A Survey on
Mucoadhesive Thermoreversible Drug Delivery System
with special Emphasis on Recto-Anal Region for the Treatment of Internal
Hemorrhoids
Firoz S1*, Rajasekaran S2
1Research Scholar,
Bhagwant University, Ajmer, Rajasthan.
2Department of
Pharmacology, Malik Deenar College of Pharmacy,
Kasaragod, Kerala.
*Corresponding
Author E-mail: firoz.kallur@gmail.com
ABSTRACT:
The concept of combination of
thermo reversibility and mucoadhesion has achieved a
much valuable interest in various fields of pharmaceutics. Mucoadhesive drug
delivery systems interact with the mucus layer covering the mucosal epithelial
surface, and mucin molecules and increase the residence time of the dosage form
at the site of absorption. Thermoreversible gels are
the hydrogels that are liquids at room temperature but undergo gelation when in
contact with body fluids or change in pH. A major
problem faced by conventional formulation in various routes of administration
viz. nasal, ocular, vaginal, rectal, etc is drainage
of instilled formulation, poor patient compliance as in the case of vaginal and
rectal delivery system. Also, blurred vision and irritation to mucosa is
observed in the case of ocular and nasal delivery respectively. The drainage of
the formulation results in inaccurate dose delivery thus decreasing the
bioavailability of the drug which demands an increase in the frequency of the
administration. To overcome these limitations, there is need of novel delivery
system such as thermoreversible mucoadhesive insitu gel which provides an ease of administration and
improved patient compliance as these smart delivery system
is free flowing liquid at ambient temperature and gels at physiological
temperature which is higher than the LCST (low critical solution temperature)
of thermoreversible polymer. The combined effect of mucoadhesion and thermoreversible
property will enhance prolongation of residence time of dosage form and the
accuracy of the dose in body cavity respectively, leading to increased
bioavailability of the drug. This review focuses on benefits of mucoadhesive thermoreversible system of drug delivery through rectum for
the treatment of internal hemorrhoids.
KEYWORDS: Mucoadhesive,
rectal, gel, drug, polymer.
INTRODUCTION:
Such systems
involve mucoadhesion1, i.e. the attachment of the drug along with a
suitable carrier to the mucous membrane. In situ polymeric systems3
represent promising means of delivering the drugs; as these polymers undergo
sol-gel transition, once administered, i.e. they are in solution phase before
administration, but gels under physiological condition4. These
systems are injectable fluids that can be introduced into the body in a minimal
invasive manner prior to solidifying or gelling within the desired tissue,
organ or body cavity. There are various physical and chemical stimuli leading
to in situ gel formation viz. temperature, pH, electric field, magnetic field
and light5. Such a combined system has both fluidity and elasticity
which is required for rectal administration. Rectal drug delivery systems used
to deliver the drug by using mucoadhesive polymers is through the mucous
membrane of the rectum. The rectal route though rarely the first choice of drug
administration, serves as an alternative to oral and invasive administration.
Rectal drug delivery is so pivotal when the oral medication is not possible,
intra venous access is not possible and when the patients have difficulty in
swallowing, nausea and vomiting and for infants or children. For a long period
of time, the rectal route was used only for the administration of local anesthetics, antihemorrhoidal, vermifugal, anti-bacterial and laxative.
Another advantage
of administering a drug rectally is that it tends to produce less nausea
compared to the oral route and prevents any amount of the drug from being lost
due to emesis. In addition, the rectal route bypasses around two thirds of the
first-pass metabolism6 as the rectum's venous drainage is two thirds
systemic and one third hepatic portal system. This means the drug will reach
the circulatory system with significantly less alteration and in greater
concentrations.
The rectal route7
of administration is useful for patients with any digestive tract motility
problem, such as dysphasia, ileus or bowel obstruction that would interfere
with the progression of the medication through the tract. The rectal route
enables a rapid, safe, and lower cost alternative to administration of
medications; it may also facilitate the care of patients in long-term care or
palliative care, or as an alternative to intravenous or subcutaneous medication
delivery in other instances.
This review
focuses on rectal membrane which is interesting for biochemical research as
well as providing a basis for the development of new formulations of poorly
absorbed drugs as the rectum offers a relatively constant environment for drug
delivery provided the drug is presented in a well absorbable form8.
