Microspheres are characteristically free flowing powders consisting of spherical particles of size between 1-1000µm. Microspheres play an important role to improve bioavailability of conventional drugs and minimizing side effects. There are two types of microspheres, - 1. Microcapsules 2. Micrometrices

1.2 GASTRORETENTIVE SYSTEM:

In most of the cases the conventional oral delivery systems show limited bioavailability because of fast gastric emptying time.

Drugs having more absorption from gastrointestinal tract (GIT) and have short half-lives are quickly eliminated from the systemic circulation. In such cases frequent dosing is required for achieving suitable therapeutic activity. Gastro retentive drug delivery is an approach to retain the dosage form in the stomach for an extended period of time and prolong gastric residence time, thereby targeting site-specific drug release in the upper gastrointestinal tract (GIT) for local or systemic effects.^[13,14,15]

1.3 FLOATING AND MUCOADHESIVE SYSTEM:

A gastro retentive dosage form releases the drug over an extended period in the upper gastrointestinal tract (GIT) and stomach thus enhancing its absorption. There have been various approaches to control the gastric residence of delivery system in the upper part of the GIT including floating drug delivery system and mucoadhesive system. Floating dosage forms are developed to float over stomach fluids and to release the drug over a desired period of time. Floating drug delivery system also name as hydro dynamically balanced system (HBS). Bioadhesion is the process by which a natural or a synthetic polymer can adhere to a biological substrate. In case of mucoadhesion biological substrate is mucosal layer. In general, the floating dosage forms release drugs at multidirections and cannot selectively release drugs on the mucosal surface a small amount of drug reaches the target site from multidirectional drug release. For an effective treatment the drug should be site specific. Mucoadhesive drug delivery systems have recently been explored for sustained release at the mucosa and increasing bioavailability of drugs. The combination of floating and mucoadhesive properties may ideally maximize drug release to the specific site, adhering to the mucous layer, in treatment of upper GIT infection.^[1,2,10,11]

1.4 FLOATING DRUG DELIVERY SYSTEM:

Floating systems are low-density systems that have sufficiently buoyancy to float over the gastric contents and remain buoyant in the stomach without affecting the gastric emptying rate. This results in an increased gastric retention time and a better control of the fluctuations in plasma drug concentration. Many buoyant systems have been developed based on granules, powders, capsules, tablets, laminated films and hallow Microsphere. FDDS is suitable for drugs with an absorption window in the stomach or the upper small intestine, for drugs which act locally in the stomach and for drugs that are poorly soluble or unstable in the intestinal fluid FDDS or hydro dynamically balanced systems have a bulk density lower than gastric fluid and thus remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. Based on the mechanism of buoyancy, two distinctly different technologies, i.e. non-effervescent and effervescent systems, have been used in the development of FDDS.^[,9,26,27]

2. AIM AND OBJECTIVE:

The aim of this research work is to formulate and evaluate floating mucoadhesive microspheres containing anti ulcer drug using Ionic gelation method.

The objectives of the present study is -

· To carry out the preformulation studies

· Formulation of floating mucoadhesive microspheres

· Evaluation of formulated microspheres.

· Kinetic data analysis.

· To perform stability study of microspheres

3. MATERIAL AND METHADOLOGY:

3.1 MATERIALS:

The main drug famotidine was obtained from Yarrow chemicals and the other excipients such as HPMC K4m, Ethyl cellulose, Guar gum, Sodium alginate, Calcium chloride were obtained from Nice chemicals.

3.2 METHODOLOGY:

3.2.1 PREFORMULATION STUDIES:

3.2.1.1 Identification of Drug:

The monograph of Famotidine signified that the substance under examination was intimately mixed with potassium bromide. FTIR spectrum of the sample was taken using potassium bromide pellet method. The spectrum of test specimen was recorded over the range from 4000cm-1 to 500cm-1 and compared with the corresponding USP reference standard.

3.2.1.2 Organoleptic Evaluation:

Organoleptic properties of drug like color, appearance and odor was observed and recorded.

