MUCOADHESIVE AGENTS 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. DEFINITION 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. SIGNIFICANCE The aim of this investigation was to prepare microemulsions containing zolmitriptan (ZT) for rapid drug delivery to the brain to treat acute attacks of migraine and to characterize microemulsions and evaluate biodistribution in rats. Zolmitriptan microemulsions (ZME) were prepared using the titration method and were 1
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MUCOADHESIVE AGENTS
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.
DEFINITION
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.
SIGNIFICANCE
The aim of this investigation was to prepare microemulsions containing zolmitriptan
(ZT) for rapid drug delivery to the brain to treat acute attacks of migraine and to
characterize microemulsions and evaluate biodistribution in rats. Zolmitriptan
microemulsions (ZME) were prepared using the titration method and were
characterized for globule size distribution and zeta potential
ABSTRACT
The aim of the investigation was to prepare and characterize
microemulsion/mucoadhesive microemulsion of tacrine (TME/TMME), assess its
pharmacokinetic and pharmacodynamic performances for brain targeting and for
improvement in memory in scopolamine-induced amnesic mice. The TME was
prepared by the titration method and characterized. Biodistribution of tacrine solution
and formulations after intravenous and intranasal administrations were evaluated
using 99mTc as marker. From the data, the pharmacokinetic parameters, drug targeting
efficiency, and direct nose-to-brain drug transport were calculated.
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CLASSIFICATION
Drug targeting can be classified on the basis of the level of selectively obtained on
the delivery process.
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). ETIN
SECOND ORDER OF TARGETING (CELLULAR TARG G)
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
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.
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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
BUCCAL DELIVERY SYSTEM
1. Sublingual Delivery system
2. Vaginal delivery system
3. Rectal delivery system
4. Nasal delivery system
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MUCOADHESIVE STUDIES
To characterize the mucoadhesive strength, the detachment force method was
used. Mouth of a glass vial fixed with a fresh section of animal tissue from fundus
portion of goat intestine, facing mucosal side out and kept in simulated gastric fluid
(pH 1.2) without pepsin. Kept another portion of mucus side of exposed tissue over a
rubber stopper and secured with an aluminum cap. The mucoadhesive tablet placed on
the exposed mucus layer (later case), kept in contact with the former tissue which is
connected with a pan in which the weight can be raised. At specific intervals, applied
weight and the force required to detach measured for mucoadhesive strength.
The shear stress measures the force that causes a mucoadhesive to slide with respect
to the mucus layer in a direction parallel to their place of contact of adhesion. The test
was done by coating either side of the two slides with natural adhesive agent followed
by the second layer coated with mucous layer. Mucus forms thin film between the two
natural adhesive coated slides the test measures the force required to separate the two
surfaces. In present study was used weight with reference to force. calculate using the
formula:
A small glass plate (2Χ5cm) was coated with 1% w/v of the mucoadhesive agent.
The mucus gel was taken from goat intestine kept in a suitable container, where the
above-mentioned glass plate can be kept in contact with gel in a balanced condition
and the temperature was maintain at 30° C. Nylon thread was attached at one end of
the glass plate. Provision was given to raise the weight (4) at the other end. At
specified intervals, weight was added to detach the coated glass plate (2) from gel and
the force required to pull the plate out of the gel (3) was determined under
experimentalcondition.
PREPARATION OF MUCOADHESIVE TABLET
Theophylline mucoadhesive tablets were prepared using Cadmach; tablet machine by the wet
granulation technique. The drug to adhesive agent ratio used was1:1, 1:2 and 1:3 .
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IN VITRO RELEASE STUDY
The in vitro release studies of theophylline 100 mg oral mucoadhesive tablet were
carried out according to U.S.P apparatus 2 (paddle method). 100 mg tablets were
taken in 900 ml of acidic buffer (pH 1.2) maintained at 37° C and rotated at 50 rpm.
At specific time intervals 5 ml of the sample withdrawn from the dissolution media
and equal volume of media was replaced immediately. Withdrawn samples were
filtered, suitably diluted and analyzed spectrophotometrically at 272 nm.
IN VIVO BIO ADHESIVE STUDY
To study the bioadhesive character and mean residence time of the natural polymer in
the stomach, barium sulphate loaded tablet was used. Two healthy rabbits weighing
2.5 kg were selected and administered orally with the tablet. X-ray photograph was
taken at different time intervals shown in the . (Animal ethical committee No: JSSCP/
IAEC/ M.PHARM/ PH. CEUTICS/ 05/ 2007 - 2008.)
Mucoadhesion is the relatively new and emerging concept in drug delivery.
