INTRODUCTION:

The discovery of HIV as the causative agent of AIDS by Sinoussi et al. in 1983 [1]. HIV/AIDS is a major theat to population health in the world. Over the past 35 years AIDS is spreading like a pandemic disease and creating major global health problem in world. WHO estimate in 2015 showed that 36.7 million people globally [2] were living with HIV, AIDS killed 1.1 million people died from AIDS related illnesses and 35 million people have died from AIDS related illness since start from epidemic.

Current highly active antiretroviral therapy (HAART) allows controlling viral replication [3] of HIV-1. Combination therapy is considered to be the standard of care of HIV infected patients. These therapeutic regimens result however in a great number of daily doses of tablets/capsules. The current formulation containing 150 mg of lamivudine and 300 mg zidovudine has been developed as an oral therapy (tablet) for the treatment of HIV-1 infection in adults. The development of this fixed dose combination [4] aims to reduce the number of daily tablets, and therefore enhance the compliance therapy and thereby minimizing the risk of emergence of resistance. The present study is to develop controlled porosity osmotic pump (CPOP) tablets of zidovudine-lamivudine combination. The delivery system of drug comprises a core with the drug surrounded by semi permeable membrane which is accomplished with different channeling agents of water soluble additives [5] in the coating membrane. The core is coated with cellulose acetate containing in situ micro pore former sorbitol. When controlled porosity osmotic pump tablets placed in biological system of fluid low levels of water soluble additives are leached from polymer materials which form sponge like structure in the controlled porosity walls. The rate of drug delivery depends upon the factors [6] such as water permeability of the semi permeable membrane, osmotic pressure of core formulation, thickness and total area of coating. The main objective of the present study was to develop controlled porosity-based osmotically controlled release tablets of zidoudine-lamivudine combination.

MATERIALS AND METHODS:

Materials:

Zidovudine and lamivudine were obtained from Hetero Drugs Pvt. Ltd. India. Sodium chloride and mannitol was purchased from Qualigens Fine Chemicals, India. Cellulose acetate (CA) was obtained from Eastman Chemical Inc, Kingsport, TN. Sorbitol, HPMC E5M LV, magnesium stearate, talc and polyethylene glycol (PEG) 400, 600, 4000, 6000 were purchased from S. D. Fine Chemicals Ltd, Mumbai, India. Microcrystaline cellulose (MCC), starch all are purchased from Signet Pharma, Mumbai, India. All other solvents and reagents used were of analytical grade.

COMPATIBILITY STUDIES:

Fourier Transform Infrared Spectroscopy (FTIR):

In this method individual samples [7] as well as the mixture of drug and excipients were ground mixed thoroughly with potassium bromide (1:100) for 3-5 minutes in a mortar and compressed into disc by applying pressure of 10kg/cm to form a transparent pellet in hydraulic press. The pellet was kept in the sample holder and scanned from 4000 to 400 cm^-1in FTIR spectrophotometer (Bruker, Germany).

Differential Scanning Calorimetry (DSC):

Physical mixtures of drug and individual excipients in the ratio of 1:1 were taken and examined in DSC (Shimadzu DSC-50, Japan). Individual samples as well as physical mixture of drug and excipients were weighed to about 5mg in DSC pan. The sample pan was crimped for effective heat conduction and scanned [8] in the temperature range of 50-300⁰C.Heating rate of 20⁰C min^-1was used and the thermogram obtained was reviewed for evidence of any interactions.

METHODS:

Preparation of Osmotic Pump Tablets:

Wet granulation technique was used to develop CPOP core tablets. Accurately weighed quantities of ingredients mentioned in Table 1 were sifted though sieve No. 30. Lubricant (magnesium stearate) and glidant (talc) were sifted though sieve No. 80. The ingredients were manually blended homogenously in a mortar by way of geometric dilution except lubricant and glidant. The mixture was moistened with aqueous solution and granulated though sieve No.30 and dried in a hot air oven at 60ºC for sufficient time (3-4 h). The dried granules were passed though sieve No.30 and blended with talc and magnesium stearate. The homogenous blend was then compressed into round tablets with standard concave punches (diameter 10 mm) using 10 station rotary compression machine (Mini press, Karnavati, India).

