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Thursday, May 14, 2009

MUCOADHESIVE AGENTS

MUCOADHESIVE AGENTS


 

Bibin K Das, Deepa P

National College of Pharmacy, Manassery, Calicut


 


 

INTRODUCTION


 


 

Most of the medicinal resource of India is from natural source. Due to modern advances in technology the dosage form could deliver the medicines of either natural, synthetic or else for days to years, 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. The reasons that the oral route achieved such popularity may be impart attributed to its ease of administration as well as the traditional belief that by oral administration the drug is as well absorbed as the food stuffs that are ingested daily.


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 

1 DEVELOPMENT OF DRUGS DELIVERY SYSTEM


 


 

    In recent years, considerable attention has been focused on the development of new drug delivery system. There are a number of reasons for the intense interest in new system. First one is possibility of repeating successful drugs by applying the concepts on techniques of controlled released drug delivery system. Second one is the need to deliver the novel. Numerous oral delivery systems have been developed to act as drugs reservoirs from which the active substance is released over a defined period of time at a predetermined and controlled rate. From a pharmacokinetic point of view, the idea of sustained and controlled release dosage forms should be comparable to an intravenous infusion, which continuously supplies the amount of drug needed to maintain constant plasma level once the steady state is reached.


 


 


 

2 GASTRO INTESTINAL TRANSIT OF DRUG DELIVERY SYSTEM.


 


 

  1. Gastric Emptying


 

After ingestion, an oral no disintegrating dosage form will stay in the stomach for an unpredictable period of time. (A. J. Moes. Et.al.). the role of the stomach in terms of its anatomical structure and motor functioning during either inter digestive or digestive phase.


 


 

During inter digestive phase, the fasted stomach exhibits a cyclic activity called inter digestive migrating motor complex (IMML). Each cycle can be divided into four phases as follows.


 


 

Phase-I


 

The most quiescent, develops few or no contractions during 45 to 60 min.


 

Phase-II


 

The Incidence of irregular and intermittent sweeping contractions gradually increases, culminating in the onset of phase III.


 

Phase-III


 

Intense bursts of peristaltic waves appear involving both the proximal and distal gastric regions and lasting about 5 to 15 min.


 


 


 


 


 


 


 

Phase – IV


 

It is transition period of decreasing activity until the next cycle begins.


 

  1. Other factors influencing gastric emptying


 


 

Numerous other factors may influence the gastric transit of sustained release dosage forms. Among the stimulatory and inhibitory mechanisms that regulate the emptying rate of meal, the characteristics of the diet components have to first be taken into account first. These include acidity, osmolality , temperature, viscosity, volume, caloric contents and relative fat, protein and carbohydrate concentrations(A.J. Moes et. al).


 


 


3. Prolongation of the Gastric Residence of Dosage forms.


 


 

From the theoretical point of view, these instances are few and mainly depend on the characteristics of the drug substances.


 

Examples


 

1. Poorly acid soluble drugs may show dissolution problems in gastric fluids.


 

2. Drugs that are unstable and destroyed in the gastric environment.


 


 

3. Corticosteroids and 5-amino salicylic acid, specifically designed oral forms may prove superior to rectal preparation in as much as small intestine release can be avoided.


 


 


 

4. Drug Targeting


 


 

Paul Enrich first introduced the Concept of drug targeting by (10990), when he had been reported, which can deliver a drug selectively to the desired site of action without harming the non-target organs or tissues. Drug targeting can be defined as the ability to direct a therapeutic agent specifically to the desired site of action with little or no interaction with target tissues. (Paul Enrich, et.al)


 

The drug targeting includes,


 

  1. The ability to reach specific cells or diseased site in the body with concomitant reduction in the dose and side effects.
  2. To reach previously unacceptable sites.
  3. To protect the drug and the body from one another until the desired site of action is reached.
  4. To control the frequency of drugs dosing to pharmaceutical receptors.


 


 


 


 

CLASSIFICATION


 


 


Drug targeting can be classified on the basis of the level of selectively obtained on the delivery process.


 

  1. First Order of Targeting(Organ Targeting)


 

It refers to the restricted distribution of drug carrier complex to the capillary bed of the site or action (Organ or tissues).


 

  1. Second Order of Targeting (Cellular Targeting)


 

It refers to the selective delivery of the drug carrier complex to specific cell.


