31|
|F5||Pourable and pleasing||6.9||+++||94.89||3sec||>12 hrs||332± 23||1414± 13|
|F6||Pourable and pleasing||7.0||+++||95.10||2sec||>12 hrs||356± 26||1486± 16|
|F7||Pourable and pleasing||7.1||+++||95.68||4sec||>12 hrs||369± 38||1526± 22|
|F8||Pourable and pleasing||7.3||+++||95.52||2sec||>12 hrs||374± 25||1598± 50|
|F9||Pourable and pleasing||7.2||+++||95.26||2sec||>12 hrs||368± 13||1468± 18|
|F10||Pourable and pleasing||7.3||+++||95.89||3sec||>12 hrs||388± 50||1518± 26|
|F11||Pourable and pleasing||7.0||+++||96.42||3sec||>12 hrs||396± 24||1548± 15|
|F12||Pourable and pleasing||6.9||+++||96.05||4sec||>12 hrs||408± 22||1592± 36|
|F13||Pourable and pleasing||7.1||+++||96.17||5sec||>12 hrs||438± 15||2556± 25|
|F14||Pourable and pleasing||7.3||+++||97.52||2sec||>12 hrs||468± 18||2594± 38|
|F15||Pourable and pleasing||7.3||+++||97.69||2sec||>12 hrs||483± 36||2608± 24|
(+++): Immediate gelations remain for an extended period
Determination of Drug Content: Content of drug in all F1 to F15 preparations were assessed, and outcomes are in the acceptable range. The ranges of drug content values of formulations are between 94 to 97.6%; hence it was clearly indicating that the drug was steady throughout its shelf life, and the results were shown in Table 3.
Floating Studies: Floating time and lag time were shown in Table 3. As on the concentration of polymer results in an increase in viscosity, hence the time taken from the sol to cohesive gelation and to appear on the surface of the medium was lowered. The in-vitro floating test revealed the ability of all formulations to keep buoyancy for above 12 h. All formulations exhibited a total floating time of>12 h. Floating lag-time varied with formulation variables. Floating lag times of F1-F15 are in between 2-5sec.
Viscosity Studies: The viscosities of the all-prepared formulations were low; a considerable increase was reported at due to the conversion of sol-gel. The pioglitazone in-situ gel (F15) viscosity was 483±36cps, a prominent raise was observed after gelation was 2608±24cps. Taking into account all the results and findings of characterization, formulation F15 was considered for further studies results were shown in Table 3.
In-vitro Drug Release Studies: The in-vitro drug release study results were shown in Fig. 4. Formulations (F1-F4) containing the composition of pioglitazone with various concentrations of Xanthan gum showed 92.36%, 94.26%, 98.05% and 97.10% drug release in 6 hrs of dissolution. Drug along with Guar gum (F5-F8) and Carbopol 934 (F9-F12) composite formulations showed drug release range in-between 84.31%-99.47% within 8hrs of dissolution.
Formulations (F13-F15) having compositions of Pioglitazone with a combination of Xanthan gum, Guar gum, and Carbopol showed extended period of drug release, as compared to all formulations based on the results of dissolution studies and other evaluation parameter values F15 can be considered as optimized formulation as it showing drug release of around 98.11% over 10 h extended period.
FIG. 4: COMPARATIVE SUMMARIZATION OF IN-VITRO DISSOLUTION STUDIES OF (F1 TO F15) PIOGLITAZONE
Kinetic Analysis of in-vitro Drug Release Studies: Zero-order analyzed the cumulative drug release data of optimized formulation (F15), first-order, Kores Mayer Peppas and Higuchi square root to find out drug release mechanism. The correlation coefficient (r2) values of F15 were specified in Table 4. Hence it can be assessed that the optimized formulation (F15) is following zero-order and diffusion mechanism for drug release. Kinetic model plots were shown in Fig. 4.
