FORMULATION AND IN-VITRO EVALUATION OF PULSATILE RELEASE TABLETS OF RITONAVIR

FORMULATION AND IN-VITRO EVALUATION OF PULSATILE RELEASE TABLETS OF RITONAVIR

Bhavya Rathod *, Gulfisha Shaikh, Anamika Singh, Sapna Malviya and Anil Kharia

Modern Institute of Pharmaceutical Sciences, Alwasa Behind Revati Range Sanwer Road Indore, Madhya Pradesh, India.

ABSTRACT: The objective of the present study was to develop a time-controlled floating pulsatile drug delivery system of Ritonavir (RIT), an antiviral drug with low oral bioavailability due to degradation by CYP3A4 enzymes, efflux by P-glycoprotein, and instability at alkaline pH. Ritonavir is primarily absorbed in the stomach; hence, a floating pulsatile release system was designed to enhance absorption and therapeutic efficacy. Core tablets of Ritonavir were prepared using different superdisintegrants and evaluated for in-vitro disintegration. The disintegration time varied from 21–44 seconds, with crosspovidone showing the fastest disintegration due to rapid water penetration compared with croscarmellose sodium and sodium starch glycolate. Since rapid disintegration is critical for burst release, the F3 formulation was selected for further studies. The rapid release core tablet (F3) was compression-coated with varying concentrations of HPMC K4M, HPMC K15M, and HPMC K100M (P1–P9). Formulations with HPMC K100M (P7–P9) showed a lag time of 4–4.5 hours followed by sigmoidal release, achieving 100% drug release by 10–12 hours. Among these, P9 (core 100 mg + 180 mg HPMC K100M coating) exhibited the most desirable profile. This was further formulated with floating agents (HPMC E15LV, sodium bicarbonate, citric acid), and N2 was optimized, showing buoyancy within 1 min and sustained floatability. The final optimized batch (F3P9N2) exhibited a lag time of 4 hours with complete drug release at 12 hours and demonstrated stability under accelerated conditions without significant changes. Thus, the floating pulsatile system of Ritonavir provides a promising approach for controlled gastric retention and timed drug release.

Keywords: Ritonavir, Floating drug delivery system, Pulsatile release, Superdisintegrants, Hydrophilic polymers (HPMC K100M)

INTRODUCTION: Oral route is one of the most popular, preferable and convenient routes for drug administration. It possesses certain advantages like ease of administration, self medication, patient compliance and flexibility with a wide range of dosage form ¹.

In the present era of drug delivery, tablet is the most successful and convenient oral dosage form and preferred by patient as well as physicians ² However with the advancement of the technologies in the pharmaceutical field, modified drug delivery systems have drawn an increasing interest.

Nowadays, the emphasis of pharmaceutical research is aimed at development of more efficacious drug delivery systems according to the requirement of body and disease state and thus achieving optimal clinical outcome with constant drug plasma concentrations ³.

In the case of certain diseases symptoms display circadian variations and hence drug release from the dosage form should also vary over time. Circadian cycles last about 24 hours, e.g. sleeping and waking patterns. The coordination of medical treatment and drug delivery with such biological clocks and rhythms is termed Chronotherapy ⁴.

If the peak of symptoms occurs during the daytime a conventional dosage forms can be administrated just before the symptoms are worsening. If symptoms of the disease became worse during the night or in the early morning the timing of drug administration and nature of the drug delivery system need careful consideration. In this case, modified-release dosage forms must be used ⁵.

The challenge of delivering drug at predetermined rate and time could be met by a wide range of newer techniques like osmotically driven pumps ⁶, matrices with controllable swelling ⁷, diffusion ⁸ or erosion rates ⁹, nonuniform drug loading profiles ¹⁰ and multi-layered matrices.

A second major challenge has been the controlled delivery of compounds in a pulsatile or staggered fashion. For this mode of delivery, it is assumed that constant plasma drug levels are not preferred and that an optimal therapeutic effect comes from a periodically fluctuating drug concentration. Two different methodologies have been broadly investigated as possible solutions to this challenge. One is the fabrication of a delivery system that releases its payload after a predetermined time delay or in pulses of predetermined sequences ¹¹.

Controlled drug delivery systems have acquired a center stage in the arena of pharmaceutical research and development. The oral controlled release system maintains the drug concentration in the therapeutic window for a prolonged period of time, thereby ensuring sustained therapeutic action. These modified-release formulations have many advantages over immediate-release formulations. With these formulations less frequent drug administration is possible, lower peak concentrations can be obtained to avoid adverse effects, and patient compliance can be improved ¹². However, in chronological diseases like bronchial asthma, rheumatic disease, ulcer, cancer, diabetes, attention deficit syndrome, hypercholesterolemia, neurological disorder, angina pectoris, myocardial infarction and hypertension a continuous release pattern is not suitable. These conditions demand release of drug after a lag time that is a pulsatile release ¹³.