3.2.1.3 Determination of Melting Point:

The melting point of drug was determined by capillary tube method. The drug was filled to capillary tube which has one end sealed. The filled capillary tube was placed inside the melting point apparatus and the temperature at which drug melted was noted.^[2,3]

3.2.1.4 Determination of Solubility of Famotidine:

Solubility of famotidine was checked in various solvents like glacial acetic acid, water, methanol etc. 100mg of drug was accurately weighed and transferred into a stoppered tube containing 0.1ml of solvent. If completely dissolved, the drug is said to be very soluble. If insoluble, added 0.9ml of solvent to it and is said to be freely soluble on complete dissolution. Otherwise, added 2ml of solvent to the same. The drug, if completely dissolved in the solvent, then it is said to be soluble. If insoluble, further 7ml of solvent was added and observed to be sparingly soluble on complete dissolution. On further addition of 10ml of solvent it is said to be slightly soluble, if completely dissolved. If it is not completely dissolved in the above solution, accurately weighed 1 mg of drug and added 10ml of solvent. If the solvent dissolves the drug, it is said to be very slightly soluble.^[16,17]

3.2.1.5 Analytical Method Used in the Determination of famotidine:

UV spectrophotometry method was developed for the analysis of drug using double beam Systronics-2202 spectrophotometer.

3.2.1.5.1 λ max of Famotidine in 0.1N HCL:

An absorption maximum of Famotidine was determined using 0.1N HCL.A sample of 1mg/ml was scanned from 200-400nm using UV spectrophotometer

3.2.1.5.2 Preparation of calibration curve of Famotidine Preparation of 0.1 N Hydrochloric acid:

Accurately measure 8.5ml of hydrochloric acid and sufficient water to make up to 1000ml.

Preparation of stock solution:

Accurately weigh 100mg of Famotidine and transfer it to a 100ml volumetric flask. Then make up the volume to 100ml with 0.1 N HCL.^[18]

Preparation of standard solution:

Pipette out 10ml of the above solution and transfer it to a 100ml volumetric flask. Then make up the volume to 100ml with 0.1 N HCL. Then from the standard stock solution withdraw 2ml, 4ml, 6ml, 8ml, and 10ml into five 100ml different volumetric flasks. Then make up the volume to 100ml with 0.1N HCL to get 2, 4, 6, 8, 10 µg/ml concentration.^[19,20]

3.2.1.5.3 Compatibility studies:

Excipients are any substance other than active or prodrug included in the manufacturing process or contained in the finished product.

3.2.1.5.4 FTIR Study:

The IR spectra were recorded using FTIR spectrophotometer. The samples were prepared by mixing the drug and the excipients in 1:1 ratio and the mixtures were stored in closed containers for 1 month. FTIR spectrum of the samples was taken using potassium bromide pellet method. The physical mixtures of famotidine and excipients were scanned in the wavelength region between 4000 and 500 cm-1 and compared to check compatibility of drug with excipients. ^[21,22,23]

3.2.1.5.5 DSC:

C study was carried out using DSC-60 instrument to check the compatibility of ingredients. The samples were prepared by mixing the drug and the excipients in 1:1 ratio. Accurately weighed samples were sealed in aluminum pans and analyzed in an inert atmosphere of nitrogen at flow rate of 25ml/min. A temperature range of 0°C to 300°C was used, and the heating rate was 10°C/min. DSC thermo grams of pure drugs and physical mixtures of drugs and excipients were studied for their interactions.^[24,25]

3.3Preparation of microspheres:

Floating mucoadhesive microspheres were prepared by ionic gelation method using varying the ratio of guar gum and Ethyl cellulose. Sodium alginate was dissolved in deionized (DI) water (3% w/v). Ethyl cellulose was dissolved separately, and HPMC mixed to above solution. In case of formulations containing guar gum, guar gum was added to the HPMC –Ethyl cellulose mixture. Famotidine (0.6:1 with alginate) was added in the Ethyl cellulose -HPMC matrix and stirred vigorously. The prepared slurry was added to sodium alginate solution and mixed continuously. Cross linking solution was prepared by dissolving calcium chloride in DI water (5% w/v) containing 10% v/v glacial acetic acid. Then the mixture, free from air bubbles, was added dropwise to the cross linking solution through a syringe containing 26G needle. The immediately formed beads were collected by filtration and air dried for 8-10 hours. Spherical dried microspheres were stored in air tight vials for further evaluation. All experiments were performed in triplicate, and the data are shown as mean±standard deviations.^[3,4,5,6]

