EXPLOITATION OF SECOND GENERATION SUPERPOROUS HYDROGEL COMPOSITES AS MATRIX RETARDANTS, IN GEL COATING OF PREGABALIN FORMULATION AND IN-VIVO CHARACTERIZATIONHTML Full Text
EXPLOITATION OF SECOND GENERATION SUPERPOROUS HYDROGEL COMPOSITES AS MATRIX RETARDANTS, IN GEL COATING OF PREGABALIN FORMULATION AND IN-VIVO CHARACTERIZATION
Ramavathu Chandrakala * 1, Dasari Varun 2, Malothu Narender 3 and R. Sunitha 4
Department of Pharmaceutics 1, Sri Kakatiya Institute of Pharmaceutical Sciences (SKIPS), Warangal - 506002, Telangana, India.
Department of Pharmaceutics 2, Hindu College of Pharmacy, Guntur - 522002, Andhra Pradesh, India.
Department of Pharmaceutical Analysis 3, Vijaya Institute of Pharmaceutical Sciences for Women, Vijayawada - 521108, Andhra Pradesh, India.
Department of Pharmaceutics 4, Malineni Perumallu Educational Society’s Group of Institutions, Guntur - 522017, Andhra Pradesh, India.
ABSTRACT: The hydro dynamically balanced gastro retentive systems of Pregabalin has been formulated and evaluated which can retard the release of drug based on Super Porous Hydrogel Composites (SPHC) thereby prolong the release rate specifically in the upper part of the GIT. Fast swelling highly porous SPHCs are synthesized by gas blowing technique. The swelling property, mechanical strength and release profile of SPHCs containing drug was investigated by changing the amount of cross-linking agents such as N,N1-methylene-bis acrylamide (BIS) and Ac-Di-Sol. SPHCs to powder form was prepared, the obtained powder material used as matrix agent for the preparation of tablets. Floating tablets were prepared by wet granulation, novel melt granulation and direct compression methods using various grades of ethyl cellulose, HPMCK 100, eudragit ESPO, geleol, compritol 888 ATO and SPHC powder in different concentrations. The prepared gastro retentive floating tablets were evaluated in-vitro buoyancy studies, in-vitro and in-vivo release studies. Formulations consisting powdered SPH Ac-Di-Sol composite as matrix agent was optimized. The floating time observed >12 h at pH 1.2. The in-vitro release studies revealed that the drug release was in controlled fashion up to 12 hrs. Pregabalin non effervescent buoyant tablet formulations (F14, F15 and F16) employing powdered SPH Ac-Di-Sol composite itself as matrix agent were selected for the novel dry gel coating by SPH Ac-Di-Sol composite. GF14 formulation optimized for in-vivo studies due to its effective retarding capability up to 12 h. Using Higuchi’s model and the Korsmeyer equation, the drug release mechanism from the floating controlled release tablets was found to be anomalous (non-Fickian) diffusion.
Floating lag time, Floating time, Gastro retentive floating tablets, Pregabalin, Swelling index
INTRODUCTION: Drug absorption from gastro-intestinal tract is a complex process and is subject to many variables.
Several methods are applied for increasing the residence time of dosage forms in the gastrointestinal (GI) tract, including magnetic systems 1, expandable system, floating system, and mucoadhesive systems 2. In addition, Super Porous Hydrogels (SPH’s) also been developed for prolonging the residence time of delivery systems in the GI tract. A SPH is a three-dimensional network of a hydrophilic polymer chains and their complete swelling occurs in less than 30 sec.
SPH’s swell very fast in spite of their size and this is due to the interconnected porous structure. The interconnected structural pores provide water absorption into the centre of the SPHs by capillary force. However, SPH’s provided drastically fast swelling kinetics and high swelling degree, the mechanical strength of the fully swollen SPH’s was besides poor to be useful. In some cases, the abundant swollen SPH’s could not be picked up and broke easily due to their very poor mechanical properties. Usually, mechanically strong SPH’s can be made by increasing the cross linking density, but this would result in a very small amount of swelling with a loss of the super absorbent property. Therefore, it is preferred to make SPH’s having fast swelling and high absorbency uniqueness as well as high mechanical strength 3, 4, 5.
Pregabalin PRG is an anticonvulsant drug used for neuropathic pain. It was reported to have specific site of absorption in the proximal region of the GI tract i.e., stomach. The short biological half life of drug (5 - 6.5 h) for oral administration favors development of a gastro retentive formulation (GRF) 6, 7. In present work, a SPH composite (SPHC) was planned for formulation. When such systems are administered would remain buoyant on gastric fluid for a prolonged period of time and the drug would be available in the dissolved form at the key site of its absorption. It would leads to improve the bioavailability of the drug. In this way it could stands an advantage over conventional dosage forms.
The present research work aims to design and evaluate hydro dynamically balanced buoyant formulations of (PRG) based on SPHC’s which prolongs the release rate of the drug while extending the residence time of the drug within the body environment, without causing any deleterious effects to the subject and to evaluate the drug release in developed formulations by in-vitro and in-vivo studies.