Table 1: Composition of CPOP Tablets

Ingredients (mg)	CS1	CS2	CS3	CS4	CZ5
ZD	300	300	300	300	300
LD	150	150	150	150	150
MCC	150	120	90	60	180
Starch	50	50	50	50	50
HPMC E5LV	60	60	60	60	60
Sodium chloride	30	60	90	120	0
Magnesium stearate	5	5	5	5	5
Talc	5	5	5	5	5
Total weight(mg)	750	750	750	750	750

Coating of Core Tablets:

The coating solution was prepared taking required ingredients from table 2 and acetone was added quantity sufficient maintaining proper viscosity of solution. The coatings of tablets were performed by spray pan coating in a perforated pan (GAC-205, Gansons Ltd, Mumbai, India). Hot air is supplied to tablet bed by rotating lower speed 5-8 rpm initially. The coating of tablets was carried out with the rotation speed of 10-12 rpm. The spray rate and atomizing air pressure were 4-6 ml/min and 1.75 kg/cm²respectively. Inlet and outlet air temperature were 50ºC and 40ºC respectively. Coated tablets were dried at 50ºC for 12 h.

EVALUATION OF GRANULES:

The prepared granules were evaluated for pre-compression parameters [9] such as angle of repose, bulk density, tapped density and compressibility index (Carr’s index). Fixed funnel method was used to determine angle of repose. The bulk density and tapped density were determined by bulk density apparatus (Sisco, India).

The Carr’s index [10] was calculated by the following formula.

et - eb

% Carr’s index = ----------- X 100 (1)

Where e_t is the tapped density of granules and e_b is bulk density of granules.

Hausner’s ratio was calculated by the taking the ratio of tapped density to the ratio of bulk density.

Evaluation of Tablets [11]:

Thickness:

The thickness of individual tablets is measured by using vernier caliper (Absolute digimatic, Mitutoyo Corp. Japan). The limit of the thickness deviation of each tablet is ±5%.

Measurement of Coat Thickness:

Film was isolated from the tablets after dissolution and dried at 40⁰C for 1 h. Thickness was measured by using electronic digital calipers (Absolute digimatic, Mitutoyo Corp. Japan)

Hardness:

The hardness of tablets can be determined by using Monsanto hardness tester (Sisco, India).

Friability Test:

Friability test of tablets was performed in a Roche friabilator (Sisco, India). Twenty tablets of known weight (W₁) were de-dusted in plastic chamber of friabilator for a fixed time of 25 rpm for 4 minutes and weighed again of weight (W₂). The percentage of friability was calculated using the following equation.

% Friability = F= ( 1 - ------) x 100 (2)

Where, W₁ and W₂ are the weight of the tablets before and after the test respectively.

Weight Variation Test:

The weight variation test is performed by weighing 20 tablets individually calculating the average weight and comparing the individual tablet weights to the average. The percentage weight deviation was calculated and then compared with USP specifications.

Uniformity of Drug Content Test:

Powder is made after triturating 10 CPOP tablets from each batch with mortar and pestle. The powder weight equivalent to one tablet was dissolved in a 100ml volumetric flask filled with 0.1N HCl using magnetic stirrer for 24h.Solution was filtered though Whatman filter paper No.1 diluted suitably and analyzed spectro photometrically

Diameter of Tablet:

The diameter of individual tablets is measured by using vernier caliper (Absolute digimatic, Mitutoyo Corp. Japan).

In Vitro Dissolution Studies:

The in vitro dissolution studies were carried out using USP apparatus type II (Lab India 8000) at 75 rpm. For the first 2 h the dissolution medium was 0.1N HCl (pH1.2) and phosphate buffer pH 6.8 from 3-8 h (900 ml), maintained at 37±0.5⁰C. At each time point 5 ml of sample was withdrawn and it was replaced with 5 ml of fresh medium. The drug release at different time interval was measured by UV-visible spectrophotometer (UV-1800, Shimadzu, Japan)

In Vitro Drug Release Kinetic Studies [12, 13]:

In order to investigate the mode of release from tablets, the release data of formulation was analyzed zero order kinetics, first order kinetics, Higuchi model, Korsmeyer-Peppas and Hixson-Crowell equations.

