Formulation and Evaluation of Gastro Retentive Floating Tablets of Ritonavir

 

Jahnabi Sarmah*, Ananta Choudhury

Faculty of Pharmaceutical Sciences, Assam down town University, Guwahati – 781026, India.

 

ABSTRACT:

Objective: The objective of this study was to formulate floating tablets (GRDDS) of Ritonavir using wet granulation technique to increase its bioavailability and the gastric residence time of the dosage form. Methods: The Ritonavir tablets were prepared by wet granulation method.  The tablets were prepared by using two different grades of polymers i.e; HPMC K 15M and HPMC K 4M which act as a release retardant polymer. Sodium bi carbonate (NaHCO₃) was used as a gas degenerating agent and MCC (Micro crystalline cellulose) was used as a diluent. Solution of gelatin and ethyl cellulose was used as a binder in the preparation of formulation.  The final   mixing was done by adding talc and magnesium stearate to the granules.  Then the prepared formulation were subjected to some evaluation parameters like hardness, friability, weight variation, drug content, buoyancy property, drug release study etc. Results: In the FT-IR study it was revealed that there is no interaction between the drug and excipients. The formulation which containing the combination of HPMC K 15M polymer and  Sodium bi carbonate  shows good drug release pattern with less floating lag time and good floating duration. Conclusion: The in vitro drug release pattern of Ritonavir floating tablets was fitted to different kinetic models which showed the highest regression for Higuchi order kinetics.

 

 

INTRODUCTION:

Oral delivery of the drug/medicine is the foremost preferred route of drug delivery due to the convenience of administration, patient compliance and adaptability in formulation. One amongst possible approaches for achieving a chronic and certain drug delivery profile within the gastrointestinal tract is to manage the stomachic duration (gastro residence time) (GRT)¹ as an example, medicines that are absorbed in the proximal part of the channel², and drugs/medicines that are less soluble in the base forming pH may be beneficial from prolonged stomachic retention^3,4.

 

Additionally, for native and sustained drug delivery to the stomach/abdomen and proximal intestine to treat certain condition, prolonged stomachic retention of the therapeutic moiety might supply varied benefits as well as improved bioavailability and therapeutic affectivity, and attainable reduction of the dose size^5,6.

 

Gastro/Stomachic Retentive (GR) drug delivery system:

After oral administration, such a dosage form would be preserved within the abdomen/stomach. It unleash the drug in a predetermined (rate) manner. In order to that medicine might be equipped to its absorption sites within the upper GI tract. Gastro retentive dosage form can stay within the intestinal or gastric region for many hours and hence considerably prolong the gastric residence time of the medication⁷.

 

Anatomical and physiological structure of GI tract:

The Gastrointestinal tract is looks like a tube which is nine meters long. It runs through the center of the body from the mouth to the anus. It includes pharynx, oesophagus, stomach, duodenum, jejunum, ileum and large intestine (cecum, appendix, colon and rectum). The abdomen is placed within the left higher part of the abdominal cavity under the diaphragm⁹. Its size varies with the number of distention which is up to 1500 ml following a meal. Once food has empty, a state is obtained with a resting volume of solely 25–50ml⁸. Anatomically the abdomen is split into 3 regions: fundus, body, and pylorus. The half part made up of fundus and the body acts as a reservoir for undigested material, whereas the antrum is that main site. Antrum is responsible for mixing motions and act as a pump¹¹.

 

Fig 1:  Structure of Stomach

 

Gastric emptying happens throughout fasting as well as fed states. The motility pattern is however distinct within two different state. During the fasting state, inter digestive series of electrical events take place. Which cycle both though abdomen and intestine every two to three hours¹². This can be referred as the inter migrating myoelectric cycle, that is further divided into following four phases¹³.

 

1. Basal phase lasts from thirty to sixty minutes with rare contractions.

2. Pre burst phase lasts for twenty to forty minutes with intermittent impulse and contractions. Because the phase progresses the intensity and frequency additionally, which use to increase step by step.

3. Burst phase lasts for ten to twenty minutes. It includes intense and regular contractions for short period. It is due to this wave that everyone the undigested material is swept out of the stomach down to the small intestine.

4. Last phase: It lasts for zero to five minutes and happens between phases iii and i of two consecutive cycles.

 

After the ingestion of a mixed meal, contractions changes from fasted to fed state. This can also be referred as digestive motility pattern. It consists of continuous contractions. These contractions end in decreasing the dimension of food particles (to less than one mm). Throughout the fed state onset of MMC is delayed leading to slowdown of gastric emptying rate^{14, 15}.

 

Fig 2:  Motility of gastrointestinal tract

 

MATERIALS AND METHODS:

Materials:

Ritonavir was obtained from Cipla (Pharmaceutical Company) Sikkim, India. HPMC K15 M, HPMC K4 M, micro crystalline cellulose, sodium bi carbonate, talc, magnesium stearate and other excipients were procured from S. D Fine Chemicals, Mumbai, India.