Advantages of
rectal drug delivery9:
1. Irritation to the stomach and small intestine
associated with certain drugs can be avoided. E.g. NSAIDs: Aspirin, Ibuprofen,
Naproxen.
2. Absorption enhancement of many low molecular
weight drugs, proteins and peptides.
3. Contact with digestive fluid is avoided,
thereby preventing acidic and enzymatic degradation of some drug. E.g.Protein peptide drug delivery by rectal offers low
levels of protease activity particularly of pancreatic origin.
4. Hepatic first pass elimination of high
clearance drug may be partially avoided. E.g. Lidocaine, Proponalol,
Morphine, etc.
5. Rectal drug delivery is useful in pediatric, geriatric and unconscious patient specially
having difficulty in swallowing oral medicine.
6. When oral intake is restricted such as prior
to x- ray studies, before surgery or in patient having diseases of upper GIT.
7. Drug delivery can be stopped by removing the
dosage form and drug absorption can be easily interrupted in cases of
accidental overdose or suicide attempts.
8. Drug which traditionally is only given
parentally may be administered rectally. E.g. Peptides
Advantages of Thermoreversible Mucoadhesive Insitu
Gel10,11:
1. Ease of administration.
2. Reduction of taste impact (in rectal delivery)
3. Reduction of irritation (in rectal delivery)
4. Improved patient compliance.
5. Accuracy of dosing as leakage of drug is
prevented.
6. Prolonged residence time.
7. Improved bioavailability.
8. Target delivery to mucosa for better
absorption.
9. Sustained and controlled drug delivery.
Factors affecting drug
absorption in rectum:
Rectal epithelium drug
absorption requires two routes of transportation: transcellular route and paracellular
route. A transcellular route uptake process relies on lipophilia where the
paracellular route is drug diffusion through a gap between epithelial cells.
Where suspensions and suppositories show slow and continuous absorption,
aqueous and alcoholic solutions are rapidly absorbed. Alkaline solutions are
consumed more easily than acid solutions. Two considerations are of major
importance for the venous drainage of the rectum and therefore the movement of
the absorbed substance into the systemic circulation: the site of absorption
and the direction of blood flow. When the drug is absorbed in the upper part of
the rectum, it is transferred to the portal system and passes through the liver
while the drug is delivered directly to the systemic circulation after
absorption in the lower rectum. It generally implies the prevention of hepatic
first-pass removal while delivering a drug in the lower part of the rectum12.
Partially it is possible to avoid first-pass hepatic removal after drug rectal
administration. On average, systemic availability after rectal administration
was increased by nearly 100 percent relative to the oral route for the same
dose.
PHYSIOLOGY OF
RECTUM AND HEMORRHOIDS:
The human rectum
is the terminal part of Gastro Intestinal Tract. The rectum is a hollow organ
that comprises of the last portion of the large intestine and extends 12 -18cm
distally. The rectal wall is formed by an epithelium which is one cell layer
thick and composed of cylindrical cells and goblet cells which secret mucus. This
mucus has no enzymatic activity. There are no villi or microvilli on the rectal
mucosa and thus a very limited surface area (200 – 400 cm2) is
available for absorption and this surface area is sufficient to absorb drugs13.
Volume of fluid in the rectum is about 1-3ml and is viscous. The rectal milieu
is constant as its pH is 7.5-814. Hemorrhoids,
also known as piles, are swollen veins in the lower part of the anus and
rectum. When the walls of these vessels are stretched, they become irritated.
Internal hemorrhoids are deep inside the rectum and
not visible from outside. Often, the first sign that internal hemorrhoids are present is rectal bleeding. Straining can
sometimes push an internal hemorrhoid so that it
protrudes through the anus. This is called a protruding or prolapsed hemorrhoid and can be painful. When an internal hemorrhoid prolapses it brings along mucus that can
irritate the sensitive area around the anus causing itching. If the hemorrhoid stays prolapsed, mucus production continues and
so does the itching.
