ISSN 0974-3618 (Print) www.rjptonline.org
0974-360X (Online)
REVIEW ARTICLE
Rectal suppository as an effective alternative for oral
administration
Vijay
D. Havaldar1*, Adhikrao V. Yadav2, Remeth J. Dias1,
Kailas K. Mali1,
Vishwajeet
S. Ghorpade1, and Nitin H. Salunkhe1
1YSPM’s,
YTC, Faculty of Pharmacy, Wadhe, Satara, 415011 India
2GIPER,
Limb, Satara, India
*Corresponding Author E-mail: vdh2006@rediffmail.com
ABSTRACT:
Rectal route is an effective alternative for oral administration of drugs
in pediatric and geriatric patient. Rectal suppository may have influence on
bioavailability and may produce sustained release of drugs. Suppository avoids
the complications associated with oral delivery of drugs such as first pass
effect, degradation of drugs by gastric enzymes, etc. Previous studies
implicated that suppositories produced local effects but recently most interesting publications claimed that
these are also producing systemic effects. Since last two decades research is
focused to improve bioavailability of drugs from suppositories. The
conventional solid suppositories have suffered from disadvantages such as
feeling of alien, pain and discomfort. Therefore, liquid suppositories were
developed which overcame the disadvantages associated with solid suppositories
such as leakage from anus, avoidance of first pass effect and irritation. The
selection of appropriate mucoadhesive polymer, surfactant and suppository base
may influence the bioavailability and sustained release of drugs. The current review
concern the physiological,
biopharmaceutical characteristics of rectum and pharmaceutical related factors
affecting bioavailability, suppository bases, bioadhesive polymers, and
surfactant. It also covers evaluation parameters for solid and liquid suppositories.
KEY WORDS: Suppository; Bioavailability; First-pass
effect; Mucoadhesion; Sustained release
INTRODUCTION:
Rectal route is the efficient and economical method for the
patients who have difficulty in swallowing especially in children and some
adults. This route is beneficial in certain conditions like nausea, vomiting,
inflammatory bowel diseases and hemorrhoids where parenteral and oral
administration of drug is not possible1. This route offers the
advantage of being relatively painless. Sometimes this route is an effective
alternative for oral and intravenous dosage forms e.g. in vomiting, the oral
administration of antiemetic drug such as ondansetron requires two daily doses2.
Received on 11.04.2015 Modified on 21.04.2015
Accepted on 11.05.2015 © RJPT All right reserved
Research J. Pharm. and Tech. 8(6): June,
2015; Page 759-766
DOI: 10.5958/0974-360X.2015.00122.5
Though the oral route is the route of choice for most of drugs it
is not suitable for the pediatric and geriatric patients. The oral absorption
of drugs mainly depends on the various factors such as gastrointestinal
environment like gastrointestinal pH, gastrointestinal enzymes, gastric
emptying time and intestinal transit time, ionic conditions of drugs, nature of
drugs, first pass effect, etc3. Also, the injectables are not
preferred by the patient due to pain and safety issues. e. g. in diabetes
patient may complain about the physical and psychic pain due to atrophy or
hyper atrophy of the subcutaneous fats at the site of injection. Therefore,
administration of medicaments by the rectal route is preferable. During last twenty years, suppositories were
not well accepted due to the cultural or emotional points of view. Initially,
it was used for the administration of local anesthetics, astringents,
antiseptic, emollient, hemorrhoids, vermifugal, and laxative agents to produce
a local effect4. Salunkhe et
al developed mucoadhesive microsphere based suppository formulations of
granisetron hydrochloride (GH) by fusion method. They used combination of
xanthan gum and sodium alginate in a hydrophilic and lipophilic polymer base5.
They found that suppositories containing xanthan -alginate microspheres is an
effective alternative to oral dosage forms as it sustains the GH release,
avoids first pass metabolism, and can be efficiently used in the management of
emesis in cancer chemotherapy and radiation therapy. But now days a variety of
natural and synthetic drugs are formulated in the form of suppositories to
produce a systemic effect such as hypnotics, tranquilizers, antispasmodics,
etc. Also, the suppository may be useful as a sustained release formulation for
the long treatment of chronic diseases such as hypertension, asthma, diabetes,
anemia, AIDS, etc6. Mokhtar and coworkers developed antihypertensive
suppositories of atenolol in hydrophilic bases of polyethylene glycol
(PEG), or hydrophobic emulsifying bases such as witepsol H15 (WH15) nonionic
surfactant span 60 (Sp 60) with or without cholesterol (CH) and HPMC 400Cp7. They found that the arterial blood pressure lowered in six hours
and persisted at normal levels within 6 h.