Effect of Osmogen Concentration:

Keeping all the parameters for tablet constant different osmogen [14] concentrations were used to prepare tablets. The drug release was compared with the different osmogen concentration of formulated batches by using USP-II dissolution apparatus.

Effect of Pore Former Concentration:

SPM for various batches were prepared by taking different concentrations of pore former [15]. The effect of pore former on in vitro release profile is compared as well as number of formation of micropores were observed.

Effect of Membrane Thickness:

Tablets with varying coating thicknesses were developed to demonstrate the effect of coating thickness on drug release. The drug release rate was measured using 0.1N HCl and phosphate buffer pH 6.8 as a dissolution medium.

Effect of Flux Regulating Agents:

To assess the effect of flux regulating agents on drug release, formulations were developed with different flux regulating agents keeping all other parameters of tablet constant. The drug release was compared with the different flux regulating agents of formulated batches by using USP-II dissolution apparatus.

Effect of Osmotic Pressure:

The effect of osmotic pressure [16] was demonstrated by adding different amount of mannitol of an osmotic agent to produce 30 atm,60atm and 90atm respectively in dissolution media 0.1N HCl for 2 h and phosphate buffer pH 6.8 for remaining hour. The drug release rate was carried out in USP type II (Paddle) apparatus at 75 rpm maintained at 37±0.5⁰C and compared for various dosage forms.

Effect of pH:

The effect of pH for developed formulations were observed by performing the release studies of optimized formulation in different media 0.1 N HCl (pH 1.2), pH 6.8 phosphate buffer and pH 7.4 phosphate buffer in USP type II dissolution apparatus at 75 rpm. The temperature was maintained at 37±0.5°C. The release was studied at predetermined time intervals.

Effect of Agitation Intensity:

The effect of agitation intensity was observed by performing the release studies of optimized formulation in USP Type II (Paddle) dissolution apparatus containing 0.1NHCl for first 2 h and phosphate buffer pH 6.8 for remaining hours at different rotational speeds of 50,100 and 150 rpm with maintaining temperature at 37±0.5°C. The samples were withdrawn at predetermined intervals and analyzed by UV spectrophotometer.

Scanning Electron Microscopy (SEM):

Coating membranes [17] of formulation were collected before and after complete dissolution of core contents and examined for their porous morphology as well as mechanism of drug release by scanning electron microscope (Leica, Bensheim, Switzerland). Scans were taken at an excitation voltage in SEM fitted with ion sputtering device.

Accelerated Stability Studies:

The packed tablets [18] in air tight container were placed in stability chambers (Thermo lab Scientific equipment Pvt. Ltd., Mumbai, India) maintained at 40±2^oC/75±5% RH conditions for accelerated testing) for 3 months. Tablets were periodically removed and evaluated for physical characteristics, drug content, in‐vitro drug release etc.

RESULTS AND DISCUSSION:

FTIR Studies:

FTIR spectra (Figure 1) of zidovudine shows the characteristic absorption peaks for the carbonyl group at 1638.76 cm^-1, N=N⁺=N stretching (azido group) at 2114.50 cm^-1, C-O stretching at 1063.08 cm^-1 and amine group stretching at 3317.86 cm^-1. Figure 2 shows characteristic absorption peaks of lamivudine for the C-H stretching at 2843.83 cm^-1, N-H bending at 1640.32 cm^-1, C-N stretching at 1010.71 cm^-1,O-H in plane bending at 1054.55 cm^-1 and amine group stretching at 3326.6 cm^-1.

The major peaks of HPMCE5LV were found at 3880.71, 3810.87, 3713.83, 3669.20, 3601.84, 3566.74, 3557.95 ,3473.68, 3222.79, 3117.03, 3066.96, 2982.59, 2887.86, 2847.2, 2803.12, 2710.75, 2618.99, 2444.13, 2335.14, 2068.70, 1661.47, 1536.52, 1500.67, 1424.62, 1071.87, 781.05 and 584.97 cm^-1.