Fig. 1: Rectal
Membrane and Internal Hemorrhoids
Home treatments
for Internal Hemorrhoids15:
Symptoms can be
relieved in the following ways. However, they will not eliminate the hemorrhoids:
1. Topical creams and ointments: Over the counter
(OTC) creams or suppositories, which contain hydrocortisone, are available to
buy online. There are also pads which contain witch hazel, or a numbing agent
that can be applied to the skin.
2. Ice packs and cold compresses: Applying these
to the affected area may help with the swelling.
3. A sitz bath using warm water: A sitz bath is
placed over the toilet. Some pharmacies sell them, and they may relieve the
burning or itching symptoms.
4. Moist towelettes: Dry toilet paper may
aggravate the problem.
5. Analgesics: Some painkillers such as aspirin,
ibuprofen, and acetaminophen may alleviate the pain and discomfort.
DIFFERENT TYPES
OF RECTAL DOSAGE FORMS:
1. Rectal semisolids: Creams, Gels, Ointments and
Suppositories
2. Rectal liquids: Solutions and Suspensions
3. Rectal aerosols
Rectal cream,
gels, suppositories and ointments:
They are largely
used for topical application to treat local conditions of anorectal pruritis,
inflammation and the pain and discomfort associated with hemorrhoids.
The drugs include: astringents (e.g. Zinc oxide), local anesthetics,
protectants and lubricants (e.g. Cocoa butter, lanolin) and antipruritis
and anti-inflammatory
agents (eg. Hydrocortisone) The use of gels, foams or
ointments for rectal administration can afford advantages over liquid
formulations because retention of the dosage form in the rectal cavity reduces
patient compliance problems. Drug release and subsequent pharmacologic action
is usually faster with semisolid formulations than with solid suppositories
since a lag time is not required for melting or dissolution. Typically, rectal
suppositories these are torpedo-shaped solid dosage forms composed of fatty
bases (low melting) or water-soluble bases (dissolving) which vary in weight
from 1 g (children) to 2.5g (adult). Suppository base composition plays an
important role in both the rate and extent of release of medications. Lipophilic
drugs are usually incorporated into water soluble bases while hydrophilic drugs
are formulated into the fatty base suppositories. For suppositories made from
fatty bases, melting should occur rapidly near body temperature (37°C). Ideally
the resultant melt would readily flow to provide thin, broad coverage of the
rectal tissue, thereby minimizing lag time effects due to slow release of the
drug from the suppository base. Suppositories are suited particularly for
producing local action but may also be used to produce a systemic effect or to
exert a mechanical effect to facilitate emptying lower bowel.
Rectal Liquids:
Rectal Solutions,
suspensions, or retention enemas represent rectal dosage forms with very
limited application; largely due to inconvenience of use and poor patient
compliance. It involves injecting a liquid, typically a laxative, with a
syringe into the rectum. The medicament is incorporated into a base such as
cocoa butter which melts at body temperature, or into one such as glycerinated gelatin or PEG which slowly dissolves in the mucous
secretions. Retention enema: The drugs like hydrocortisone (local effect) or
aminophylline (systemic effect) etc are used in this dosage form.
Rectal Aerosols:
Rectal aerosols
or foams products are accompanied by applicators to facilitate administration.
The applicator is attached to the container and filled with a measured dose of
product. Metered dose aerosols are available. The inserter is inserted in to
the anus and the plunger is pushed to deliver the drug product.
The major
disadvantages of rectal suppositories, creams and liquids which are not
preferred by patients are they are inconvenient. Rectal absorption of most
drugs is frequently erratic and unpredictable. Some suppositories and liquids "leak"
or are expelled after insertion. To overcome the drawbacks of above rectal
dosage forms, a novel combined system of rectal dosage form minimizing the
disadvantages of all other dosage forms has been developed utilizing the
concept of mucoadhesion and thermoreversibility
in the form of a gel. Such a combined system has both fluidity and elasticity.
Rectal
Mucoadhesive Thermoreversible gels:
One of the major
drawbacks of vaginal and rectal suppositories and pessaries is the leakage from
the site of action as they melt in the cavities. Also these routes have poor
patient compliance. Thermoreversible mucoadhesive insitu gel16 can be an alternative means of
administering the drug with the help of a syringe device. The residence time is
increased by the reduction in the leakage. Thus it enhances the bioavailability
and effectiveness of the drug. Drugs such as an antifungal, an antiseptic, an
antibiotic, a contraceptive or a combination of two or more of these can be
delivered through vaginal and rectal formulations in the form of a gel17.