Further,
suppositories have application in post operative pains. Therefore,
administration of medicaments in the form of suppository is the preferable
route of administration due to the advantages that include: a) improved
enzymatic drug stability b) higher drug content c) constant and static
environment of rectum d) avoidance of overdosing e) improved patient compliance
f) avoidance of first pass elimination8.
A conventional
suppository is a semisolid dosage form meant for insertion into body cavity
that melts or softens at body temperature. It is acceptable dosage form for
infants, children and unconscious patients. A major advantage of suppositories
over oral dosage forms is that it does not undergo the first pass effect in the
gastrointestinal tract and liver. However, the conventional solid suppositories
suffer from disadvantages such as feeling of alien, discomfort and therefore,
refusal by the patient. If such solid suppositories without mucoadhesivity
reach the end of colon, drugs may undergo the first-pass effect. The problem of
conventional solid suppositories can be overcome by developing a liquid
suppository which: (1) forms a gel at body temperature; (2) has a suitable gel
strength not to be leaked out from the anus after administration; and (3) has a
suitable bioadhesive force so as not to reach the end of the colon9.
Choi and coworkers fabricated ibuprofen loaded liquid suppository using
eutectic mixture system with menthol and poloxamer P 188 as a base and noted
that the eutectic mixture with menthol improved the solubility of ibuprofen and
such suppositories could be inserted into the rectum of rats without difficulty
and leakage10. Further, they suggested that drug from liquid
suppository could be more absorbed than that from solid one in rats. Mucoadhesive polymers have recently gained
interest among pharmaceutical scientists as a means of improving drug delivery
by promoting residence time and contact time with the mucous membranes. Barkat
developed and evaluated rectal etodolac poloxamer gel system composed of
poloxamer and bioadhesive polymers11. They concluded that in situ
gelling suppository with etodolac and mucoadhesive polymers such as
microcrystalline cellulose and carbopol was safe, convenient and effective
dosage form of etodolac. In this review, attempts are made to discuss effective
administration of drugs. It focuses on rectal bioavailability of drugs, factors
influencing bioavailability, role of surfactant and mucoadhesive polymers in
enhancing bioavailability. It also highlights on suppository bases, evaluation
parameters for solid and liquid suppositories.
BIOAVAILABILITY OF DRUGS
FROM SUPPOSITORIES:
I) Physiology and biopharmaceutical characteristics of rectum:
Human colon
consists of ascending, descending, transverse and sigmoid colon. Sigmoid colon
turns medially and downward into the rectum and anal canal. The rectum is about
13 cm long and the anal canal is of few centimeters of the colon that surrounds
the anus. The terminal end of colon is usually referred as rectum clinically12. The rectum has relatively small absorption
surface 0.02-0.05m2 and is characterized by absence of villi13. Viscous rectal fluid (0.5 - 1.25ml) spread
over the surface having pH 7.4 with a low buffer capacity. The rectum is
usually empty except when fecal matter arrives from higher part of the colon
temporarily. This material is either expelled or transported back into colon,
depending on the voluntary control exhibited by the anus sphincter. A drug has
greater opportunity to make contact with the absorbing rectal surface in the
absence of fecal matter. Other conditions such as diarrhoea, colonic
obstruction and tissue dehydration can influence the rate and degree of drug
absorption from rectal site14. Absorption of drug from rectal
suppositories depends on diffusion of drug to the site of rectal mucosa. The
diffusivity of drug depends on nature of drug and physiological state of the
colon that is amount and chemical nature of fluids and solids present. The
rectum is usually empty except when fecal matter arrives from higher part of
the colon temporarily. This material is either expelled or transported back
into colon, depending on the voluntary control exhibited by the anus sphincter.
A drug has greater opportunity to make contact with the absorbing rectal
surface in the absence of fecal matter. Other conditions such as diarrhoea,
colonic obstruction and tissue dehydration can influence the rate and degree of
drug absorption from rectal site. Rectal administration of drug avoids partly
hepatic first-pass elimination. The superior rectal vein and middle rectal vein
are connected to the portal system and inferior rectal vein is directly connected
to inferior vena cava thus entering drug into the systemic circulation15.
However, there is no sharp distinction between these venous drainages, since
the rectal veins are linked by an extensive anastomoses network. With this route, 50-70% of a drug suitable
for rectal administration is absorbed. In one study, it was observed that on
lidocaine, avoided hepatic first-pass elimination following rectal
administration of the drug16. Systemic availability was found to be
increased by almost 100% following rectal administration compared with the oral
route for the same dose. The absorption of drug through rectal administration
is related with pH partition theory. Thus, rectal absorption involves simple
diffusion process through the lipoidal membrane.
