DESIGN, DEVELOPMENT AND EVALUATION OF GASTRIC FLOATING IN-SITU GEL OF PIROXICAM

DESIGN, DEVELOPMENT AND EVALUATION OF GASTRIC FLOATING IN-SITU GEL OF PIROXICAM

Shaikh Siraj N. ^{* 1}, Jain Vrushabha G. ¹ and G. J. Khan ¹

Department of Pharmaceutics, Ali-Allana College of Pharmacy Akkalkuwa, Nandurbar - 425415, Maharashtra, India.

ABSTRACT: The present study involves the formulation and evaluation of floating in-situ gel containing piroxicam for the treatment of arthritis. In the FTIR and DSC study for compatibility of piroxicam with polymers, there are no significant changes observed so it is confirmed the absence of drug-polymer interactions. The gastric floating in-situ gel was prepared by using Sodium Alginate, HPMC K 200 M & other ingredients. The prepared situ gel of piroxicam was evaluated for pH, gelling capacity, floating lag time, total floating time, drug content, viscosity, in-vitro drug release. An optimization study was carried out by using was 3² factorial designs to find the effect of independent variables, i.e., amount of Sodium Alginate (X1) and HPMC K 200 M (X2) on dependent variables i.e., floating lag time & % CDR. The results showed that all the formulations exhibited a very short floating lag time. Most of the formulations floated within 1 min. All the formulations exhibited a basic pH in the range of 6.7 to 7.9 which is suitable for oral consumption and gastric delivery. Increasing the calcium carbonate content in the formulation simultaneously increased the viscosity at all polymer concentrations. The comparing G1 to G9 formulations it was observed that the drug release pattern of formulation G1 is about 99.25% at the end of 12 h & have sufficient gelling property, viscosity & floating lag time so it is selected as an optimum batch. 3² full factorial design optimization technique was successfully used in the development of this in-situ gel.

Piroxicam, In-situ gel, HPMC K200M, Sodium alginate, Floating, Optimization

INTRODUCTION: Oral drug delivery is the most popular route of drug administration but conventional oral dosage form has many problems like short gastrointestinal transit time, fluctuation in blood plasma concentration, low bioavailability so there is a need for novel drug delivery like Gastroretentive drug delivery (GRDDS) ^{1, 2}.

GRDDS can be defined as a system which remains in the stomach for a sufficient period of time and releasing active moiety in a controlled manner and finally metabolized in the body ³. Gastro retentive drug delivery system plays a vital role among novel drug delivery systems ⁴.

The retention of oral dosage forms in the upper GIT causes prolonged contact time of drug with the GI mucosa, leading to higher bioavailability and hence therapeutic efficacy, reduced time intervals for drug administration, potentially reduced dose size, and thus patient compliance ⁵. Over the last two decades, numbers of GRDDS have been designed to prolong GRT. The main aim of preparing GRDDS is to minimize the problem associated with existing oral sustained release dosage form and to develop patient benefited drug delivery. In GRDDS most popular one is in-situ gel ⁶. The gastro-retentive in-situ gel-forming system provides controlled drug delivery within the stomach. In-situ gel formation occurs due to one or a combination of different stimuli like pH change, temperature modulation and solvent exchange ⁷.

In-situ is a Latin word which means ‘In its original place or in position’. Extensive researches focused on the development of new drug delivery systems with improving efficacy and bioavailability together, thus, reducing dosing frequency to minimize side effects. As a progress, they design in-situ forming polymeric delivery systems sparked by the advantages of easy administration, accurate dose as well as prolong the residence time of the drug in contact with mucosa compared to conventional liquid dosage form, improved patient compliance and comfort ⁸. In-situ gel formation occurs due to one or a combination of different stimuli like pH change, temperature modulation and solvent exchange. Smart polymeric systems represent promising means of delivering the drugs; these polymers undergo in-situ gel transition upon administration ⁹.

