Design and in vitro characterization of novel pulsatile delivery system of biguanide antidiabetic drug

INTRODUCTION Diabetes has become an epidemic. In 2017, as per the International Diabetes Federation, an estimated 451 million people had diabetes. Its prevalence is increasing rapidly, and by 2030, this number is estimated to be almost double.[1] There are many conventional dosage forms available in the market to treat the condition of diabetes. This study emphasizes on treating diabetes based on circadian rhythm. Hence, the pulsatile type of delivery system was designed and was characterized. The terminology pulsatile consists of the word “Pulse,” indicating a rhythmic beat. The pulsatile system is often misunderstood as a chronotherapeutic system. It comprises the release of drug after a definite lag time followed by abrupt or prompt release. Pulsatile systems are gaining a lot of interest as they deliver the drug at the right site of action at the right time, thus providing spatial and temporal delivery and increasing patient compliance. These systems are designed according to the circadian rhythm of the body. The circadian rhythm regulates many body functions in humans, namely metabolism, physiology, behavior, sleep patterns, and hormone production. It has been reported that more shocks and heart attacks occur during morning hours. The patients with diabetes are reported to have high blood sugar levels after meals compared to other timings. Almost all chronotherapeutic systems intended for treating the conditions following the circadian rhythms release the drug after a lag phase in one single attempt. There is no single system developed for such conditions, which can release the drug in multiple pulses unless the formulation is intended to be taken more than once daily.[2] These systems are beneficial for drugs having a high first-pass effect, drugs administered for diseases that follow chronopharmacological behavior, drugs having a specific absorption site in gastrointestinal tract (GIT), targeting to the colon, and cases where night-time dosing is required. Chronotherapy targets the medication administered at the time when they are required the most.[2] Metformin hydrochloride is widely used for the treatment of Type-2 diabetes mellitus. It is a biguanide developed from galegine, this guanidine derivative is found in Galega officinalis.[3] Chemically, metformin hydrochloride is a hydrophilic base; however, it is usually present in oral dosage forms in its hydrochloride salt form. Metformin hydrochloride has acid dissociation constant values (pKa) of 2.8 and 11.5, and therefore exists very large as the hydrophilic cationic species at physiological pH values (>99.9%).[3] This chemical parameter indicates low lipophilicity, and therefore rapid passive diffusion of metformin through cell membranes is not prevalent.[3] The lipid solubility of the unionized species is low as shown by its low water–oil partition coefficient value (logP = 1.43).[4] On the basis of these properties, metformin hydrochloride is defined as class III (low permeability, high solubility) by the Biopharmaceutics Classification System (BCS).[5] The reason for the selection of metformin hydrochloride is that it has an extensive first-pass metabolism, develops biological tolerance, and exhibits poor bioavailability and erratic absorption. The pulsatile drug delivery of metformin hydrochloride will overcome first-pass metabolism in liver as the drug is absorbed in the GIT. The pulsatile drug delivery system will overcome the biological tolerance of the drug. The bioavailability of the drug is improved with adequate absorption at the GIT. Pulsatile drug release system allows the release of active pharmaceutical material in single or successive pulses at precise and well-controlled time. Assuming that physiological processes and biological functions display constancy over time, much effort had been done in the past in developing the drug delivery systems that maintain a flatter plasma level for an extended period. The major objectives of the study include design and characterization of capsular pellets–based pulsatile drug delivery system for the treatment of diabetes mellitus with the lag time of 6 h (±0.20) and perform in vitro studies and stability studies of the optimized formulation. MATERIALS AND METHODS Chemicals and reagents Metformin hydrochloride was obtained as a gift sample from Sun Pharma, Gurugram, India. Hydroxy propyl cellulose (HPC) Type H, Eudragit L-100, and Eudragit S-100 from Jubilant Generics Limited, Noida, India; sodium hydroxide, methanol (high-performance liquid chromatography [HPLC] Grade), and ethanol (95%) from Merck India, Mumbai, India; sodium chloride, triethyl citrate, and ethyl cellulose from S.D. Fine Chemicals, New Delhi, India. All the chemicals used in this study were of analytical grade. Preformulation study Characterization of drug Physical description/organoleptic properties: The organoleptic properties refer to the appearance, color, odor, and taste of the substance. Characterization of these properties is the primary step in the preformulation study and helps with the primary identification of the drug substance and in the determination of the likely patient acceptability of the odor, taste, and color of the raw material and the possible inclusion in the final dosage form. Melting point Melting point of the drug was determined by taking a small amount of drug in a capillary tube closed at one end and was placed in Thiele’s melting point apparatus (Flinn Scientific Canada Inc., Hamilton, Canada). The temperature at which the drug melted was reported. Differential scanning calorimetry The physical state and melting point of the drug was determined by differential scanning calorimetry (DSC) (Perkin Elmer, Rostock, Germany). Samples containing 3 mg of drug was placed in pan in the instrument and heated from 50°C to 250°C, at a heating rate of 10°C/min, under inert atmosphere flushed with nitrogen at the rate of 20 mL/min. Alumina was used as the reference standard. The onsets of melting points and enthalpies of fusion of samples were calculated by the instrument.