Formulation and Optimization of Porous Osmotic Pump based Controlled release System of Ritonavir for the Treatment of HIV Infection

 

Chinmaya Keshari Sahoo1, Surepalli Ram Mohan Rao2, Muvvala Sudhakar3,

D. Venkata Ramana4, K.Satyanarayana5

1Ph.D Scholar, Department of Pharmaceutics, Faculty of Pharmacy, University College of Technology, Osmania University, Hyderabad, Telangana-500007.

2Professor, Mekelle Institute of Technology, Mekelle University, Mekelle, Ethiopia.

3Professor and Principal, Department of pharmaceutics, Malla Reddy College of Pharmacy(Affiliated to Osmania University), Maisammaguda, secunderabad, Telangana-500014.

4Professor, Department of pharmaceutical Technology, Netaji Institute of Pharmaceutical Sciences, Toopranpet, Yadadri Bhongir, Telangana-508252

5Professor and Principal, Department of pharmacognosy, Princeton College of Pharmacy, Korremula, Ghatkesar, R.R.District, Telangana-500088

*Corresponding Author E-mail: sahoo.chinmaya83@gmail.com

 

ABSTRACT

The current research involves the development of controlled porosity osmotic pump (CPOP) tablets of ritonavir for the treatment of HIV infection. Core tablets were prepared by wet granulation method using hydroxyl propyl methyl cellulose (HPMCE5LV) polymer, mannitol as osmogen, MCC as diluents and other additives. The CPOP tablets were coated with cellulose acetate as wall forming material, poly ethylene glycol as flux regulating agent, and sorbitol acts as pore forming material in SPM. The prepared tablets were evaluated for FTIR, DSC, pre compression parameters, post compression parameters, in vitro drug release study and scanning electron microscopy study. The optimized formulation RM5 showed 94.83% at the end of 14 hrs with zero order drug release. The difference factor (f1) and similarity factor (f2) for RM5 were observed 14.61 and 75.12 respectively. Optimized formulation did not show any significant change on the pH and agitation intensity, but it depends on osmotic pressure of dissolution media indicated that mechanism of drug release was due to osmotic pressure. SEM micrographs confirmed that no pores were found before dissolution and after dissolution had shown the porous nature of the membrane. Short term stability study at 40±2ºC/75±5% RH for three months on the RM5 formulation indicated that there was no significant change weight variation, % friability, drug content and in vitro drug release.

 

KEYWORDS: Ritonavir, wet granulation, CPOP, difference factor, in vitro drug release, stability study.

 


 

INTRODUCTION:

AIDS is the final stage of infection where HIV damages the immune system, the body lacks fighting against opportunistic infections. AIDS is spread by unprotected sexual intercourse, contaminated blood transfusions, hypodermic needles and from mother to child during pregnancy, delivery or breastfeeding and certain body fluids from a person infected with HIV such as semen, pre seminal fluid, vaginal fluid and breast milk [1].

 

People living with AIDS experiences CD4+ count of less than 200cells/µL in blood. Without treatment people with AIDS can survive about 3 years. There is no cure for HIV infection, but medicines can prevent advancing of disease by inhibiting growth of HIV in body and helps people with HIV live longer. Ritonavir, a protease inhibitor inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein [2], resulting in noninfectious, immature viral particles. Ritonavir is able to reduce HIV viral load and increase CD4 cell counts in the majority of people. It is prescribed 300 mg orally twice a day initially and the
maintenance dose is increase by 100 mg twice daily every 2 to 3 days to the full dose of 600 mg orally twice a day for conventional tablets.Ritonavir belongs to BCS class II and of half life 3-5 hrs [3]. It has dose related side effects such as nausea, vomiting, stomach pain by taking multiple doses. Hence the frequency of doses can be reduced to one time daily in the form of extended release [4] dose 600mg once daily.