The major peaks of sodium chloride were found at 3398.38, 2133.90, 2062.19, 1787.75, 1187.17, 906.53, 709.01, 668.53 and 634.66 cm^-1. In the optimized formulation CS4 peak at 1450.51, and 1251.44 cm^-1were due to presence of the polymer HPMCE5LV.In the formulation the peaks present due to sodium chloride were 700.76 and 670.31 cm^-1. Peak at 1055.39cm^-1 were due to presence of the drug zidovudine in the optimized formulation and peaks at 1649.05 and 2901.21 cm^-1 were due to presence of the drug lamivudine. So, from the study it can be concluded that the major peaks of drug 2901.21, 1649.05, and 1055.39 cm^-1 remain intact and no interaction was found between the drug, polymer and osmogen.

Figure 1: FTIR spectroscopy study of pure zidovudine

Figure 2: FTIR spectroscopy study of pure lamivudine

Figure 3: FTIR spectroscopy study of CS4

DSC STUDY:

Figure 4 indicates that the endothermic peak of zidovudine is at 114.5⁰C. For lamivudine the endothermic peak was found at 162.2⁰C (Figure 5).The optimized formulation CS4 shows endothermic peak for zidovudine at 112.5⁰C and the endothermic peak for lamivudine at 171.3⁰C (Figure 6).There is no significant changes in the endotherm peak between drug and formulation.

Figure 4: DSC Study of Zidovudine

Figure 5: DSC Study of Lamivudine

Figure 6: DSC study of CS4

Pre-compression Parameters:

All the compressible excipients for various batches were evaluated for angle of repose, bulk density, tapped density, Carr’s index and Hausner’s ratio. All the values were within acceptable limits. It is given in Table 3.

Post Compression Parameters

Tablets were evaluated for different post compression parameters such as thickness, coat thickness, hardness, %friability, drug content and diameter. All evaluated values were in acceptable limits. It is mentioned in Table 4.

N.B. All values are expressed as mean±S.D, ^an = 3

Table 4: Post Compression Parameters of Cpop Tablets

Formulation code	Thickness (mm)^a± S.D	Coat thickness (µm)^a± S.D	Hardness (kg/cm²)^a ±S.D	%Friability (%)^b± S.D	%Weight variation (%)^b	%Drug content (%)^a± S.D(ZD)	%Drug content (%)^a± S.D (LM)	Diameter (mm)^a± S.D
CS1	4.04±0.12	250.9±3.4	6.7±0.12	0.16±0.11	1.04±0.13	99.44±0.44	98.42±0.44	10.08±0.09
CS2	4.05±0.11	200.3±3.5	6.8±0.11	0.21±0.12	1.08±0.21	98.33±0.86	98.51±0.86	10.08±0.03
CS3	4.09±0.12	150.4±2.8	6.9±0.14	0.14±0.09	1.01±0.25	99.16±0.67	99.28±0.67	10.19±0.04
CS4	4.01±0.13	100.2±2.6	7.0±0.16	0.10±0.08	0.98±0.16	99.72±0.68	99.62±0.68	10.1±0.03
CZ5	4.08±0.12	251.3±3.1	6.9±0.12	0.15±0.04	1.16±0.12	98.88±0.62	98.08±0.62	10.11±0.04

N.B.-All values are expressed as mean S.D, ^an = 10,^bn = 20

Table 5: Fitting of Ivdr Data for Zidovudine from Combination in Various Mathematical Models

Models(Z)	Zero order		First order		Higuchi		Korsmeyer-Peppas			Hixson-Crowell
Batches	R²	K₀	R₁²	K₁	R_H²	K_H	R_K²	Kkp	n	R²	Ks
CS1	0.961	10.00	0.988	0.225	0.985	30.85	0.988	23.98	0.605	0.994	0.261
CS2	0.948	10.33	0.989	0.255	0.988	32.15	0.981	26.66	0.576	0.994	0.285
CS3	0.937	10.69	0.978	0.306	0.988	33.46	0.971	30.47	0.532	0.990	0.321
CS4	0.883	10.86	0.986	0.403	0.993	35.12	0.990	37.93	0.466	0.991	0.377
CZ5	0.964	9.779	0.989	0.204	0.973	29.94	0.980	21.13	0.649	0.991	0.243

Table 6: Fitting of IVDR data for lamivudine from combination in various mathematical models

