Mucoadhesive Agents(2)
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Transcript of Mucoadhesive Agents(2)
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.
1
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.
2
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
3
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 .
4
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.
5
6
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.
7
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.
8
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.
9
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
10
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.
11
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
12
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)
13
sealed with closures of 50 mm (Spectrum Labs). The release medium was 100 mL
0.1M citrate-phosphate buffer (pH 5.5) containing 1% Tween 80, providing sink
conditions for clotrimazole. The medium was maintained at 37ºC and stirred at 100
rpm. At various time intervals, 5 mL of dissolution fluid was collected. Levels of
clotrimazole in the samples were analyzed with a Shimadzu UV-VIS 1760A
spectrophotometer at λ = 262 nm. The exact amount of clotrimazole released from the
formulation was calculated with a calibration curve with an analytically validated
method (r2 =0.9958, repeatability coefficient of variation (CV) = 0.11%,
reproducibility CV = 2.2%).
ANTIFUNGAL EFFICACY STUDIES:
The antifungal efficacy study against Candida albicans was determined by agar
diffusion method employing ‘cup plate technique’. Sterile solutions of CT in DMSO
(standard solution) and the developed organogel having the pH adjusted to 7.0 were
poured into cups (0.1 ml of 0.1% w/v) bored into sterile malt yeast agar previously
seeded with test organism. After allowing diffusion of the solutions for 2 h, the agar
plates were incubated at 37°Cfor 48 h. The zone of inhibition (ZOI) was measured
and compared with that of pure drug. The entire operation was carried out in aseptic
condition throughout the study. Each solution was tested in triplicate. Both positive
and negative controls were maintained throughout the study[26].
RESULTS AND DISCUSSION
The organogel formulations were optimized by factorial design method (using
Design Expert software). Concentration of Soya lecithin, Pluronic F 127 and
Carbopol 934, were three factors selected for optimization of formula.Compositions
of various formulations used in the prepared PLOs are given in table 1.
14
TABLE 1: COMPOSITION OF VARIOUS FORMULATIONS
Formulation
Clotrimazole
(%)
Soya Lecithin (%)
Carbopol 934 (%)
Pluronic F127 (%)
Isopropyl myristate upto
(ml)
Sorbic acid (%)
Water upto (ml)
F1 1 2 0.8 50 100 0.2 100
F2 1 2 0.8 32.5 100 0.2 100
F3 1 2 0.2 15 100 0.2 100
F4 1 2 1.4 50 100 0.2 100
F5 1 4 1.4 50 100 0.2 100
F6 1 4 1.4 15 100 0.2 100
F7 1 4 0.2 15 100 0.2 100
F8 1 4 0.2 50 100 0.2 100
F9 1 6 0.8 50 100 0.2 100
F10 1 6 0.8 15 100 0.2 100
F11 1 6 0.2 32.5 100 0.2 100
F12 1 6 1.4 32.5 100 0.2 100
The prepared PLOs formulations were characterized on the basis of spreadibility,
rheological behavior, drug content (%), mucoadhesive force, gelling capacity and in-
vitro release profiles. The prepared PLOs formulations were white to pale yellow
viscous creamy preparation with a smooth and homogeneous appearance. The pH
values of all prepared formulation ranged from 5.5 to 6.5, which is considered
acceptable to avoid the risk of irritation upon application to the skin as pH of skin
5.5.The values of spreadability indicate that the organogel is easily spreadable by
small amount of shear. The spreadability of all formulations from 10.01 to 13.1.
Viscosity determinations of the prepared organogels were carried out by cone and
plate geometry viscometerusing spindle No 7. The highestviscosity was found in
organogel contain high level of the Cabopol 934 concentration.The drug content in
organogel was found in range of 92.8 % to 99.7 %. The higher drug content found in
F11 i.e. 99.7% due to the optimum concentration of pluronic F127 and soya lecithin.
The in vitro release profiles of clotrimazole from its various organogel. formulations
are represented in Table 3. Higher drug release was observed with formulations F11.
15
This finding may be due to presence of optimum level of carbopol 934 (1%) and soya
lecithin (4%). Further increase in concentration of lecithin decreased cumulative %
drug release which might be due to extensive formation of network like structure with
very high viscosity 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
lectin-coated microspheres were resistant to repeat washings compared to the
control (BSA-microsphere).