 

Oral route is the most convenient route for the administration of various drugs. Conventional drug delivery system lacks control drug release and effective concentration of drug at the target site and mostly affected by physiological conditions of body. To avoid the drawbacks of conventional drug delivery system modified release drug products can be designed to control release rate of drug and time of drug release. Out of various modified drug release product extended release dosage forms allow at least a twofold reduction in frequency in dosage frequency as compared to conventional dosage form. Controlled release dosage forms is a part of extended release dosage form  cover a wide range of prolonged action which provide continuous release of their active ingredients at predetermined rate and predetermined time. Out of various controlled drug delivery systems osmotic controlled drug delivery system (OCDDS) is one of the most promising drug delivery technologies that use osmotic pressure for controlled delivery of drugs [5].

 

OCDDS deliver the drug in a large extent and the delivery nature is independent of physiological factors of gastrointestinal tract ,independent of pH , hydrodynamic condition of the body and agitation intensity

 

CPOP tablet preparation is a novel drug delivery system with eternally drug delivery rate as characteristic and controlled with the osmotic pressure difference between inside and outside of SPM as drug delivery power. In CPOP delivery orifice is formed by the incorporation of water leachable component in the coating. Once the tablet comes in contact with aqueous environment, the water soluble additives dissolves and osmotic pumping results. Hence water diffuses into the core through the micro porous membrane setting up an osmotic gradient and followed by controlling the release [6] of drug. The present study is to develop controlled porosity osmotic pump tablets. The rate of drug delivery depends upon the factors such as water permeability of the semi permeable membrane, osmotic pressure of core formulation, thickness and total area of coating.

 

MATERIALS AND METHODS:

Materials:

Ritonavir was obtained from Hetero Drugs Pvt. Ltd. India. Mannitol (Qualigens Fine Chemicals,India) and Cellulose acetate (CA) was obtained from Eastman Chemical Inc, Kingsport, TN. Sorbitol, HPMC E5LV,polyethylene glycol (PEG) 400, 600, 1500, 4000, 6000, Magnesium stearate and talc were purchased from S.D. Fine Chemicals Ltd, Mumbai, India.Microcrystaline cellulose(MCC), PVPK30 were purchased from Signet Pharma,Mumbai,India.All other solvents and reagents used were of analytical grade.

 

Calculation of dose in sustained release tablets containing single drug:

For a sustained release matrix tablet formulation containing single drug, the dose required for loading dose and sustained release layer was estimated by using following four equations. The equations that were given by Robison and Erikson [7] are based on the available pharmacokinetic data following one compartment model with simultaneous release of loading dose and maintenance dose with a zero order release kinetic. The equations are presented as follows:

 

                                                                                (1)

                                                                                (2)

                                                                (3)

                                                                                (4)

 

DL=Loading dose,

DM = maintenance dose,

DI=Initial dose;

T = time for sustained action;

Tmax = Time to reach peak plasma concentration;

 

Elimination half-life (t1/2) of ritonavir is 3 to 5 hour (average 4); time to reach peak plasma concentration (Tmax) = 4.2 hour; initial dose (DI) = 300 mg.

 

Elimination rate constant                  (5)

                                                 = 0.693/4h

                                                 = 0.1732 h-1

Zero-order release constant K0 = DI × KE                        (6)

                                                = 300 mg × 0.1732 h-1

                                                = 51.975 mg/h

Loading dose DL = DI − (K0 × Tmax)                                  (7)

                                                = 300 – (51.975 × 4.2 h)

                                                = 300 – 218.295

                                                = 81.705 mg

So, maintenance dose = Total dose – loading dose      (8)

                                                 = 600 mg – 81.705 mg

                                                = 518.295 mg.

 

Hence, the CPOP tablet should contain a total dose of 600 mg for 14 hours in dosage form and it should release 300 − 218.295 = 81.705 (13.61%) mg in the 1st hour like conventional dosage form and the remaining dose (600 − 81.705) in remaining 13 hour, i.e. 518.295 (86.382%) mg or 39.868 (6.644%) mg per hour up to 14 hours.