TABLE 4: KINETIC MODELS AND THEIR SLOPE VALUES AND R² VALUES
|S. no.||Model||R2 and Slope values|
|1||zero order kinetic||y = 10.01x + 0.921
R² = 0.998
|2||First order kinetic||y = -0.098x + 2.082
R² = 0.519
|3||Higuchi kinetic||y = 33.18x - 16.56
R² = 0.946
|4||Koresmayerpeppas kinetic||y = 1.319x + 1.835
R² = 0.031
FIG. 5: KINETIC MODELS AND THEIR GRAPHS OF THE PIOGLITAZONE OPTIMIZED FORMULATION
In-vivo X-ray Imaging Studies: An in-vivo X-ray imaging study was performed on a healthy New Zealand rabbit. The optimized formulation added with Barium Chloride at the concentration of 15% w/v was administered to the rabbit through the oral route and its abdomen X-ray images were taken to confirm the floating ability of optimized gel formulation (F15) of the pioglitazone. The X-ray imagings were taken as i) X-ray image of Immediately after administration ii) X-ray image After 0.5 hr after gel administration iii) X-ray image after 1 hr. of gel administration and iv, v, vi, vii-viii & ix are X-ray images after 2, 4, 6, 8, 10 and 12 h of gel administration. It was found that oral floating in-situ gel was float immediately after feeding to rabbit and it was observed to be floating in the stomach for more than 12 h and results of x-ray imaging’s are given in Fig. 6.
In-vivo Pharmacokinetic Studies for the Optimised Formulation: The percent of drug concentration in plasma was evaluated and plasma concentrations versus time curve for pioglitazone was shown in Fig. 5. Pharmacokinetic parameters are presented in Table 5. As compared to the pure drug (4.945ng/ml) F15 formulation showing Cmax value of 6.886 ng/ml in blood and bioavailability and Tmax of F15 was 4 h and the pure drug was 1 h.
AUC is an important parameter for evaluating the bioavailability of a drug from a dosage form as it represents the total integrated area under the blood concentration-time profile and represents the total amount of drug reaching. The F15 formulation and pure drug have had maximum variations in the case of AUC parameter.
FIG. 6: IN-VIVO X-RAY IMAGING STUDIES OF THE PIOGLITAZONE OPTIMIZED FORMULATION. i) x-ray image of Immediately after administration ii) x-ray image After 0.5 hr after gel administration iii) X-ray image after 1 h of gel administration and iv, v, vi, vii-viii & ix are X-ray images after 2, 4, 6, 8, 10 and 12 h of gel administration.
TABLE 5: PHARMACOKINETIC STUDIES OF OPTIMIZED FORMULATION F15, AND PURE DRUG
|Pharmacokinetic Parameters for pioglitazone in Rabbits|
|Formulation||AUC 0→24||t1/2 (hrs)||Cmax(ng/ml)||Tmax (hrs)|
FIG. 7: PLASMA CONCENTRATIONS VERSUS TIME CURVE OF FORMULATIONS [F15], PURE DRUG
CONCLUSION: Diabetes is the most common disorder; for the management of diabetes many anti-diabetic drugs are available in the market in solid dosage forms. Pioglitazone is an oral anti-diabetic agent, which is used in treating of type – II diabetes mellitus. The biological half-life of pioglitazone was a maximum 3 h and is eliminated rapidly. The optimized formulation F15 Thereby, the 1.5% concentration of sodium alginate along with Xanthan gum and Carbopol-934 had shown an extended period of drug release for above 12 hours. The in-vivo drug release studies and x-ray studies also confimed that the optimised formulation showing extended bioavailability as above 12 h. Hence it is concluding that the main objective of the study to increase its bioavailability of pioglitazone as a convenient dosage form in the treatment of diabetes mellitus had been achieved.
ACKNOWLEDGEMENT: The authors would like to acknowledge Mr. D. Prasanth, Asst. Professor, Sri Venkateswara College of Pharmacy, for the support in performing in vivo studies.
CONFLICTS OF INTEREST: All the authors declare that they have no conflict of interest.
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How to cite this article:
Padmasri B and Nagaraju R: Formulation and evaluation of oral anti-diabetic in-situ gel system of pioglitazone. Int J Pharm Sci & Res 2021; 12(10): 5595-03. doi: 10.13040/IJPSR.0975-8232.12(10).5595-03.
All © 2021 are reserved by the International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
B. Padmasri * and R. Nagaraju
Department of Pharmaceutical Technology, Sri Venkateswara College of Pharmacy, Etherla, Srikakulam, Andhra Pradesh, India.
21 March 2021
22 May 2021
02 June 2021
01 October 2021