MATERIALS AND METHODS:
Drug Analysis: A liquid chromatographic method was developed for quantitative estimation of PRG using an isocratic Agilent LC 1100 series HPLC instrument with a hypersil BDS C8 column (250 mm × 4.6 mm, 5µ). The instrument is equipped with a binary pump and variable wavelength UV-Visible detector. A 20 µL Hamilton syringe was used for injecting the samples. Data was analyzed by using Chemstation software. Elico SL 159 UV-Visible spectrophotometer was used for spectral studies. Degassing of the mobile phase was done by using a Loba ultrasonic bath sonicator.
Standard Stock Solution: About 50 mg of standard drug was weighed and transferred into a 50 mL of the mobile phase. The solution was sonicated for 15 min and then volume was made up to get a concentration of 1 mg/mL solution. 5 mL of this solution was further diluted to 50 mL of mobile phase to get the final concentration 100 µg/mL.
Mobile phase : Acetonitrile: Phosphate buffer
(95:5 % v/v)
Pump mode : Isocratic
Buffer : 1 mM Phosphate buffer
pH of buffer : 6.5
Column : Hypersil BDS C8, 250mm ×
4.6 mm, 5.0µ
Column temp : Ambient
Wavelength : 221 nm
Injection volume : 20 µL
Flow rate : 1.0 mL/min
Run time : 10 min
Determination of Solubility: 8, 9 An excess amount of drug was added to 250 mL of respective buffer and subjected to mechanical shaking at 200 rpm for 24 h. The resultant solutions were collected and filtered through 0.45 µ membrane filters and the concentration of drug was determined from absorbance at respective wavelengths for different media. Solubility studies were done for model drug by the above procedure in different media like 1.2 SGF, Milliq water, acetate buffer pH 4.0, Phosphate buffer (pH 6.8 & 7.2).
Synthesis of SPH Ac-Di-Sol Composites by Gas Blowing Technique: 11, 12 All the ingredients except sodium bicarbonate Table 1 were subsequently added into a test tube at 25 ºC with vigorous shaking. The required amount of Ac-Di-Sol was selected based on primary studies. The SPH was prepared using double distilled water.
100 mg of sodium bicarbonate was added very quickly to the solution and mixed well. Polymerization was allowed to continue for approximately 10 min. Synthesized SPHC was removed with a forceps, allowed to air dried for 48 h and cut into pieces of required size. Then SPHC was submerged in an organic solvent overnight. This treatment dehydrated the SPHCs followed by drying and finally stored in an air tight container.
TABLE 1: THE COMPOSITION OF DIFFERENT INGREDIENTS USED IN THE SYNTHESIS OF Ac-Di-Sol BASED SPHC
|Ingredients||Ac-Di-Sol based SPHC|
|Acryl amide [AM] (50% w/v)||300 µL|
|Acrylic acid[AA] (50% v/v)||200 µL|
|BIS (2.5% w/v)||70 µL|
|Span 80 (10% v/v)||30µL|
|Ammonium per sulfate [APS] (20% w/v)||25 µL|
|TEMED (20% w/v)||25 µL|
|Sodium bicarbonate||100 mg|
Characterization of SPHC’s: 13
Scanning Electron Microscopy Analysis (SEM): The dried SPHC’s were cut to expose their inside structure and used for SEM studies. The morphology and porous structure of the SPHC was examined using ESEM EDAX XL-30 scanning electron microscope
Measurement of Initial Size: The initial size of the dried hydrogel was determined by using vernier calipers and ordinary scale. Assuming that the shape of the hydrogel is cylindrical in shape, the size was expressed in mm2. The area (size) of the gel was determined by
A = 2πr(r+h)
The diameter of the dried hydrogel was determined by vernier calipers according to the following formula
Diameter = M.S.R + (V.S.R × L.C)
The height of the hydrogel was determined by ordinary scale.
Measurement of Density: 14 For density determination, solvent displacement method was used. Dried SPHC was used for density measurement, which actually showed the apparent density of SPHC. A piece of SPHC was taken and weighed in order to determine the mass of the piece. A piece of the polymer was immersed in a pre-determined volume of hexane in a graduated cylinder and the increase in hexane volume was measured as the volume of the polymer. The density was measured using formula, D = MSPHC / VSPHC.
Measurement of Porosity: The dried SPHC was submerged in hexane overnight and weighed after excess hexane on the surface was blotted. It was calculated by formula, Porosity = Vp/VT.
Determination of Swelling Time: Swelling time was calculated by immersing the SPHC in de-ionized water as well as in 0.1 N HCl and calculating the time required to attain equilibration in swelling, which is expressed in min.
Swelling Index: The swelling behavior of dosage forms can be measured by studying its dimensional changes, weight gain, or water uptake. The swelling property of the formulation was determined by various techniques. The study is performed by immersing the tablets in 0.1 N HCl at 37 ± 5 °C and determined these factors at regular interval.