 

Table 1: Theoretical profile of ritonavir

Time(h)

Amount of drug release(mg)

%Drug release

1

81.705

13.617

2

121.573

20.262

3

161.441

26.907

4

201.309

33.552

5

241.177

40.196

6

281.045

46.841

7

320.913

53.486

8

360.781

60.13

9

400.649

66.775

10

440.517

73.42

11

480.385

80.064

12

520.253

86.709

13

560.121

93.354

14

600

100

 

Compatibility studies:

Fourier Transform Infrared Spectroscopy (FTIR):

Infrared spectrum of individual samples, drug and drug with mixture of optimized formulation was observed using Bruker FTIR spectrophotometer. The scanning range [8] of pellet was 4000 to 400 cm-1 and the IR spectra of samples were observed using KBr pellet method. The sample with KBr in the ratio 1:100 were triturated thoroughly for 3-5mins in mortar compressed into disc by applying 10kg/cm to form a transparent pellet in hydraulic press.

 

Differential Scanning Calorimetry (DSC):

Physical mixtures of drug and individual excipients in the ratio of 1:1 were taken and investigated by DSC (Shimadzu DSC-50, Japan).Individual samples as well as physical mixture [9] of drug and excipients were weighed to about 5mg in DSC pan. The sample pan was crimped for effective heat conduction and scanned [9] in the temperature range of 50-3000C.The rate of heating was 200C min-1 and the thermo gram observed was reviewed for evidence of any interactions

 

Methods:

Preparation of osmotic pump tablets:

The tablets were prepared by wet granulation technique. Accurately weighed quantities of ingredients mentioned in Table 2 were passed through sieve No. 30. Lubricant (magnesium stearate), glidant (talc) were passed through sieve No. 80. All the ingredients except lubricant, and glidant were manually blended homogenously in a mortar by way of geometric dilution. 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. The homogenous blend was then compressed into round tablets with standard concave punches using 10 station rotary compression machine (Minipress, Karnavati, India).

 

Table 2: Composition of CPOP ritonavir tablets

Ingredients (mg)

 RM1

RM2

RM3

RM4

RM5

RV

600

600

600

600

600

MCC

170

150

130

110

90

PVP K30

50

50

50

50

50

HPMC E5LV

100

100

100

100

100

Mannitol

20

40

60

80

100

Magnesium stearate

5

5

5

5

5

Talc

5

5

5

5

5

Total weight(mg)

950

950

950

950

950

 

Coating of core tablets:

The composition of coating solution is given in table 3.The CA was passed through sieve No.80 then mixed with PEG of various grades 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). 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/cm2 respectively. Inlet and outlet air temperature were 50ºC and 40ºC respectively. Coated tablets were dried at 50ºC for 12 hrs.


 

 

Table 3: Coating composition for CPOP tablets

Formulation code

CA (g)

PEG 400 (g)

PEG 600 (g)

PEG 1500(g)

PEG 4000 (g)

PEG 6000 (g)

Sorbitol (g)

Acetone (ml)

RM1

6

2

0

0

0

0

0.4

300

RM2

6

0

2

0

0

0

0.8

300

RM3

6

0

0

2

0

0

1.2

300

RM4

6

0

0

0

2

0

1.6

300

RM5

6

2

0

0

0

2

2

300

 


Evaluation of tablets:

Pre compression parameters of osmotic pump tablets:

The prepared granules were evaluated for pre compression parameters [10] 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 can be calculated by the following formula.

                           et - eb

% Carr’s index= --------   X 100                                         (9)

                                   et

Where, et is the tapped density of granules and eb is bulk density of granules.

 

The Hausner’s ratio can be calculated by the taking the ratio of tapped density to the ratio of bulk density.