Thermoreversible Polymers:
Thermoreversible polymers are a
novel state of matter having both solid and liquid like properties.
Thermosetting systems are in the sol form when initially constituted, but upon
heating, they set into their final shape. This polymer can be delivered as a
fluid and solidifies within the body’s microenvironment where the temperature
is higher than the sol-gel transition temperature. This sol-gel transition is
known as curing. But if this cured polymer is heated further, it may lead to
degradation of the polymer as shown in figure 2. The examples of Mucoadhesive
and Thermoreversible polymers were given in Table 1.
Fig. 2: Curing
of Thermoreversible Polymer
FACTORS
AFFECTING THERMOREVERSIBLE GEL FORMATION18:
Physiological
Condition:
1.
Membrane transport
2.
pH of tissue fluid
3.
Mucociliary clearance
Physicochemical
Properties of Polymers:
1.
Concentration of Thermoreversible polymer
2.
Molecular weight
3.
Transition temperature
4.
Hydration value
5.
Polymer morphology
6.
Crystal state and polymorphism of polymer
7.
Phase separation behavior of polymers.
Formulation
factors:
1.
Clarity
2.
pH
3.
Gelation temperature
4.
Viscosity
5.
Osmolarity
6.
Spreadability.
FACTORS
AFFECTING MUCOADHESION:
Polymer-Related
factors:
1.
Hydrophilicity
2.
Molecular weight
3.
Cross linking and swelling
4.
Spatial Conformation
5.
Concentration of active layer
6.
Drug Excipient Concentration
7.
Flexibility of Polymer chains
Environment
related factors:
1.
Applied Strength
2.
pH at Polymer Substrate Interface
3.
Initial contact time
Physiological
Variables:
1.
Mucin Turnover
2.
Disease states
MECHANISM OF
MUCOADHESION:
There are two steps which are
responsible for the mucoadhesion as shown in figure
3.
Contact
stage:
An intimate contact (wetting)
occurs between the polymer and mucus membrane. It has been demonstrated that
the intimacy of contact between the polymer and mucus membrane is improved when
the surface of latter is rough. The surface roughness is defined by the aspect
ratio (d/h) of the maximum depth (d) to the maximum width (h). The polymers
with the aspect ratio less than 1/20 exhibit poor mucoadhesion18.
Consolidation
stage:
Various physicochemical
interactions occur to consolidate and strengthen the adhesive joint, leading to
prolonged adhesion, which improves the mucoadhesive strength18.
Fig. 3: Two stages of Mucoadhesion
Table 1:
Examples of Mucoadhesive and Thermoreversible
Polymers19
|
S. No. |
Nature |
Thermoreversible polymer |
Structure |
|
1. |
Synthetic |
Methyl Cellulose |
|
|
2. |
Hydroxy propyl methyl cellulose |
|
|
|
3. |
Poloxomer (Pluronic) |
|
|
|
4. |
Poly-(N-isopropylacrylamide) (PNIPAM) |
|
|
|
5. |
Poly (N-isopropylacrylamide-co-acrylic acid) PNIPAM-co-AA |
|
|
|
6. |
Poly(acrylic acid-co-acrylamide) |
|
|
|
7. |
Alginate-polyethylene glycol acrylate |
|
|
|
8. |
Sodium alginate |
|
|
|
9. |
Natural |
Gelatin |
|
|
10. |
Carrageenan |
|
|
|
11. |
Xyloglucan |
|
|
|
12. |
Xanthum gum |
|
|
|
13. |
Chitosan |
|
|
|
14. |
Gellangum |
|
FORMULATION
AND EVALUATION OF THEMOREVERSIBLE MUCOADHESIVE IN-SITU GEL:
Thermoreversible
mucoadhesive insitu gel is prepared by
cold method20-23.