[6] Particle size distribution by sieve method The sieves were weighed separately before the beginning of the experiment. They were arranged in ascending order of their mesh size (ASTM No.), that is, 30, 40, 60, 85, 100, 150, and pan. The assembled sets of sieves were placed in test sieve apparatus, and 30g of drug was added on the top of each sieve. After 30 min of shaking, the assemblies were opened and each sieve along with the retained samples was weighed. The weights of the individual sieves were subtracted from the initial weight of the empty sieves. Table 1 gives the results of the particle size distribution (PSD) analysis by the sieve method. A bar chart was prepared between sieve size and % of the materials retained.Table 1: Particle size distribution by sieve analysisFlow properties of metformin hydrochloride powder Flowability It is the term used to describe the flow properties of the solid particles. Uniform and reproducible feeding of the powder or granules from the hopper into the extrusion and spheronizer was done to achieve weight uniformity of the product.[7] Angle of repose The angle of repose is a simple practical measurement for indicating the flow of (particles). It is found to be the angle between the free-standing surface of powder heap and horizontal plane and is given by the following equation: Where Tanθ = tangent of angle, r = radius of the heap (cm), and h = height of the heap (cm). Thus, the angle of repose is independent of the mass of powder. The fix base cone method was used to determine the angle of repose in this study.[8] In this method, the cone was kept in an upright position on a piece of white printing paper and filled with the test powder. Then the filled cone was smoothly and gently lifted allowing the flow of powder on the paper. The heap of powder was collected on a paper and the radius and height of the heap of powder was measured and angle of repose was calculated using the aforementioned formula. Density studies This is another property, which improves the characterization of the flow of powders. The tapped density of the powder provides a relationship between the degree of compaction and the flow properties. Bulk density Approximately 30g of metformin hydrochloride was weighed accurately and transferred into 100 mL capacity cylinder. After settling the powder, the volume was measured, which came out to be 62 mL. The bulk density was determined by the following formula: Where M = mass of the sample and V = unsettled apparent volume. Tapped density Approximately 30g of the drug was weighed accurately and transferred into 100 mL cylinder. Cylinder was tapped mechanically by raising the cylinder. It is allowed to drop under its own weight with fixed drop of 14 ± 2mm at a normal rate of 300 drops per minute. The cylinder was tapped 500, 750, and 1250 times initially, and tapped volumes were measured. where M = mass of the test sample and Vf = final tapped volume. Powder compressibility The compressibility index and the Hausner ratio are the measures of porosity of a powder to be compressed. They are calculated by the following equations: Compressibility index: where Vo = unsettled apparent volume (under bulk density determination) and Vf = final tapped volume. Hausner ratio: where Vo = unsettled apparent volume and Vf = final tapped volume. pH solubility studies The pH solubility in distilled water with 100ppm stock solution was prepared by dissolving 10 mg drug in 100 mL of vehicle, and then it was sonicated for 30 min. Identification: metformin hydrochloride analysis Ultraviolet spectral analysis The stock solutions of drug in different media were scanned for absorbance in the region of 400–200nm and ultraviolet (UV) absorption spectra were obtained using UV spectrophotometer (Shimadzu, Kitakyushu, Japan). Fourier transform infrared spectroscopy The infrared (IR) spectrum of drug was taken by using KBr pellet method. Mass spectroscopy The mass spectrometer was operated in positive ion selected reaction monitoring (SRM) mode. Metformin hydrochloride was monitored at a parent mass of 130.097 and a daughter mass of 71.14 with a tube lens voltage of 54.56 V and a collision energy of 22 V. The internal standard for phenformin was monitored at a parent mass of 206.167 and a daughter mass of 105.08, the tube lens and collision energy were 58.07 and 105.08 V, respectively. The capillary temperature was set at 270°C, collision pressure at 1.5 mTorr. The mass spectrometer software used for data capture was Xcalibur 2.0.7 and QuickQuan 2.3 (Thermo Fisher Scientific, San Jose, California).