Tremendous advances have been seen in oral controlled drug delivery systems in the last two decades. In the development of oral controlled drug delivery system, one of the main challenges is to modify the GI transit time. Gastric emptying of pharmaceuticals is highly variable and is dependent on the dosage form and the fed/fasted state of the stomach. Normal gastric residence times usually range between 5 minutes and 2 hours. Drugs having a short half-life are eliminated quickly from the blood circulation. Various oral controlled delivery systems like gastro retention dosage forms have been designed to overcome this problem and release the drug to maintain its plasma concentration for a longer period of time.^[1] It includes various advantages like, the principle of HBS can be used for any particular medicament or class of medicament. The HBS formulations are not restricted to medicaments, which are principally absorbed from the stomach. The HBS are advantageous for drugs absorbed through the stomach e.g. ferrous salts and for drugs meant for local action in the stomach and treatment of peptic ulcer disease e.g. antacids. The efficacy of the medicaments administered utilizing the sustained release principle of HBS has been found to be independent of the site of absorption of the particular medicaments.^[2] Formulation of floating drug delivery system for antihypertensive medications is of great use in the case of drugs with lower bioavailability. Nowadays, a variety of methods have been employed to extend the residency period, including systems that expand and swell, polymeric bioadhesive systems, self modified form systems etc. Benazepril is an ACE Inhibitor used to treat high blood pressure and heart failure. It is primarily dissolved and absorbed from the upper part of the GI tract.  Hence, the main objective of this study is to formulate and evaluate Benazepril floating tablets which will remain buoyant in the stomach for an extended period thereby increasing the bioavailability and improved therapeutic effect.^[3]

MATERIALS AND METHODS:

Benazepril, a gift sample from Yarrow chem Mumbai, HPMC K100M  and Carbopol 940  Obtained from Otto Chemika-Biochemika reagents Mumbai, Guar gum obtained from Loba Chemie Pvt Ltd Mumbai. All other the chemicals were of analytical grade.

Formulation Development of Benazepril Floating Tablets:

Direct compression was used to prepare nine formulations of floating drug delivery systems (FDDS) for Benazepril, labeled F1 to F9. All ingredients were (Table 1) accurately weighed, and the drug was mixed with polymers and excipients in ascending order of weight. The mixture was blended for 20 minutes for uniformity, followed by a brief 1-minute mixing with magnesium stearate for lubrication. Finally, 500 mg of the powder mix was accurately weighed and compressed using a single punch machine with 12 mm flat-surface punches.

Preformulation studies:

FTIR study:^[4]

FTIR was used to identify if there is any drug excipient interaction. FTIR studies were performed on drug, polymer and optimized formulation. Samples were analyzed by potassium bromide pellet method in an IR spectrophotometer in the region between 4000-400 cm^-1.

Standard curve of Benazepril:^[5]

A Standard Solution of  Benazepril  was  prepared  by dissolving accurately weighed 100 mg of  Benazepril  with little quantity of 0.1N HCl solution, in a 100 ml  volumetric flask. The volume was made up to 100 ml with 0.1N HCl, to obtain a stock solution of 1000µg/ml. From the above solution several dilutions are made to obtain 2, 4, 6, 8, 10 (µg/ml) solutions. The absorbance of the drug solutions were estimated at ? _max 242nm.

Precompression parameters of powder blends:     

1. Angle of repose:^[6]

Angle of repose is defined as the maximum angle possible between the surface of the pile of powder and the horizontal plane. The angle of repose is designated by ?. It was determined by             funnel method. The powder blend was passed through funnel so that it forms a pile. The height (h) of the pile and the radius of the pile (r) were measured and angle of  repose was calculated using following formula

? = tan^-1(h/r)

2. Bulk density & Tapped density:^[7]

Bulk  and  tapped  densities  were  measured  by using  10  ml  of  graduated  cylinder.  The sample poured in cylinder was tapped mechanically for 100 times, then tapped volume was noted down and bulk density and tapped density were calculated using following formula,

Bulk Density =Mass of powderVolume of powder(Bulk)   Tapped Density =Mass of powderVolume of powderTapped  

3. Compressibility index:^[8]

  CI of the powder was determined from the bulk and tapped density as follows,

                               Percentage Compressibility index =100 ×  Tapped density-Bulk densityTapped density

4. Hausner’s ratio:

   It was calculated as,

Hausner's ratio=Tapped DensityBulk Density

Post-Compression Evaluation:

1. Weight variation test:^[9]

20 tablets were  chosen  at random and each one was weighted. It was determined what the typical tablet weighed. The variations  between  the individual tablet weights and the average weight were compared.

2. Thickness :

Thickness  of  the  tablet   was   measured   by   using  vernier  caliper.  Tablet  thickness should be controlled  within  a  ± 5%  variation  of  standard  value. Thickness   values   were   expressed   in millimetre.

3. Hardness test:^[10]

Tablet hardness has been defined as the force required for breaking or cracking or crushing a tablet in a diametric compression test. A tablet was placed in between two anvils of the hardness tester (Monsanto type), force was applied  to  the  anvils and   the crushing strength that caused the tablet to break was recorded.

4. Content uniformity:^[11]

It is the quantity that is contained in each formulation for tablets. Tablets from the formulation  were taken and dropped into a beaker of 100ml 0.1N HCl. The same sample (approximately 1ml) was removed after 24 hours or when the medication has entirely been released, diluted to 10 ml with 0.1N HCL, and the absorbance was measured at 242nm using a UV spectrometer. Calculations of drug release were made using the usual graph.

5. Friability:^[12]

A sample of pre weighted 20 tablets was placed in Roche friabilator which was then operated for 100 revolutions i.e. 4 mins. The tablets were then dusted and reweighed. Percent friability (%F) was calculated as follows,  % F= (loss in weight / initial weight) x 100.

6. Swelling Index:^[13]

  0.1 N HCl solution having pH 1.2 was used to determination of the swelling index of tablets at room

at room temperature.   Weight  of  the  tablets  after  the  swollen  was  determined  at   specific  time      

intervals.  The Swelling index was calculated using following formula,

    Swelling index = W_t -W₀

                                     W₀

Where, W₀= initial weight of tablet, W_t = weight of the tablet in t (time)

7. In-vitro Buoyancy Study:^[14]

The  in -vitro buoyancy was determined  by  floating  lag time,  and  total  floating  time. The tablets

  were  placed  in  a  100ml beaker containing 0.1N HCl. The time required for the tablet  to rise to the    

  surface and float  was  determined as floating lag time (FLT) and   the duration of the time  the tablet  

  constantly   floats  on the dissolution medium  was  noted  as the Total    Floating  Time  respectively  

  (TFT).

8. In-vitro Dissolution Study:^[15]

Benazepril floating tablets were kept in a 0.1N HCl (900 ml) dissolution buffer for the first two   hours while being run at a temperature of 37°C and 50 rpm. Then, as a dissolving medium, 900 ml of pH 6.8 phosphate buffer was utilised. Always use freshly produced dissolving medium. The  usage  of  paddle devices. Every 2, 4, 6, 8, 10 and 12  hours , 10ml    of  the dissolution medium were pipetted out and the volume was changed by substituting 10 ml  of 0.1N HCl or pH 6.8 phosphate buffer. At 242nm, a UV spectrometer was used to evaluate the samples that were gathered.

9. Stability studies:^[16]

The optimized formulation were packed in aluminium pouch and subjected to accelerated stability studies at 40±2°C/75%RH for a period of three months. Samples from the formulation which were kept for examination  and  withdrawn at definite time intervals and  evaluated for their drug release and drug content.

Results and Discussion:

FTIR studies:

Drug polymer compatibility studies were carried out using Fourier Transform Infra Red spectroscopy to establish or rule out any possible interaction of Benazepril with the polymers used in the formulation. The FT-IR spectra of the formulations were compared with the FT-IR spectra of the pure drug. The results are shown in fig 1-4, indicating that the characteristic absorption peaks due to pure Benazepril have appeared in the formulated tablets, without any significant change in their position after successful formulation, indicating the absence of any chemical interaction between Benazepril and Polymers.

       
           
       
Figure 1 : FTIR Spectra of Benazepril

       
           
       
Figure 2 : FTIR Spectra of Benazepril + Carbopol 940

       
           
       
Figure 3: FTIR Spectra of Benazepril + Guar gum

       
           
       
Figure 4: FTIR Spectra of Benazepril + HPMC K100M

Table 2: FTIR absorption spectra of different functional groups of drug and drug polymer mixture

Table 4: Characteristics of final blend of Benazepil Floating tablets.

All values represented as mean ± standard deviation (n=3)

The pre- compression parameters obtained for all formulations was tableted in the table 5 . The value of angle of repose was found to be in the range of  22.17⁰±0.15 to 26.21⁰±0.12.  This indicates good flow property of powder blend. The bulk density and tapped density values ranged from 0.471±0.11 to 0.522±0.13 g/ml for bulk density and 0.476±0.12 to  0.527±0.15 g/ml for tapped density respectively So, it shows that all formulations having good flow properties and packability. The values of Compressibility Index & Hausner's ratio ranged from 12.36 and 18.09 % and 1.07 and 1.21,  respectively. This showed that the powder combination has good flow properties and  hence all parameters were within the limit as per IP specifications.

Post-Compression Evaluation:

The prepared floating tablets were evaluated for Average weight variation, Hardness, Friability, Drug content and Thickness all the studies were performed and the results have shown in the table 5.

Table 5: Post compression of Benazepril floating tablets

Table 6: Swelling index (%) of Formulations

All values represented as mean ± standard deviation (n=3)

       
           
       
Figure 6: Graph for comparison of swelling index of all the formulation

Swelling index for all the formulations was carried out in the 0.1N HCl. The formulations showed different indices in the swelling media and it is shown in the table 6. Tablets containing  HPMC K100M (F9) showed maximum swelling  in 12 hr with sharp increase up to 8 hr this may due to increased concentration of HPMC K100M which retain water and form thick swollen mass.

In-vitro buoyancy studies:

All the formulations were tested for floating properties like Floating lag time and Floating duration. The results of the In vitro buoyancy study were shown in table 7.

Table 7: Buoyancy studies of Formulations

All values represented as mean ± standard deviation (n=3)

Figure 7: In vitro buoyancy studies of optimized Formulation

The In-vitro floating behavior of the tablets was studied by placing them in beaker containing 0.1 N HCl (pH 1.2). The gas generating agents immediately evolves carbon dioxide in presence of HCl solution generating sufficient porosity which helped the dosage unit to float. Formulation F1-F3 prepared with carbopol 940 started floating after 52.2 seconds and remains buoyant for 8 hr till they were completely eroded. On the other hand formulation F4-F6 prepared with Guar gum  which  shows  a  floating time of 6.5 hrs and formulation of F7-F9 prepared with HPMC K100M show decrease in floating lag time to 34 seconds and increased floating duration time to 12 hrs. This might be due to high viscosity polymer HPMC K100M maintains the integrity of the tablets for longer duration by reducing the effect of erosion thus resulting in increase in floating time. The results are shown in table 7. Thus it can be concluded that the batch containing HPMC polymers showed good floating lag time and total floating time.

In-Vitro drug release studies:

In-vitro drug release studies were carried out using USP dissolution apparatus II at 50 rpm. The dissolution medium consisted of  900 ml of pH 1.2 acid buffer (0.1N HCl), maintained at 37.5?C . The drug release at different time intervals was measured using an  uv spectrophotometer at 242 nm.

Table 8: In-vitro dissolution test of Benazepril Floating tablet.

Table 9: Stability studies with optimized Formulation