A Novel Bimodal Release Strategy for Atazanavir And Ritonavir: Mini-Tablet in Capsule Formulation with Ph-Dependent Coatings and Simultaneous Estimation Via UV Spectroscopy

The Human Immunodeficiency Virus persists as one of the major global health issues, with a large number of people being infected worldwide. Infection with HIV is characterized by progressive deterioration in immune function, particularly the loss of CD4+ T-cells, which reduces resistance to opportunistic infections [1]. This is supported by the fact that effective management of HIV requires a suppressed viral load; interruption of ART is associated with resurgence of viral load, reducing treatment efficacy and increasing drug resistance [2]. One of the important factors in HIV therapy is the diurnal variation in immune cell activity. It was shown that the activity of CD4+ T-cells is low during early morning hours and increases gradually throughout the day [3]. This temporal variation in immune function poses a challenge, as it demands consistent antiretroviral drug availability to support the immune system when its activities are low [4]. For the solution of such problems, drug delivery in the bimodal form of immediate and controlled release has been developed which gives an initial surge to cater for immune deficiency at the beginning of the day with continued release to maintain therapeutic levels throughout increased activity of CD4+ T cells. HAART, or highly active antiretroviral therapy, combines antiretroviral drugs that attack the virus at different stages in its lifecycle, and is extremely effective. These include Atazanavir and Ritonavir, which are considered to be complementary in their pharmacokinetic profiles. Atazanavir is a protease inhibitor that requires the boosting action of Ritonavir to reach optimal therapeutic concentration. However, long-term use of such drugs, like many other antiretrovirals, is associated with considerable adverse side effects, including hepatotoxicity, dyslipidemia, gastrointestinal disturbances, and cardiovascular risks [5]. In order to minimize these side effects and enhance patient compliance, we propose a strategy of reducing the overall doses of Atazanavir and Ritonavir without compromising their therapeutic efficacy [6, 7]. This is achieved by using a loading dose and maintenance dose, which are incorporated as mini-tablet-in-capsule bimodal DDS. The loading dose ensures an immediate therapeutic effect at times of immune vulnerability, while the maintenance dose gives steady-state levels to support CD4+ T-cell activity throughout the day. It is further envisioned that such chronobiologically timed drug release according to the body's immune rhythms will lead to better therapeutic outcome with reduced toxicity and improved long-term adherence to therapy. This work aims at the development and in-vitro evaluation of this new bimodal mini-tablet-in-capsule drug delivery system combining Atazanavir and Ritonavir for an effective viral load suppression and the mitigation of temporal dynamics of immune function besides reducing the side effects of HIV therapy.

MATERIALS AND METHODS:

MATERIALS:

Atazanavir (ATV), Ritonavir (RTV) was gifted from Sai Mirra Innopharm, Chennai, India. β Cyclodextrin was procured from Manus Aktteva Bio Pharma LLP and Poloxamer 188, Starch 1500 (pregelatinized starch) were gifted by Corel Pharma Chem. Hydroxypropyl Methylcellulose K4M, K15M and K100M CR Premium were gifted by Colorconasia Pvt. Ltd. Eudragit L 55-100, S 100 were procured from Evonik Rohm GmbH, Pharma polymers, Germany. Coloring agents Quinoline Yellow WS and Sunset Yellow Supra were procured from Color Trendz. Solvents like dichloromethane and isopropyl alcohol along with purified water was supplied by Lab Chemicals while sodium citrate was procured from Corel Pharma Chem.

Dose calculation:

The dose for the combination therapy of Atazanavir and Ritonavir was calculated in order to minimize the side effects, reduce production costs, and enhance the adherence of the patients. A proposed reduction in the currently marketed dosage of 300 mg/100 mg was developed by utilizing a loading dose meant for the rapid achievement of therapeutic plasma concentrations, followed by a maintenance dose that will maintain time-dependent drug levels. These reduced doses achieve similar therapeutic results as the usual doses through pharmacokinetic adjustments, thus improving the patient's compliance.mThe dosing schedule can be calculated based on two important formulae: one for the loading dose and one for the maintenance dose.

              Loading dose = Cp x Vd/F

Where,

Cp is the target plasma concentration,

Vd is the volume of distribution,

F is the bioavailability of the drug.

To determine the loading dose of Atazanavir, Cp (target plasma concentration) [8] = 150 ng/ml = 0.00015 g/L = 1.5×10−4g/L.

