INTRODUCTION:

Controlled drug delivery delivers the drug at a predetermined rate, locally or systemically, for a specified period of time. The basic rationale of controlled drug delivery [1] system is to optimize the biopharmaceutical, pharmacokinetics and pharmacodynamic properties of drug in such a way that its utility Is maximized through reduction in the side effects and cure or control of condition in the shortest possible time by the most suitable route. Advanced drug delivery technologies can improve products clinical and commercial value, differentiate a product, and serve as an effective resource to outsmart competition. Drug delivery technologies make medicine more convenient and acceptable to a patient by simplifying the dosing regimen and improving administration.

Osmotic pumps belong to the class of rate-controlled systems [2] providing continuous delivery and offer a set of distinct advantages. Osmotic technologies can be used to improve the pharmacokinetic properties of drugs by better adjustment of the release rate with respect to conventional tablets or pills. Osmotic devices [3] are most promising strategy based systems for controlled drug delivery.

The present study is to develop controlled porosity osmotic pump (CPOP) tablets of stavudine. 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 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 [4].

Stavudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1) which is chemically 2’,3’-didehydro-3’-deoxythymidine.The active metabolite stavudine 5’ triphosphate is an inhibitor of the HIV reverse transcriptase and acts as a chain terminator during DNA synthesis [5,6]. Stavudine is absorbed rapidly orally producing peak plasma concentration within 1hour with 86% bioavailability and elimination half life of 1 to 1.5 hour following single or multiple doses [7]. The conventional dose of stavudine is 40 mg twice daily. Converting twice daily regimen of stavudine into once daily formulation of controlled release dose enhances the effectiveness of antiretroviral therapy. The main objective of the present study was to develop controlled porosity-based osmotically controlled release tablets of stavudine using different concentrations of osmogen.

MATERIALS AND METHODS:

Materials:

Stavudine (SD) was obtained from Hetero Drugs Pvt. Ltd. India. Fructose and mannitol were purchased from Qualigens Fine Chemicals, India. Cellulose acetate (CA) was obtained from Eastman Chemical Inc, Kingsport, TN. Sorbitol and polyethylene glycol (PEG) 400, 600, 4000, 6000 were purchased from S.D. Fine Chemicals Ltd, Mumbai, India. Microcrystaline cellulose (MCC) and PVPK30 are purchased from Signet Pharma, Mumbai, India. All other solvents and reagents used were of analytical grade.

Compatibility studies:

Fourier Transform Infrared Spectroscopy (FTIR):

The FTIR study [8, 9] of pure drug, formulation and individual excipient were carried out by KBr pellet method. In this method sample mixture and potassium bromide in the ratio of 1:100 was finely ground using mortar and pestle. A small amount of mixture was placed under hydraulic press compressed at10kg/cm to form a transparent pellet which was kept in the sample holder and scanned from 4000cm to 400cm ^-1in FTIR spectrophotometer (Bruker, Germany).

DSC:

Physical mixtures of drug and individual excipients in the ratio of 1:1 were taken and examined in DSC. Individual samples as well as physical mixture of drug and excipients were weighed to about 5mg in DSC pan (Shimadzu DSC-50, Japan). The sample in pan was scanned [10] 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. Then the themograms were compared with pure samples versus optimized formulation.

METHODS:

Preparation of CPOP tablets:

Wet granulation technique was used to develop CPOP core tablets. Accurately weighed quantities of ingredients mentioned in Table 1 were sifted through sieve No. 30. Lubricant (magnesium stearate) and glidant (talc) were sifted through 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 through sieve No.30 and dried in a hot air oven at 60ºC for sufficient time (3-4 h). The dried granules were passed through sieve No.30 and blended with talc and magnesium stearate [11]. The homogenous blend was then compressed into round tablets with standard concave punches using 10 station rotary compression machine (Mini press, Karnavati, India).

