RECENT TRENDS IN GASTRORETENTIVE MUCOADHESIVE MICROSPHERE

Presented by:-

Mr. Madhav S. Mule

M.Pharm (Semester-3) Department of Pharmaceutics

Guided by:-

Mr. Kshirsagar R.V.

Asst. Professor
School of Pharmacy, S.R.T.M.U. NANDED Maharashtra, India.
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Contents:
Introduction. Approaches To Gastric Retention. Muco-adhesive Systems. Need For Mucoadhesive Microsphere. Advantages. Mechanism of Mucoadhesion. Theories of Mucoadhesion. Polymers Used In Mucoadhesive Microsphere. Factors Affecting Mucoadhesion. Techniques of Formulation Mucoadhesive Microspheres. Evaluation Method of Mucoadhesive Microsphere. Limitation of Gastroretentive Mucoadhesive System.
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Introduction

The control of gastrointestinal transit of orally administered dosage forms using Gastroretentive drug delivery systems (GRDDS) can improve the bioavailability of drugs that exhibit site-specific absorption.

Prolonged gastric retention can be achieved by using floating, swelling, bioadhesive, or high-density systems.

Approaches To Gastric Retention

Floating Systems. Swelling and Expanding Systems . High density systems. Ion exchange resins. Osmotic regulated systems. Low density approach. Bio/Muco-adhesive Systems.

Floating Systems.
Floating Drug Delivery Systems (FDDS) have a bulk density lower than gastric fluids thus remain buoyant in stomach. the system floats on gastric contents, the drug is released slowly at a desired rate from the system

Swelling and Expanding Systems .

These are dosage forms, which after swallowing swell to an extent that prevents their exit from the pylorus. As a result, the dosage form is retained in stomach for a long period of time. These systems may be named as plug type system, since they exhibit tendency to remain logged at the pyloric sphincter
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Ion exchange resins.

Ion exchange resins are loaded with bicarbonate and a negatively charged drug is bound to the resin. The resultant beads are then encapsulated in a semi-permeable membrane to overcome the rapid loss of carbon dioxide.

Osmotic regulated systems.

The osmotic controlled drug delivery device consists of two components drug reservoir compartment and osmotically active compartment. Due to Osmotic pressure microsphere floated in Stomach.
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High density systems.

1. 2.

Gastric contents have a density close to water (~1.004). A density close to 2.5g cm-3 is necessary for significant prolongation of gastric residence time.

3.

The commonly used excipients in high density system includes barium sulphate, zinc oxide, iron powder, and titanium dioxide.

Low density approach.

In this approach, the density of pellets should be less than 1 g/ml, so as to float the pellets or tablets in the gastric fluid and, release the drug slowly for a longer period of time.
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Bio/Muco-adhesive Systems.

The technique involves coating of microcapsules with bioadhesive polymer, which enables them to adhere to intestinal mucosa and remain for longer time period in the GI while the active drug is released from the device matrix.

The cationic chitosan polymers are pharmaceutically acceptable to be used in the preparation of bioadhesive formulations owing to their known ability to bind well to gastric mucosa.

Need For Mucoadhesive Microsphere

Are locally active in the stomach (misoprostol, antacids antibiotics against H.pylori). Have an absorption window in stomach or in the upper small intestine (L-dopa, P-aminobenzoic acid, furosemide). Are unstable in the intestine or colonic environment (captopril). Exhibit low solubility at high pH values (diazepam, verapamil). Alter normal flora of the colon (antibiotics). Absorbed by transporter mechanism (paclitaxel).
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Advantages
Prolongs the residence time of the dosage form at the site of absorption. Due to an increased residence time it enhances absorption and hence the therapeutic efficacy of the drug. Excellent accessibility. Rapid absorption because of enormous blood supply and good blood flow rates. increase in drug bioavailability due to first pass metabolism avoidance. Drug is protected from degradation in the acidic environment in the GIT. Improved patient compliance- ease of drug administration. faster onset of action is achieved due to mucosal surface.
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MECHANISM OF MUCOADHESION
Mucoadhesion has the following mechanism, Intimate contact between a bioadhesive and a membrane (wetting or swelling phenomenon). Penetration of the bioadhesive into the tissue or into the surface of the mucous Membrane (interpenetration).

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THEORIES OF MUCOADHESION
Electronic theory
Electron transfers occur upon contact of adhesive polymer with a mucus glycoprotein network because of difference in their electronic structures. This results in the formation of electrical double layer at the interface and provides an intimate contact between a dosage form and absorbing tissue.

Absorption theory
After an initial contact between two surfaces, the material adheres because of surface force acting between the atoms in two surfaces. Two types of chemical bonds resulting from these forces can be distinguished as primary and Secondary chemical bond.
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Diffusion theory
The polymer chains and the mucus mix to a sufficient depth to create a semi permanent adhesive bond.