Determination of Void Fraction: The void fraction inside SPH’s was determined by immersing the hydrogels in HCl solution (pH 1.2) up to equilibrium swelling. By using these data, the dimensions of the swollen hydrogels, sample volumes were determined. The difference between the weight of the swollen hydrogel and the weight of dried hydrogel gives the amount of buffer absorbed into the hydrogels and it indicates the total volume of pores in the hydrogels.
The void fraction was calculated by the following equation:
Void Fraction = Dimensional volume of the hydrogel / Total volume of pores
Measurement of Swollen Size: The swollen size of SPHC was determined after 24 h. Assuming that the shape of the hydrogels cylindrical in shape, the size [Area = 2πr(r+h)] was expressed in mm2.
Evaluation of Mechanical Properties: 15 Penetration Pressure (PP): The compressive strengths of different SPH formulations were determined by a bench comparator. Briefly, after the fully swollen hydrogel was put longitudinally under the lower touch of a bench comparator, different scale loads were sequentially applied on the upper touch until the point where the hydrogel could not support any more weight and completely fractured. The pressure at this point was denoted as penetration pressure (PP) and calculated [PP = Fu/S].
Mechanical Strength: Mechanical strength of dried SPHC was measured by applying the weight on swelled SPHC’s until the hydrogels fractured.
Measurement of Gelation Kinetics: As the polymerization reaction proceeded, the viscosity continuously increased until the complete network structure (gel structure) was formed.
The gelation time was defined as the time duration for gel formation after addition of initiator APS. It was measured by a simple tilting method after adjustment of pH to 5.0 with sodium hydroxide solution. It was determined by the duration time until the reactant mixture was no longer descending in the tilted tube position (Park et al., 2006).
Effect of cross-linking agent on SPH Ac-Di- Sol Composites Table 2: To investigate the effect of cross-linker on the behavior of the gel, concentration of BIS in the feed mixture was varied in the range 1-3.5% w/v. Different characterization parameters like % porosity, swelling studies (swelling time, swelling ratio), void fraction, penetration pressure and mechanical strength were determined.
TABLE 2: EFFECT OF CROSS-LINKING AGENT ON SPH Ac-Di-Sol COMPOSITES
|Ingredients||SPH 2A||SPH 2B||SPH 2C||SPH 2D||SPH 2E||SPH 2F|
|AM (300 µL)||50% w/v||50% w/v||50% w/v||50% w/v||50% w/v||50% w/v|
|AA (200 µL)||50% v/v||50% v/v||50% v/v||50% v/v||50% v/v||50% v/v|
|BIS (70 µL)||1%||1.5%||2%||2.5%||3%||3.5%|
|Span 80 (30 µL)||10% v/v||10% v/v||10% v/v||10% v/v||10% v/v||10% v/v|
|APS (25 µL)||20% w/v||20% w/v||20% w/v||20% w/v||20% w/v||20% w/v|
|TEMED (25 µL)||20% w/v||20% w/v||20% w/v||20% w/v||20% w/v||20% w/v|
|Ac-Di-Sol||50 mg||50 mg||50 mg||50 mg||50 mg||50 mg|
|NaHCO3||100 mg||100 mg||100 mg||100 mg||100 mg||100 mg|
Evaluation of Degradation Kinetics: The degradation kinetics of the hydrogels was examined by measuring the swelling ratio as a function of water retention.
Determination of Water Retention: For determination of the water retention capacity of the hydrogels as a function of the time of exposure at 37 ºC, the water loss of the fully swollen polymer at timed intervals was determined. The hydrogels were placed in 0.1 N HCl (pH 1.2) medium at 37ºC for 12 h and the samples were periodically weighed for 6 h interval.
The following equation was used to determine the water retention capacity (WRt) as a function of time:
WR t = (Wp - Wd) / (Ws - Wd)
Optimization of Ac-Di-Sol concentration Table 3: Ac-Di–Sol, as an optimized composite is responsible for maintaining the capillary structure required for fast swelling, hence the effect of Ac-Di-Sol on the behavior of SPH was assessed by increasing its concentration from 2D-1 to 2D-6.
TABLE 3: OPTIMIZATION OF Ac-Di-Sol CONCENTRATION
|AM (50%W/V)||300 µL||300 µL||300 µL||300 µL||300 µL||300 µL|
|AA (50%V/V)||200 µL||200 µL||200 µL||200 µL||200 µL||200 µL|
|BIS (2.5%W/V)||70 µL||70 µL||70 µL||70 µL||70 µL||70 µL|
|Span 80 (10%V/V)||30 µL||30 µL||30 µL||30 µL||30 µL||30 µL|
|APS (20%W/V)||25 µL||25 µL||25 µL||25 µL||25 µL||25 µL|
|TEMED (20%W/V)||25 µL||25 µL||25 µL||25 µL||25 µL||25 µL|
|Ac-Di-Sol||50 mg||75 mg||100 mg||125 mg||150 mg||175 mg|
|NaHCO3||100 mg||100 mg||100 mg||100 mg||100 mg||100 mg|
Preparation of PRG Formulations using SPHC Material as Matrix Agent: SPHC’s was subjected to comminution by using motor and pestle. Resulted powder material used as matrix agent for the preparation of tablets. PRG gastro retentive non effervescent formulations are prepared by traditional Wet Granulation Method (F1-F6, Table 4), a novel Melt Granulation Technique (F7-F10, Table 4), Direct Compression Technique (F11-F16, Table 5). Tablets were prepared by different methods were subjected to in-vitro and in-vivo evaluation.
