Mucoadhesive Gastro Intestinal Drug Delivery System : An Overview
By - 12/17/2007
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Prof. G.S. Asane
Mucoadhesion is a topic of current interest in the design of drug delivery systems. Mucoadhesive drug delivery system prolong the residence time of the dosage form at the site of application or absorption and facilitate an intimate contact of the dosage form with the underline absorption surface and thus contribute to improved and / or better therapeutic performance of the drug. In recent years many such mucoadhesive drug delivery systems have been developed for oral, buccal, nasal, rectal and vaginal routes for both systemic and local effects. This paper lays emphasis mainly on gastrointestinal dosage forms along with concepts, mechanism of mucoadhesion, factors affecting mucoadhesion, anatomy of gastrointestinal tract and evaluation methods.
Introduction
Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs via various pharmaceutical products of different dosage forms. The reasons that the oral route achieved such popularity may be in part attributed to its ease of administration as well as the traditional belief that by oral administration the drug is well absorbed as the food stuffs that are ingested daily. In fact, the development of a pharmaceutical product for oral delivery, irrespective of its physical form (solid, semi-solid or liquid dosage forms) involves varying extents of optimization of dosage forms characteristics within the inherent constraints of GI physiology1.
In the exploration of oral controlled release drug administration, one encounters three areas of potential challenge2.
1.Development of a drug delivery system: To develop a viable oral controlled release drug delivery system capable of delivering a drug at a therapeutically effective rate to a desirable site for duration required for optimal treatment.
2.Modulation of gastro intestinal transit time: To modulate the GI transit time so that the drug delivery system developed can be transported to a target site or to the vicinity of an absorption site and reside there for prolonged period of time to maximize the delivery of a drug dose.
3.Minimization of hepatic first pass elimination: If the drug to be delivered is subjected to extensive hepatic first pass elimination, preventive measures should be devised to either bypass or minimize the extent of hepatic metabolic effect.
Mucoadhesive Drug Delivery System
Definition
Adhesion can be defined as the bond produced by contact between a pressure - sensitive adhesive and a surface3. The American Society of testing4 and materials has defined it as the state in which two surfaces are held together by interfacial forces, which may consist of valence forces, interlocking action or both.
Concepts
In biological systems, four types of bioadhesion could be distinguished5:
1. Adhesion of a normal cell on another normal cell.
2. Adhesion of a cell with a foreign substance.
3. Adhesion of a normal cell to a pathological cell.
4. .Adhesion of an adhesive to a biological substance.
For drug delivery purpose, the term bioadhesion implies attachment of a drug carrier system to a specific biological location. The biological surface can be epithelial tissue. If adhesive attachment is to a mucus coat, the phenomenon is referred to as mucoadhesion. Bioadhesion can be modeled after a bacterial attachment to tissue surfaces, and mucoadhesion can be modeled after the adherance of mucus on epithelial tissue6.
Mechanism of Mucoadhesion7,8
For bioadhesion to occur, a succession of phenomena, whose role depends on the nature of the bioadhesive, is required. The first stage involves an intimate contact between a bioadhesive and a membrane, either from a good wetting of the bioadhesive surface, or from the swelling of the bioadhesive. In the second stage, after contact is established, penetration of the bioadhesive into the crevices of the tissue surface or inter penetration of the chains of the bioadhesive with those of the mucus take place. Low chemical bonds can than settle.
On a molecular level, mucoadhesion can be explained based on molecular interactions. The interaction between two molecules is composed of attraction and repulsion. Attractive interactions arise from Vander walls forces, electrostatic attractions, hydrogen bonding and hydrophobic interactions. Repulsive interactions occur because of electrostatic and steric repulsion. For mucoadhesion to occur, the attractive interaction should be larger than non -specific repulsion.
Factors affecting Mucoadhesion 9,10
1. Polymer related factors:
i) Molecular weight
ii)Concentration of active polymer
iii)Flexibility of polymer chains
iv)Spacial confirmation
v)Swelling
2.Environment related factors:
i)pH of polymer - substrate interface
ii) Applied strength
iii)Initial contact time
3.Physiological factors:
i)Mucin turns over 11
ii)Disease state12
Anatomy and Physiology of the gastrointestinal tract13
Systems used for the delivery of therapeutic agents via the oral route must be designed conscious of the physiology of the gastrointestinal tract. The anatomy and physiology of route of administration may dictate many of the requirements for the systems. For example, the device must be able to withstand the saliva, as saliva contains digestive enzymes and other reagents for breaking down whatever is placed in the mouth. The stomach, the main digestive organ of the body, contains many digestive enzymes and very low pH. The pH of the stomach has been measured from 1.4 to 2.1.This harsh environment causes the destruction and denaturation of proteins without protection. The pH of the stomach changes when food is present increasing to nearly 4.0.14
Once through the harsh conditions of the stomach a device reaches the small intestine, which is divided into three regions. The first region, closest to the stomach, is the duodenum, followed by the jejunum and ileum. Fewer nutrients are taken into the bloodstream, the further down the small intestine they move. The duodenum, about 10 inches in length, composes the first 5% and the jejunum, the following 40% of the length of the small intestine. The entire length of the small intestine is 5 meter and residence time within the organ typically ranges from 2-4 hr.