Vd (volume of distribution) [9] = 1.604 L/kg. For an average human weight of 75 kg, the total volume of distribution is 1.604 x 75=120.3L.

F (bioavailability) [10] = 60% to 68%.

By using the formula,

          L.D = Cp x Vd/F

= (1.5 x ?10?^ (-4) g/L x 120.3L)/0.6

=0.018045/0.6

=0.030075g

 = 30.08mg.

Hence, to account for potential variability in patient pharmacokinetics, the calculated loading dose of 30.08 mg has been approximated to 35 mg, while remaining within a safe and effective dosing range.

To determine the loading dose of Ritonavir,

Cp (target plasma concentration) = 0.06 mcg/ml = 0.00006 g/L = 6×10−5g/L.

Vd (volume of distribution) [11] = Ritonavir's volume of distribution is estimated at 0.6 L/kg. Assuming an average human body weight of 75 kg,

Vd = 0.6 L/kg x 75kg = 45L.

F (bioavailability) [12] = The bioavailability of Ritonavir is typically around 60% or 0.60.

By using the loading dose formula,

L.D = Cp x Vd/F

= (6 x ?10?^ (-5) g/L x 45L)/0.6

= (2.7 x ?10?^ (-3) g)/0.6

= 4.5 x ?10?^ (-3) g = 4.5mg.

The loading dose of Ritonavir is approximated to 5mg. This slight adjustment simplifies the dosing while maintaining therapeutic relevance, ensuring that the plasma concentration reaches the desired level efficiently.

Since initial loading dose concentration is calculated. Now, to maintain the therapeutic concentration, the maintenance dose (MD) is calculated using the formula,

           Maintenance dose = Cp x Cl x τ/F

Where,

Cp is the target plasma concentration,

Cl is the clearance rate of the drug,

τ (tau) represents the dosing interval,

F is the bioavailability of the drug.

To determine the maintenance dose of Atazanavir,

First will determine the given parameters,

Cl (Clearance) = Vd x Ke = 120.3L x 0.08662 hr−1

Cl = 10.42L/hr.

τ = 24 hrs (24 hours for once-daily dosing)

F = 68%.

By using the formula,

M.D = Cp x Cl x τ/F

=1.5 x 10-4g/l) x (10.42 L/hr)x 24hr0.68

= 3.75072 x 10-2g0.68

= 0.0551g = 55mg.

Here, hence the calculated maintenance dose of Atazanavir is approximately 55 mg. This dose ensures that the target plasma concentration is maintained over the 24-hour dosing interval, taking into account the drug’s clearance and bioavailability.

To determine the maintenance dose of Ritonavir,

Given parameters,

Cl (Clearance) = 9L/hr.

τ = 24 hrs (24 hours for once-daily dosing)

F = 60% to 68%, F = 0.60.

By using the formula,

M.D = Cp x Cl x τ/F

= 6 x10-5glx9Lhrx 24 hr0.6

= 0.01296g0.6

= 0.0216g = 21.6mg.

The calculated maintenance dose of Ritonavir is approximated to 25mg. With the loading dose and maintenance dose of Atazanavir at 35mg and 55mg and Ritonavir at 5mg and 25mg respectively is fixed, the next phase involves formulating IR and CR mini-tablet.

Preparation of immediate release mini-tablet (IRMT):

The ingredients were weighed as per the formulation requirement. For L1 and L3, mixture of Atazanavir and Ritonavir with β-cyclodextrin (10% and 20%) were taken under solvent evaporation method in order to improve their solubility. β-cyclodextrin was dissolved in the methanol and drugs were added to this solution, and the solvent was removed under rotary vacuum. For L2 and L4, Atazanavir and Ritonavir were combined with Poloxamer 188 (10% and 20%) in a similar manner, later, the solvent was evaporated. The complex mixture were mixed with Starch 1500 (as binder), Crospovidone XL 10 (as disintegrant), Aerosil (as glidant), and Magnesium Stearate (as lubricant). The mixture was thoroughly homogenized and compressed into 100 mg mini-tablets utilizing a 6.5 mm punch. The weight and thickness of the tablets were controlled during compression to ensure uniformity.