Table No.1: Formulation of floating mucoadhesive microspheres loaded with an antiulcer drug

Sl No	Ingredients	Formulation
		F1	F2	F3	F4	F5	F6
1	Famotidine (g)	0.1	0.1	0.1	0.1	0.1	0.1
2	Ethyl cellulose (g)	2	2.1	2.2	2.3	2.4	2.5
3	HPMC (g)	0.3	0.3	0.3	0.3	0.3	0.3
4	Guar gum (g)	0.1	0.15	0.2	0.25	0.3	0.35
5	Sodium alginate (%)	5	5	5	5	5	5
6	Calcium chloride(%w/v)	10	10	10	10	10	10
7	Water	q.s	q.s	q.s	q.s	q.s	q.s

3.4 EVALUATION:

The various evaluation parameters suitable for the developed formulation like Angle of repose, Bulk density, Tapped density, Compressibility index, Hausner ratio, Morphology and size, Percentage yield, Drug entrapment efficiency, In-vitro mucoadhesion study, in-vitro buoyancy, in –vitro drug release, release kinetics and stability studies was performed.

4. RESULT AND DISCUSSION:

4.0.1 Identification of drug:

The sample spectrum of famotidine was compared with the reference spectrum and there was no significant changes in the functional groups.

4.0.2 Organoleptic Evaluation:

· Colour: White to pale yellowish white

· Odor: Odorless

· Appearance: Crystalline in nature

· Taste: Bitter taste

4.0.3 Determination of Melting Point:

The standard melting point of famotidine was found in the range of 163-164℃

4.0.4 Determination of solubility:

The solubility was determined by dissolving the drug in different solvents like water, methanol, glacial acetic acid ,0.1N HCL, ether, ethyl acetate, chloroform and acetone. It was very slightly soluble in water, freely soluble in glacial acetic acid and 0.1N HCL and insoluble in acetone, alcohol and chloroform.

4.0.5 Analytical method for the determination of famotidine:

4.0.5.1 Determination of λ_maxof famotidine in 0.1N HCL:

The 1μg/ ml sample was prepared and scanned between 200 to 400nm. The drug showed maximum absorption at 265nm. So, the λ max of Famotidine was found to be 265nm.

4.0.5.2 FTIR:

FTIR studies were carried out for drug [Famotidine] and for the drug-excipients physical mixtures. The FTIR spectrum of famotidine exhibited peak signals at 777.34 cm^-1, 1143.83cm^-1, 1252.81cm^-1, 2898.14cm^-1 and 3331.89cm^-1 respectively. There were no significant changes in the frequency of the functional groups of famotidine. So, the drug was compatible with other excipients.

4.0.5.3 DSC Studies:

The DSC studies were carried out for drug [famotidine] and drug-excipients physical mixtures. The recorded DSC thermo grams showed the profile of Famotidine with melting point at 163.6ºC. The melting point remains almost same for famotidine with other excipients indicated that the drug and excipients are compatible with each other.

5.CONCLUSION:

There are different types of ulcer and the most common are peptic ulcer. There is no single cause has been found for ulcers. Ulcers are mostly caused by an infection with a type of bacteria called Helicobacter pylori. Peptic ulcer will get worse if not treated. Treatment may include medicines to reduce stomach acids or to kill H.pylori.

Famotidine is a potent histamine H2-receptor antagonist with a short biological half-life (2.5-4 h). Famotidine is readily but incompletely absorbed with site-specific absorption in the upper part of the gastrointestinal tract (GIT) with an oral bioavailability of 40-45% due to narrow absorption window in GIT. Therefore the development of formulation in the form of combined floating and mucoadhesive drug delivery system (FMDDS) would be an ideal approach to delivery such drug.

Here the formulated floating mucoadhesive microsphere containing famotidine prepared with varying ratio of guar gum and ethyl cellulose prolong the gastric retention and maximize drug release to the specific site by floating on gastric fluid and adhering to the mucous layer in the treatment of peptic ulcer.