Mucoadhesion keeps the delivery system adhering to the mucus membrane.
Transmucosaldrug delivery systems show various merits over conventional drug
deliversystem. Mucoadhesive polymers facilitate the mucoadhesion by their specific
properties.This article reviews desirable properties of mucoadhesive polymers and the
latest advancement in the field.
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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.
GASTRO INTESTINAL TRANSIT OF DRUG DELIVERY SYSTEM.
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.
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IMPORTANT FACTORS OF MUCOADHESION
High molecular weight (up to 100,000), High viscosity (up to an optimum),
Long chain polymers, Optimum concentration of polymeric adhesive, Flexibility
of polymer chain, Spatial confirmation, Optimum cross-linked density of polymer,
Charge and degree of ionization of polymer (anion >cation >unionized),
Optimum medium pH, Optimum hydration of the polymer, High applied strength
and duration of its application and High initial contact time, are some basic
properties which a polymer must have to show a good mucoadhesive profile20. The
physiochemical properties of the mucus are known to change during diseases
conditions such as common cold, gastric ulcers, ulcerative colitis, cystic
fibrosis, bacterial and fungal infections of the female reproductive tract and
inflammatory conditions of the eye, thereby changing the degree of mucoadhesion.
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The focus of pharmaceutical research is being steadily shifted from the
development of new chemical entities to the development of novel drug delivery
system (NDDS) of existing drug molecule to maximize their effective in terms of
therapeutic action and patent protection1,2. Moreover the
development of NDDS are going to be the utmost need of pharmaceutical industry
especially after enforcement of Product Patent3,4.The development of NDDS has been
made possible by the various compatible polymers
to modify the release pattern of drug5,6. In the recent years the
interest is growing to develop a drug delivery system with the use of a mucoadhesive
polymer that will attach to related tissue or to the surface coating of the
tissue for the targeting various absorptive mucosa such as ocular, nasal,
pulmonary, buccal, vaginal etc. This system of drug delivery is called as
mucoadhesive drug delivery system.
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NEXT GENERATION MUCOADHESIVE POLYMERS
With the disappointment in the merger
of mucoadhesive systems into pharmaceuticals in the site-specific drug delivery
area, there has been an increasing interest from researchers in targeting
regions of the GIT using more selective compounds capable of distinguishing
between the types of cells found in different areas of the GIT. Loosely termed
“cytoadhesion,” this concept is specifically based on certain materials that
can reversibly bind to cell surfaces in the GIT22. These next
generation of mucoadhesives function with greater specificity because they are
based on receptor-ligand-like interactions in which the molecules bind strongly
and rapidly directly onto the mucosal cell surface rather than the mucus itself .One
these unique requirements is called lectins. Lectins are proteins or
glycoproteins and share the common ability to bind specifically and reversibly
to carbohydrates. They exist in either soluble or cell-associated forms and
possess carbohydrate-selective and recognizing parts. They are found mostly in
plants, to a lesser extent in some vertebrates (referred to as endogenous
lectins), and can also be produced from bacteria or invertebrates24.
Lectin-based drug delivery systems have applicability in targeting epithelial
cells, intestinal M cells, and enterocytes. The intestinal epithelial cells
possess a cell surface composed of membrane-anchored glycoconjugates. It is
these surfaces that could be targeted by lectins, thus enabling an intestinal
delivery concept.One lectin which has been studied to
considerable extent in vitro binding and uptake is tomato lectin (TL),
which has been shown to bind selectively to the small intestine epithelium. In
one study, using the everted gut sac model, this lectin was bound to
polystyrene microspheres. Uptake of (TL) into the serosal fluid was reported as
eight-fold higher than the control (BSA)25. Furthermore,
BSA-coupled microspheres were shown to have slower uptake than TL-coupled
microspheres by a factor of two. In another study, specific binding by tomato
lectin-coated polystyrene microspheres (0.98 mm) to enterocytes in vitro was
examined26. fluorescently labelled polystyrene microspheres were
coated with TL, and incubated in a CaCo-2 cell line. It was observed that the
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lectin-coated microspheres were resistant to repeat washings compared to the
control (BSA-microsphere).For optimal buccal mucoadhesion, Shojaei and Li have
designed,synthesizedand characterized a copolymer of PAA and PEG monoethylether
monomethacrylate(PAA-co-PEG).