Models (L)	Zero order		First order		Higuchi		Korsmeyer-Peppas			Hixson-Crowell
Batches	R²	K₀	R₁²	K₁	R_H²	K_H	R_K²	Kkp	n	R²	Ks
CS1	0.903	10.49	0.988	0.310	0.993	33.52	0.987	34.27	0.488	0.985	0.322
CS2	0.871	10.36	0.990	0.336	0.990	33.69	0.988	38.99	0.434	0.980	0.335
CS3	0.866	10.55	0.987	0.382	0.989	34.38	0.985	40.73	0.423	0.985	0.363
CS4	0.838	10.46	0.975	0.442	0.983	34.57	0.989	44.87	0.385	0.985	0.389
CZ5	0.850	8.896	0.963	0.198	0.985	29.18	0.985	34.11	0.435	0.936	0.231

Effect of Osmogen Concentration:

The various batches of stavudine were developed with various concentration of osmogens. It was observed that osmogent enhances the drug release of drug and thus had a direct effect on drug release. The drug release profile was shown in figure 7 for zidovudine and figure 8 for lamivudine.

Effect of Pore Former Concentration:

The core formulations were coated with various concentration of sorbitol with compared to CA. It confirms that as the level of pore former increases the membrane becomes more porous after coming contact with aqueous environment resulting in faster drug release. The drug release profile was shown in figure 7 for zidovudine and figure 8 for lamivudine.

Effect of Membrane Thickness:

Release profiles of stavudine from various batches varying the coating thickness were evaluated. It was clearly evident that drug release was inversely proportional to coating thickness of the semi permeable membrane. The drug release profile was shown in figure 7 for zidovudine and figure 8 for lamivudine.

Effect of Flux Regulating Agents:

The concentrations of flux regulating agents (PEG400, PEG600, PEG4000, and PEG6000) were 33.3% w/w of CA in coating solution in CS1, CS2, CS3, and CS4 respectively, and CZ5 does not contain any flux regulating agent. The cumulative drug release was in order CS4CS3CS2CS1. It is observed that type of flux regulating agents have pronounced effect on drug release. Hence the type of flux regulating agents on drug release is written as PEG6000 PEG4000PEG600PEG400. The drug release profile was shown in figure 7 for zidovudine and figure 8 for lamivudine.

Effect of Osmotic Pressure on Optimized Formulation:

The results of release studies of optimized formulation in media of different osmotic pressure indicated that the drug release is highly dependent on the osmotic pressure of the release media. The release was inversely related to the osmotic pressure of release media. This finding confirms that the mechanism of drug release is by osmotic pressure. The drug release of zidovudine for CS4 was found to be 92.451.26% for 30atm, 88.961.29% for 60atm and 85.681.25% for 90atm respectively. It is shown in figure 9. Similarly, the drug release of lamivudine for CS4 was found to be 94.091.32% for 30atm, 89.721.36% for 60atm and 85.341.38% for 90atm respectively. It is shown in figure 10.

Figure 9: In vitro release profiles showing Zidovudine release from best CS4 in different osmotic pressures

Figure 10: In vitro release profiles showing Lamivudine release from best CS4 in different osmotic pressures

Effect of pH:

The optimized formulation CS4 was subjected to in vitro drug release studies of zidovudine and lamivudine differently in buffers with different pH like pH 1.2, pH 6.8 and pH7.4. It is depicted in figure 11 and figure 12 respectively. It is observed that there is no significant difference in the release profile for lamivudine and zidovudine from combination, demonstrating that the developed formulation shows pH independent release.

Figure 11: In vitro dissolution study of zidovudine from optimized formulation CS4 in various pH media

Figure 12: In vitro dissolution study of lamivudine from optimized formulation CS4 in various pH media.

Effect of agitation intensity:

The optimized formulation of CS4 batch was carried out in USP dissolution apparatus type-II at varying rotational speed (50,100 and 150rpm) for zidovudine and lamivudine from combination (Figure 13,14). It shows that the release of both the drugs from CPOP is independent of agitation intensity.

Figure 13: In vitro dissolution study of zidovudine from optimized formulation CS4 in various agitation speeds.