TABLE 4: COMPOSITION OF PRG TABLETS (F1 - F10)
|HPMC K 100||100||300|
|Compritol 888 ATO||100||300|
|PVP K30 in IPA||10||10||10||10||10||10||---||---||---||---|
|MCC PH 102||---||---||---||---||---||---||20||20||20||20|
TABLE 5: COMPOSITION OF PRG TABLETS EMPLOYING SPH Ac-Di-Sol COMPOSITE MATRIX POLYMERS (F11 - F16)
|MCC PH 102||20||20||20||20||20||20|
Post Compression Studies of the Prepared Matrix Tablets: Post compression studies such as hardness (Monsanto hardness tester), weight variation, uniformity of thickness and friability (Roche Friabilator) studies were performed as per USP 2000 on the prepared matrix tablets with appropriate methodologies.
In-vitro Buoyancy Study: 16, 17 The in-vitro buoyancy was determined by floating lag time as per the method described by Rosa et al., 1994. Prepared multi unit granules and single unit systems were placed in a 100 ml glass beaker containing 0.1 N HCl.
In-vitro Dissolution Studies: 18 The prepared matrix tablets were subjected to in-vitro dissolution studies using an 8 station USP dissolution apparatus (Lab, TDT-08L, Mumbai). The dissolution studies were carried out in pH 1.2 for 12 h at 37 ± 0.5 ºC and 75 rpm. At regular time interval, 5 ml of sample was withdrawn from the dissolution medium and replaced with equal volume of fresh medium. After filtration and appropriate dilution, the samples were analyzed at 205 nm for PRG against blank using UV-Visible spectrophotometer. The amount of drug present in the samples was calculated using standard curve.
Analysis of Release Data: 19, 20, 21 Mathematical models, zero-order, first-order, Higuchi & Peppas were applied to analyze the release rate mechanism and pattern.
Fourier Transforms Infrared Spectrum Measurement (FT-IR): 10 The FT-IR spectrums of pure PRG, initial formulation and stability samples of matrix tablets formulations were determined. A FT-IR (Thermo Nicolet 670 spectrometer) was used for the analysis in the frequency range between 4000 and 400 cm-1 and 4 cm-1 resolution. A quantity equivalent to 2 mg of pure drug was used for the study.
In-vivo Evaluation of PRG Gastro Retentive Floating Dosage Forms: A standard calibration curve for PRG in rabbit plasma (approval no: HCOP/IAEC/P.CEUTICS/10/2011-12) was assessed with the help a validated bio-analytical HPLC method in the concentration range 0.25-5.00 µg/mL. The optimized chromatographic conditions were used with sodium dihydrogen phosphate monohydrate (10 mM), methanol and acetonitrile (92:4:4% V/V/V at pH 4.8) as mobile phase at 40ºC with a flow rate of 1.25 mL/min and detection wavelength at 270 nm for these studies. The blood samples were collected at scheduled time intervals viz., 0.25-12, and 48 h. The drug was extracted from plasma (0.5 mL) by using protein precipitation method with help of acetonitrile.
The desired pharmacokinetic parameters from the plasma kinetic data were assessed by using SIGMAPLOT 9 software. Comparative plasma profiles of PRG 100 mg conventional formulation (reference, R) with PRG 100 mg extended release formulation (test, T) were performed.
RESULTS AND DISCUSSSION:
Drug Analysis: 20 µL of PRG standard solution (100 µg/mL) were injected for HPLC analysis. The drug peak observed at retention time 3.153 min. The typical chromatogram of PRG showed in Fig. 1.
FIG. 1: TYPICAL HPLC CHROMATOGRAM OF PRG
Solubility Data: The highest solubility observed in 0.1 N HCl (216.06 mg/mL) and in Phosphate buffer (pH 6.8, 189.37 mg/mL). It was poorly soluble in water and acetate buffer (pH 4.5) at 124.81 and 76.48 mg/mL, respectively.
Characterization of Ac-Di-Sol SPHC Material for Density & Swelling Parameters: Second generation SPHC’s synthesized employing composite agent Ac-Di-Sol, were subjected to density and swelling properties. The density was found to be 1.14 ± 0.08 gm/cm3. (The swelling properties were found to be i.e., Swelling Time: 57 ± 19 min and Swelling Ratio (Q): 310 ± 29. The morphology of hydrogels in SEM analysis showed in Fig. 2.