 

Evaluation of controlled porosity osmotic pump 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:

After dissolution the film was isolated from the tablets 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:

Friability [12] of tablets was performed in a Roche friabilator (SISCO, India).After weighing (W initial) 20 tablets from each batch were de-dusted in plastic chamber of friabilator for a fixed time of 25 rpm for 4 minutes and weighed again of weight (Wfinal).The percentage loss of weight in terms of friability was calculated using the following equation

                       

                    W intial - W final

% Friability =  ----------------  X  100               (10)

                            W intial

 

Weight variation test:

Twenty tablets were randomly [13] selected from each batch and weighed individually. The average weight and standard deviations of 20 tablets was calculated and compared with USP specifications.

 

Uniformity of drug content test:

Ten tablets from [14] each batch of CPOP formulations were taken and triturated to form powder. 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 spectrophotometrically

 

Diameter of tablet:

The diameter [15] of individual tablets is measured by using vernier caliper (Absolute digimatic, Mitutoyo Corp. Japan). 

 

In vitro dissolution studies:

In vitro dissolution test [16] was carried out by using USP type II (paddle) apparatus. The tablet is kept in 900ml of dissolution fluid of 0.1N HCl (pH1.2) and stirrer rotating with 75 rpm and maintaining the temperature 37±0.50C of dissolution media for first 2 hours then dissolution fluid is changed to phosphate buffer pH 6.8 maintaining same condition for next 14 h. In specified time intervals an aliquot of 5ml samples of the solution were withdrawn through 0.45-μm cellulose acetate filter from the dissolution apparatus and with replacement of fresh fluid to dissolution medium. Absorbance of these solutions was measured at specific λmax using a UV/Visible Spectrophotometer (Shimadzu UV-1800, Japan). The drug release was plotted against time to determine the release profile of various batches.

 

Statistical data analysis by model independent approach [17]:

The difference factor (f1) calculates the percent error between the drug release profiles of two formulations usually one is test and other is standard over predetermined time points. It is expressed as

 

f1 = 100                                              (11)

 

Where n is the sampling number,Rj and Tj are the percent dissolved of the reference and test products at each time point j. Dissolution profile of test formulations are usually said to be satisfactory if f1 values lie below 15.

 

The similarity factor (f2) is a logarithmic transformation of the sum squared error of differences between the test Tj and reference products Rj over all time points.

 

f2 = 50log [1+]-0.5100         (12)

 

Where wj is an optional weight factor. The similarity factor fits the result between 0 and 100. Generally if f2˃50, the release profiles are deliberated to be similar.For the calculation of similarity and difference factors of all the mentioned formulations in present studies three time points were taken i.e. Ist, 2nd and 3rd hours and dissolution profiles of theoretical release(reference) and test formulations at same time point were used.

 

In vitro drug release kinetic studies:

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 and Peppas equations and Hixson Crowell model [18]. The kinetic model used were zero order as cumulative amount of drug release versus time, first order as log cumulative percentage of drug remaining versus time,Higuchi model as cumulative percentage of drug release versus square root of time, Korsmeyer-Peppas model (KP Model) as log cumulative percentage drug release versus log time and Hixson and Crowell model as cube root of drug percentage remaining in matrix versus time[19].

 

Effect of osmogen concentration:

To assess the effect of osmogen concentration [20, 21] on drug release formulations were developed with different concentrations of osmotic agent keeping all other parameters of tablet 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:

Different concentrations of pore [22, 23] former were used in semi permeable membrane formation. To know drug release characteristics and surface morphology in SPM in vitro drug release data as well as number of formation of micropores were compared.

 

Effect of membrane thickness [24, 25]:

Tablets with varying coating thicknesses were prepared to determine the effect of coating thickness on drug release. The drug release rate was measured using 0.1NHCl for 2hrs and phosphate buffer pH 6.8 for rest 14 hrs as a dissolution medium and compared with coating thickness variation of various dosage forms.

 

Effect of osmotic pressure [26, 27]:

To confirm the mechanism of drug release the optimized formulation was observed in release media of different osmotic pressures.Mannitol was added to increase osmotic pressure of release media to produce 30 atm, 60 atm and 90 atm respectively at 370C±1°C.The drug release rate was tested and compared.