Gels are an intermediate state of matter containing both solid and liquid components. The solid component comprises a 3D network of interconnected molecule or aggregates which immobilizes the liquid continuous phase. Gels may also be classified as chemical gels that arise when strong covalent bonds hold the network together and physical gels when hydrogen bonds, electrostatic and Vander walls interaction maintain the gel network ^{10, 11}. Gastroretentive floating in-situ gel refers to a polymer solution of low viscosity which upon coming in contact with the gastric fluids; undergoes a change in polymeric conformation and a viscous strong gel of density lower than the gastric fluids is produced. The gelation can be triggered by temperature modulation, pH change, and ionic cross-linking. In-situ gels can be administered by oral, ocular, rectal, vaginal, injectable and intra-peritoneal routes ¹². Piroxicam is one of the most effective non-steroidal, anti-inflammatory drugs of the piroxicam derivative which also having antipyretic and analgesic activity in numerous types of pains such as used in the treatment of rheumatoid arthritis and osteoarthritis ¹³. The main objective of the present work is the formulation and evaluation of Floating in-situ gel containing piroxicam for the treatment of Arthritis.

MATERIALS AND METHODS:

Materials: Piroxicam was obtained from Shree Swami Samarth Ayurvedic Pharmacy Jalgaon (Allopathic division). HPMCK 200 M, Sodium alginate, Calcium Carbonate, Trisodium citrate, Propylparaben, Calcium chloride and Carbopol 934 was purchased from Research Lab Fine Chem Industries, Mumbai. All other ingredients used were of analytical grade.

Drug and DSC - Excipient Compatibility Study: FTIR and DSC studies were conducted to know the compatibility between drugs and excipients.

FTIR: Infrared Spectrophotometry is a useful analytical technique utilized to check the chemical interaction between the drug & other excipients used in the formulation. 1 mg of the sample was powdered & intimately mixed with 10 mg of dry powdered potassium bromide. The powdered mixture was taken in a diffuse reflectance sampler & the spectrum was recorded by scanning in the wavelength region of 4000-400 cm^-1 in an FTIR spectrophotometer. The IR spectrum of the drug compared with that of the physical mixture to check for any possible drug-excipient interaction.

Differential Scanning Calorimetry Analysis: Method for estimating the physical interaction between drugs and polymers used for the formulation of the different dosage forms is a thermal analysis by DSC. In the present studies, the DSC analysis of drug and Polymers were carried out using a Shimadzu DSC 60, Japan; to evaluate any possible polymer-drug thermal interaction. Exactly weighed 5 to 6 mg samples were hermetically sealed in an aluminum crucible and heated at a constant rate of 10 ºC/min over a temperature range of 40 to 300 ºC. Inert atmosphere was maintained by purging nitrogen gas at a flow rate of 50 ml/min.

Methods:

Preparation of in-situ Gel: Specified quantity of piroxicam, trisodium citrate, sodium alginate, calcium carbonate, calcium chloride, Propyl Paraben, Carbopol 934 and HPMC K 200M  were weighed accurately ^{14, 15, 16}.  Accordingly, in about 30 ml of deionized water, HPMC K200M was allowed to hydrate overnight. Piroxicam was then dissolved in the HPMC K200M solution and CaCO₃ (gas generating agent) was added to it while stirring to facilitate dispersion. Sodium alginate solutions were prepared by adding the remaining amount of deionized water (up to 50 ml) containing sodium citrate and calcium chloride and heating to 60 ºC while stirring on a heating magnetic stirrer. After cooling to below 40 ºC, it was added to the HPMC K200M solution while stirring to achieve uniform dispersion. The solution of methylparaben and Carbopol 934 was added and mixed properly. Finally, the formulations were adjusted to volume, filled and stored in amber-colored bottles until further tests were done.

Optimization by Using Full Factorial Designs: In the present study, a 3² full factorial design was employed to find the effect of independent variables, i.e., amount of Sodium Alginate …(X1) and HPMC K 200M (X2) on dependent variables i.e. Floating lag time & % CDR.

TABLE 1: LAYOUT OF 3² FULL FACTORIAL DESIGN BATCHES G1-G9 OF FLOATING IN-SITU GEL

TABLE 2: TRANSLATION OF CODED VALUE IN AN ACTUAL UNIT

TABLE 3: OPTIMIZATION BATCHES AS PER FACTORIAL DESIGN

Evaluation of Optimized Batches of in-situ Gel Formulations:

Determination of pH 17-24: The pH values of all in-situ gel formulations of Piroxicam were measured using a calibrated digital pH-meter at room temperature, and results were recorded.