FIG. 2: SEM PICTURES OF CONVENTIONAL HYDROGEL (A) AND ETHANOL TREATED SPH Ac-Di-Sol (B)
Effect of Cross-Linking Agent on SPH Ac-Di- Sol Composites: From porosity and void fraction measurement, it was observed porosity was gradually decreased as the concentration of BIS increased. The void fraction of SPH was decreased by the increase in the amount of BIS. Also the penetration pressure was found to be gradually increased with BIS concentration, thus increasing the mechanical stability. As the swelling ratio was being decreased beyond 2.5% concentration of BIS, hence this concentration of BIS (SPH 2D) is considered to be the optimized concentration for further characterization Table 6.
TABLE 6: RESULTS DESCRIBING EFFECT OF CROSS-LINKING AGENT ON SPH-Ac-Di-Sol
|Formulation||Porosity (%)||Void Fraction (ml/g)||Penetration Pressure
|Swelling Studies||Mechanical Strength (gm)|
|Swelling Time (min)||Swelling Ratio|
|SPH 2A||77.6 ± 1.9||1.31 ± 0.02||52||55||280± 12||126|
|SPH 2B||74.2 ± 1.4||1.25 ± 0.04||72||50||286 ± 14||139|
|SPH 2C||65.1 ± 2.3||1.12 ± 0.02||85||45||298 ± 17||184|
|SPH 2D||54.3 ± 2.3||0.97 ± 0.03||104||37||308 ± 18||234|
|SPH 2E||39.1 ± 2.9||0.89 ± 0.05||102||32||302 ± 13||252|
|SPH 2F||26.4 ± 2.5||0.79 ± 0.04||115||25||298 ± 12||253|
Water Retention Studies: The weight loss of Ac-Di-Sol hydrogels occurred after 12 h. Lower the concentration of the cross-linking agent, the faster was the loss of water from the SPH. The SPH’s consisting of higher amount of BIS decreased polymer rigidity, thus improving the resiliency of the polymer in response to compression and prevention of the water loss efficiently. Hence an increase in the amount of BIS decreased the rate of loss of water Fig. 3.
FIG. 3: WATER RETENTION STUDIES
Optimization of Ac-Di-Sol Concentration: As the Composite (Ac-Di-Sol) concentration increased swelling time and swelling ratio was gradually increased with increase in composite agent concentration. Thus, 175 mg of Ac-Di-Sol (SPH 2D-6) was used as the optimum concentration showed in Table 7.
TABLE 7: RESULTS DESCRIBING EFFECT OF Ac-Di-Sol ON SWELLING RATIO AND MECHANICAL STRENGTH
|Formulation Code||Swelling studies||Mechanical strength (gm)|
|Swelling Time (Min)||Swelling Ratio
(n=3); Mean ±S.D
|SPH 2D-1||39||307 ± 28||236|
|SPH 2D-2||30||301 ± 16||244|
|SPH 2D-3||25||295 ± 15||262|
|SPH 2D-4||23||291 ± 15||276|
|SPH 2D-5||17||285 ± 20||284|
|SPH 2D-6||13||280 ± 16||291|
Gelation Kinetics: The gelation kinetics gave good information determining the introduction time of blowing agent (sodium bicarbonate).
Effect of Drying Conditions and Wetting Agents on Behavioral Characteristics of SPH Ac-Di- Sol Composites: When the swollen SPHC’s were dried at 60ºC over night (condition II) the swelling time was around 12 min Fig. 4. When a SPH’s dried under condition II (placed in n-hexane), the outer region swelled to equilibrium only seconds after contact with water. When the SPH’s were dried under condition III (i.e., dehydrated in ethanol first before drying), the swelling time was reduced to about 7.2 min. When SPH’s were dehydrated with ethanol containing 1% SLS before drying, the swelling time was reduced even further to less than 5 min Table 8.
FIG. 4: MECHANICAL PROPERTIES OF SPH Ac-Di-Sol COMPOSITES A) 100 g WEIGHT IS PLACED ON THE DRIED SPH, B) ADDITION OF WATER, C) IMMEDIATE SWELLING OF SPH, D) LIFT OF 100 g WEIGHT
TABLE 8: RESULTS DESCRIBING EFFECT OF DRYING CONDITIONS AND WETTING AGENTS ON BEHAVIORAL CHARACTERISTICS OF SPH Ac-Di-Sol COMPOSITES
|Gel type||Drying condition||Wetting agent||Size in dried state||Density [ρ] (gm/cm3)||Swelling ratio (G)||Swelling time (min)|
|Conventional||I||---||5 × 2||1.42 ± 0.09||175 ± 11||642 ± 10.6|
|SPH-Ac-Di-Sol||II||---||6 × 3||1.26 ± 0.08||282 ± 16||14 ± 22|
|SPH-Ac-Di-Sol||III||---||10 × 5.5||0.72 ± 0.03||304 ± 24||7.4 ± 1.2|
|SPH-Ac-Di-Sol||IV||1 % SLS||9 × 4||1.146 ± 0.02||336 ± 16||4.3 ± 0.8|
Post Compressional Parameters of PRG Byouant Tablets: The prepared tablets F1-F8 Table 9 and F9-F16 Table 10 were evaluated for physical parameters like weight variation, thickness, hardness and friability. All the parameters lie within the acceptable limits in all the formulations.