 

Effect of pH [28, 29]:

In order to evaluate 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 0.1N HCl (pH 1.2), phosphate buffer pH 6.8 and phosphate buffer pH 7.4 in USP type II dissolution apparatus at 75rpm of maintained temperature at 37±0.5°C..

 

Effect of agitation intensity [30, 31]:

To demonstrate the effect of agitation intensity on drug release profiles three different agitation intensities such as 50,100 and 150 rpm were selected for optimized batch.Dissolution was carried out in USP-II (Paddle) in suitable dissolution media of maintained temperature at 37±0.5°C. The samples were withdrawn at predetermined intervals and analyzed by UV-Visible spectrophotometer and the drug release for various batches was compared.

 

Scanning Electron Microscopy (SEM) [32, 33]:

In order to observe the mechanism of drug release and surface morphology from the developed optimized formulation surface coated tablets before and after dissolution studies was examined using scanning electron microscope. The specimens were fixed on a brass stub using double sided tape and then gold coated in vacuum by a sputter coater. Scans were taken at an excitation voltage in SEM fitted with ion sputtering device.

 

Accelerated stability studies [34, 35]:

The optimized formulation was subjected to accelerated stability studies as per ICH (The International Conference of Harmonization) guidelines by packing in air tight bottles that can withstand stressed conditions. 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, weight variation,%friability,drug content, invitro drug release etc.

 

RESULTS ANS DISCUSSION:

FTIR studies:

In the optimized formulation RM5 668.60 cm-1.Peaks at 2040.45, 1394.30 and 1014.43 cm-1 were due to presence of the drug ritonavir (Figure 1A), peaks present due to mannitol were 2900.96, 1647.50, 1409.35 cm-1(Figure 1B) and peak at 2332.24, 1522.25, 927.62, and 741.05 cm-1 were due to presence of the polymer HPMCE5LV(Figure 2). So from the study it was observed that the major peaks of drug 2040.45, 1394.30 and 1014.43 cm-1 remain intact and no interaction was found between the drug, polymer and osmogen. Hence drug-excipient mixture reveals that here is no incompatibility was observed between ritonavir.


 

A) ritonavir

 

 

Figure 1: FTIR spectroscopy study of A) ritonavir, and B) RM5 DSC thermo grams

 


From the figure 2A it was found that the endothermic peak of ritonavir was at 122.50C.The endothermic peak of RM5 formulation (Figure 2B) was observed at121.30C.No significant change in the endotherm was observed between drug and formulation. Hence it was clear that there was no specific interaction between the drug and excipients.


 


 

A) Ritonavir

 

  B)RM5


Figure 2: DSC thermogram of A) ritonavir, and B)RM5

 

 


 

 

Pre compression parameters:

Powder blends for 5 formulations were assessed for rheological properties such as angle of repose, bulk density, tapped density, Carr’s index and Hausner’s Ratio. The angle of repose was found in the ranges from 24.76± 0.08 to 28.27±0.11degrees, bulk density of pre-compression blends was found to be in the range of 0.516±0.08 to 0.523±0.06 gm/ml, tapped density in the range of 0.548±0.06 to 0.565±0.04 gm/ml, the Carr’s index values were in the range of 5.26±0.06 to 7.78±0.04%, and the Hausner’s ratio was in the range between 1.05±0.08 to 1.08±0.06. It is mentioned in Table 4.