Gelling Capacity of Formulations: Accurately measured 10 mL of the formulation was added to 100 mL of 0.1 N hydrochloric acid (pH 1.2) at 37 ºC in a beaker with mild agitation that avoids breaking of formed gel.

The in-vitro gelling capacity was graded in three categories on the basis of the stiffness of formed gel, gelation time and the time period in which, formed gel remains without a change. (+) Gels after a few min, dispersed rapidly. (++) Gelation immediate remains for a few hours. (+++) Gelation immediate remains for an extended period.

Determination of Viscosity: Viscosity of the prepared in-situ gel formulations of piroxicam was determined using a brook field viscometer. Viscosity was measured at different angular velocities (from 20 to 100 rpm) using spindle number 2 at room temperature.

Determination of Drug Content: Accurately, 10 mL of a formulation containing the equivalent of 100 mg piroxicam from different batches were measured and transferred to a 100 mL volumetric flask. To this 50-70 mL of 0.1 N HCl was added and sonicated for 30 min. Volume was adjusted to 100 ml. Complete dispersion of contents was ensured visually and the dispersion was filtered using Whatman filter paper. From this solution, 10 mL of sample was withdrawn and diluted to 100 mL with 0.1 N HCl. Contents of piroxicam were measured at maximum absorbance at 242 nm using UV 1800 -Visible Spectrophotometer at (SHIMADZU, Japan).

In-vitro Floating Study: The in-vitro floating study was determined by means of USP dissolution apparatus II having 500 ml of simulated gastric fluid (0.1 N HCl) maintained at 37±1 ºC with a paddle speed of 50 rpm. 10 ml of the prepared in-situ gelling formulations were withdrawn with a disposable syringe and added into the dissolution vessel containing simulated gastric fluid. The time the formulation took to emerge on the medium surface (Floating lag time, FLT) and the time the formulation constantly floated on the dissolution medium surface (duration of Floating, TFT) were recorded.

In-vitro Drug Release Study: The release rate of Piroxicam from in-situ gel formulations was determined using USP dissolution testing apparatus type-II at 50 rpm. The dissolution medium was used 900 ml of 0.1 N HCl, and the temperature was maintained at 37 ºC.

1 ml of the sample of the solution were removed at the pre-determined interval for analysis and replace with 1 ml of fresh 0.1 N HCl. The drug concentration of each sample was determined spectrophotometrically at 242 nm.

RESULTS AND DISCUSSION:

FT-IR study of Drug: FT-IR spectra of the pure drug confirms its identity as piroxicam and formulation showed no interaction of excipients with the drug and hence, it was concluded that the drug is compatible with the excipients used. As shown in Fig. 1 and 2.

The endothermic peak of the drug was found to be 200 ºC and which corresponds to the melting point is 198-202 ºC as reported in Pharmacopoeia. In physical mixture also Endothermic peak of the drug was found to be 200 ºC and which corresponds to the melting point is 198-202 ºC as reported in the pharmacopoeia. The drug, drug-excipients physical mixture studies reveal that there was no significant change in position of the peak in thermogram of the drug, drug-excipients was recorded. From Fig. 4 of drug excipients compatibility study, it was concluded that the given drug was compatible with all the excipients and it was confirmed by FTIR & DSC study.

Evaluation of Optimized Batches G1-G9:

TABLE 4: CHARACTERISTICS OF PREPARED FLOATING IN-SITU GELS OF PIROXICAM

Determination of pH: The pH of prepared formulations was measured using a calibrated digital pH meter at 35 °C. All the formulations exhibited a basic pH (>6) which is suitable for oral consumption and gastric delivery. The pH of optimized formulations G1 to G9 was in the range of 6.7 to 7.9.