 

Methods:

Formulation of gastro retentive tablets of Ritonavir:

All the formulations were prepared using different grades of HPMC polymers in varied ratios. The Ritonavir and all other ingredients were one by one passed through sieve ≠ 60. All the ingredients were mixed thoroughly by triturating up to 15-20 min. The powder mixture was lubricated with talc and magnesium stearate. In the floating tablet formulation, NaHCO₃ (sodium bi carbonate) was used as the gas degenerating agent. It helps to decrease the floating lag time. HPMC K15M and HPMC K4M were used as the release retardant polymer.

 

Table 1: Composition of different formulations

 

MCC was used as a diluent in the formulation. Magnesium stearate and talc were used as the lubricants¹⁶. The tablets were prepared by using the direct compression technique. Ingredients except lubricator all the other ingredient are totally mixed. Granulation was done with a solution of calculated quantity of gelatin (binding agent) and Ethyl cellulose solution. The final ultimate mixing (blending) were lubricated with magnesium stearate and talc and at last compressed into tablets using tablet punching machine¹⁷.

 

Characterization of tablets:

Tablets were made from blends by direct compression technique and wet granulation technique. The quality of tablet is mostly dependents on the quality of physicochemical properties of blends¹⁸. There are various formulations and method variables are involved in mixing step. And all these can effect on the properties of final blend. The characterization or properties of final mixed blend done for the flow property of powder and those are and angle of repose, bulk density, tapped density, Compressibility index and Hausner’s ratio¹⁹.

 

Evaluation parameter of floating tablets:

Determination of hardness of tablets:

Hardness of tablets was determined by using the hardness tester. First 3 tablets from every batch of formulations were selected. The mean hardness of sample and standard deviation were calculated for each batch. The study was conducted in triplicate for each individual sample to avoid errors. It is expressed in kg/cm^20-22.

 

Determination of weight variation:

Ten tablets were randomly selected and weighted out accurately. After that, their average weights were also calculated. The deviation of individual weight from the average weight and the standard deviation were calculated to find out weight variation value^21,23.

 

Determination of thickness of tablets²⁴:

The thickness of tablets was determined by using Vernier caliper. The individual crown-to-crown thicknesses of 10 tablets were determined for each batch. After that, the sample mean and standard deviation of every tablet were determined.

 

Drug content study:

To perform these study 3 tablets randomly from each batch was selected. Then transfer one by one to a 100ml volumetric flask²⁴. The flask were filled up to the mark with 0.1(N) HCl severally and kept it for 24hr. Then again take 1ml solution from each and every of the volumetric flask and transferred into the tubes. Sample was than suitably diluted and filtered. After that it is analyzed spectro photometrically at an appropriate wave length²⁵.

Floating properties:

In order to provide quantitative measurements of floating lag time (initial time taken by the formulation to float) and floating duration (time period during which formulation stay floatable condition) continuous manual floating observance was perform²⁵. For the fulfillment of this study, the formulation was dropped in one thousand (1000) ml beaker containing five hundred (500) ml of dissolution medium. The floating lag time and floating duration were measured under continuous manual supervision²⁶.

 

In vitro dissolution study:

The in vitro drug dissolution study was used for study and determines the drug release from the floating tablets of Ritonavir. In the dissolution study requirement are given below:

Apparatus: USP Type II i.e; paddle apparatus

Speed (rpm): 50

Medium:  0.1 N HCL

Volume of dissolution medium: 900ml

Temperature: 37.0 ± 0.5 C

Time: 0.5, 1, 2, 3, 4, 5, 6hr interval

Wavelength: 284 nm

 

The dissolution study was done for almost twelve hours²⁷. And the samples were withdrawn continuously after 0.5, 1, 2, 3, 4, 6, 8, 10, and 12hr interval. After that, samples are filtered, diluted and finally analyzed by using UV spectrophotometer at 248nm wavelength.

 

Drug release kinetic study:

The data which is obtained from in vitro drug release studies were plotted in various kinetic models which are zero order release kinetics, first order release kinetics and Higuchi release kinetics²⁷.

 

RESULTS AND DISCUSSION:

Pre compression parameters:

Table 2: Pre compression parameter

 

Pre formulation studies (Angle of repose, Hausner’s ratio, compressibility, bulk density, tapped density) were done in order to determine the flow property of the all formulation. And it is given in the table 2. All the formulation was found to be the range of powder and it has good flow properties.

 

Fig 3: Comparative study graph plot of pure drug Ritonavir and Formulation 1(F₁, F₂ and F₃) and formulation 2 (F₄, F₅ and F₆).