Table 1: Composition of CPOP tablets of stavudine

Ingredients (mg)	SF1	SF2	SF3	SF4	SF5
SD	80	80	80	80	80
MCC	175	155	135	115	95
PVPK30	20	20	20	20	20
HPMC E5LV	100	100	100	100	100
Fructose	20	40	60	80	100
Magnesium stearate	2	2	2	2	2
Talc	3	3	3	3	3
Total weight(mg)	400	400	400	400	400

Coating of core tablets:

Table-2 summarizes the components of coating solution. The coatings of tablets were performed by spray pan coating in a perforated pan (GAC-205, Gansons Ltd, Mumbai, India). Initially tablets were pre heated by passing hot air through the tablet bed and by rotating at a lower speed of 5-8 rpm. Coating process was started with 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 [12] were evaluated for pre compression parameters such as angle of repose, bulk density, tapped density and compressibility index (Carr’s index).Fixed funnel method was used to estimate angle of repose. The bulk density and tapped density were evaluated by bulk density apparatus (Sisco, India).

The Carr’s index [13] is calculated by the following formula.

etap-ebulk

% Carr’s index= --------------------- X100 (1)

etap

Where e_tap is the tapped density of granules and e_bulk is bulk density of granules.

According to the specifications the Carr’s index values between 5-15 indicates excellent flow whereas between 12-16 indicates good flow. Values between 18-21 indicates fair passable where as between 23-35 indicates poor and values between 33-38 indicates very poor and greater than 40 indicates extremely poor.

Hausner’s ratio was calculated by the taking the ratio of tapped density to the ratio of bulk density. According to specifications values less than 1.25 indicate good flow (=20% of Carr’s index) whereas greater than 1.25 indicates poor flow (=33% of Carr’s index).

Evaluation of CPOP tablets [14]:

Thickness

The thickness of individual tablets is calculated 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 1hr.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 of tablets was performed in a Roche friabilator (Sisco, India). Twenty tablets [15] were initially weighed (W_initial) together and then placed in the chamber. The friabilator was operated for 25 revolutions for 4mins and the tablets are then dusted and reweighed (W_final).The percentage of friability was calculated using the following equation.

1-Wfinal)

% Friability=------------------------------- X 100 (2)

Winitial

Where, W_initial and W_final are the weight of the tablets before and after the test respectively

Weight variation test:

The weight variation test is conducted 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 24hr.Solution was filtered through 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 hr the dissolution medium was 0.1N HCl (pH1.2) and phosphate buffer pH 6.8 from 3-18 hr (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)

Mathematical modeling of in vitro release kinetics:

For the determination of the drug release kinetics [16,17] from the porous osmotic pump tablet, the in vitro release data were analyzed by zero order, first order, Higuchi, Korsmeyer and Peppas and Hixson-Crowell equations.

Zero order kinetics can be expressed by the equation

Q_t=Q₀K₀t (3)

Where

Q_t is the amount of drug dissolved in time t, Q₀ is the initial amount of drug in the solution and K₀ is the zero order release constant.

First order kinetics can be expressed by the equation:

Log C=log C₀K₁t/2.303 (4)

Where C₀ is the initial concentration of drug, C is the amount of drug remaining to be released in time t, K₁ is the first order release constant.

Higuchi’s classical diffusion equation can be expressed as

Q=K_H√ t (5)

Where Q is the amount of drug release in time t, K_H is the Higuchi dissolution constant.

Korsmeyer-Peppas model (KP Model) for the drug release for this model is expressed as

Log (M_t/M_∞) Log K ₊n Log t (6)

Where M_t is the amount of drug release at time t, M_∞ is the amount of drug release after infinite time, K is the release rate constant incorporating structural and geometric characteristics of the tablet and n is the release exponent indicative of mechanism of drug release.

Hixson and Crowell model is expressed by the equation

W₀^1/3W_t^1/3=κ t (7)

Where W₀ is the initial amount of drug in the pharmaceutical dosage form, W_t is remaining amount of drug in the pharmaceutical dosage form at time t and κ is proportionality constant incorporating the surface volume relation.