 

Example: Tumor Cells.


 

  1. Third Order of Targeting (Sub-Cellular Targeting)


 

It refers to the carrier directed release of drug at selected intracellular sites.


 


 


 


 


 


 


 


 


 


 


Example: Lysosomes


 


 


 

  1. Controlling of GIT Transmit


 


 

To control and to prolong the GIT transmit of oral controlled delivery system for all kind of drugs are through the polymers mainly, and the polymers may be of either natural or synthetic.


 

Hence it may be emphasized that the polymers are playing a key role in all types controlled/ sustained release dosage formulations and requires almost importance in selection of polymers, which should be therapeutically and chemically insert so that the untoward effects may not occur when administered into the human system(Paul Enrich.et.al)


 

The main objective of this is, polymers can be used to over come physiological barriers in long-term drug delivery.


 

MUCOADHESION DRUG DELIVERY SYSTEM


 


 

Mucoadhesion in drug delivery systems has recently gained interest among pharmaceutical scientists of promoting dosage form residence time as well as improving intimacy of contact with various absorptive membranes of the biological system (Wong, L.F. et.al).


 

The concept of mucosal adhesives or Mucoadhesives, was introduced into the controlled drug delivery are in the early 1980s (ALKa Ahuja et.al)


 

Mucoadhesives are synthetic or natural polymers, which interact with the mucus layer covering the mucosal epithetical surface and mucin molecules constituting a major part of mucus.


 

The mucoadhesive drug delivery system may include the following


 


 

  1. Buccal delivery system
  2. Sublingual Delivery system
  3. Vaginal delivery system
  4. Rectal delivery system
  5. Nasal delivery system
  6. Ocular delivery system
  7. Gastro Intestinal delivery system


 


 

USE OF MUCOSAL ADHESIVE PREPARATIONS


 


 

    The drug absorption is limited by the residence time of the drug at the absorption site. For example, in ocular drug delivery, less than 2mts are available for drug absorption after instillation of a drug solution into the eye, since it is removed rapidly by solution drainage, hence the ability to extend contact time of an ocular drug delivery system in front of the eye would undoubtedly improve drug bioavailability.


 

In oral drug delivery, the drug absorption is limited by the gastrointestinal transit time of the dosage form. Since many drugs are absorbed only form the upper small intestine, localizing oral drug delivery systems in the stomach or in the duodenum would significantly improve the extent of drug absorption. The mucus layer, which covers the epithelial surface, has various roles.


 

1. Protective Role


 


 

The Protective role results particularly from its hydrophobicity and protecting the mucosa from the lumen diffusion of hydrochloric acid from the lumen to the epithelial surface.


 

2. Barrier /role


 


 

The mucus constitutes diffusion barrier for molecules, and especially against drug absorption diffusion through mucus layer depends on molecule charge, hydration radius, ability to form hydrogen bonds and molecular weight.


 

3. Adhesion Role


 


 

Mucus has strong cohesive properties and firmly binds the epithelial cells surface as a continuous gel layer.


 


 

4. Lubrication Role


 


 

The mucus layer keeps the mucosal membrane moist. Continuous secretion of mucus from the goblet cells is necessary to compensate for the removal of the mucus layer due to digestion, bacterial degradation and solubilisation of mucin molecules.


 

5.
Mucoadhesion


 


 

One of the most important factors for bioadhesion is tissue surface roughness. Castellanos et.al(1) showed that adhesive joints may fail at relatively low applied stresses if cracks, air bubbles, voids, inclusions or other surface defects are present. Viscosity and wetting power are the most important factors for satisfactory bioadhesion.


 


 

THEORIES OF BIOADHESION


 


 

Several theories have been proposed to explain the fundamental mechanisms of adhesion. They are,


 

  • Electronic Theory


 

  • Adsorption Theory


 

  • Wetting Theory


 

  • Diffusion Theory


 

  • Fracture Theory


 


 


 


 


 


 

1. Electronic Theory


 


 

Electron transfer occurs upon contact of an adhesive polymer with a mucus glycoprotein network because of difference in their electronic structures. This results in the formation of an electrical double layer at the interface. Adhesion occurs due to attractive forces across the double layer.


 


 

2. Adsorption Theory


 


 

    After an initial contact between two surfaces, the material adheres because of surface acting between the atoms in the two surfaces.