Uniformity of Drug Content: Drug content determination was done for all batches of prepared in-situ gels. It was done to ascertain the drug distribution in the formulations. Since the prepared formulations are liquid in nature, uniform distribution of drug will benefit the patient in ensuring the availability of proper dose each time the dose is administered. From the results of drug content evaluation, it was found that the drug loading was uniform and there was the proper distribution of the drug in the in-situ gel formulations. The drug content in the formulations was in the range of 97.82 ± 0.25 to 99.63 ± 0.09% of the total amount of the drug added during the preparation. Hence, it can be concluded that the drug distribution was satisfactory in the prepared formulation.

Gelling Capacity of Formulations: An oral in-situ gelling gastro retentive formulation should undergo rapid sol to gel transition when it comes in contact with the gastric fluid. Also, to facilitate sustained drug release, the in-situ formed gel should preserve its integrity without dissolving for a prolonged period of time. It is the time taken by the prepared formulations (sol) to get converted into a gel state when placed in specific conditions (pH 1.2). The gelation time of the formulations should be less, so as to avoid drug release when the formulations are still in sol state. Once they are converted into a gel (in-situ) they possess a 3 dimensional network that can retard the drug release by increasing the diffusional path for the drug during diffusion/ release.

From the results, it was found that the formulations showed an immediate sol to-gel transition when placed in pH 1.2 buffer. Almost all the sol-gels responded to the study. This quick gelation of formulations can be attributed to the concentrations of both Carbopol 934 and calcium carbonate. It was noticed that as the concentration of Carbopol 934 increased, the gelation time decreased and the calcium carbonate also played a significant role in the gelation of sol-gels.

Floating Lag Time: The time taken by the formulation to emerge on the medium surface (floating lag time) and the time for which the formulation constantly floated on the surface of the dissolution medium (duration of floating) are studied. When the formulation is placed in the medium, the CO₂ released from the formulation was entrapped in the gel network producing buoyant formulation. Further, calcium ion reacted with HPMC K 2OOM produced a cross-linked 3-D gel network which swelled and entrapped with more CO₂.

This entrapment in the network structure caused buoyancy and flotation for an extended period of time. Further, the gel network retarded the drug release and thus exhibiting sustained release pattern. All the formulations exhibited a very short floating lag time. Most of the formulations floated within 1 min after they were placed in the dissolution medium. Formulation G4 showed the least lag time of 16 sec, whereas the formulation G1 showed about 24 sec. The variation in this lag time is mainly due to the amount of calcium carbonate present in the formulations.

Mathematical relationship in the form of the polynomial equation for the measured response floating lag time was obtained and given in the equation below.

Floating Lag Time: +19.76, -1.50 * A, +0.000B, +2.75AB, +1.84 A², -2.66 * B²

Duration of Floating: It is the total time duration where the formulation is constantly floating on the surface of the dissolution medium. The duration is considered once the formulation appears on the surface till it again sinks in the dissolution medium. This test is very important for an in-situ floating formulation since the formulations need to be floating until the drug release is complete from the unit. The study was conducted for a period of 12 hrs since the prolonged retention of the dosage form in the stomach is not intended as they may be forced away to the small intestine. All the formulations were studied for the duration of floating. Formulation G9 exhibited a floating duration of less than 12 h, whereas all other formulations were floating even after the study period i.e., 12 h. The requirement of the formulations was to float for a period of 12 hrs which was achieved by all formulations except G9.

Viscosity Studies: The rheological properties of in-situ gel containing different concentrations of Sodium alginate and HPMC K 200M were studied. Viscosity determination was done for all the formulations using Brookfield viscometer at 3 different rpm (20, 30 & 40 rpm) using spindle no. 63 at 25 °C.

From the observations, it was noticed that there was the in-situ gel demonstrated a considerable increase in viscosity with an increasing amount of sodium alginate. It was attributed to an increasing chain interaction with sodium alginate concentration. Similarly, an increase in the amount of calcium carbonate also increases the viscosity of the in-situ gels at all three sodium alginate percentage.

It could be due to the high concentration of finely dispersed particles of calcium carbonate in the gelling solution. Formulation G4 contained the concentration of HPMC K 200 M and hence exhibited higher viscosity amongst all other formulations. But the formulations G1 and G9 showed the formation of slimy and scattered gel on contact with 0.1N HCl due to their low viscosity.