[9] High-performance liquid chromatography A stock solution of metformin hydrochloride having 1 mg/mL was made by dissolving 100 mg drug in 100 mL of mobile phase, RPC18 (LiChroCART, 250–4 i.d., 5 µ particle). Flow rate of mobile phase was 1.3 mL/min and injection volume 20 µL. Elute was analyzed at 236nm. The mobile phase consisted of 2.4008g sodium chloride in 1.7009g of pentane sulfonate, dissolved in 200 mL of water mixed well. The pH was adjusted to 3.5 with orthophosphoric acid.[10] Analytical methodology of active pharmaceutical ingredients (API) Ultraviolet method validation UV absorption spectroscopic methods were used for the estimation of drug. The drug showed λmax 236nm in different vehicles. It was found stable in different vehicles, that is, in distilled water, phosphate buffer of pH 6.8, 0.1N HCl, and methanol when stored in room temperature for 24 h, as their UV absorption spectra were found identical to the fresh samples. The standard curve of the drug was prepared in the following media: Distilled water Phosphate buffer of pH 6.8 0.1 N HCL Methanol Preparation of calibration curve of metformin hydrochloride in different media at 236 nm Accurately weighed quantity of metformin hydrochloride (10 mg) was dissolved in a small amount of media, and the volume was made up to 100 mL in a volumetric flask. This gave a concentration of 100 μg/mL. Dilutions were prepared as 5, 10, 15, 20, 25, and 30 μg/mL. The absorbance of these was determined at 236nm by UV spectrophotometric method; values at 236nm corresponding to each concentration were then statistically evaluated. Calibration curve was plotted taking absorbance on y-axis and concentration on x-axis. Compatibility study of the drug with different excipients Each excipient was weighed accurately to 100 mg. Further, 100 mg of metformin hydrochloride was added to them separately. Six sets of the prepared physical mixture were placed in a glass vial, which were hermetically sealed. These vials were kept at and for The sets were kept for and were opened and for and or studies the of excipients with the the studies were A solution of was prepared by dissolving each excipient separately in the phosphate buffer 1 mL of stock of mL of solution was and the solutions were scanned in UV spectrophotometer from of for pulsatile drug delivery system of and was used for the of was used as a and 30 as a powder was in the mixture for min. The quantity of and gave mass for which was determined by and method. were in 10, with standard and Further, the were to spheronizer with a at mg of was accurately weighed and was taken in 10 different The lag time Type and Eudragit were used for cellulose were taken in 10 and were mixed method cellulose and triethyl were used for the The final were in with an of 50°C for 20 min. the different size were by methods with a set of standard sieves with for formulation of different was used as and the granules were to extrusion and The was and the time was 3 min. The liquid was used in a quantity of mL per and was taken in quantity in each It was by the and as shown in and of different and % of different vitro In vitro study was out in Type apparatus in mL of different media pH for h, the pH 6.8 for the 10 at at Samples were at and analyzed by UV spectrophotometer at 236nm. The samples were at 5, 10, and h, and were with to maintain the of selected optimized formulation 5 The optimized formulation was for following physical Angle of repose Angle of repose was measured by using a having of were placed in and were allowed to from on a level the height and radius of the the angle of repose was bulk density Approximately were through a into a mL tapped on a and volume was measured. Bulk density was measured using weight and volume of Tapped density The aforementioned cylinder was measured times using tapped density and tapped volume was measured. index and Hausner ratio index and Hausner ratio were determined to study the by and The test of was done on with of glass using Inc., New Delhi, was at for min. The of pellet weight with to initial weight was then calculated as Particle size distribution method was used to determine of different 20 and mesh size were placed on The was for a definite time The retained on different sieve were and particle size was calculated 1 and data of metformin of coefficient of and of the data of optimized is the of the and of sieve and is the % of the and surface of optimized were by scanning using These were to and with and studies of 5 with excipients of of metformin hydrochloride with the excipients and used in the optimized studies were In this the optimized formulation 5, the and were to Fourier transform infrared spectroscopy and Fourier transform infrared spectrum analysis In this KBr was used along with spectra of drug formulation. The optimized formulation was and compared of study of metformin hydrochloride with excipients scanning calorimetry of and optimized were and studies of number 5 studies were out to determine the of or on the stability of the drug. The determination of physical stability under stability condition of temperature and was Further, the study of temperature and on of optimized was The stability studies were out according to International for The quantity of optimized was kept in The were placed in having ± and Samples were at 30, 60, and They were for the following stability study as per and determination The optimized pellet were placed in an inert glass and stored at ± 50°C ± and ± for The samples were at 30, 60, and and were analyzed for their drug by method using a standard of the drug was plotted time of each was and rate constant was calculated