Wetting theory
If two substrate surfaces are brought in contact with each other in the presence of the liquid, the liquid may act as an adhesive among the substrate surface.

Cohesive theory
The cohesive theory proposes that the phenomena of bioadhesion are mainly due to intermolecular interaction amongst like molecule
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Polymers Used In Mucoadhesive Microsphere

1. Hydrophilic polymers 2. Hydrogels 3. Newer second generation polymers a. Lectins b. Thiolated polymers c. Polyox WSRA

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Factors Affecting Mucoadhesion

Physiological Factors. Environment-related factors. Polymer-related factors. Physiological Factors. 1. Molecular weight 2. Concentration of active polymer 3. Flexibility of polymer chains 4. Spatial conformation 5. Swelling Environment-related factors. 1. PH of polymer-substrate interface 2. Applied strength 3. Initial contact time

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Techniques of Formulation of Mucoadhesive Microspheres

I. II. III. IV. V. VI.

Hot Melt Microencapsulation Solvent Removal Hydrogel Microspheres Phase Inversion Microencapsulation Solvent Evaporation Spray Drying
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Solvent Evaporation

Techniques Of Formulation Of Mucoadhesive Microspheres

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Spray Drying

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Evaluation Method Of Mucoadhesive Microsphere

In-vitro drug release In vivo drug release In-vitro Mucoadhesivity Determination of drug entrapment efficiency Measurement of adhesive strength/in vitro tests Tensile stress measurement 1. Wilhelmy plate technique 2. Novel electromagnetic force transducer 3. Shear stress measurement
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Tests to measure the adhesive strength

1. 1. 1. 1. 1. 2. 3. 4. 1. 2. 1. 1. 2. Adhesion number Particle size analysis Swelling index of microspheres Production Yield In vitro wash-off test for microspheres Falling liquid film method Everted sac technique Novel rheological approach Measurement of the residence time/in vivo techniques GI Transit using radio-opaque microspheres Scanning Electron Microscopy (SEM) Gamma scintigraphy technique Surface characterization of the mucoadhesive microspheres
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Other in vivo evaluation test

Application Of Gastroretentive Mucoadhesive Drug Delivery Systems

Sustained drug delivery Enhanced bioavailability Site specific drug delivery Reduced fluctuation of drug concentrations Improved selectivity in receptor activation

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Gastroretentive Products Available In The Market

Sr.No. 1 2 3 4 5 6 7 8 9 10 Cytotec Cifran OD Oflin OD Madopar Prolopa Valrelease Conviron Topalkan Almagate FlatCoat Liquid Gavison Brand Name Active Ingredient Misoprostal Ciprofloxacin Ofloxacin L-DOPA and Benserazide L-DOPA and Benserazide Diazepam Ferrous sulfate Aluminum -magnesium antacid Aluminum -magnesium antacid Aluminium hydroxide, magnesium carbonate
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Limitation Of Gastroretentive Mucoadhesive System

Bioadhesion in the acidic environment and high turnover of mucus may raise questions about the effectiveness of this technique. Not suitable for drug that may cause gastric lesions eg. Non- steroidal antiinflammatory drug. The mucus on the walls of the stomach is in a state of constant, resulting in unpredictable adherence. Drugs that are irritant to gastric mucosa are not suitable for GRDDS. The bioadhesion system in patients with achlorhydria can be questionable in case of swellable system, faster swelling properties are required and complete swelling of the system should be achieved well before the gastric emptying time.
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Rferences
Deshpande, A. A., Shah, N.H., Rhodes, C.T., Malick, W., Development of a novel controlled release system for gastric retention, Pharm. Res. 1997; 14 (6): 815-9. Prance Tanagra, N.V.Satheesh Madhav Recent Advances In Oral Mucoadhesive Drug Delivery Systems: A Review IJPRD , ISSN0974-9446. Pandey Shivanand, Different Techniques of Formulation And Evaluation of mucoadhesive Microspheres International Journal of Pharma and Bio Sciences V1(2)2010.
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References
Atyabi, F., Sharma, H.L., Mohammad, H., Fell, J. T., In-vivo evaluation of a novel gastroretentive formulation based on ion exchange resins, J. Control. Rel. 1996; 42: 105-13. Vyas SP, Khar RK. Gastroretentive systems. In: Controlled drug Delivery. Vallabh Prakashan, Delhi, India. 2006. p. 197-217. Chawla G, Gupta P, Bansal AK. Gastroretentive drug delivery systems. In: Jain NK. editor. Progress in controlled and novel drug delivery systems. CBS Publishers and Distributors. New Delhi. 2004. p. 76-97.
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