Incorporation
of thermoreversible polymer:
Preliminarily concentration of
thermoreversible polymer is screened at various
concentration (% w/v) for determination of lowest possible concentration that
gives thermoreversible gelling property below
physiological temperature. Thermoreversible polymer
is added to solution containing drug, and is left at 4°C in refrigerator until
a clear solution is obtained20,21,22. Active substances that are
insoluble in water are dissolved prior to addition in Ethanol, Isopropyl
alcohol or Propylene glycol at 5˚C to form a homogeneous mass23.
Incorporation
of mucoadhesive polymer:
Mucoadhesive polymer is
screened at various concentrations in thermoreversible
polymer solution under gentle stirring for formulation of optimum
thermosensitive and mucoadhesive gel. Mucoahesive
polymer is slowly added to the above solution with continuous agitation, and is
stored in refrigerator until clear solution is obtained20,21.
Thermoreversible mucoadhesive insitu
gel is evaluated by the following parameters:
1. pH of
Formulation:
1ml
quantity of each formulation was transferred to the 10ml volumetric flask and
diluted by using distilled water to make 10ml. pH of resulting solution was
determined by using pH meter24.
2. Viscosity
and rheology:
This is
an important parameter for the in situ gels,
to be evaluated. The viscosity and rheological properties of the polymeric
formulations, either in solution or in gel made with artificial tissue fluid
(depending upon the route of administrations) instead of 5% mannitol, were
determined with Brookfield rheometer or some other type of viscometers such as
Ostwald's viscometer. The viscosity of these formulations should be such that
no difficulties are envisaged during their administration by the patient,
especially during parenteral and ocular administration.
3. Measurement
of gelation temperature:
a. Visual
inspection:
10ml
volume of solution is transferred to 20ml transparent vial containing a
magnetic stirrer bar. The vial is heated at an increasing rate of 1°C/min with
constant stirring at 100rpm. The temperature at which rotation of bar stopped
is taken as the gelation temperature20,21.
b. Rheological
method:
A
rheological study is performed with a thermostatically controlled Brookfield
Programmable Rheometer fitted with CP-52 spindle. The cone/plate geometry is
used. The shear stress is controlled to maintain a shear rate of 10/sec shear
rate for precise determination of the gelling temperature. The temperature is
increased in steps of 1°C/min, from 20-40°C to locate the solution/gel
transition point. The gelling temperature is determined graphically as the
inflection point on the curve of the apparent viscosity (mPas)
as a function of the temperature (°C)20.
4. Gel-Strength:
This
parameter can be evaluated using a rheometer. Depending on the mechanism of the
gelling of gelling agent used, a specified amount of gel is prepared in a
beaker, from the sol form. The probe is slowly pushed through the gel by
placing the weights on the probe, resulting in rising of gel in a beaker at
certain rate. The changes in the load on the probe can be measured as a
function of depth of immersion of the probe below the gel surface24.
5. Evaluation
of the mucoadhesive strength:
The
mucoadhesive potential25 of each formulation is determined by
measuring the force required to detach the formulation from mucosal tissue by
using a modified chemical balance.
A
section of mucosa is instantly fixed with mucosal side out onto each glass vial
using a rubber band. The vials with mucosa are stored at 37°C for 5 mins. Then
next vial with a section of mucosa is connected to the balance in inverted
position while first vial is placed on a height adjustable pan. Fixed amount of
sample of each formulation is placed onto the mucosa of first vial. Then the
height of second vial is adjusted so that mucosal surfaces of both vials come
in intimate contact. Then weight is kept rising in the pan until vials get detached.
The bioadhesive force is determined from the minimal
weights that detached the tissues from the surface of each formulation using
following equation21.
Detachment
stress (dyne/cm2) = m × g /A,
Where,
m = Weight required for detachment of two vials (gms)
g =
Acceleration due to gravity [980cm/s2]
A =
Area of tissue exposed
6.
Effect of initial contact time on mucoadhesive strength:
Formulation
is allowed to be in contact with mucosa26 for varying contact times,
and the bioadhesive force is determined as discussed
above. Contact time that resulted in maximum bioadhesive
strength is selected as optimum contact time required for adequate adhesion20.