by the formula: where is the rate analysis The data were to analysis of followed by The was calculated using the software Preformulation studies properties: was found to be white in color, to taste, and Melting The value of the melting point was to be with the reported was shown in 1: Differential scanning calorimetry of metformin size distribution by sieve method pH solubility The pH was measured with pH which was found to be and that with the reported value of as per the of analysis by Sun UV spectral The stock solutions of the drug in different media were for absorbance in the region of and UV absorption spectra were The aforementioned samples of the drug in media were stored for 24 h at room temperature in and their UV absorption spectra were The spectrum of the drug was measured by using KBr pellet method. The at were to out of plane and as shown spectroscopy The mass spectrometer was in positive and with for metformin and ratio obtained in positive were much than in mode. The ion in the and the were 85, 30 were Mass spectrum of The time was found to be for metformin hydrochloride High-performance liquid chromatography of methodology of UV method The values of the coefficient of and of the are given in Table 5 and for per the the standard or the coefficient of in the spectroscopic analysis be than the of the be than of the absorbance of the The coefficient values and of the for all standard are given in Table and positive values of the coefficient of in all cases the The coefficient values were found to be very to Hence, was Compatibility study of the drug with different excipients was given in Table studies a single showed absorbance at and the results are shown in Ultraviolet of metformin hydrochloride with excipients at 236 and of In vitro study of selected optimized formulation 5 5 was selected and for the following physical and data are shown in Table It was found to be Particle size The retained on different sieve were and particle size was calculated Particle size distribution of optimized showed and surface of as shown in and of optimized of studies of 5 with excipients spectrum KBr was used and spectra of the and optimized formulation were and compared and spectroscopy of optimized spectroscopy of Differential scanning of the and optimized were and compared Differential scanning calorimetry of metformin HCl, optimized and as and studies of number 5 stability study according to and the determination of at and of metformin hydrochloride in formulation 5 at ± and of metformin hydrochloride according to analysis The data were to followed by test for the using the software The curve of metformin hydrochloride showed an followed by a single It the melting of the substance in the = = and = The aforementioned showed an with a melting point at was to the reported The showed the of the drug. The drug was found to have flow the aforementioned it was that the particle size of the was in the of The drug was found to have flow The of the an in the of the to a constant volume to the required Particle surface and the the flow properties of the powder. Particle size than usually more than size powder with particle size than 10 flow under of the of the The angle of repose was found to be more than for indicating that is not having flow property, and the of improved flow The compressibility index gives the between and compressibility and can be used to a method of pellet It showed very poor of and was added to this The and mass spectrum showed that the the of analysis by the it was It was found that the drug not with almost all the and Type H, ethyl and at no was at Hence, the drug was with or excipients of the showed absorbance at 236nm. Thus, it was that the excipients not with the analysis of the drug. 5 was selected as an optimized formulation having and for into the with and the was which was of all After the of the formulation and the lag time shown by the as 5 was selected for as it showed a lag time of 6 h to the quantity of type and release in the pH to Eudragit 100 and in pH 6.8 to Eudragit 100, and the release of drug from 6 to h and rapid release of drug from to 10 10 and for formulation 5 in pH for h and phosphate buffer pH 6.8 for the 10 for 10 formulation in pH for h and phosphate buffer pH 6.8 for the 10 showed a surface of and showed surface or to extrusion and method. of and showed for optimized and of in the of the of metformin hydrochloride were Hence, showed no between drugs and In the of and obtained by simple to the of of the single indicating the of and allowing the of in all the a of the of no in the of samples of and were after their and Thus, no definite be for the of all the out the of and the curve of the the rate constant was determined in and it was found to be of the drug The data were to followed by and in all the was as On the basis of the of pellet an between the amount of lag time present and the rate of the drug was The pulsatile drug delivery of metformin hydrochloride with release was developed and in The were prepared with different of lag time material using extrusion and method, which were in the of of metformin with lag time up to 6 The in vitro studies that the the concentration of the drug at time The optimized formulation was found to be with of and of interest There are no of the from Sun Pharma, Gurugram, India, for providing metformin hydrochloride as a gift and Jubilant Generics for providing

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