(PEGMM)27. By adding PEG to these polymers, many of the shortcomings
of PAA for mucoadhesion, outlined earlier, were eliminated. Hydration studies,
glass transition temperature, mucoadhesive force, surface energy analysis
and effect of chain length and molecular weight on mucoadhesive force were
studied. The resulting polymer has a lower glass transition temperature than
PAA and exists as a rubbery polymer at room temperature. Copolymers of 12
and 16-mole% PEGMM showed higher mucoadhesion than PAA. The effects of
hydration
on mucoadhesion seen by the copolymers revealed that film containing lower
PEGMM content, which had higher hydration levels, had lower mucoadhesive
strengths.. Polymers investigated in this study also showed that
the molecular weight and chain length had little or no effect on the mucoadhesive
force.Lele, et al, investigated novel polymers of PAA
complexed with PEGylated drug conjugate29. Only a carboxyl group
containing drugs such as indomethacin could be loaded into the devices made
from these polymers. An increase in the molecular weight of PEG in these
copolymers resulted in a decrease in the release of free indomethacin,
indicating that drug release can be manipulated by choosing different molecular
weights of PEG.
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FORMULATION AND EVALUTION OF MUCOADHESIVE
DETERMINATION OF MUCOADHESIVE FORCE:
The mucoadhesive force of organogel onvaginal mucosal tissues was determined
by means of mucoadhesive force measuring apparatus, fabricated in our laboratory.
Vaginal mucosal tissues were removed from Sprague-Dawley ratsand tissue were
stored frozen in phosphate buffer at pH 5.5, and thawed to the room temperature
before use. At the time of testing, a section of tissue was secured (keeping the
mucosal side out) to the upper side of a glass vial using a cyanoacrylate adhesive. The
diameter of each exposed mucosal membrane was1.5 cm. The vials were equilibrated
and maintained at 37° for 10 min. One vial with a section of tissue was connected to
the balance and the other vial was fixed on a height adjustable pan. To the exposed
surface of the tissue attached on the vial, a constant amount of 0.1 g organogel was
applied. Before applying the organogel, 150 μl of simulated vaginal fluid was evenly
spread on the surface of the test membrane. The height of the vial was adjusted such
that the organogel could adhere to the mucosal surface of both vials. Immediately, a
constant force of 0.5 N (Newton) for 2 min was applied to ensure intimate contact
between the tissue and the sample. The upper vial was then moved upwards at a
constant force, while it was connected to the balance. Weights were added at a
constant rate to the pan on the other side of the modified balance until the two vials
were separated.The mucoadhesive force, expressed as the detachment stress in
dynes/cm2, was determined from the minimal weights needed to detach the tissues
from the surface of each formulation, using the following Eqn.
Detachment stress (dynes/cm2) = (m×g)/a,
Where ‘m’ is the weight added to the balance in grams; ‘g’ is the acceleration due to
gravity taken as 980 cm/s2; and ‘a’ is the area of tissue exposed.Effect of varying
contact time (1, 2, 3, 5 and 10 min) was investigated for some of the organogel
preparations to optimize initial contact time. In brief, formulations were allowed to be
in contact with mucosa for carrying contact time (1, 2, 3, 5, and 10 min.), and the
mucoadhesive force was determined as discussed above
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MEASUREMENT OF VISCOSITY OF ORGANOGELS:
Viscosity determinations of the prepared organogels were carried out by cone and
plate geometry viscometer (Model: RV DV-E 230), using spindle No 7. Viscosity of
organogels was measured at 10 rpmat a temperature of 25°C[24].The averages of three
readings were used to calculate the viscosity. Evaluations were conducted in
triplicate.
SPREADABILITY:
For the determination of spreadability, excess of sample was applied between
the two glass Slides and was compressed to uniform thickness by placing 1000 g
weight for 5 min. Weight (50g) was added to the pan. The time required to separate
the two slides, i.e. the time in which the upper glass slide moves over the lower plate
was taken as measure of spreadability (S)[25]. S=M×L/T,
Where M = weight tide to upper slide, L = length moved on the glass slide, T
= time taken.
GELLING CAPACITY:
The gelling capacity was determined by placing a drop of the system in a vial
containing 2 ml of simulated vaginal fluid (pH 5.5) freshly prepared and equilibrated
at 37°Cand visually assessing the organogel formation and noting the time for
gelation and thetime taken for the organogel formed to dissolve. Different grades
were allotted as per the organogel integrity, weight and rate of formation of organogel
with respect to time.
IN VITRO RELEASE STUDIES:
The in vitro release of from different formulations was determined using a dialysis
bag placed in a sealed glass vial under constant magnetic stirring. The gel
formulations (2.5 g) were packed into the dialysis bags (Spectra/Por Cellulose
EsterMembrane MWCO: 100 000 Da, Spectrum Labs, Rancho Dominguez, CA)
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sealed with closures of 50 mm (Spectrum Labs). The release medium was 100 mL