 

Table 4: Pre compression parameters of CPOP granules

Formulation code

Angle of repose (degree)a± S.D

Bulk density (gm/ml)a± S.D

Tapped density

(gm/ml)a± S.D

Carr’s Index (%)a± S.D

Hausner’s Ratioa± S.D

RM1

28.27±0.11

0.516±0.08

0.548±0.06

5.83±0.06

1.06±0.04

RM2

27.12±0.12

0.523±0.06

0.559±0.08

6.44±0.06

1.06±0.03

RM3

26.13±0.08

0.518±0.08

0.556±0.06

7.33±0.05

1.07±0.06

RM4

25.32±0.06

0.521±0.06

0.565±0.04

7.78±0.04

1.08±0.06

RM5

24.76±0.08

0.522±0.08

0.551±0.06

5.26±0.06

1.05±0.08

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

 


Post compression parameters:

Tablets were evaluated for different post compression parameters. The thickness of the tablet formulations was found to be in the range of 4.51±0.02 to 4.62±0.06 mm,coat thickness in the range of 101.2±3.3 to 501.1±3.5 µm, the hardness values were in the range of 6.0±0.16 to 6.7±0.14 kg/cm2,the friability values were in range of 0.18±0.05 to 0.31±0.06, average weight of tablet was in the range of  950.3±1.06 to 952.2±1.15 mg, drug content of tablet was in the range of 99.03±1.09 to 101.28±1.11 and diameter of tablets values were ranges of 11.98±0.09 to 12.06±0.03 mm.It is mentioned in Table 5.


 

Table 5: Post compression parameters of CPOP tablets

Formulation code

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

RM1

4.54±0.06

501.1±3.5

6.3±0.12

0.29±0.08

951.1±1.14

101.28±1.11

12.06±0.03

RM2

4.58±0.09

402.12±4.5

6.6±0.14

0.24±0.06

952.2±1.15

99.68±1.14

11.98±0.09

RM3

4.62±0.06

301.08±2.9

6.1±0.15

0.23±0.08

950.9±1.16

100.32±1.12

11.99±0.11

RM4

4.53±0.04

200.4±3.1

6.0±0.16

0.31±0.06

951.2±1.14

99.35±1.04

12.05±0.13

RM5

4.51±0.02

101.2±3.3

6.7±0.14

0.18±0.05

950.3±1.06

99.03±1.09

12.02±0.08

 


In vitro drug dissolution study:

The in vitro drug release characteristics were studied in 900ml of 0.1N HCl (pH1.2) for a period of first 2 h, and 3 to 14 h in phosphate buffer pH 6.8 using USP type II dissolution apparatus (Paddle type).The cumulative percentage drug release (% CDR) for RM1, RM2, RM3, RM4 and RM5 were 82.46, 83.95, 85.36, 86.71 and 94.83 respectively of ritonavir at the end of 14 h. It is shown in figure 3. Similarity (f2) and difference (f1) factors of ritonavir for various batches were calculated comparing with theoretical release. It is depicted in          table 6.

 

Table 6: Similarity (f2) and difference (f1) factor with dissolution profile of all formulations (RM1 to RM5)

F.No.

Difference factor (f1)

Similarity factor(f2)

Dissolution profiles

RM1

40.82

53.93

Dissimilar

RM2

29.22

60.98

Dissimilar

RM3

24.34

64.81

Dissimilar

RM4

14.61

75.12

Similar

RM5

6.19

89.65

Similar

 

Kinetic model:

From the kinetic it was observed that all formulations following Fickian diffusion mechanism. The optimized formulation RM5 follows zero order kinetics. It is shown in table 7.

 

Figure 3: In vitro dissolution study showing ritonavir release from various fabricated formulations RM1-RM5


Table 7: Fitting of IVDR data in various mathematical models

Models

Zero order

First order

Higuchi

Korsmeyer-Peppas

Hixson-Crowell

Batches

R2

K0

R12

K1

RH2

KH

 RK2

Kkp

n

R2

Ks

RM1

0.999

6.002

0.954

0.1197

0.928

24.41

0.999

5.874

1.011

0.981

0.144

RM2

0.999

5.980

0.946

0.1220

0.933

24.39

0.998

7.655

0.901

0.977

0.147

RM3

0.998

6.019

0.942

0.1266

0.936

24.6

0.996

8.472

0.863

0.976

0.150

RM4

0.997

6.026

0.939

0.1312

0.942

24.73

0.994

9.749

0.813

0.975

0.153

RM5

0.996

6.738

0.894

0.1911

0.949

27.77

0.996

11.091

0.811

0.960

0.2

 


Effect of osmogen concentration:

The CPOP formulations were prepared with various concentrations of osmogens. The drug release profile is shown in figure 3.It is observed that osmogent enhances the drug release of drug and thus had a direct effect on drug release.