Physico-chemical
and physiological properties may have influence on permeability of drugs across
the intestinal epithelium and may differ in various intestinal regions17.
Permeability of drug across the rectum depends on mucosal area, fluid volume
and pore size. In rectum, absorption of water is low as compared to other parts
of the gastrointestinal tract18.
This is due to smaller pore radius, tighter epithelium, less fluidity in
the rectal membrane, lower number of pores in the rectal region, and decreased
mucosal surface area. There is a
difference in the transport of electrolytes and water. These are transported
transcellularly in the colon/ rectum that is different from more high permeable
tissue in which the transportation of electrolytes takes place by the
paracellular route13. It was observed that an unstirred water layer
is an essential factor as it may be thick and more coherent in the
colonic-rectal region in the jejunum of human.
In suppository where drug substance dissolves or disperses in the
vehicle, the absorption may depend on the particle size, solubility in water
and partition coefficient. In other cases where drugs dissolve either fully or
in parts in base the absorption will depend on solubility in the base, water
distribution coefficient and relative phase volume ratio19.
According to Kakemi, drug may be absorbed only when it is dissolved completely
in aqueous rectal fluid as there is a little absorption of drug from the oily
solution.
If M0 is the amount of drug in oil and Mw is
amount of drug in water and Ø is a relative phase volume ratio, then the
release of drug from suppository will be represented by the following equation
Mw = M0/ (K Ø)
Where K is the partition coefficient
Above equation describes the equilibrium conditions. If the rate
of partioning of drugs is slower than the absorption from aqueous phase,
equilibrium will never be reached. In such situation, rate determining process
will be transfer of drug from oil to water. Hence, for in vitro drug release
sink conditions should be maintained. The larger volume of dissolution medium
will be required for transportation of dissolved drug from molten mass so that
it will provide an adequate area of contact between two phases in order to make
release kinetics to in vivo. A fat-like base should be used for a water-soluble
drug and a hydrophilic base for water insoluble drug. Diffusion rate of a drug
suspended in a fat base having low hydroxyl number and viscosity is increased.
II) Pharmaceutical aspects related to
bioavailability:
Rectal absorption of drug through suppository involves a chain of
effects leading to the bioavailability of the drug. The sequence of such drug
absorption from the anorectal area can be represented as follows:
Drug in vehicle Drug in colon fluids
Absorption through the rectal mucosa
Drugs should be released from suppository and distributed by
surrounding fluids to the sites of absorption so that it will be available for
absorption. A suppository will either dissolve in the rectal fluid
(water-soluble bases) or melt on the mucous layer (fatty bases) depending on
the character of its vehicle.
i) Particle size, solubility in water and
interfacial tension:
Drug absorption by rectal route is governed by particle size,
solubility in water and interfacial tension. Process of release of drug from
suppository involves the various steps such as melting, spreading,
sedimentation, wetting and dissolution19, 20. Usually, absorption of
drug depends on the rate of dissolution which is related to the particle size.
Smaller the particle size better will be the absorption as smaller particle
size increases the surface area which increases the rate of dissolution. In
suppository, drug should have particle size less than 50µm. In suppository,
though the smaller particle size of drug does not increase the blood levels but
for its dissolution in the rectal fluid requires smaller particle size. For the
release of an insoluble drug from vehicle, larger particles of drug which are
soluble in the rectal fluid will be preferred to increase its transport
rate.
Surface
properties of the drug particles is an important consideration in evaluation of
rate of drug release as drug particles in suppository dosage form transfers
from one phase to another. If drug particles do not wet in the vehicle or base,
it may agglomerate, which in turn may affect the uniformity of dispersion of
drug particles. It may occur due to the increased tendency for the agglomerated
powder to sediment prior to the setting of suppository. Therefore, it is
necessary to add surfactant to formulation to reduce the surface effects of
poorly wettable drug particles and to improve the wetting of drug particles
that will facilitate dissolution of drug in the suppository and in rectal
fluids.