7. Spreadibility:
As
evident from the theory of mucoadhesion, a
mucoadhesive formulation that is having high spreadability
and high surface tension will adhere strongly to the mucus membrane. The spreadability in terms of flow ability of various
mucoadhesive thermoreversible gels is determined
using a rectangular, hollow, glass chamber (10cm×6cm×4cm) with inlet and outlet
of hot water. The mucosa from serosal side is pasted on chamber. Hot water is
circulated for acquiring physiological temperature. One drop of formulation is
placed on mucosa at an angle of 120° and the distance traveled by drop before
it gets converted into gel is determined21.
8. Texture
analysis:
The
firmness, consistency and cohesiveness of formulation are assessed using
texture analyzer which mainly indicates the syringe ability of sol so the
formulation can be easily administered invivo5.
9. Fourier
transform infra-red spectroscopy:
During
gelation process, the nature of interacting forces can be evaluated using this
technique by employing potassium bromide pellet method27.
10. Thermogravimetric analysis:
It can
be conducted for in situ forming polymeric systems to quantitate the
percentage of water in hydrogel28.
11. Differential scanning calorimetry:
It is
used to observe if there are any changes in thermograms as compared with the
pure ingredients used thus indicating the drug- excipient incompatibility5.
12. In-vitro drug release studies:
The
drug release studies are carried out by using the plastic dialysis cell. The
cell is made up of two half cells, donor compartment and a receptor
compartment. Both half cells are separated with the help of cellulose membrane.
The sol form of the formulation is placed in the donor compartment. The
assembled cell is then shaken horizontally in an incubator. The total volume of
the receptor solution can be removed at intervals and replaced with the fresh
media. This receptor solution is analyzed for the drug release using analytical
technique5.
13. Histopathological studies:
Two
mucosa tissue pieces (3 cm2) are mounted on in vitro diffusion
cells. One mucosa is used as control (0.6 mL water) and the other is processed
with 0.6mL of optimized organogel (conditions similar
to in vitro diffusion). The mucosa tissues are fixed in 10% neutral carbonate
formalin (24 hours), and the vertical sections are dehydrated using graded
solutions of ethanol. The subdivided tissues are stained with hematoxylin and
eosin. The sections under microscope are photographed at original magnification
×100. No change on the ultrastructure of mucosa morphology and the epithelial
cells on microscopic observations indicate that the organogel
has no significant effect on the structure of the mucosa5.
CONCLUSION:
Rectal administration is truly
explored as a potential drug delivery system particularly for drugs that are
either too irritating for the gut or undergo extensive first pass metabolism28.
The rectal drug delivery system offer patients an
option that is less invasive and the drug can be administered in unconscious
and pediatric patients. Rectal drug delivery with the advantages of enhancement
in drug absorption with enhancers, and its usefulness as a Sustained-release
formulation for the long-term treatment of chronic diseases will undoubtedly be
a pioneer in formulation of various challenging compounds. The recto-anal
region is the drug delivery route of choice for a range of therapeutic indications.
Conventional suppositories are solid forms which often cause discomfort during
insertion. The leakage of suppositories from the rectum also gives
uncomfortable feelings to the patients. In addition, when the solid
suppositories without mucoadhesivity reach the end of
the colon, the drugs can undergo the first-pass effect. To solve these
problems, a novel mucoadhesive thermoreversible
gelling system is to be developed which uses a suitable mucoadhesive polymer
that increase the residence time of drug whereas thermoreversible
polymer will convert the formulation in to gel. The designs of new and improved
mucoadhesive thermoreversible gel formulations allow
easier insertion and retention in the rectal cavities which aims to expand
patient choice, compliance and consequently therapeutic outcome. Further,
animal models act as a preliminary study for the future development of rectal
preparations based on the combination of drugs with synergistic therapeutic
effects on hemorrhoid disease.
ACKNOWLEDMENT:
The authors are immensely
grateful to Sree Vidyanikethan
College of Pharmacy, A. Rangampet, Tirupati for
providing all the facilities required to carry out the review work.
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Received on 27.03.2020
Modified on 09.06.2020
Accepted on 06.08.2020
© RJPT All right reserved
Research J. Pharm. and Tech.
2021; 14(5):2878-2886.
DOI: 10.52711/0974-360X.2021.00506