TABLE 9: POST COMPRESSIONAL PARAMETERS OF PRG BYOUANT TABLETS (F1 - F8)
|Weight variation (%)||1.38±0.97||1.72±0.84||1.24±0.98||1.71±0.96||1.98±0.99||1.83±0.88||1.92±0.76||1.94±0.78|
|Hardness (kg/cm2)||5 .4±0.46||5.5±0.52||5.5±0.32||4.5±0.43||6 .2±0.45||5.7±0.48||3.5±0.54||3.25±0.37|
TABLE 10: POST COMPRESSIONAL PARAMETERS OF PRG BYOUANT TABLETS (F9 – F16)
|Weight variation (%)||1.83±0.97||1.94±0.79||1.78±0.95||1.62±0.89||2.37±1.12||1.67±0.67||1.83±0.78||1.76±0.73|
|Hardness (kg/cm2)||3.23±0.97||2.5±1.11||5.5±0.78||5.5±0.65||5.4±0.45||5.8±0.76||5.5 ±0.88||5.2±0.66|
In-vitro Buoyancy Characterization: The tablet swelled radially and axially during in-vitro buoyancy studies. Formulations F7, F8, F9, F10, F14, F15 and F16 were found to exhibit short floating lag times in the artificial gastric fluid and the floating time of formulations were more than 12 hrs except for F9 (4 h) and F10 (5 h) Table 11.
In-vitro Release Data: PRG non effervescent buoyant formulations such as F7, F8, F9, F10, F14, F15 and F16 were subjected to in-vitro drug dissolution studies Table 12. The formulations F14, F15 and F16 employing powdered SPH Ac-Di-Sol composite as matrix agent were showed effective retardation of drug release Table 12. The release of drug and its retardation by the powdered SPH material clearly signifies that as the polymer concentration is increased, the drug is being retarded to a greater extent. In-vitro dissolution results primarily revealed that powdered second generation SPH Ac-Di-Sol composite agents has a better ability to retard the drug release as a matrix agent Fig. 5.
TABLE 11: IN-VITRO BUOYANCY CHARACTERIZATION OF BUOYANT FORMULATIONS
|Formulation||Floating lag time (sec)||Total floating time (h)||Matrix integrity|
|F9||30||4||up to 2 hrs|
|F10||20||5||up to 3 hrs|
TABLE 12: DISSOLUTION PROFILE OF PRG TABLETS
Application of Dry SPH Composite Gel Coating to PRG SPH Matrix Tablets: By conducting in-vitro dissolution studies of dry gel coated PRG matrix buoyant formulations (GF14, GF15 and GF16) Table 13, it was clearly evident that the release rate of PRG matrix buoyant formulations (F14, F15 and F16) were further retarded by dry gel coating Fig. 6. GF14 formulation due to its effective retarding capability up to 12 h, it was optimized for further in vivo studies. The results of in-vitro dissolution studies showed the dry gel coating of SPH Ac-Di-Sol composite material was found to be effective in retarding the release rate of PRG at a rate controlled fashion Fig. 7.
TABLE 13: IN VITRO DISSOLUTION STUDIES OF DRY GEL COATED PRG MATRIX BUOYANT FORMULATIONS
Analysis of Release Data: The optimized formulations were studied for drug release kinetics using zero order, first order, higuchi, korsmeyer-peppas and R2 values of all the formulations. In order to assess the exact release mechanism, dissolution data of PRG formulations were fitted to Korsemeyer Pappas (Power Law) plot. All the exponent (n) values were found to be between 0.5-1, which specified that the formulations were exhibiting Anomalous (Non-Fickian) transport mechanism for the drug release at constant rate controlled fashion Fig. 8, 9, 10, 11 and 12. Relative regression coefficient (R2) and exponent (n) values of PRG formulations showed in Table 14.
TABLE 14: RELATIVE REGRESSION COEFFICIENT (R2) AND EXPONENT (N) VALUES OF PRG FORMULATIONS
FT-IR Studies of PRG Buoyant Formulations: Pure PRG, powdered SPH composite, physical mixture of PRG-powdered SPH composite and optimized formulation of PRG (GF14) gel coated buoyant matrix tablets were subjected to FT-IR characterization to check compatibility among them. No prominent difference was observed in the IR peaks of PRG optimized SPH coated formulation upon comparison with the peaks of drug and polymer alone, which may considered that PRG and SPH composite agents are compatible enough without any interactions Fig. 13.