Preparation of controlled release mini-tablet (CRMT):

Atazanavir and Ritonavir were complexed with Poloxamer 188 by the solvent evaporation method. Poloxamer 188 was dissolved in methanol, drugs were added to form a homogeneous solution, and then dried under vacuum. For matrix formation, HPMC grades K4M, K15M, and K100M CR Premium in different concentrations (15% and 20%) in formulations M1 to M6 were used. HPMC was mixed with the drug-Poloxamer complex, and further blended with Microcrystalline Cellulose PH 102, Crospovidone XL 10 and Magnesium Stearate. The final blend was compressed into 125 mg mini-tablets using a 6.5 mm punch and was optimized with increased tablet thickness at a reduced compression pressure. The tablet weight and thickness were monitored for their specific parameters. 

In-vitro dissolution study of immediate and controlled release mini-tablets (IRMT and CRMT):

The dissolution test was conducted using USP Type-II paddle apparatus at 50 RPM and maintained at 37°C ± 0.5°C. For IRMT batches L1 to L4, dissolution media was composed of acidic medium (0.1M HCl) with 500 ml at intervals ranging from 5 to 60 min. The CRMT batches M1 to M6 were introduced in 900 ml of sodium acetate buffer (pH 5.5) and samples were withdrawn at intervals of 1 to 12 hours. All samples taken out (5 ml for IRMT and 10 ml for CRMT) were filtered and replaced with the same volume of fresh dissolution media throughout the entire dissolution [13]. Drug release was analyzed spectrophotometrically at 249 nm and 270 nm using the simultaneous estimation method via UV spectrophotometry.

Preparation of pH 5.5 and pH 7 hydro-alcoholic coating solutions:

The coating procedure was done by using the pan coating method with a spray gun for the selected controlled-release mini-tablet (CRMT) formulation which showed the most favorable in-vitro dissolution profile. Sodium citrate was dissolved in purified water while Eudragit L 100-55 (for pH 5.5) and Eudragit S 100 (for pH 7) was dissolved in a mixture of dichloromethane (DCM) and isopropyl alcohol (IPA) at concentrations of 5% or 10%. Quinoline Yellow WS (pH 5.5) and Sunset Yellow Supra (pH 7) were added for coloring. Then, the sodium citrate solution was slowly added into the polymer mixtures under constant stirring, and the pH was controlled at 5.5 or 7 with the help of a pH meter. The prepared coating solutions were applied on CRMT in a pan coater set at an inlet temperature of 30°C, bed temperature of 28°C, and a rotation speed of 8–15 rpm. The final coated tablets were visually inspected for uniformity and evaluated for quality.

Preparation of encapsulated mini-tablets (EMT):

The coated mini-tablets were encapsulated into ‘0’ size capsules. Each capsule has one immediate release mini-tablet (IRMT) and two controlled release mini-tablets (CRMT) coated with pH 5.5 and pH 7 layer. The CRMTs are at the base of the capsule, followed by the IRMT, ensuring uniform arrangement in the capsule. The capsules were securely sealed and completed the encapsulation process.

Drug content evaluation [14]:

Preparation of standard and sample solutions:

Standard solutions were prepared by dissolving 30 mg of Atazanavir and 20 mg of Ritonavir in 100 ml of a methanol: water mixture (1:1) and sonicating the solution. From each stock solution, 10 ml was diluted to 50 ml, and 5 ml of this intermediate solution was further diluted to 50 ml, yielding final concentrations of 30 μg/ml (Atazanavir) and 10 μg/ml (Ritonavir).

For sample solutions, ten encapsulated mini-tablets (EMTs) were crushed, and the average weight was dissolved in 100 ml of methanol: water (1:1) with sonication for 15 minutes. The resulting solution was filtered using a 0.45 μm syringe filter, and 5 ml of the filtrate was diluted to 50 ml in a volumetric flask.

Analysis via simultaneous equation method:

Absorbance at 270 nm and 249 nm was measured, and concentrations of Atazanavir (Ca) and Ritonavir (Cr) were calculated using:

          Ca = A2ay1- A1ay2 / ax2ay1- ax1ay2

          Cr = A1ax2- A2ax1 / ax2ay1-ax1ay2

Where,

A1 and A2 are absorbances of formulation at 270 and 249nm respectively,

Ca and Cr are the concentration of Atazanavir and Ritonavir respectively,

ax1 and ax2 are absorptivities of Atazanavir at 270 and 249nm,

ay1 and ay2 are absorptivities of Ritonavir at 270 and 249nm.