6. REFERNCES:

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9. Vasr JK, Tambwekar K, Garg S. Bioadhesive microspheres as a controlled dug delivery Drug delivery system. Int. J. Pharm. 2003; 255:13-32.

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11. Desai, Julan. U. Floating drug delivery systems: An approach to gastro retention Pharmaceutical Reviews. Pharma info.net. 2007; 3(5):54-60.

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13. Jassal M, Nautiyal U, Kundlas J, Singh D. A review: Gastroretentive drug delivery system (grdds). Indian J. Pharm. Biol. Res. 2015; 3(1):82-92.

14. Sanjay Garg, Shringi Sharma. Gastroretentive Drug Delivery Systems. Pharmatech.2003; 5(6): 160-66.

15. Vedha Hari. The Recent Developments on Gastric Floating Drug Delivery Systems: An Overview. Int J Pharmtech Res.2010; 2(1): 524-34.

16. Rajeshwar, Kamal Kant, Arya, Ripudam Singh, Vijay Jujal. Mucoadhesive Microspheres of Famotidine: Preparation Characterization and In vitro Evaluation. Int. J. of Eng Sci Tech. 2010; 2(6):1575-80.

17. Shah SH, Patel JK, Patel NV. Stomach specific floating drug delivery system: A review. Int J Pharm Tech Res. 2009; 1(1):623–33.

18. Arora S, Ali J, Ahuja A, Khar R K, Baboota S. Floating Drug Delivery Systems: A review. AAPS Pharm Sci Tech. 2005; 6(3): 372‐90.

19. M. Najamuddin, Aejaz Ahmed, Sachin Shelar, V. Patel, T. Khan. Floating Microspheres of Ketoprofen: Formulation and Evaluation. Int. J. Pharm. Sci. 2010; 2(2):164-8.

20. Shaikh R, Singh TRR, Garland MJ, Donnelly RF. Mucoadhesive Drug Delivery Systems. J Pharm Bio Sci.2011; 3(1):89-100.

21. Mohan M, Sujitha H, Dr. Rao V. U. M, Ashok M, Arun Kumar B. A brief review on mucoadhesive microspheres. Int J Res Rev Appl Sci. 2014; 4(1):975-86.

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25. Vikram K, Nitin S, Pratap K, Shubhini A. Formulation and evaluation of floating-mucoadhesive microspheres of novel natural polysaccharide for site specific delivery of ranitidine hydrochloride. Int J App Pharm .2017; 9(3):15-19.

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Received on 20.09.2019 Modified on 24.11.2019

Research J. Pharm. and Tech. 2020; 13(8):3759-3764.

DOI: 10.5958/0974-360X.2020.00665.4

Formulation	Bulk Density	Tapped Density	Compressibility Index	Angle of Repose	Hausners Ratio
F1	0.5634±0.002	0.678±0.0025	13.1±0.003	26.25±0.03	1.082±0.001
F2	0.5839±0.0035	0.612±0.0026	12.5±0.002	26.52±0.01	1.099±0.02
F3	0.582±0.0038	0.687±0.003	12.9±0.02	27.392±0.003	1.125±0.009
F4	0.603±0.0029	0.678±0.0021	13.7±0.0032	27.52±0.00321	1.164±0.003
F5	0.571±0.0015	0.665±0.0035	15.1±0.0021	28.53±0.01	1.163±0.0012
F6	0.562±0.0035	0.692±0.005	15.9±0.019	29.592±0.002	1.152±0.00035

Formulation	Zero order R²	First order R²	Higuchi Model R²	Hixon- Crowell model R²	Korsmeyer peppas N
F1	0.982	0.987	0.955	0.993	1.41
F2	0.964	0.985	0.978	0.988	1.32
F3	0.944	0.991	0.991	0.988	1.3
F4	0.997	0.954	0.920	0.980	1.48
F5	0.993	0.999	0.935	0.968	1.55
F6	0.998	0.992	0.994	0.927	1.54

Sampling interval (month)	Storage condition (40℃±2℃/75%RH)
Parameters	Percentage buoyancy	Percentage yield	Entrapment efficiency	*In vitro* mucoadhesion
Initial	91.3±0.71	81.72±0.028	89±0.071	84±1.27
Third	91.2±0.71	81.69±0.027	89±0.07	83±1.27