16
MATERIALS AND METHODS
MATERIALS
Poly(methylvinylether-co-maleic anhydride) (Gantrez S97) and polyvinylpyrollidone
(Plasdone K-90, Mv 1.3 M) were kindly donated by International Specialty Products
(Ohio, U.S.A.). Hydroxyethylcellulose (Natrosol 250-HHX-Pharm, Mv 1.3 M, DS
2.0) and polycarbophil (Noveon AA1, a divinyl glycol cross-linked poly(acrylic acid))
were also kindly donated by Aqualon (Warrington, U.K.) and Noveon Pharma GmbH
& Co KG (Raubling, Germany), respectively. Pluronic (Lutrol F127, a copolymer of
polyoxyethylene and polyoxypropylene, Mv 12600) was purchased from BTC
Specialty Chemical Distribution Limited (Cheshire, U.K.). Erioglaucine disodium salt
(792.85 MW) was purchased from Sigma (Poole, Dorset, U.K.). Replens was supplied
by AAH Hospital Service (Belfast, U.K.). Replens is a commercially available
vaginal moisturizer containing carbomer 934P, glycerin, hydrogenated palm oil
glyceride, mineral oil, polycarbophil, purified water, and sorbic acid. All other
chemicals were purchased from Sigma (Poole, Dorset, U.K.) and were of AnalaR
grade or equivalent quality.
PREPARATION OF RHEOLOGICALLY STRUCTURED VEHICLES (RSV)
Sorbic acid (0.1% w/w) and the required amount of sodium hydroxide to achieve a
final pH = 6 were added to water in a HiVac mixing bowl (Summit Medical,
Gloucestershire, U.K.). The mucoadhesive component, polycarbophil or
poly(methylvinylether-co-maleic anhydride) (PC or Gantrez; 3% w/w), was
subsequently introduced and mixed under vacuum. Following complete dissolution of
the mucoadhesive component, Pluronic F127 (PL; 0 or 10% w/w),
hydroxyethylcellulose (HEC; 5% w/w), and polyvinylpyrrolidone (PVP; 4% w/w)
were added in a stepwise fashion and mixed under vacuum. To remove all entrapped
air, formulations were transferred to McCartney bottles, gently centrifuged, and stored
at 4 °C for 48 h prior to testing. Formulations containing erioglaucine (100 μg per 3 g
dose) were prepared using a similar method with the exception that erioglaucine was
added to the aqueous phase (1.36 mL of 11.18 mg/mL) prior to addition of F127.
17
PREPARATION OF SIMULATED VAGINAL FLUID
For the purposes of gel dilution studies, simulated vaginal fluid (SVF) was prepared
as described by Owen and Katz.(14) NaCl (3.51 g), KOH (1.40 g), Ca(OH)2 (0.222 g),
bovine serum albumin (0.018 g), lactic acid (2 g), acetic acid (1 g), glycerol (0.16 g),
urea (0.4 g), and glucose (5 g) were dissolved in 1 L of deionized water, followed by
adjustment to pH 4.2 with HCl.
IN VITRO EVALUATION OF MUCOADHESION
The mucoadhesive properties of RSVs were determined using a TA-XT2 Texture
Analyzer (Stable Microsystems, Surrey, England) and a previously described mucin
disk test.(15) In summary, porcine mucin discs (250 mg, 13 mm diameter), prepared
by direct compression (10 tonne, 30s), were horizontally attached onto the lower face
of an inert horizontal polycarbonate probe and immersed in a mucin solution (5%
w/w) for 30s. The mucin disk was brought into contact with the formulation under
examination and a force of 1 N was then applied for 30 s to ensure intimate contact
between the disk and formulation.
MEASUREMENT OF WORK OF SYRINGEABILITY
The work done to expel formulations from a model vaginal applicator was determined
using a TA-XT2 Texture Analyzer in compression mode. RSVs (3 g) were packed
into a model applicator and an inert polycarbonate probe was used to expel the
syringe contents at a rate of 2.0 mm/s through a distance of 30 mm. The work done to
expel the syringe contents was calculated from the area under the resultant force-time
plot. In addition to RSVs, a commercially available formulation, Replens was also
studied for comparison purposes.
TEXTURE PROFILE ANALYSIS (TPA)
The compressional flow (hardness and compressibility) properties of RSV
formulations were determined using a TA-XT2 Texture Analyzer in compression
mode, as described previously.(15) In brief, samples (16 g) were packed into identical
McCartney bottles and centrifuged to remove entrapped air. An analytical probe (10
mm diameter) was compressed twice into each formulation at a defined rate (2 mm/s)
to a defined depth (15 mm), allowing a 15 s delay period between the end of the first
18
and beginning of the second compression. From the resultant force-time plot the
mechanical parameters including hardness (the force required to attain a given
deformation) and compressibility (the work required to deform the formulation during
the first compression of the probe) were derived.
RHEOLOGICAL (DYNAMIC) ANALYSIS
Oscillatory (dynamic) rheometry was conducted using an AR2000 rheometer (T.A.
Instruments, Surrey, England) at 25 ± 0.1 °C using a 2 cm diameter parallel plate
geometry and a gap of 1000 μm, as previously reported.(16) Samples were carefully
applied to the lower stationary plate and the upper plate was adjusted to the
predefined gap size. Formulations were then retained for an equilibrium period to
facilitate relaxation of internal stresses introduced during sample loading. During
testing, samples were subjected to a predetermined oscillatory stress value (selected
from within the linear viscoelastic region) over a frequency range from 0.1 to 10 Hz.