 

Effect of pore former:

The CPOP formulations were coated with various concentration of sorbitol with compared to CA in different batches. It is observed that pore former enhances the drug release of drug and thus had a direct effect on drug release. Release profile from these formulations is shown in figure 3.It shows that as the level of pore former increases the membrane becomes more porous after coming contact with aqueous environment resulting in faster drug release.

 

Effect of membrane thickness:

The osmotic pump coated tablets having varying the coating thickness are evaluated for drug release study. Release profile of these formulations is shown in figure 3.It is clearly evident that drug release is inversely related to coating thickness of the semi permeable membrane.

 

 

Effect of osmotic pressure:

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 was found to be 87.65 % for 30 atm, 82.67 % for 60 atm and 79.46 % for 90 atm respectively. It is shown in figure 4.

 

 

Figure 4: In vitro release profiles showing ritonavir release from best RM5 in different osmotic pressures

 

Effect of pH:

The optimized formulation was subjected to in vitro drug release studies in buffers with different buffers like HCl buffer pH 1.2, phosphate buffer pH 6.8, and phosphate buffer pH 7.4. It is observed that there is no significant difference in the release profile, demonstrating that the developed formulation shows pH independent release. It is shown in figure 5.

 


 

Figure 5: In vitro dissolution study of best formulation RM5 in various pH media

 

Figure 6: In vitro dissolution study of best formulation RM5 in various agitation speeds

 


Effect of rpm:

The optimized formulation was carried out in USP dissolution apparatus type-II at varying rotational speed (50,100 and 150rpm).It shows that the release from CPOP is independent of agitation intensity. Hence it can be expected that the release from the developed formulation will be independent of the hydrodynamic conditions of the absorption site. It is shown in figure 6.

 

SEM analysis:

Figure 7a confirms that there was no evidence of development of pores in the membrane before dissolution study of optimized formulation. On the other hand figure 7b showed that more pores were formed after dissolution. From the comparison study it was observed that the membrane that contained a higher level of porogen became more porous after dissolution studies.

 

                                A                             B

Figure 7SEM micrographs of RM5 A) before dissolution study, and B) after dissolution study

 

Stability studies:

From short term stability studies of optimized formulation, it was confirmed that there was no significance changes in physical appearance, thickness, hardness, friability, weight variation drug content and diameter. It is shown in table 8.


 

Table 8: Comparative physicochemical characterization of RM5 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

4.51±0.02

4.51± 0.02

4.50±0.05

4.50±0.08

3.

Hardness(kg/cm2)a ± S.D

6.7 ±0.14

6.7± 0.14

6.6±0.11

6.5±0.12

4.

Friability(%)a ± S.D

0.18± 0.05

0.18± 0.05

0.17±0.06

0.16±0.05

5.

Weight variation(mg)b ± S.D

950.3±1.06

950.3± 1.06

949.8±1.06

949.5±1.06

6.

Drug content(%)a ± S.D

99.03±1.09

99.03± 1.09

98.01±1.09

97.99±1.09

7.

Diameter(mm)a ± S.D

12.02± 0.08

12.02± 0.08

12.01±0.07

12.01±0.07

N.B.-All values are expressed as mean± S.D, a n = 10, b n = 20

 

 


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 31.12.2017          Modified on 06.02.2018

Accepted on 25.02.2018            © A&V Publications All right reserved

Asian J. Pharm. Tech. 2018; 8(1):13-22.

DOI: 10.5958/2231-5713.2018.00003.X