Effect of osmogen concentration:

To check the effect of osmogen [18] concentration on drug release formulations were prepared with different concentration of osmotic agents and all other parameters of tablet kept constant. The drug release was compared with the different osmogen concentration of formulated batches by using USP-II dissolution apparatus.

Effect of pore former concentration [19]:

Different concentrations of pore former are used in semi permeable membrane formation. In order to compare the effect of different concentrations of pore formers in vitro release profiles as well as number of formation of micro pores are compared.

Effect of coating thickness [20]:

The tablet is kept in 900ml of dissolution fluid 0.1N HCl for first 2hrs and next followed by 3 to 18hrs in phosphate buffer pH 6.8 of USP type II dissolution apparatus at 75 rpm and maintaining the temperature 37±0.5⁰C of dissolution media. The sample 5ml was withdrawn through 0.45-μm cellulose acetate filter at different time intervals replaced with fresh medium and analyzed in UV-Visible spectrophotometer.

Effect of osmotic pressure:

The effect on osmotic pressure [21] on the optimized formulation was studied in media of different osmotic pressure and the release profile with varying osmotic pressure is compared. To increase the osmotic pressure of the release media mannitol was added to produce 30 atm, 60 atm and 90 atm respectively.

Effect of pH:

In order to study the effect of pH of release medium in the drug release of optimized formulation, the in vitro release study was carried in dissolution media having different pH media [22]. Dissolution can be carried in 900 ml of 0.1 N HCl( pH 1.2), pH 6.8 and phosphate buffer pH 7.4 in USP type II dissolution apparatus at 75 rpm with maintaining temperature at 37±0.5°C. The sample (5ml) was withdrawn at predetermined intervals and analyzed after filtration through 0.45-μm cellulose acetate filter.

Effect of agitation intensity:

The drug release of optimized formulation was subjected to dissolution at various rotation speeds [23, 24] to demonostrate the effect of agitation intensity. Dissolution was carried out in USP-II (Paddle) at 50, 100 and 150 rpm. The samples were withdrawn at predetermined intervals through 0.45-μm cellulose acetate filter and analyzed by UV-Visible spectrophotometer.

Scanning Electron Microscopy (SEM):

In order to observe the mechanism of drug release and surface morphology [25,26] from the developed formulations surface coated tablets before and after dissolution studies was examined using scanning electron microscope (Leica, Bensheim, Switzerland).

Accelerated stability studies:

The formulation was subjected to accelerated stability studies as per ICH (The International Conference of Harmonization) guidelines [27, 28]. The packed tablets 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 for 3 months. Tablets were periodically removed and evaluated for physical characteristics, drug content, in‐vitro drug release etc.

RESULTS ANS DISCUSSION:

FTIR studies:

The study of the FTIR spectra of stavudine demonstrated that the characteristic absorption peaks for the N-H bending at 1640.34 cm^-1,C-H stretching at 2981.35 cm^-1,C-O stretching at 1054.71 cm^-1 and amine group stretching at 3336.44 cm^-1(Figure 1). In the optimized formulation SF5 peak at 3673.38, 1455.30, 1251.34, and778.47 cm^-1were due to presence of the polymer HPMCE5LV.In the formulation the peaks present due to fructose were 2308.77, 1507.63, 1394.07 and 669.83 cm^-1Peaks at 3327.77, 2986.89, 1623.95 and 1066.23 cm^-1 were due to presence of the drug stavudine in the optimized formulation. The major peaks of drug 3327.77, 2986.89, 1623.95 and 1066.23 cm^-1 remain intact and no interaction was found between the drug, polymer and osmogen.

Figure 1: FTIR spectroscopy study of pure stavudine

Figure 2: FTIR spectroscopy study of SF5

DSC study:

Figure 3 indicates that the endothermic peak of stavudine is at 160.1⁰C.The endothermic peak of SF5 formulation (Figure 4) is observed at159.3⁰C.There was no significant changes in the endotherm peak between drug and formulation. Hence the formulation was stable and compatible.