 


 


 

3. Wetting Theory


 

    It is predominantly applicable to liquid bioadhesive systems. It analyses adhesive and contact behavior in terms of the ability of a liquid or paste to spread over a biological systems.


 


 

4. Diffusion Theory


 

    The Polymers chain and the mucus mix to a sufficient depth to create a semi permanent adhesive bond. The exact depth to which the polymer chains penetrate the mucus depends on the diffusion co-efficient and the time of contact.


 


 

5. Fracture Theory


 

    In this theory, attempted to relate the difficulty of separation of two surfaces after adhesion. Fracture theory equivalent to adhesive strength is given by,


 


 


 

G = (È € I L )1/2


 

È = Young's Modulus of elasticity


 

€ = Fracture energy


 

L = Critical crack length


 


 

 


 

AIM AND SCOPE OF WORK


 


 

    Mucoadhesives are synthetic or natural polymers or agents, which interact with the mucus, layer covering the mucosal epithelial surface and mucin molecules constitutioning the major part of mucus.


 

    The adhesives firmly stick to the mucosal surface and prolonged its gastric residential time, until removes it over of mucin.


 

    Most of the routes of drug administration such as ocular, nasal, buccal, respiratory, gastrointestinal, rectal and gaginal route are coated with mucus layer, mucoadhesive are expected to increase the residence time. They provide intimate contact between a dosage form and the absorbing tissue, which may result in high drug concentration in local area and hence high drug flux through the absorbing tissue.


 

    Furthermore, the performance of mucoadhesive can be tested by various methods. Such as


 


 


 

  1. Measurement of Bioavailability
  2. Measurement of Residence Time
  3. Measurement of Tensile Strength
  4. Thumb test
  5. Falling liquid film method
  6. Mucin gold staining


 


 


 


 


 

    The performance or the capacity of mucoadhesive can be accessed by analyzing the parameters which will provides the degree of adhesion and the possible methods to be studied in this laboratory are as follows.


 

  1. Measurement of shear and peel strength
  2. Wilhelmy's method
  3. Falling sphere method
  4. Invivo evaluation studies


 

These studies may open up new links to identify the exploited mucoadhesive for the therapeutic aspects.


 


 


 


 


 


 


 


 


 

REVIEW OF LITERATURE


 

    A review of literature survey has been carried out through various Indian and international journals that are view the properties and evaluation of Polymers and related aspects. Some of the important works are revealed here.


 

    A method using texture analysed equipment and chicken pouch as the biological tissue was evaluated for measuring the bioadhesive properties of some polymers (Wong, C.F.et.al)


 

    Vila –Jato, et. al., have carried out a discussion of bioadhesive systems is presented including mucus structure, types of mucous – bioadhesion binding , the use of bioadhesion models in the prediction of bioadhesive characteristic of a polymer, and practical application.


 

    The tablet prepared with HPMC K4M showed greatest bioadhesion was reported I invitro bioadhesion to rabbit intestine (Madhusudan Rao et. al)


 


 

    Evaluation of mucoadhesive buccal patch for delivery of peptides and invitro study of bioadhesives was done by Li,C.Bhatt, et.al.


 

    Minarro, et.al has carried out the technological aspect of modified release of oral dosage form: matrix floating and bioadhesive system.


 

    The modeling mucoadhesion by use of surface energy terms obtained from the Lewis acid – base approach and studies on anionic, cationic and nonionic polymers(Rillosi,et.al).


 

    Achar, L. Peppas, N.A, have carried out the preparation characterization and mucoadhesive ineractions of Poly (methacrylic acid) co polymers with rat mucus.


 

    
 

    Gupta, A. et.al have carried out interpolymer complexation and its effect on bioadhesive strength and dissolution characteristics of buccal drug delivery system.


 

    Kopecek, J.et.al has carried out the study of potential of water-soluble polymeric carries in targeted and site specific delivery.


 

    A review of bioadhesion/mucoadhesion polymers, assessment and determination bioadhesion strength, mucoadhesion dosage form, equipment and methods for measuring mucoadhesion and several controlled release mucoadhesive dosage forms are discussed. (Gandhi et.al).


 

    Hassan, E.E. ,gallo, J.M. have studied the rheological method for the in vitro assessment of mucin- polymer bioadhesive bond strength.