FIG. 1: DRUG RELEASE PROFILE OF PULSATILE DRUG DELIVERY SYSTEM A: IDEAL SIGMOIDAL RELEASE B&C: DELAYED RELEASE AFTER INITIAL LAG TIME

Floating Drug Delivery System: There are numerous approaches to prolong gastric retention, floating drug delivery system is the most widely used technique and offers a simple practical approach to increased gastric residency through inherent buoyancy.

Floating systems significantly extend the period of time, over which drug may be released and prolong dosing intervals and increase patient compliance. These systems retain in stomach and improve the absorption window and thus enhance the bioavailability ²⁶.

Floating drug delivery systems or hydrodynamically balanced systems were first described by Davis (1968). Floating system also known as dynamically controlled systems low density systems that have sufficiently buoyancy to float over the gastric contents and remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time Fig. 2.

This results in an increased gastric retention time and a better control of the fluctuations in plasma drug concentration. Many buoyant systems have been developed based on granules, powders, capsules, tablets, laminated films and hallow Microspheres ²⁷.

FIG. 2: FLOATING DRUG DELIVERY SYSTEM IN STOMACH

MATERIALS AND METHODOLOGY:

Preparation of Floating Pulse Release Tablets ⁶⁰: A pulsatile–floating drug delivery system consists of three different parts, a core tablet, containing the active ingredient, an erodible outer shell, and a top cover buoyant layer. Floating pulsatile release tablet of RIT was prepared by compression with different composition ratio of erodible coating (press-coated systems). Rapid release core tablet (RRCT) of RIT was first prepared and optimized. RRCT was then press coated with polymers in two steps to formulate Pulsatile release tablet (PRT). Finally, PRT were compressed with effervescent floating layer to prepare floating pulsatile released tablets (FPRT).

Preparation of the Rapid Release Tablet (RRCT) ^61-62: Core tablets containing Ritonavir were prepared by using direct compression method. All the ingredients were passed through 60# mesh sieve separately and collectively. Different preliminary batches of core tablets were prepared by mixing all ingredients with different superdisintegrants. Powder mixture of RIT, Crospovidone, crosscarmellose sodium, Sodium Starch Glycolate and MCC were dry blended for 20min followed by addition of magnesium stearate. The mixtures were then further blended for 10 min and resultant powder blend was compressed using rotary tablet machine with a 6mm punch and die to obtain the core tablet containing 25mg of RIT. For the above batches disintegration study was conducted from which optimized batches were selected and only that batch was conducted for further study Table 1.

TABLE 1: COMPOSITION OF RAPID RELEASE CORE TABLET OF RIT

Preparation of Pulsatile Release Tablet (PRT) ⁶²: The optimized RRCT (F3) was taken as core for the preparation of PRT. For dry coating of F3 formulation 250mg coatings of HPMC K4M, Na CMC, HPMCE14 and Magnesium stearate were used with two steps: In the first 125mg coatings were filled into the die (11.8mm in diameter), followed by RRCT placed in the center of die, and slightly pressed to fix the coatings around and under the core, and then the rest of the coatings were filled and compressed Table 2.

TABLE 2: COMPOSITION OF PULSATILE RELEASE TABLETS

Preparation of Floating Pulsatile Release Tablets (FPRT) ⁶¹: On the basis of drug release profile of PRTs best formula composition (F3P9) was selected for the preparation of FPRT Table 3. Floating tablets were prepared by placing 50% of pulsatile release layer in 11.8 mm die and optimized RRCT was placed on it. Further remaining quantity of pulsatile release layer was added in cavity so as to cover the RRCT and finally pre-compressed it with lower compression pressure (hardness, 3-4 kg/cm²) by using single punch tablet machine. The weighed amount (100 mg) of floating layer powder composition was kept on pre-compressed tablet (PRT) in die, and then finally compressed it to give certain hardness (6-7Kg/cm²). The total weight of each FPRT tablet was adjusted to 500mg.

TABLE 3: COMPOSITIONS OF THE BUOYANT LAYER

Evaluation of Floating Pulsatile Release Tablet:

Hardness ⁶³: Hardness (Kg/cm²) of RRCT and FPRTs were determined by Monsanto hardness tester. Tablet hardness testing is the test to determine the breaking point and structural integrity of a tablet "under conditions of storage, transportation, and handling before usage".