Figure 3: DSC thermogram of stavudine

Figure 4: DSC thermogram of SF5

Pre compression parameters:

Angle of repose is appropriate phenomenon that can be used for estimation of flow characteristics. The angle of repose of all formulations ranged from 24.81⁰±0.12 to 28.32⁰±0.01.The angle of repose is less than 30⁰ usually indicate good flow properties that were noticed for all the formulations of stavudine. The bulk densities of stavudine of all formulations were found in the range of 0.479±0.08 to 0.491±0.07 g/ml. The tapped densities were found to be in between 0.517±0.06 to 0.549±0.08 g/ml. These results pointed out that the granules had good packing capacity. The values of Carr’s index for all formulations of stavudine ranged from 6.53±0.04 to 10.56±0.06.The values of Carr’s index falls between 5-15% showing excellent flow property of granules.In all the formulations the Hausner’s ratio values were ranged from 1.06±0.04 to 1.11±0.06 for granules of Stavudine. The values of Hausner’s ratio of granules below 1.25 usually indicate an excellent flow property that was observed for all the formulations. It is given in Table 3.

Table 3: Pre compression parameters of granules

Batches	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
SF1	28.32±0.08	0.479±0.08	0.517±0.06	7.35±0.04	1.07±0.08
SF2	27.24±0.12	0.484±0.12	0.526±0.11	7.98±0.06	1.08±0.06
SF3	26.02±0.06	0.487±0.08	0.538±0.06	9.48±0.07	1.10±0.04
SF4	25.03±0.11	0.491±0.07	0.549±0.08	10.56±0.06	1.11±0.06
SF5	24.81±0.12	0.486±0.06	0.520±0.06	6.53±0.04	1.06±0.04

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

Table 4: Post compression parameters of CPOP tablets of stavudine

Batches	Thickness of tablet (mm)^a±S.D	Coat thickness (m)^a±S.D	Hardness (kg/cm²)^a±S.D	Friability (%)^b±S.D	Average wt. of 1tablet(mg)^b±S.D	%Drug content (%)^a ±S.D	Diameter (mm)^a ±S.D
SF1	2.99±0.03	501.2±3.5	7.1±0.08	0.21±0.14	400.9±1.12	101.23±1.03	7.9±0.08
SF2	3.14±0.06	402.4±3.2	6.7±0.02	0.28±0.16	401.2±1.13	98.76±1.02	8.2±0.03
SF3	3.15±0.05	301.6±3.7	7.3±0.06	0.19±0.12	400.4±1.06	99.38±1.11	8.1±0.04
SF4	3.11±0.04	200.8±3.1	6.9±0.08	0.23±0.08	402.1±1.04	100.3±1.16	8±0.07
SF5	3.0±0.03	100.5±3.9	7.8±0.06	0.11±0.06	400.2±1.02	99.07±1.12	8±0.02

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

Table 5: Fitting of IVDR data in various mathematical models

Models	Zero order		First order		Higuchi		Korsmeyer-Peppas			Hixson-Crowell
Batches	R²	K₀	R₁²	K₁	R_H²	K_H	R_K²	Kkp	n	R²	Ks
SF1	0.952	3.692	0.959	0.0806	0.984	18.26	0.970	19.678	0.461	0.974	0.094
SF2	0.935	3.627	0.953	0.0806	0.984	18.11	0.962	22.130	0.425	0.967	0.095
SF3	0.928	3.627	0.944	0.0852	0.979	18.13	0.953	24.322	0.395	0.961	0.098
SF4	0.914	3.677	0.922	0.0967	0.966	18.39	0.917	28.054	0.355	0.949	0.105
SF5	0.930	4.291	0.806	0.1727	0.982	21.45	0.949	28.906	0.394	0.933	0.155

Effect of osmogen concentration:

The various batches of stavudine were developed with various concentration of osmogens. The concentrations of fructose varied 20, 40, 60, 80 and 100mg/tab in SF1, SF2, SF3, SF4 and SF5 respectively. 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 5.

