Model drug used in present investigation has relatively short plasma half-life and low bioavailability (~50%). Two to three times administration was required for larger doses, this can decrease the patient compliance. Sustained release formulation maintains plasma level for 10-12hrs and it might be sufficient for daily dosing of bosentan. Main objective of the present investigation was to develop an oral sustained release bosentan formulation by using different polymers in combination with Hydroxy propyl methyl cellulose (HPMC). Tablets were prepared by direct compression method. In vitro dissolution studies were carried out for all nine formulations in simulated gastric fluid using USP type II dissolution apparatus for 10-12hrs. Dissolution data was analyzed using different kinetic models. B7 formulation with combination of polymers HPMC and ethyl cellulose (EC) shows sustained drug release upto 12hrs. Kinetic modeling of In-vitro drug release study of optimized formulation indicates dissolution follows zero order, fitting dissolution data to higuchi model revealed super case II transport.

Keywords:Hydroxy propyl methyl cellulose, Sustained release, Simulated gastric fluid, Kinetic models, Ethyl cellulose.

Model drug used in present investigation has relatively short plasma half-life and low bioavailability (~50%). Two to three times administration was required for larger doses, this can decrease the patient compliance. Sustained release formulation maintains plasma level for 10-12hrs and it might be sufficient for daily dosing of bosentan. Main objective of the present investigation was to develop an oral sustained release bosentan formulation by using different polymers in combination with Hydroxy propyl methyl cellulose (HPMC). Tablets were prepared by direct compression method. In vitro dissolution studies were carried out for all nine formulations in simulated gastric fluid using USP type II dissolution apparatus for 10-12hrs. Dissolution data was analyzed using different kinetic models. B7 formulation with combination of polymers HPMC and ethyl cellulose (EC) shows sustained drug release upto 12hrs. Kinetic modeling of In-vitro drug release study of optimized formulation indicates dissolution follows zero order, fitting dissolution data to higuchi model revealed super case II transport.

Keywords:Hydroxy propyl methyl cellulose, Sustained release, Simulated gastric fluid, Kinetic models, Ethyl cellulose.

Most conventional oral drug products, such as tablets and capsules, are formulated to release and complete systemic drug absorption immediately after oral administration of prodrug. Such immediate release tablets result in relatively rapid drug absorption and onset of accompanying pharmacodynamic effects. In recent years, various modified-release drug products have been developed to control the release rate of the drug and/or the time for drug release [1].

The term modified-release drug product is used to describe products that alter the timing and/or the rate of release of the drug substance. A modified-release dosage form is defined “as one for which the drugrelease characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving dosage forms as presently recognized” [2-5].

Extended-release drug products: A dosage form that allows at least a twofold reduction in dosage frequency as compared to that drug presented as an immediate-release (conventional) dosage form. Examples of prolonged-release dosage forms include controlled-release, sustained-release, and long-acting drug products [6].

The term controlled-release drug product was previously used to describe various types of oral extended-release-rate dosage forms, including sustained-release, sustained-action, prolongedaction, long-action, slow-release, and programmed drug delivery [7].

Sustained drug release(SR): The goal of sustained –release dosage form is to maintain therapeutic blood or tissue levels of the drug for an extended period. Commonly, the release rate of drug is not altered and does not result in sustained delivery once drug release has begun [8-10].

A.Diffusion Sustained Systems: Reservoir devices and Matrix devices

B. Dissolution controlled systems: Matrix systems and Encapsulation systems

C. Diffusion and Dissolution Controlled System: In a bio-erodible matrix, the drug is homogenously dispersed in a matrix and it is released either by swelling controlled mechanism or by hydrolysis or by enzymatic attack [11-14].

Bosentan drug was gifted sample from Chandra labs, Hyderabad. Polymers Hydroxy propyl methyl cellulose (HPMC), Ethyl cellulose (EC), Xanthan gum, Acacia were purchased from MYL chemicals, Mumbai. Micro crystalline cellulose (MCC), Magnesium stearate and Talc were laboratory standards.

Pre-formulation studies: 4.2.1.1 Analytical study: Drug description, solubility studies in different solvents, determination of melting point and scanning of drug using UV Visible spectrophotometer.

Construction of standard graph of Bosentan in 0.1N HCL: Bosentan drug dissolved in 0.1N HCL and preparae concentrations from 2-10 μg/ml and absorbance were noted at 204nm using UV Visible spectrophotometer. Linearity graph was plotted with these observations against concentrations

Construction of linearity curve of Bosentan in pH 6.8 Phosphate buffer: 2-10 μg/ml concentrations of drug solutions were prepared using pH 6.8 Phosphate buffer as solvent and note the absorbance for the same concentrations using UV Visible spectrophotometer at lamda max 204nm. Concentrations were plotted on X-axis and noted absorbance for respective concentrations were plotted on Y-axis to achieve calibration curve.

Drug – excipient compatibility study: The IR spectrum of the physical mixture was compared with that of the pure drug to check any possible drug-excipient interaction.

Formulation of sustained release tablets: 4.2.3.1 Precompression parameters: Mixed blend was evaluated for flow properties like Bulk density, Tapped density, Angle of repose, Hausner ratio and compressibility index.

Preparation of Bosentan SR tablets: Bosentan SR tablets were prepared using direct compression method shown in table 1.

Evaluation of SR tablets: Prepared tablets were evaluated for Physical appearance, Size & shape, weight variation test, Friability, Hardness, Drug content and In-vitro dissolution studies.

In-vitro drug release studies: Bosentan SR tablets dissolution studies were conducted in USP type II dissolution apparatus, first two hours in 0.1N HCL and remaining time for 6.8pH phosphate buffer to simulate in vivo gastric conditions.

Kinetic analysis of dissolution data: To analyze the in vitro release data various kinetic models were used to describe the release kinetics: Zero order kinetics, First order kinetics, Higuchi plot and Kosmeyar Peppas model explained in table 2.

Drug description: Observations were found as per specifications only showed in table 3.

Solubility: Bosentan drug solubility increases with increasing the pH of the solvent and poorly soluble in water discussed in table 4.

Melting point: Bosentan (API) melting point was observed at 138⁰c and within the limits only.

Scanning of API: Figure 1

Figure 2 and Figure 3

Figure 4 and Figure 5

Table 5

Table 6

Figure 6 and Figure 7

Table 7 and Figures 8-11

Present study was undertaken with an aim to formulate ........

Patient was suffering from liver cirrhosis secondary to hepatitis which is irreversible state. Her chief complaints were abdominal pain, abdominal distension and pedal edema. USG report showed end stage liver cirrhosis, coarse and necrotic liver. The risk behind this severe suffering was the hepatitis in the past left untreated which appeared as a complication, patient was on palliative care to provide patient with relief from the symptoms, pain, and stress of a serious illness, such as cirrhosis. The goal of palliative care is to improve quality of life for both the patient and the patient’s family and it is appropriate at any stage and for any type of cirrhosis.[11] Desired outcomes of such patient should be to minimize continued liver damage, optimize nutrition, maximize hepatic circulation, minimize and prevent respiratory complications.[9]Lifestyle interventions are beneficial including smoking cessation and stop drinking alcohol, limit salt in diet, get vaccinated for hepatitis A & B, and pneumococcal pneumonia. Liver damage from cirrhosis cannot be reversed, but the treatment could stop or delay further progression and reduce complications. [12]