 

FT-IR analysis:

Spectra were obtained after FTIR spectrophotometer analysis of drug, different grades of polymer and other excipients which were used to prepare the formulation. And after the FT-IR analysis, characteristic peaks were observed. Spectra of the mixtures containing drug reveal the presence of some characteristic peaks However, the spectra indicate that there is not any interaction happen between the drug/polymer and excipients.

 

 

 

 

 

 

 

Different physical parameters of the prepared formulation:

Table 3: Different physical parameters of the prepared formulation

 

 

 

 

The Ritonavir floating tablets were prepared and the compositions of different formulations were shown in Table 1. The tablets were prepared by using different concentration ( 10mg, 15mg and 20mg) of sodium bi carbonate as a gas generating agent, different grades of polymer (HPMC K 15M, HPMC K 4M) and MCC as diluent in different concentration. MCC causes dimensional stability for a longer period of time in the all formulation. Due to high crosslinking structure of MCC, it may be attributed to their insoluble nature.

 

The evaluation like hardness, thickness, weight variation and friability were found to be within the limits. And it was summarized/ given in the table 3. This study indicated that all the prepared formulations were good. In case of hardness of F₆ formulation (5.7kg), it shows good floating time (12 hours) and an acceptable lag time.

 

Floating lag time and floating duration of the formulation:

Table 4: Data of floating lag time, floating duration and % drug content study

 

All the formulations (F₁, F₂, F₃, F₄, F₅, F₅ and F₆) were tested for buoyancy floating properties i.e; floating lag time and total floating duration. The results of the all formulation were given in the table. Time taken for floating of various formulations depends on various factors such as concentration of NaHCO_3, (10mg, 15mg and 20mg) and nature of polymer. All the drug formulations floated within almost 1 to 3 minutes. And total floating/buoyancy duration was up to 24 hours of all formulations. All the (Ritonavir) drug formulation consist of NaHCO₃ (Sodium bi carbonate) as a gas degenerating agent which produces CO₂. It helps to float in the medium by reducing density of the systems. All floating tablets which contain HPMC K 15M polymer floated well over a long period of time (up to 24 hours). And also it shows minimum floating lag time (1 to 3 minutes). The batch with highest concentration (20mg per tablet) of sodium bicarbonate shows an acceptable lag time i.e; 1 min for floating and floats over desired period of time (24 hr). The drug content of the different prepared batches (F₁, F₂, F₃, F₄, F₅, and F₆) of tablets was given in the table 8.  The drug content was good and in the range of (90.40 to 96.20)mg.  It was found that the formulations of F₄ and F₆ have highest drug content i.e; 95.08mg and 96.20mg respectively.

Dissolution data of different formulation of ritonavir floating tablets:

Table 5: Dissolution data of different formulation of Ritonavir floating tablets

 

 

Fig 4: Dissolution profile of Ritonavir floating tablets (F₁, F₂and F₃) formulation

 

 

Fig 5: Dissolution profile of Ritonavir floating tablets (F₄, F₅ and F₆) formulation

 

Release kinetic study:

Table 5: Partition coefficient (r²) values of different kinetic model

 

The release data obtained from each batch prepared by two different grades of HPMC (K 15M and K 4M) were substituted to different mathematical models like Zero order, First order and Higuchi kinetic models. The results which are obtained based on the (r²) value given on the table 11. It shows that formulations like F2, F3 and F4 shows zero order kinetics and F5 and F6 shows higuchi kinetics. And the F1 formulation shows First order kinetic.

 

CONCLUSION:

We concluded that HPMC K 15M in combination with sodium bi carbonate and microcrystalline cellulose can be promising polymers or approach for effervescent gastro retentive floating drug delivery system. The developed floating tablets of Ritonavir may be used for prolonged drug release, thereby improving the bioavailability and patient compliance. 

 

Sodium bicarbonate has some significant effect on the buoyancy lag time and floating duration. While HPMC K4M and HPMC K15M have predominant effect on total floating time and drug release. MCC also shows significant effect on drug release. In-vitro release rate studies showed that the maximum drug release was observed in F₁ and F₆ formulations upto 6 hrs. The release of Ritonavir from the most of the formulations was found to follow Zero order and Higuchi order kinetics.

 

Combinations of different grades of HPMC (HPMC K 15M and HPMC K 4M) are good polymer systems for the formulation of floating delivery system. The drug-polymer compatibility was evaluated by using FTIR spectroscopy and there was not any evidence of any interaction between drug and polymers and the other excipient with in the prepared system. It was also concluded that the prepared floating tablets of Ritonavir showed satisfactory physicochemical properties and floating behavior.

 

CONFLICTS OF INTEREST:

The authors declare no conflict of interest.

 

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Accepted on 31.01.2020           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(9):4099-4104.