Effect of pore former concentration:

The core formulations were coated with various concentration of sorbitol with compared to CA. For the batches SF1 to SF5 the coating composition of pore forming agent of sorbitol were 6.6%, 13.3%, 20% ,26.6% and 33.3% w/w of CA of sorbitol respectively. The drug release order for for SF1 to SF5 batch is SF5SF4SF3SF2SF1 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. Release profile of various batches was shown in figure 5.

Effect of membrane thickness

Release profiles of stavudine from various batches varying the coating thickness were evaluated. The order of coating thickness for SF1 to SF5 is SF1SF2SF3SF4SF5 It was clearly evident that drug release was inversely proportional to coating thickness of the semi permeable membrane. It is shown in figure 5.

Effect of osmotic pressure:

The drug release for SF5 was found to be 92.31% for 30 atm, 86.07% for 60 atm and 82.98% for 90 atm respectively. Hence it was concluded that drug release was inversely proportional to the osmotic pressure of release media. It is shown in figure 6.

Figure 6: In vitro dissolution study showing stavudine release from best SF5 in different osmotic pressures (n=3)

Effect of pH:

The optimized formulation SM5 was evaluated for in vitro drug release studies in buffers with different pH like 0.1NHCl (pH 1.2), phosphate buffer pH 6.8 and phosphate buffer pH7.4. It was concluded that there was no significant difference in the release profile, demonstrating that the developed formulation showed pH independent release. It is shown in figure 7.

Figure 7: In vitro dissolution study of optimized formulation SF5 in various pH media (n=3)

Effect of agitation intensity:

The optimized formulation was carried out in USP dissolution apparatus type-II at varying rotational speed(50,100 and 150rpm).It showed that the release of stavudine from core was independent of agitation intensity and the release from the developed formulation was independent of the hydrodynamic conditions of the absorption site. It is shown in figure 8.

Figure 8: In vitro dissolution study of optimized formulation SF5 in various agitation speeds (n=3)

SEM analysis:

The coating membrane of the osmotic delivery system before and after dissolution was examined or porosity with the help of SEM. Before dissolution less pores were found in the coating membrane. But after dissolution 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 (Figure9 a, b).

A b

Figure 9: SEM photographs of membrane structures of (a) Optimized formulation before dissolution, and (b) After dissolution

Stability studies:

From short term stability studies of optimized formulation SF5, it was confirmed that there was no significance changes in physical appearance, weight variation, %friability, drug content and diameter. It is reported in table 6.

CONCLUSION:

From the developed CPOP formulations it was evident that increase in concentration of osmogen the drug release from the system was found to be increased. The optimized formulation was independent of pH and agitation intensity. Finally, it was concluded that the release of optimized formulation is significantly controlled from the controlled porosity osmotic delivery system and thus it is a promising approach for the treatment of AIDS.

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 18.01.2018 Modified on 19.03.2018

Res. J. Pharma. Dosage Forms and Tech.2018; 10(3):179-187.

DOI: 10.5958/0975-4377.2018.00028.9

Batches	CA (g)	PEG 400 (g)	PEG 600 (g)	PEG 1500(g)	PEG 4000 (g)	PEG 6000 (g)	Sorbitol (g)	Acetone (ml)
SF1	6	2	0	0	0	0	0.4	300
SF2	6	0	2	0	0	0	0.8	300
SF3	6	0	0	2	0	0	1.2	300
SF4	6	2	0	0	2	0	1.6	300
SF5	6	0	0	0	0	2	2	300

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	3.0±0.03	3.0±0 03	3.0±0.03	3.0±0.03
3.	Hardness(kg/cm²)^a ± S.D	7.8±0.06	7.8±0.06	7.8±0.06	7.7±0.05
4.	Friability(%)^b ± S.D	0.11±0.06	0.11±0.06	0.11±0.06	0.15±0.04
5.	Weight variation(mg)^b ± S.D	400.2±1.02	400.2±1.02	400.1±1.04	399.9±1.02
6.	Drug content(%)^a ± S.D	99.07±1.12	99.07±1.12	99.07±1.12	98.06±1.14
7.	Diameter(mm)^a ± S.D	8±0.02	8±0.02	8±0.02	7.9±0.02