In-vitro Drug Release Study: In-vitro drug release studies were done for all floating in-situ gelling formulations. From the release data, it was observed that the concentration of polymers (Carbopol 934 and HPMC K 200 M) affected the drug release from the floating in-situ gels. The drug release profiles are depicted in Fig. 9. As the concentration of polymers increased, the amount of drug release decreased from the formulations. The comparing G1 to G9 formulations it was observed that the drug release pattern of formulation G1 is about 99.25% at the end of 12 h.

FIG. 9: IN-VITRO DRUG RELEASE PROFILE FROM PIROXICAM IN-SITU GELS (G1-G9)

Mathematical relationship in the form of polynomial equation for the measured response % CDR was obtained and given in equation below. % CDR = +98.63, -3.08 ^* A, -2.19 ^* B, -1.28 ^* A ^* B, -4.23 ^* A2, +0.14 ^* B2. Responses observed for nine formulations were fitted to Design Expert software. Outcome of ANOVA is as shown in Table 5 below.

TABLE 5: RESULT OF ANOVA

CONCLUSION: The aim & objectives of this work is design, develop & evaluate Floating in-situ gel containing piroxicam for the effective management of Arthritis. The gastric floating in-situ gel was prepared by using sodium alginate, HPMC K 200 M & other ingredients. From the FTIR & DSC study, it was concluded that the compatibility of piroxicam with polymers in the formulation blend. All the formulations exhibited very short floating lag time. The formulations G1 to G9 showed the formation of slimy and scattered gel on contact with 0.1 N HCl due to their low viscosity. Formulation G1 showed a drug release of about 99.25% at the end of 12 h & selected as an Optimized batch 3² Full factorial design and optimization technique successfully used in the development of in-situ gel.

ACKNOWLEDGEMENT: The authors are thankful To Hazrat G. M. Vastanvi, President of Ali Allana College of Pharmacy Akkalkuwa for providing the research facilities, Shree Swami Samarth Ayurvedic Pharmacy, Jalgaon for gift samples of piroxicam, Maliba College of Pharmacy Bardoli Dist. Surat for FTIR study, R. C. Patel College of Pharmacy Shirpur for DSC study.

CONFLICTS OF INTEREST: The author declares no conflicts of interest.

REFERENCES:

1. Pashikanti S and Jyothsna B: formulation and evaluation of floating in-situ gel of Ciprofloxacin. International Journal of Applied Pharmaceutics 2019; 198-04.
2. Formulation development and evaluation of in-situ floating gel of Domperidone Salunke NP, Patil DS, Tadvi SA and Pawar SP: World Journal of Pharmacy and Pharmaceutical Sciences 2019; 8(7): 2019; 1038-51.
3. Nayak AK, Maji R and Das B: Gastroretentive drug delivery systems: a review. Asian Journal of Pharmaceutical and Clinical Research 2010; 3(1): 2-10.
4. Rajinikanth PS, Balasubramanium J and Mishra B: Development and evaluation of a novel floating in-situ gelling system of amoxicillin for eradication of helecobacter pylori. Int J of Pharma 2007; 335(1): 114-22.
5. Shaikh RG, Shah SV, Patel KN, Patel BA and Patel PA: A review on polymers used in in-situ gel drug delivery systems. Int J for Pharma Res Scholars 2012; 1(2): 17-34.
6. Bhushan M, Jyotsana R, Adokar R and Dua K: Development and evaluation of in-situ gel of pregabalin. International Journal of Pharmaceutical Investigation 2015; 5: 226-33.
7. Kushal P, Piyush A, Ashok D, Deepak S, Rahul G, Lalit PK, Mukesh M and Bhavesh J: Formulation and evaluation of oral floatable in-situ gel of ranitidine hydrochloride. J of Drug Deli and Thera 2013; 3(3): 90-97.
8. Debnath S, Babu MN, Kusuma G, Saraswathi K, Sramika NR and Reddy AK: Formulation and Evaluation of floatable in-situ gel as carrier for stomach-specific drug delivery of Metoclopramide Hcl. IJPFR 2011; 1(1): 53-64.
9. Jayswal BD, Yadav VT, Patel KN, Patel BA and Patel PA: Formulation and evaluation of floating in-situ gel based gastro retentive drug delivery of cimetidine. International Journal for Pharma Research Scholars 1(2): 77-7873.
10. Agarwal P, Tanwar YS, Sharma P and Batra A: Formulation and evaluation of in-situ nasal gel of Rizatriptan benzoate. Journal of Drug Delivery and Therapeutics 2017; 7(2): 132-40.
11. Shastri DH, Dodiya HD, Shelat P and Bhanupriy AK: Formulation development and evaluation of a gastroretentive in-situ oral gel of cefuroxime axetil. J Young Pharm 2016; 8(4): 324-29.
12. NM Harish, P Prabhu, RN Charyulu, MA Gulzar and EVS Subrahmanyam: Formulation and evaluation of in-situ gels containing clotrimazole for oral candidiasis. Indian Journal of Pharmaceutical Sciences July - August 2009 DOI: 10.4103/0250-474X.57291
13. Mirza S, Miroshnyk I, Habib MJ, Brausch JF and Hussain MD: Enhanced dissolution and oral bioavailability of piroxicam formulations: modulating effect of phospholipids Pharmaceutics 2010; 2: 339-50.
14. Kajale AD and Chandewar AV: Design development and evaluation of gastroretentive oral floating in-situ gel of metoprolol succinate. Indo American Journal of Pharmaceutical Research 2016; 6(5).
15. Tandle RL and Singh S: Gastroretentive in-situ Gel Formulation System. Indo American Journal of Pharmaceutical Research 2016; 6(08): 122-44.
16. Thomas LM: Formulation and evaluation of floating oral in-situ gel of metronidazole. International Journal of Pharmacy and Pharmaceutical Sciences 2014; 6.
17. Sandhyakumari SJ, Patel J and Shah S: Formulation and evaluation of stomach specific drug delivery system for cefpodoxime proxetil. World J of Phar Res 6(4): 1719-36.
18. Harish NM, Prabhu P, Charyulu RN, Gulzar MA and Subrahmanyam EVS: Formulation and evaluation of in-situ gels containing clotrimazole for oral candidiasis. Ind Journal of Pharmaceutical Sciences 2009; 71(4): 421-27.
19. Patel A, Shah D, Modasiya M, Ghasadiya R and Patel D: Development and evaluation of cefpodoxime proxetil gellan gum based in-situ gel. IJPRBS 2012: 1(2): 179-90.
20. Sharma A, Sharma J, Kaur R and Saini V: Development and characterization of in-situ oral gel of spiramycin. Bio Med Research International 2014; 1-7.
21. Mathew George, Lincy Joseph and Kanaka VS: Formulation and evaluation of floating oral in-situ gel of microwave induced piroxicam-cyclodextrin solid dispersion. International Journal of Institutional Pharmacy and Life Science 2017; 7(6): 2249-07.
22. Jafar M, Salahuddin M and Bolla SR: Gastric floating in-situ gel as a strategy for improving anti-inflammatory activity of meloxicam. Journal of Applied Pharmaceutical Science 2018; 8(11): 95-102.
23. Vipul V and Basu B: Formulation and characterization of novel floating in-situ gelling system for controlled delivery of Ramipril. Int Journal of Drug Delivery 2013; 5: 43-55.
24. Asadullah JM, Saleem MA, Shadab SM, Abdul M and Shakir S: Formulation and evaluation of novel floating in-situ gelling system of macrolide antibiotic using different gelling polymers. Journal of Drug Delivery and Therapeutics 2015; 5(5): 48-55.
    

    ---

    How to cite this article:

    Siraj NS, Vrushabha GJ and Khan GJ: Design, development and evaluation of gastric floating in-situ gel of piroxicam. Int J Pharm Sci & Res 2020; 11(7): 3409-16. doi: 10.13040/IJPSR.0975-8232.11(7).3409-16.

    ---

    All © 2013 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.

    ---