FIG. 13: FT-IR SPECTRUM OF A) PRG, B) POWDERED SPHC, C) OPTIMIZED PHYSICAL MIXTURE OF PRG AND POWDER, D) GEL COATED FORMULATIONS OF PRG AND POWDERED SPHC
In-vivo Evaluation of PRG GRF Dosage Forms: The plasma concentration profile of PRG immediate release tablets (R) 100 mg and extended release tablets (T) 100 mg were summarized in Table 15 and 17. After conduction of the in-vivo clinical study Table 15 and Table 17 in rabbit plasma, overall assessment of the PRG pharmacokinetic data had revealed that Cmax, Tmax, AUC0-t, KE and t1/2 parameters were totally varied between both reference (R) and test (T) formulations Table 16 and Table 18.
The mean peak plasma concentration Cmax of test (T) formulation was found to be 1324.4 ng/ml reached up to 4.5 h. It was which was varied with of conventional formulation (Cmax 1612 ng/ml reached up to 1.4 h). Increase in Tmax values indicates the drug release in controlled manner Table 17 and Table 19.
Area under the curve (AUC0-t) in test (T) formulation was found to be 23850.14 ng.min/mL which was more than reference (R) formulation (4762.8 ng.min/mL). The overall elimination rate constant (KE) was decreased to 0.0612 h-1 over reference was 0.5127 h-1. Elimination half life’s (t1/2) were found to be 1.216 and 8.23 h for reference and test formulation, respectively. The comparative plasma profile of PRG with respective to subjects in conventional tablet dosage form (R) and extended tablet dosage form (T) was graphically represented in Fig. 14 - 16. Variations in all these parameters clearly indicated the drug released in controlled manner in prolonged period i.e., up 12 h.
Hence the optimized PRG non effervescent GRF formulation was observed to be releasing the drug effectively at a rate controlled manner for a prolonged period of time Table 16, 17, 18 and 19.
TABLE 16: PLASMA CONCENTRATION PROFILES OF PRG IMMEDIATE RELEASE TABLETS 100 mg (R) AT DIFFERENT TIME INTERVALS
TABLE 17: PHARMACOKINETIC DATA OF PRG (100 mg) IMMEDIATE RELEASE TABLETS (R)
|Treatment||Subject||Tmax||Cmax||AUC 0-t||AUC 0-inf||KE||t ½||Extrapolated AUC|
TABLE 18: PLASMA CONCENTRATION OF PRG EXTENDED RELEASE (100 mg) GRF DOSAGE FORMS (T) AT DIFFERENT TIME INTERVALS TABLETS
TABLE 19: PHARMACOKINETIC DATA OF PRG 100 mg EXTENDED RELEASE MULTIUNIT DOSAGE FORMS (T)
|Treatment||Subject||Tmax||Cmax||AUC0-t||AUC 0-∞||KE||T1/2||Extrapolated AUC|
CONCLUSION: The present work has been carried with an in house experimental design to prepare hydro dynamically balanced buoyant formulations of PRG employing second generation SPH Composite agents (Ac-Di-Sol). SPH Composite without polymer formulation was developed in order to assess the capability of SPHC in retarding the release rate of active molecules. In vitro dissolution results primarily revealed that powdered second generation SPH Ac-Di-Sol composite agents has a better ability to retard the drug release as a matrix agent. Since PRG non effervescent buoyant formulations (F14, F15 and F16) employing powdered SPH Ac-Di-Sol composite as matrix agent showed different degree of drug retardation, they were subjected to post formulation processing by application of novel attempt of applying dry SPH Composite gel coating on to the PRG SPH matrix tablets (GF14, GF15 and GF16). Dry gel coated PRG matrix buoyant formulations GF14, GF15 and GF16 showed 98.41%, 81.49% and 73.68% of drug release at the end of 12 h, respectively.
The results of in-vitro dissolution studies the dry gel coating of SPH Ac-Di-Sol composite material was found to be effective in retarding the release rate of PRG at controlled fashion. In order to assess the exact release mechanism, dissolution data of PRG formulations were fitted to Korsemeyer Pappas (Power Law) plot. All the exponent (n) values were found to be between 0.5-1, which specifies that the formulations were exhibiting Anomalous (Non-Fickian) transport mechanism for the drug release at constant rate controlled fashion. By conducting the in vivo clinical study, overall assessment of the PRG pharmacokinetic data revealed that Cmax, Tmax, AUC0-t, KE and T1/2 parameters were totally varied between both reference (R) and test (T) formulations.
Hence the optimized PRG non effervescent GRF was observed to be releasing the drug effectively at a rate controlled manner for a prolonged period of time. Very interesting in-vitro and in-vivo results were observed with SPHC dry gel coated formulations of PRG, further there is a scope to conduct the bioavailability studies in human volunteers to know the exact pharmacokinetics of the developed Buoyant non effervescent GRFDDS of PRG.
ACKNOWLEDGEMENT: The authors would like to thank Management and Principal, Hindu College of Pharmacy for providing facilities to conduct the present study. The authors are also thankful to Vijaya Institute of Pharmaceutical Sciences for Women and Malineni Perumallu Educational Society for their co-operation in completion of the present research work.
CONFLICT OF INTEREST: The authors declare that they have no competing interests.
- Lopes CM, Bettencourt C, Rossi A, Buttini F and Barata P: Overview on gastroretentive drug delivery systems for improving drug bioavailability. International Journal of Pharmaceutics 2016; 510 (1): 144-158.