Friability (F) ⁶³: RRCT and FPRT formulations (20) were weighed and placed in the Roche Friabillator that revolves at 25 rpm for 4 minutes dropping them from a distance of six inches with each revolution. After the operation the tablets were de-dusted and reweighed. A loss of less than 1 % in weight is generally considered acceptable. The % friability was then calculated by the following formula:

F = Initial Weight - Final weight / Initial weight × 100

Weight Variation Test ⁶³: FPRT formulations ²⁰ were individually weighed, calculated the average weight, and compared the individual tablet weights to the average. The tablets met the IP tests that were not more than 2 tablets were outside the percentage limit and no tablets differed by more than 2 times the percentage limit. The maximum percentage difference allowed is 5% for the average weight of tablets more than 250mg Table 4.

TABLE 4: SPECIFICATIONS OF % WEIGHT VARIATION ALLOWED IN TABLETS

Disintegration Time ⁶³: USP disintegration test apparatus was used to determine the disintegration time of RRCT formulation. To test the disintegration time of tablets, one tablet was placed in each tube, and the basket rack was positioned in a 1-liter beaker containing 0.1N HCl at 37°C ± 1°C such that the tablet remains 2.5 cm below the surface of the liquid. The time taken for the complete disintegration of the tablets was noted.

Drug Content ⁶⁴: Total 10 tablets were weighed and powder equivalent to 25 mg of RIT was weighed and dissolved in 0.1N HCl then filtered through Whatman filter paper. Solution was analysed for RIT content by UV Spectrophotometer at 246 nm using 0.1N HCl as blank.

Floating Lag Time ^63-64: The floating lag time is determined in order to assess the time taken by the dosage to float on the top of the dissolution medium, after placing the dosage form in the medium. Floating characteristics of the prepared formulations were determined using USP paddle apparatus at a speed of 50 rpm in 900ml of 0.1N HCl solution. The time required to float is noted.

Floating Time ^63-64: Floating time of the prepared formulations were determined using USP paddle apparatus at a speed of 50 rpm in 900ml of 0.1N HCl solution at 37±0.2°C for 24 hours. The time during which the dosage form remains buoyant (floating duration) was measured.

In-vitro Dissolution Studies of PRT & FPRT Tablets ⁶⁴: Dissolution studies on PRT & FPRT tablet of RIT were performed under gastric conditions. The test was performed using the USP dissolution apparatus type II at 50 rpm. A tablet containing 25mg of RIT was placed in a dissolution vessel containing 900mL of 0.1N HCl maintained at 37±0.5°C. At predefined time intervals, samples from the dissolution medium were withdrawn, filtered and concentration of RIT was determined spectrophotometrically at λ_max 246nm.

Stability Studies ⁶⁴: Stability studies were performed to determine the changes on the final formulation at different storage conditions. In the present study the selected formulation (F3P9N2) exposure up to 3 months stability studies at accelerated condition. Initial drug content was considered as 100 percent and drug content at each time interval was determined.

RESULT AND DISCUSSION:

Preformulation Studies:

Organoleptic Properties: Identification studies showed that the drug supplied by Arysta Life science India Limited, Indore, matched with the official standard as prescribed Table 5.

TABLE 5: PHYSICAL IDENTIFICATION TESTS OF RITONAVIR

Determination of Wavelength Maxima (λ_max): UV spectrum of drug was obtained by scanning drug solutions (10µg/ml) showed maximum absorption at 246 nm. Reported λmax of RIT is 246nm Fig. 3. So it can be concluded that the given drug was Ritonavir.

FIG. 3: UV SCAN OF RITONAVIR DRUG SAMPLE

FTIR Spectroscopy of Drug: FTIR spectra of RIT was obtained and compared with reference IR spectra for identification and confirmation of various functional groups. Interpretation of FTIR spectra of RIT suggests that the observed peak list meets with that of the reference peak list Table 6 and Fig. 4. The observation confirms that the drug obtained is pure. At cm 3131, 3417.

TABLE 6: IMPORTANT BAND FREQUENCIES IN IR SPECTRUM OF RIT

FIG. 4: FTIR SPECTRUM OF RIT

Melting Point of Drug: A capillary melting point method was used to determine the melting point of the drug. It was observed that the melting point of Ritonavir was found to be similar to the reported value which proved that the received drug samples meet the reported properties Table 7. Any impurity, if present, will cause variation in the melting point of a given drug substance. From the above test it was found that the sample drug complies with the standard test of Ritonavir.

TABLE 7: MELTING POINT OF RITONAVIR

Solubility Studies: The solubility profile of RIT shows its hydrophillic nature as it was found to be freely soluble in water, 0.1N HCl, PBS pH 7.4 and ethanol. However, it is slightly soluble in acetone and insoluble in ether Table 8.

TABLE 8: SOLUBILITY OF RIT IN DIFFERENT SOLVENTS

Partition Coefficient: The partition coefficient of RIT was determined in n-octanol: water system. The partition coefficient of RIT was found to be 4.15 which shows its diffusion in oil phase. This value is close to that of the literature citation Table 9.

TABLE 9: PARTITION COEFFICIENT OF RIT IN N-OCTANOL: DISTILLED WATER

Calibration Curve of Drug: Calibration curve was prepared in 0.1N HCl at 246nm and linearly regressed. The correlation coefficient for standard curves was found to be very near to one which indicates good co-linear correlation between concentration 2-10 µg/ml Table 10 and Fig. 5. Hence, drugs are following Beer Lambert Law in the above range Table 11.

TABLE 10: CALIBRATION CURVE OF RIT AT 246NM

FIG. 5: CALIBRATION CURVE OF RIT AT 246 NM

TABLE 11: REGRESSION ANALYSIS OF RITONAVIR IN 0.1N HCL

Drug-Excipients Compatibility Study: This study was performed to determine any physical change in the drug when kept in contact with various formulation excipients. Drug excipient compatibility studies were performed for drug and physical mixtures. Drug excipients compatibility study showed no change in physical appearance as well as color of the contents which indicates that there is no interaction between drugs and excipients Table 12.

TABLE 12: DRUG EXCIPIENTS COMPATIBILITY STUDY FOR 4 WEEKS

TABLE 13: POST-COMPRESSION EVALUATION OF RAPID RELEASE CORE TABLET

TABLE 14: POST COMPRESSION CHARACTERIZATION OF PULSATILE RELEASE TABLETS

TABLE 15: DISSOLUTION STUDY OF PULSATILE RELEASE TABLETS

TABLE 16: POST COMPRESSION EVALUATION OF FLOATING PULSATILE RELEASE TABLET

FIG. 6: CUMULATIVE % RIT RELEASE FROM PULSATILE RELEASE TABLETS (P1-P9)

TABLE 17: IN-VITRO RELEASE PROFILE OF OPTIMIZED FLOATING PULSATILE RELEASE TABLETS (F3P9N2)

Value represent mean ± SD (n=3)

FIG. 7: CUMULATIVE % RIT RELEASE FROM FLOATING PULSATILE RELEASE TABLETS

Stability Studies: It was found that the percent drug content after a period of 3 months for RIT was 99.29±1.6% at 40±2°C & 75±5% Table 18.

Stability studies on final formulation demonstrated its better stability profile at 4.0 °C and 25°C however it was found a little unstable at higher temperature and humidity conditions.

TABLE 18: STABILITY STUDIES AT DIFFERENT CONDITIONS

Values are mean± SD (n=3).

CONCLUSION: The present work was based on the floating pulsatile drug delivery of Ritonavir. The core containing crosspovidone disintegrates the tablet within a short time due to easy and high-water penetration ability of as compared to Cross Carmellose Sodium and Sodium starch glycolate. The PRT containing buoyant material, such as HPMC E15LV, NaHCO₃, and citric acid achieved a satisfactory buoyant force in-vitro, whereas the floating onset time was less than 1 min. The pulsatile releasing mechanism of PRT is based on the exploitation of the peculiar interaction between hydrophilic polymeric coating and the aqueous gastrointestinal fluids.

The in-vitro release profiles of RIT from pulsatile release tablet prepared using HPMC K100M as retarding polymer are characterized by a predetermined lag time (4 hr), the duration of which depends on the kind and amount of the polymeric layer applied on the cores as well as type of superdisintegrant in core tablet. The developed system offers a simple and novel technique for pulse release of drugs. From the results it is concluded that the pulsatile release tablet we prepared could achieve a rapid release after a lag time of 4hr with relatively low variability.

ACKNOWLEDGEMENTS: Nil

CONFLICTS OF INTEREST: Nil

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    How to cite this article:

    Rathod B, Shaikh G, Singh A, Malviya S and Kharia A: Formulation and in-vitro evaluation of pulsatile release tablets of ritonavir. Int J Pharm Sci & Res 2025; 16(9): 2642-51. doi: 10.13040/IJPSR.0975-8232.16(9).2642-51.

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