Once the concentrations of Atazanavir (Ca) and Ritonavir (Cr) are determined using the simultaneous equation method, the next step is to calculate the actual amount of each drug in the sample. The drug amount can be calculated with the following formula:

Amount of drug= Concentration Ca or Cr x Dilution factor x Average weight of tablet x Standard concentration (μg/ml)Test weight (mg)

Once the amount of drug is calculated, the percentage of drug content (purity % assay) can then be determined as follows:

% Purity= Amount of drug (mg)Label claim x 100

In-vitro dissolution study of encapsulated mini-tablet (EMT) [15]:

In-vitro dissolution tests for the EMT, IRMT and coated CRMTs were conducted across five separate dissolution runs, with dissolution media adjusted at calculated gastric emptying time intervals. A USP Type-2 (Paddle) apparatus with a paddle rotation speed of 50 RPM and a controlled temperature of 37°C ± 0.5°C was used. For the IRMT sample, 500 ml of 0.1M HCl (8.5 ml HCl to 1000 ml of water) was used as the primary dissolution medium. Samples were withdrawn at specified intervals of 5, 10, 15, 20, 30, 45, 60, and 120 minutes with dissolution medium replaced after each sampling. At the 3rd hour, the pH of the medium was adjusted from 1.2 to 5.5 by gently adding 250 ml of a 6.34 g ammonium phosphate solution without disturbing the dissolved medium content. Additional samples were taken at intervals of 3, 4, and 5 hours, with the medium replaced after each sampling. At the 6th hour, the pH of the medium was further adjusted to 7 by gently adding 250 ml of a 9.5 g ammonium phosphate buffer solution to the existing 750 ml, and subsequent samples were withdrawn at intervals of 6, 7, 8, 9, and every hour up to the 15th hour. Each sample was filtered and analyzed using a UV spectrophotometer at wavelengths of 249 nm and 270 nm. The same dissolution procedure was followed for the 5% pH 5.5 coated CRMT, 10% pH 5.5 coated CRMT, 5% pH 7 coated CRMT, and 10% pH 7 coated CRMT samples.

In-vitro release kinetics studies:

The dissolution profiles of the EMT capsule were analyzed in different kinetic models: Zero-order, First-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell. The best-fit model for each formulation was identified based on the highest regression values of the correlation coefficients, ensuring an accurate drug release mechanism [16, 17].

Stability study:

Stability testing of IRMT and CRMT was performed following ICH guidelines to assess quality variations under environmental factors such as temperature, humidity, and light. Mini-tablets were kept in HDPE containers under accelerated conditions at 40°C ± 2°C, 75% ± 5% RH [18]. They are assessed at predetermined intervals on the physical appearance, hardness, friability, and drug content.

RESULTS:

The main objective of this research was to develop a mini-tablet-filled capsule formulation aimed at reducing the drug dosage while ensuring prolonged drug presence in system. To achieve this, calculated doses of Atazanavir and Ritonavir were incorporated into mini-tablets using different concentrations of individual polymers.  The mini-tablets were filled into a size '0' capsule, selected to be the largest size readily accepted by the humans. Each capsule contained one immediate release mini-tablet, IRMT and two controlled release mini-tablets CRMT, coated with pH dependent polymers targeting release at pH 5.5 and 7 respectively as shown in figure 1. The total dose of drug per capsule was 145 mg of Atazanavir and 55 mg of Ritonavir.

Figure 1: Schematic diagram of the EMT formulation process. During preparation, two pH-dependent coated CRMTs are placed into the capsule, followed by one IRMT, and the capsule is properly closed

Pre-compression studies:

Flow characteristics of the lubricated blend, as shown in table 1, were of good flow properties. All batches, except a few, exhibited free-flowing characteristics with a high compressibility index; hence, the flowability was excellent. Consequently, all lubricated blends were considered suitable for compression.

Table 1: Pre-compression parameters of IRMT and CRMT

The crushing strength, friability, thickness, and weight variation of the IRMT and CRMT were evaluated, with the summary of results shown in table 2. The changes in formulation characteristics had no negative impact on these attributes. The selected batches, L4 (IRMT) and M6 (CRMT), compressed at a pressure of 5–7 kN, shown favorable post-compression results. All data were within pharmacopoeia specifications as shown in table 2.