- Ayre A, Dand N and Lalitha KG: Gastroretentive floating and mucoadhesive drug delivery systems- insights and current applications. Journal of Pharmacy and Biological Sciences 2016; 11(3): 89-96.
- Bhagadia A, Kapadiya M and Mehta L: Superporous hydrogel: A promising tool for gastoretentive drug delivery system. International Journal of Pharmacy and Technology 2011; 3(4): 1556-1571.
- Omidian H, Park K and Rocca JG: Recent developments in superporous hydrogels. Journal of Pharmacy and Pharmacology 2007; 59: 317-327.
- Gupta NV and Shivakumar HG: Development of a gastroretentive drug delivery system based on superporous hydrogel. Tropical Journal of Pharmaceutical Research 2010; 9(3): 257-264.
- Madan JR, Adokar BR and Dua K: Development and evaluation of in situ gel of Pregabalin. Int J Pharm Investig. 2015; 5(4): 226-233.
- Kanwar N, Kumar R, Sarwal A and Sinha VR: Preparation and evaluation of floating tablets of pregabalin. Drug Development and Industrial Pharmacy 2016; 42(4): 654-660.
- Baka E, Comer J and Krisztina TN: Study of equilibrium solubility measurement by saturation shake-flask method using hydrochlorothiazide as model compound. Journal of Pharmaceutical and Biomedical Analysis 2008; 46(2): 335-341.
- Bard B, Martel S and Carrupt PA: High throughput UV method for the estimation of thermodynamic solubility and the determination of the solubility in bio-relevant media. European Journal of Pharmaceutical Sciences 2008; 33: 230-240.
- Siegel RA and Rathbone MJ: Overview of controlled release mechanisms. Fundamentals and Applications of Controlled Release Drug Delivery 2011; 19-43.
- Sadeghi M and Soleimani F: Synthesis and characterization superabsorbent hydrogels for oral drug delivery systems. International Journal of Chemical Engineering and Applications, 2011; 2(5): 314-316.
- Nagpal M, Singh SK and Mishra D: Superporous hybrid hydrogels based on polyacrylamide and chitosan: Characterization and in-vitro drug release. Int J Pharm Investig. 2013; 3(2): 88-94.
- Vishal GN and Shivakumar HG: Preparation and characterization of superporous hydrogels as gastro retentive drug delivery system for rosiglitazone maleate. DARU 2010; 18(3): 200-210.
- Phani DBV, Varun D, Gopal PNV, Banu RC and Sumalatha G: Super porous hydrogels - supreme drug delivery. Research J Pharm and Tech. 2011; 4(8): 1206-1209.
- Senjoti FG, Mahmood S, Jaffri JM and Mandal UK: Design and in-vitro evaluation of sustained release floating tablets of metformin HCl based on effervescence and swelling. Iran J Pharm Res. 2016; 15(1): 53-70.
- Shah SS, Pandia SJ and Waghulade MK: Development and investigation of gastro retentive dosage form of weekly basic drug. Asian Journal of Pharmaceutics 2010; 4: 11-16.
- Rohith G, Sridhar BK and Srinatha A: Floating drug delivery of a locally acting H2 antagonist: an approach using an in-situ gelling liquid formulation. Acta Pharm. 2009; 59: 345-35.
- Reddy KR, Mutalik S and Reddy S: Once-daily sustained release matrix tablets of nicorandil: Formulation and in vitro evaluation. AAPS Pharm Sci Tech. 2003; 4: 61-65.
- Jagdale SC, Agaveker AJ, Pandya SV, Kuchekar BS and Chabhukswar AR: Formulation and evaluation of gastro retentive drug delivery system of propranolol hydrochloride. AAPS Pharm Sci Tech. 2009: 10(3); 1071-1079.
- Hassan MA, Barakat, NS, El-Badry M and Shehata SM: Formulation and in-vitro / in-vivo evaluation of naproxen mucoadhesive buccal patches for local effect. Journal of Drug Delivery Science and Technology 2011; 21(5): 423-431.
- Lian-Dong HU, Wei Liu, Jian-Xue Yang and Li Li: Optimization of gastric floating microspheres of dextromethorphan hydrobromide using a central composite design. Indian Journal of Novel Drug delivery 2011: 3(3); 185-191.
How to cite this article:
Chandrakala R, Varun D, Narender M and Sunitha R: Exploitation of second generation superporous hydrogel composites as matrix retardants, in gel coating of pregabalin formulation and in-vivo characterization. Int J Pharm Sci & Res 2018; 9(12): 5131-44. doi: 10.13040/IJPSR.0975-8232.9(12).5131-44.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
R. Chandrakala *, D. Varun, M. Narender and R. Sunitha
Department of Pharmaceutics, Sri Kakatiya Institute of Pharmaceutical Sciences (SKIPS), Warangal, Telangana, India.
30 March, 2018
12 June, 2018
27 June, 2018
01 December, 2018