 

    Mikos, A.G.et.al have been analysed a simple invitro method for testing and classifying the bioadhesive behaviour or polymeric micro particle with or without drugs is presented.


 

    Review the application of controlled released bioadhesive formulation developed for different route of administration including oral, buccal, nasal and vaginal etc (Garcia gonazalez, et.al)


 

    The effects of aging on the rheological, dielectric and mucoadhesive properties of gel system were reported by Tamburic,s.Craig, DQ.et.al.


 

    Drug release from oral mucosal adhesive tablets of chitosan and sodium alginate were also reported by Miyazaki S. Nkayama et.al.


 

    In the Invitro / ex vivo methods for evaluation of bioadhesive polymers, the apparatus for the evaluation of bioadhesive properties of pharmaceutical polymers are described and tested (Maggi, L.et.al).


 


 

DESCRIPTION OF THE POLYMERS AND CHEMICALS


 

Hydroxy propyl methyl cellulose


 

    Hydroxy propyl cellulose is mixed alkyl hydroxyl alkyl cellolosic ether and may be regarded as the propylene glycol ether of methyl cellulose.


 


 

Chemical name        : Cellulose, 2-hydroxy propyl methyl ether.


 

Empirical formula        : C8H15O6-(C10H8O6)-C8H15O5


 

Molecular weight        : (Approx.) 86,000


 

Density            : 0.25-0.70 g/cm3


 

PH                : 6.0 – 8.0(1 % aqueous solution)


 

Stability            : solutions are stable at PH 3.0 to 11.0


 


 


 

Applications:


 

    It is suspending, viscosity – increasing and film forming agent. It is also used as a tablet binder and as an adhesive ointment ingredient.


 


 


 

RESULTS AND DISCUSSION


 

    Mucoadhesive drug delivery system of dosage forms generally increases the residential time of dosage forms. The extension of residential time of dosage form mainly depends on the release rate of a drug from the core material and from the matrix in which the drug is loaded.


 

    The release rate is mainly controlled by the polymers and in this study, it is brought out that the natural substance, which possess the gummy nature was subjected for evaluation studies as per the existing literatures.


 

    The mucoadhesiveness of a sample is due to interaction between the mucin, a glycoprotein present in the mucosa of the intestine and the drug polymer matrix. Generally hydrophilic groups such as –OH and _NH2 groups are responsible for such interactions. Most of the natural gums possess the said groups and which may be responsible for the increase of residential time by adhering the complex or drug matrix on the intestinal area and the slow release of drug maintains the therapeutic effect.


 

    The observation reveals that the natural and synthetic substances subjected fir invitro evaluations possess the bioadhesive characteristics. Among which the natural gum obtained from Albizia odoratissima possess considerable gm of weight was required to detach 1% w/v coated plate from the mucous gel. Among the synthetic polymers, Carbopal NF-940 was found to possess good adhesiveness. 1.4 gm force was required to detach.


 

CONCLUSION


 

    The polymers are playing an important role in the field of controlled (or) sustained release drug delivery system.


 

    Mucoadhesives are synthetic or natural polymers, which interact with the mucus layer covering the mucosal epithetical surface and mucin molecules constituting a major part of mucus.


 

    As a result it will release the drug slowly. So we get a prolong duration of action of drug.


 


 


 


 


 


 

BIBILIOGRAPHY


 

  1. Chitnis, VS, et.al , Drug Development and Industrial pharmacy,17(6):pp 879-892. 1991.


 

  1. Indian Pharmacopoeia , 1996


 

  1. Craig, DQ. Et.al. Journal of Pharmacy and Pharmacology 49(Feb): pp 119 – 126, 1997.


 

  1. Bio – Pharmaceutics and Pharmacokinetics a Treatise by D.M. Brahmakar and Sunil B. Jaiswal.


 

  1. Hassan.EE, et.al , Pharmaceutical Research, 7(May): pp 491-495, 1990


 

  1. Madhusudan Rao., Y., et. al , Indian Drug, 35(sep): pp 113 – 121. 1997.


 

  1. Tamburic et.al. Pharaceutical Research , 13(Feb): pp : 279-283, 1996.


 

  1. Magi. L. et. al ., S.T.P. Pharma Sciences, 4(5): pp 343-348. 1994.


 


 


 

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