Table 2: Post-compression parameters of IRMT and CRMT

FTIR spectral analysis confirmed that the drug and its formulations showed similar characteristic peaks with minimum variations, indicating no considerable chemical interactions between the drugs and excipients. The compatibility of formulation components is thus assured as shown in figure 2.

Figure 2: FTIR spectral interpretation of EMT formulation

In-vitro dissolution study of immediate and controlled release mini-tablets (IRMT and CRMT):

The study was carried out to identify the optimum formulation of an encapsulated mini-tablet single-unit dosage form. From the in-vitro dissolution analysis, formulations L2, L3, and L4 were noted to release almost 50% of the drug in 5 minutes. Among these, the most favorable release profile in a medium of pH 1.2 was observed with L4, which achieved a cumulative drug release of 100.03% for Atazanavir and 98.74% for Ritonavir. This favored release was due to the increased concentration of Poloxamer 188 (20%) and, more importantly, the inclusion of Starch 1500, which acted both as a super-disintegrant and a binder. Although Crospovidone XL 10 was uniformly used as a super-disintegrant in all formulations, the nature and concentration of solubilizing agents could significantly influence the drug release. Based on these observations, formulation L4 was selected for the mini-tablet encapsulation. Consolidated data is presented in the following table and is shown in figure 3.

Table 3: In-vitro dissolution test of IRMT

Figure 3: In-vitro drug release profile of Atazanavir and Ritonavir from L1 to L4 IRMT

The cumulative drug release of CRMT formulations was between 98.77% and 101.75% for Atazanavir and 96.01% to 101.55% for Ritonavir as presented in table 4 and figure 4. Formulation M1 and M4 containing HPMC K4M showed nearly complete but a bit faster drug release, which may be attributed to the faster hydration of this polymer with low viscosity. In contrast, M2 and M5, prepared with HPMC K15M, showed suboptimal release, probably due to the insufficient gel-forming capacity of this polymer grade. On the other hand, formulations M3 and M6, prepared with HPMC K100M CR premium grade, reached extended drug release up to 12 hours, and the cumulative release exceeded 98%-99%, most likely because of the high viscosity of the grade and its dense gel-forming ability. Notably, formulation M6 with a higher percentage (20%) of HPMC K100M CR premium was found to have a well-controlled and steady release profile, making it the most suitable choice for further coating procedures.

Table 4: In-vitro dissolution test of CRMT

Figure 4: In-vitro drug release profile of Atazanavir and Ritonavir from M1 to M6 CRMT

Drug content evaluation:

The drug content was analyzed in selected formulations of the immediate release mini-tablet (IRMT) and controlled release mini-tablets (CRMT) combined in an encapsulated mini-tablet (EMT) as a single unit dosage form. The concentrations of active ingredients in each mini-tablet were spectrophotometrically determined by using the simultaneous equation method where measurements were taken at their respective absorbance wavelengths of 249 nm and 270 nm to evaluate the specific absorbance values for each drug. The results, as presented in the table 5.

Table 5: Drug content of Atazanavir and Ritonavir

In-vitro dissolution study of encapsulated mini-tablet (EMT):

In in-vitro dissolution study, the immediate release mini-tablet, IRMT, (L4) and controlled release mini-tablet, CRMT, batches with 5% and 10% coatings were tested at pH 5.5 and pH 7, to simulate gastric emptying time and gastrointestinal pH conditions. The results are shown in table 6. All mini-tablets were first tested in 500 ml of pH 1.2 medium for 2 hours in order to assess initial release characteristics. During this period, the CRMT batches with pH 5.5 and pH 7 coatings were closely monitored especially for coating integrity and resistance to drug release in the acidic medium. The 5% coating concentration for both pH 5.5 and pH 7 CRMTs showed drug release greater than the target limit of no more than 10% (NMT 10%) during this period and were thus discontinued from further testing. After 2 hours and 30 minutes, 250 ml of ammonium phosphate solution was added to adjust the medium to pH 5.5. During this period, samples were also drawn from the IRMT, which had fully dissolved within the initial 2 hours, supporting the planned assessment of cumulative release if the IR mini-tablet were encapsulated as part of a single EMT capsule.  At 5 hours and 30 minutes, the medium was further adjusted to pH 7 by the addition of the same solution. Burst releases were observed at the respective pH transitions, validating the pH-triggered activation mechanism of the coatings. The cumulative release profiles and results are presented in table 6 and illustrated in figure 5.