The lining of the small intestine are composed of the serous, muscular, areolar, and mucous layers. Only the mucous and areolar layers are the important layers with respect to drug delivery. Transport of the nutrients into the body occurs through the mucious cell layer and into the areolar layer where the nutrients are taken into the blood stream. In the mucosal layer, there are cell layers that stick out of it and into the open areas of the duodenum.15 (See table 1)
Oral Gastrointestinal Bioadhesive dosage form applications
Several dosage forms for oral use have been reported.
Tablets
Multilayer tablet allows a variety of geometrical arrangement. Such systems that consist of acrylic polymers or cellulose provide immediate and high adhesion strength at a certain site for prolonged period of time16.
Micro and/or Nanoparticles
Despite the limited loading capacity of drug, bioadhesive micro-and /or nanoparticles have been widely investigated for three major features:
1. Immobilization of particles on the mucosal surface by adhesion after modification of surface
properties via bioadhesive polymers.
2.Very large specific surface between the dosage forms and the oral mucosa.
3.Sustained release of entrapped drug, leading to higher absorption.17
Capsules
Capsules, usually gelatin capsules, containing a suspension or liquid, include bioadhesive polymers such polycarbophil or carbopol. Gelatin interacts with bioadhesive polymer during or following dissolution, and thus bioadhesiveness of the polymer is lost before the bioadhesive polymer has a chance to interact with the mucus layer.18 (table 2)
Evaluation methods to study bioadhesion
Buccoadhesive polymers can be characterized by testing their adhesion strength by in vitro and in vivo tests. These tests are necessary not only for screening a large number of candidates for mucoadhesive, but also to study their mechanisms. The various methods reported are as follows.
1. In vitro / Ex vivo methods
In vitro tests were initially designed to screen potential bioadhesive with a view to in vivo testing, if successful. Presently, more emphasis is being placed on elucidating the precise mechanisms of bioadhesion because; an evaluation of bioadhesive properties is fundamental to the development of new bioadhesive. The most commonly employed in vitro techniques are:
i.Methods based on measurement of tensile strength.27,28
ii.Methods based on measurement of shear strengths.29Other in vitro methods are:30-36
iii.Adhesion weight method.
iv.Fluorescent probe method.
v. Flow channel method.
vi.Mechanical spectroscopic method.
vii.Falling liquid film method.
viii.Colloidal gold staining method.37
ix.Viscometric method.
x.Thumb method
xi.Adhesion number.
xii.Electrical conductance.
2. In vivo methods
The most common in vivo techniques to monitor bioadhesion include:
i.Use of radioisotopes.
ii.Use of gamma scintigraphy.38,39
iii.Use of pharmacoscintigraphy.40
iv.Use of Electron paramagnetic resonance (EPR) oximetry.41
v. Isolated loop technique
vi.X-ray studies42
Conclusion
There is no doubt that the oral route is the most favored and probably most complex route of drug delivery. Critical barriers43,44 such as mucus covering the GI epithelia, high turnover rate of mucus, variable range of pH, transit time with broad spectrum, absorption barrier, degradation during absorption, hepatic first pass metabolism, rapid luminal enzymatic degradation ,longer time to achieve therapeutic blood levels, and intrasubject variability,are all possible issues with oral route. The idea of bioadhesive began with the clear need to localize a drug at a certain site in the GI tract. Therefore a primary objective of using bioadhesive systems orally would be achieved by obtaining a substantial increase in residence time of the drug for local drug effect and to permit once daily dosing.
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Table 1. Gastrointestinal Tract: Physical Dimensions and Dynamics2
Where, a= Isotonic Saline Solution, 500 ml was ingested, b=Residual Volume (50 ml), c= Taking intestinal mircovilli into account, d=Solid food, 50 gm was ingested, e=Food first appeared at the Cecum after 4 hrs and all indigestible material entered the large intestine within 9 hr.
Table 2. Some reported mucoadhesive oral drug delivery system
Where, CP=Carbopol, CMC=Carboxymethyl Cellulose, EC= Ethyl Cellulose, HPMC= Hydroxypropyl methyl cellulose, PEG= Polyethylene Glycol, PAA= Polyacrylic Acid.
About Authors:
Kiran B. Aher
Loni kd, Near Marathi School. Tal. Rahata, Dist. Ahmednagar. MS 413713, Tel.no. 0242-2273410
E-mail: aherkiran@rediffmail.com
Devendra K. Jain
AISSMS College of Pharmacy, Kennedy road, Near RTO, Pune-411001,he is working on projects “Formulation development and evaluation of topical drug delivery system of antifungal drug-Fluconazole”.
Sanjay G. Bidkar
Prof. S. G. Bidkar working in the Dept. of pharmaceutics AISSMS College of Pharmacy, Pune-1. He is also working as technical consultant to many Pharmaceutical Companies, Cosmetic Industries and Food Industries.
G.S. Asane
Prof. G.S. Asane Head, Research Division, Pravara Rural College of Pharmacy, A/P-Loni, (413736) Mob: 09822954743