Calculation of the storage modulus (G′), loss modulus (G′′), loss tangent (tan δ), and
dynamic viscosity (n′) were performed using proprietary software (TA Instruments,
Leatherhead, England).
IN VITRO GEL DILUTION
Given that vaginal semisolids will experience dilution in vivo it is important to
characterize this effect by dilution of the prepared RSVs with simulated vaginal fluid
(SVF). In summary, a defined mass (3 g) of RSV was thoroughly mixed in a HiVac
mixing bowl (Summit Medical, Gloucestershire, U.K.) with 0.1, 0.3, 0.5, 0.7, and 0.9
mL of SVF. Gels were transferred to McCartney bottles, gently centrifuged to remove
entrapped air and storage at +4 °C for 24 h prior to dynamic rheological analysis (37
°C). The dilution ratio was selected to represent that normally encountered in the
vagina following insertion of the delivery vehicle.(17)
19
FLOW ANALYSIS UNDER CONTINUOUS SHEAR
Flow rheometry was conducted at 25 ± 0.1 °C using an AR 2000 rotational rheometer
operating in continuous flow mode using a parallel plate and a constant gap of 1000
μm. Sample geometry (2, 4, or 6 cm plate) was selected according to formulation
consistency. Flow rheology was conducted using a loop test in which the shearing rate
was increased gradually from a minimum (0.001 s−1) up to a predetermined maximum
(2 s−1) within 60 s and then returned to the starting shear rate under the same
conditions. For comparison purposes, the commercially available vaginal gel,
Replens, was also studied. Modeling of the flow properties of the various
formulations was performed using the Ostwald-de Waele equation, as follows:
where σ is the shearing stress, is the rate of shear, k is the consistency, and n is the
pseudoplastic index.
IN VITRO RELEASE OF ERIOGLAUCINE FROM RSVS
A defined mass (5 g, n = 6) of each formulation was placed in a cylindrical vessel and
anchored at the bottom of a stoppered 100 mL glass vial containing 50 mL of SVF,
and the glass containers were placed in a shaking orbital incubator (Sanyo
Gallenkamp, 100 rpm) maintained at 37 °C. The release medium was sampled (7 mL)
at predetermined time intervals and analyzed by UV spectroscopy at 630 nm. At each
sample point an equal volume of fresh prewarmed dissolution media was added to the
dissolution vessels to replace the volume sampled. The mass of erioglaucine (EG)
released was calculated with reference to a calibration curve (concentration range 0−8
mg/mL, r > 0.999).
20
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).
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.
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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,
The ability to reach specific cells or diseased site in the body with concomitant reduction in the dose and side effects.
1. To reach previously unacceptable sites.2. To protect the drug and the body from one another until the desired site of
action is reached.3. To control the frequency of drugs dosing to pharmaceutical receptors.
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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.
23
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.
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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
25
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
Measurement of Bioavailability
Measurement of Residence Time
Me1asurement of Tensile Strength
Thumb test
Falling liquid film method
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.
Measurement of shear and peel strength
Wilhelmy's method
Falling sphere method
Invivo evaluation studies
26
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. AlEvaluation 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 presentedReview 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,
27
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).
28
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
29
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.
30
SUMMARY
Transmucosal drug delivery systems, are gaining popularity day by day in
the global pharma industry and a burning area of further research and development.
To summarize, polymers with certain specific characters like high molecular
weight and viscosity, long chain length, flexibility of chain length etc.
are needed for the design of transmucosal drug delivery systems.
There is no doubt that mucoadhesion has moved into a new area with these
new specific targeting compounds (Tomato lectins, Corplex™ adhesive hydrogels
etc.) with researchers and drug companies looking further into potential involvement
of more smaller complex molecules, proteins and peptides, and DNA for future
technological advancement in the ever-evolving drug delivery arena.
31
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.
32
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Chitnis, VS, et.al , Drug Development and Industrial pharmacy,17(6):pp 879-892.
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Indian Pharmacopoeia , 1996
Craig, DQ. Et.al. Journal of Pharmacy and Pharmacology 49(Feb): pp 119 – 126,
1997.
Bio – Pharmaceutics and Pharmacokinetics a Treatise by D.M. Brahmakar and Sunil
B. Jaiswal.
Hassan.EE, et.al , Pharmaceutical Research, 7(May): pp 491-495, 1990
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Madhusudan Rao., Y., et. al , Indian Drug, 35(sep): pp 113 – 121. 1997.
Tamburic et.al. Pharaceutical Research , 13(Feb): pp : 279-283, 1996.
Magi. L. et. al ., S.T.P. Pharma Sciences, 4(5): pp 343-348. 1994.
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