Table 6: In-vitro dissolution of encapsulated mini-tablet (EMT)

Figure 5: In-vitro drug release profile of Atazanavir and Ritonavir in EMT

In-vitro release kinetics studies:

The kinetics of dissolution of pH 5.5 and pH 7 coated CRMTs were fitted into respective multiple models and the results are shown in table 7 with the R² values. Both showed the best fit for zero-order kinetics, indicating constant and controlled release (R²: 0.981 for pH 5.5, 0.940 for pH 7). The Higuchi and Korsmeyer-Peppas models indicated diffusion-dominant mechanisms with "super case II transport," matrix swelling and erosion dominate. The Hixon-Crowell kinetic model for IRMT indicated the surface area and diameter changes of the tablets were significant in affecting the rate of drug release from the matrix over time, as demonstrated by the R² values (Atazanavir: 0.964, Ritonavir: 0.876) [19].

Table 7: Kinetic models with R2 value

A 30-day stability study was conducted on the mini-tablets stored at both room temperature and 40 ± 0.2°C with 75 ± 5% relative humidity (RH). The results confirmed (in table 8, 9) that the optimized mini-tablets for the EMT formulation showed no significant changes in physical appearance, hardness, friability, or drug content when compared to the initial tablets. Drug content was stable, Atazanavir at 100.26% and Ritonavir at 99.02%, indicating minimal deviations. Such findings suggest that the formulation was stable under accelerated conditions. Therefore, the optimized formulation met the stability requirements according to ICH guidelines.

Table 8: Stability profiles of EMT formulation

Table 9: Drug Content analysis under the Stability profile of the EMT formulation

DISCUSSION:

This study successfully developed a bimodal release tablet-in-capsule formulation for Atazanavir and Ritonavir. Compatibility studies confirmed the physical and chemical stability of the drugs and excipients that guaranteed formulation integrity. Solubility studies validated methanol as the solvent and calibration curves confirmed the adherence to Beer-Lambert's law, leading to quantitative determination. Pre-compression and post-compression evaluations confirmed that the blends were appropriate for direct compression, exhibiting good flow properties and uniform tablet characteristics. The disintegration times for different formulations of IRMT highlighted the influence of Starch 1500 and Poloxamer 188 on release kinetics. Dissolution studies revealed that IRMT formulations enabled rapid drug release within 2 hours, whereas CRMT formulations sustained release over a period of 12 hours, based on objective of the study. Batch M6 was selected for coating due to its controlled release behavior. The coating enabled targeted release in specified gastrointestinal pH levels by using pH-dependent polymers, as demonstrated during simulated gastric emptying studies. The kinetic modeling confirmed that the CRMT formulations follow zero-order kinetics. The Higuchi and Korsmeyer-Peppas models showed a diffusion-controlled complex mechanism of release with matrix swelling and erosion contributing to drug release. Stability studies at various conditions confirmed the robustness of the formulations without significant changes in the key parameters. These findings demonstrate that the developed formulation has the potential to enhance therapeutic efficacy, reduce dosing frequency, and improve patient compliance. Limitations include the need for in-vivo studies to validate in-vitro findings and assess bioavailability. Further studies in the area of biodistribution, pharmacokinetics, and bioequivalence are recommended to establish the clinical utility of this formulation for the treatment of HIV.

CONCLUSION:

The study was focused on the development of a tablet-in-capsule formulation of Atazanavir and Ritonavir designed for bimodal drug release in HIV patients to ensure prolonged drug activity and suppression of viral load resurgence. The main purpose was to reduce the dose, which was attained by calculating the loading and maintenance doses very precisely. The loading dose was formulated for immediate release in acidic media, while the maintenance dose was formulated for controlled release at intestinal pH. The results demonstrate that this mini-tablet formulation using bimodal release mechanisms in three different pH systems provides a versatile drug delivery system. This system reduces the high conventional dose and ensures sustained drug release for better therapeutic effectiveness, lesser side effects, and greater patient safety and adherence. The results of in-vitro dissolution tests showed sustained drug release up to 15 hours, which may be an indication of improved bioavailability. This was further supported by the accurate results obtained in the simultaneous analytical estimation method. This formulation is the cost-effective alternative to the conventional dosage form for chronic treatment of HIV.

ABBREVIATIONS: