Formulation And Evaluation of Floating Gastroretentive Drug and Delivery System

Oral route for the delivery of the medication is considered as one of the oldest and most convenient method. With the new innovations and novelty in this method has made it possible to deliver the medication in a more sustained and controlled manner. GRDDS is the desirable approach for the optimized therapeutic benefit for a drug with narrow absorption window. Gastroretentive Drug Delivery System is a Novel Drug Delivery which is mainly comprised of Floating, Mucoadhesive, Swellable and High Density system. Floating drug delivery systems was first described by Davis in 1968. These are low-density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period and one of the important approaches to achieve gastric retention and to obtain sufficient drug bioavailability. This system is desirable for drugs with low absorption window in the stomach or in the upper small intestine. FDDS having a bulk density lower than gastric fluids and thus, that remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time.

Dexlansoprazole is a proton pump inhibitor (PPI) used primarily for the treatment of gastroesophageal reflux disease (GERD) and other conditions involving excessive stomach acid. It is the R-enantiomer of lansoprazole which provides extended acid suppression.

The present study aims to formulate and evaluate floating gastroretentive drug delivery system to enhance its gastric residance time and to increase its bioavailibility. The insitu gel system is prepared using appropriate polymers through a pH triggered method and evaluated for its physicochemical properties, drug release behavior, and floating duration.

AIM, OBJECTIVE AND NEED OF STUDY :

Aim:Formulation and Evaluation of Floating Gastroretentive Drug Delivery System .

Objective :

The main objective of present study are as below.

1.To formulate various batches of  Gastroretentive floating drug delivery system by   using various polymers.

2. To study the effect of polymer concentration on rate of release of drug from floating               drug delivery system.

3.To study the effect of polymers and other excipients on floating lag time and total floating time .

4.To increase gastric residence time of dosage form in the stomach.

5.To reduce dosing frequency.

6.To enhance oral  bioavailability of drug .

DRUG PROFILE

1. IUPAC Name: (R)-2-([3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl)-1H-benzimidazole

50. Molecular Formula: C16H14F3N3O2S
50. Molecular Weight: 369.36 g/mol
50. Drug Class: Proton pump inhibitor (PPI)
50. Chirality: R-enantiomer of lansoprazole

2. Mechanism of Action

Dexlansoprazole selectively inhibits the H+/K+ ATPase enzyme system (proton pump) in the gastric parietal cells. This inhibition blocks the final step of acid production, thereby reducing gastric acidity. The dual delayed-release system allows for two separate releases of the drug, resulting in prolonged plasma concentration and acid suppression.

3. Pharmacokinetics

• Absorption: Rapid absorption with peak plasma levels at 1–4.5 hours post-dose (biphasic peaks due to DDR).
• Bioavailability: Not affected significantly by food
• Protein Binding: Approximately 96–98%.
• Metabolism: Extensively metabolized in the liver via CYP2C19 and CYP3A4.
• Half-life: Approximately 1–2 hours, though acid suppression lasts longer due to irreversible enzyme binding.
• Excretion: Primarily renal and fecal metabolities.

4. Dosage & Administration

• Non-erosive GERD: 30 mg once daily for 4 weeks
• Erosive esophagitis: 60 mg once daily for up to 8 weeks
• Maintenance of healed EE: 30 mg once daily

5. Advantages of Dexlansoprazole

• Once-daily dosing improves compliance
• Effective even when taken without regard to meals
• Reduced nocturnal acid breakthrough compared to other PPIs

6. Adverse Effects:

• Common: Diarrhea, abdominal pain, nausea, vomiting, flatulence
• Serious: Clostridioides difficile infection, vitamin B12 deficiency, hypomagnesemia, bone fractures, acute interstitial nephritis

EXCIPIENTS PROFILE:

1. Analytical chacterization of drug sample:

Stock solution (100μg/ml) of dexlansoprazole  was prepared in 0.1 HCL. This solution was appropriately diluted with 0.1 N HCl separately to obtain a concentration of 100 µg/ml dexlansoprazole in 0.1 N HCl and water respectively. The UV spectrum was recorded in the range of 200-400 nm on UV Visible Spectrophotometer.

2. FT-IR SPECTROSCOPY:

The FTIR studies are performed to observe any interaction between drug and polymers in the formulation. FTIR study of optimized floating insitu gel(F6 batch) was carried out. The FTIR spectra indicate that there is no interaction betweensodium alginate  & drug within insitu gel.

The spectrum of optimized floating insitu gel was found to be similar to pure dexlansoprazole drug.FTIR spectra shoes key functional peak of dexlansoprazole are retained in physical mixture spectrum such as C=C,C=O,C-H that confirms integrity of drug structure .There are additional broad peak such as at 3246.79cm-1 due to hydroxyl group from sodium alginate and shift around 1749.44 cm^-1 likely due to Eudragit RSPO ester carbonyl. These donot overlap or mask drug peak, suggesting no major chemical interaction has occured.

3. Prepartion of floating insitu gel:

The formulation were prepared as given in table by heating polymer at 60⁰C in deionized water with continious stirring .After cooling below 40⁰C gas forming agent Calcium carbonate ,cross linking agent Calcium chloride ,buoyancy enhancer Sodium carbonate ,Dexlansoprazole were added with continious stirring.

Table no 2: Prepartion of floating insitu gel

1. Determination of pH: In this study pH was determined by using digital pH meter. Add prepared formulation in a 100 ml beaker. Place the digital pH meter into the beaker contained prepared in-situ gel formulation. 
2. Determination of Drug content: Accurately 10 ml of formulation from different batches was measured and transferred into a 100 ml volumetric flask. To this was added 50-70 ml of 0.1 N HCl and stirrer for 1 hr on mechanical stirrer .The volume was set to 100 ml. The complete dispersion of the content was visualized and the dispersion was filtered using what-man filter paper, 1 ml of sample was taken from this solution and diluted to 10 ml with 0.1 N HCl. Drug content was measured by UV-Visible spectrophotometer at maximum absorption at 285nm.
3. In-vitro Floating Study :The in vitro floating test was performed by introducing 10 ml of the formulation without too much disturbance in a 100 ml of beaker contained 0.1N HCl (pH 1.2) at 37⁰C. The time required for the in situ gel to rise on the surface and float was determined as floating lag time. The time the formulation constantly floated on surface of the 100 ml of 0.1N HCl was determined as duration of floating, results were. The in vitro floating test revealed the ability to buoyant of all the formulations.
4. Gelation time:For this study accurately measured 10 ml of the formulation added to 100 ml of 0.1N HCl (pH 1.2) at 37^?C with gentle agitation for gelation time determination. For each formulation were performed in triplicate observed gelation time.The gelation time decreases with increasing polymer concentration .
5. Viscosity measurement:  The viscosity of the in-situ gel was determined using a Brookfield Digital Viscometer (NDJ-5S Viscometer). Samples (100ml) were run at 10 rpm /min using spindle No: 62 at room temperature 32. For each sample were performed in triplicate. The viscosity values of all the formulations .
6. In-Vitro Drug Release Studies:In-vitro drug release studies of the Dexlansoprazole floating insitu gel finished product were conducted using the USP Apparatus II(rotating Paddle method) at a stirring speed of 50 rpm. The dissolution was performed at 37 ± 0.5°C in 900 mL of 0.1 N HCL solution as the dissolution medium for 12hours.1 ml of sample withdrawn at interval of 1, 2,3,4…. 12, hours for Floating insitu gel finished product with the replacement of equal volume of dissolution media.  Dilute the sample with 0.1N HCL upto the 10 ml. The samples were measured at 285 nm by UV spectrophotometer (UV-1800 SHIMADZU).

RESULTS AND DISCUSSION

Preformulation studies

Physical Characterization of Dexlansoprazole:

The recived sample of Dexlansoprazole was found to show the following characteristics.

1. Description

Nature: Pale yellowish color

Melting point :139⁰C-140⁰C

Solubility: highly soluble in water, methanol, ethanol.

Identification of drug:

1. Calibration curve of Dexlansoprazole in 0.1 NHCL

Standard calibration curve of Dexlansoprazole at 285 nm follows Beer’s -Lamberts Law in the concentration range 2-10 mcg /ml.

Table no.3.  Absorbance of Dexlansoprazole in 0.1N HCl

Fig no. 1. Calibration curve of Dexlansoprazole in 0.1 N HCl

2. Drug and polymer comptibility study:

Drug excipient interaction plays a vital role in the release of drug from formulation .The pure drug Dexlansoprazole and its physical mixture with sodium alginate and Eudragit RSPO were scanned using FTIR instrument .Here we observed that key functional peak of dexlansoprazole are retained in physical mixture spectrum such as C=C,C=O,C-H that confirms integrity of drug structure .There are additional broad peak such as at 3246.79cm-1 due to hydroxyl group from sodium alginate and shift around 1749.44 cm-1 likely due to Eudragit RSPO ester carbonyl. These donot overlap or mask drug peak, suggesting no major chemical interaction has occured.

Fig no2.  FTIR of Dexlansoprazole

Fig no3.   FTIR of drug and polymer

Physicochemical characteristics of formulated insitu gel:

Table no. 4. Physico-chemical studies

1. pH of formulation :

The pH of each formulation was measured using a calibrated digital pH meter at 27⁰C. The pH of all formulation was found to be within range of 8.4-10.2. It was found that the optimized batche F6 showed 10.2 pH respectively.

2. Viscosity measurement:

The viscosity of all formulation was determined by Brrokfield viscometer DV-II( Brrokfield,USA) using spindle number 62 with cuo and bob setting at 30 rpm .It was found that the optimized batches F6 showed 9.58 cps viscosity respectively.

3. Gelation time:

The gelling capacity of prepared formulation was observed by visual examination.All the prepared batches show gelling time 2-6 sec to immediate after entering in 0.1N HCl .The optimized batch show gelling time 1-2 sec after getting contact wit 0.1 N HCl and remain in the form of gel for upto more than 12 hrs.

4. Floating lag time:

Floating lag time of all the prepared formulations were observed by visual examination. AlI prepared formulations show floating lag time 2 sec -10 sec and the optimized batch show 1-2 sec floating lag time after entering in 0.1 N HCl and show floating for more than 12 hr respectively.

5. Floating duration

Floating duration time of all the prepared formulations was observed by visual examination. All the prepared formulations show floating duration time from 12 to 24 hrs. The optimized batch F6 showed more than 12 hrs respectively.

6. Drug Content Uniformity:

The optimized batch F6 showed 93.75% respectively.

7. In vitro dissolution study:

The dug release study was performed using USP Type II dissolution test apparatus in 0.1N HCI buffer of with pH 1.2. The temperature and speed of the apparatus were maintained at 37^oC and 50 rpm respectively. The samples were withdrawn at predetemined time interval and analyzed for drug concentration at 285 nm by UV-Visible

Table no.5.   Invitro drug release

Fig no. 4. Invitro drug release graph