Figure 14: In vitro dissolution study of lamivudine from optimized formulation CS4 in various agitation speeds Scanning Electron Microscopy (SEM)

The coating membrane of the osmotic delivery system before and after dissolution was examined with the help of SEM. Before dissolution (Figure15a) no pores were found in the coating membrane. But after dissolution (Figure15b) comparatively more numbers of pores were found in the membrane might be due to leaching or removal of entrapped drug from the formulation. The porosity nature of the membrane was due to the presence of pore forming agent sorbitol in the formulation.

(A) SEM before dissolution

(b) SEM after dissolution

Figure 15: a) SEM of membrane structure of optimized formulation before dissolution, b) SEM of membrane structure of optimized formulation after dissolution.

Stability Studies;

From short term stability studies of optimized formulation CS4, it was confirmed that there was no changes in physical appearance, thickness, hardness, friability, weight variation, and drug content. It is shown in table 7.

Table 7: Comparative physicochemical characterization of CS4 at accelerated conditions:

Sl.no.	Parameters	Initial	After 30 days	After 60 days	After 90 days
1.	Physical appearance	Pale white, circular, concave smooth surface without any cracks	No change	No change	No change
2.	Thickness(mm)^a ± S.D	4.01±0.13	4.01±0.13	4.01±0.13	4.02±0.14
3	Hardness(kg/cm²)^a ± S.D	7.0±0.16	7.0±0.16	6.9±0.12	6.9±0.14
4.	Friability (%)^a ± S.D	0.10±0.08	0.10±0.08	0.11±0.06	0.12±0.05
5	Weight variation(mg)^b ± S.D	0.98±0.16	0.98±0.16	0.98±0.16	0.99±0.18
6.	Drug content (%)^a ± S.D(ZD)	99.72±0.68	99.72±0.68	99.54±0.16	99.02±0.26
7.	Drug content (%)^a ± S.D(LM)	99.62±0.68	99.62±0.68	99.55±0.62	99.51±0.66

N.B.-All values are expressed as mean S.D, ^an = 10,^bn = 20

CONCLUSION:

The controlled release of optimized formulation from CPOP was gained though careful optimizing of the selected formulation variables. It was evident that increase in concentration of osmogen the drug release from the system was found to be increased. The optimized formulation CS4 releases drug from core is independent of pH, agitation intensity. Hence it was observed that the release of present formulation can be significantly controlled from the controlled porosity osmotic delivery system.

ACKNOWLEDGEMENTS:

The authors would like to acknowledge the contributions of Pharmaceutics Department, Faculty of Pharmacy, University College of Technology Osmania University, Hyderabad, Telangana, India for providing necessary facilities to carry out the research work. This study was part of a Ph.D thesis under Osmania University, Hyderabad.

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Received on 06.08.2017 Modified on 19.08.2017

Res. J. Pharm. Dosage Form. & Tech. 2017; 9(3): 114-122.

DOI: 10.5958/0975-4377.2017.00020.9

Formulation code	Angle of repose (degree)^a± S.D	Bulk density (g/ml)^a± S.D	Tapped density (g/ml)^a± S.D	Carr’s Index (%)^a± S.D	Hausner’s Ratio^a ± S.D
CS1	27.36 ±0.12	0.493±0.09	0.537±0.11	8.19±0.08	1.08±0.11
CS2	26.06±0.08	0.497±0.08	0.546±0.09	8.97±0.09	1.09±0.08
CS3	24.98±0.06	0.496±0.12	0.553±0.06	10.30±0.06	1.11±0.07
CS4	24.11±.07	0.491±0.13	0.529±0.06	7.18±0.04	1.07±0.06
CZ5	27.36 ±0.12	0.493±0.09	0.537±0.11	8.19±0.08	1.08±0.11

Formulation code	CA (g)	PEG 400 (g)	PEG 600 (g)	PEG 4000(g)	PEG 6000 (g)	Sorbitol (g)	Acetone (mL)
CS1	6	2	0	0	0	0	300
CS2	6	0	2	0	0	0.6	300
CS3	6	0	0	2	0	1.2	300
CS4	6	0	0	0	2	1.8	300
CZ5	6	0	0	0	0	1.8	300