ii) Hardening effect:
Hardening
effect leads to increase in the melting time of suppositories. It occurs during
storage of suppositories. This effect arises in bases with higher melting
ranges (Witepsol H37, 36-38°C). Minor changes occur in bases with the lowest melting
points (e.g. Witepsol H 32, 31-32 ° C). It can be inhibited by the addition of
2% soya lecithin. It is considered that hardening effect occurs due to
polymorphic phase transitions, increase in crystallinity and
transesterification. Crystallization of polymorphs can be prevented by blending
suppository bases with surface-active agents in optimum concentrations as at
higher surface-active agent concentrations produce retardant and/or irritative
effects. Varnshey and coworker studied effect of different surfactants such as
sodium lauryl sulphate, span 60 and 80, tween 60 and 80 and sodium
tauchocholate on the release pattern of cocoa butter suppository containing
flurbiprofen sodium21. They
observed that on addition of surface active agents to the formulation enhanced
the drug release with respect to surfactant which can be arranged as- SLS >
Span 80 > Tween 80 > Tween 60 > Sodium taurocholate > Span 60 >
cocoa butter.
Suppository bases
Suppository bases must melt, soften or dissolve in order to facilitate
or promote the release of drug in such way that it is readily available for
absorption8. A chemical and/or physical interaction between drug and
base may influence the stability and/or bioavailability of drug. Potential
chemical and/or physical interactions between a drug and the components of a
formulation should be investigated during preformulation studies and in the
early stages of formulation development. The base may irritate mucous membranes
and initiate a colonic response thus promoting unwanted bowel movements
resulting in the expulsion of the dosage form, thereby negating any potential
drug absorption via the rectal route. The spreading of suppository base with a
suspended drug in the recto colon is dependent on the pressure exerted through rectal
wall by abdominal organs and/or by rectal wall muscles. The final spreading
area decreases with increasing apparent viscosity of the spreading system20.
There are two
types of suppository bases, oleaginous bases and water miscible bases.
Oleaginous bases
Fatty bases
melt at body temperature. Cocoa butter
(CB) is the most commonly used oleaginous suppository base but it poses several
technical challenges with respect to the manufacture of dosage forms of
suitable quality19. It has several disadvantages such as it can
become rancid due to oxidation of the unsaturated glycerides, melt in warm
weather and liquefy when incorporated with certain drugs. It does not contain
emulsifiers and therefore does not take up large quantities of water. As CB can
easily melt and become rancid, it must be stored in cool, dry place and
protected from light. CB exhibits marked polymorphism (the ability to exist in
different crystalline forms, namely α, β, β’ and γ), a
phenomenon probably attributed to the high proportion of unsaturated
triglycerides22. The most stable β form is preferable for
suppositories. The formation of the various crystalline forms depends on the
conditions and degree of heating and cooling. Prolonged heating above 36oC
leads to the formation of the unstable crystal with lower melting points. Lo
and coworkers formulated thermogelling and bioadhesive liquid suppositories of
epirubicin using varying concentrations of polyacylic acid (PAA) and pluronic23.
Also, they prepared solid suppositories using the same concentrations of PAA
and pluronic in cocoa butter base. They found that solid suppositories prepared
with cocoa butter base melted and gelled instantly in the rectum. It remains
adhered to the mucous membrane and sustained release of drug. Further, they
stated that cocoa butter has antioxidant property, which granted it a storage
life of two to five years and thus protected the enclosed Plu/PAA/Epi mixture.
Semi-synthetic
fats are usually white, brittle, solid, odorless and unctuous to touch and
produce suppositories that are white and have an attractive, clean, polished
appearance. Hard fats are available in a variety of grades with different
melting ranges, hydroxyl values and other physicochemical characteristics.
Examples of semi-synthetic fatty suppository bases that are available
commercially include fractionated palm kernel oil B.P and hard fats such as
Massa Estarium®, Massupol®, Suppocire® and Witepsol®. Kamalinder S et al.,
developed suppocire based solid suppositories of paracetamol with the help of
additives such as sodium lauryl sulfate (SLS), dioctyl sulfosuccinate (DOSS),
Labrasol, lecithin, Miglyol 812, aerosil, Capryol PGMC (CPGMC) and span 80 and
they found that addition of DOSS and aerosil showed prolonged drug release
whereas newly used Labrasol and C PGMC exhibited much faster release24.
Water
miscible bases
Macrogol or
polyethylene glycols (PEGs) are amongst the most widely used hydrophilic
polymer suppository bases. PEGs are polymers of ethylene oxide and water,
prepared in a variety of chain lengths, molecular weights and physical states25.
PEGs with a molecular weight ranging between 200 and 600 exist as liquids and,
as the molecular weights increase to above 1000; they exist as wax-like solids26.
In addition, as the molecular weights increase, their water solubility and
hygroscopicity decreases. The wide range of melting points and solubilities
make possible the formulation of suppositories with various degrees of heat
stability and with different dissolution rates. PEGs of different molecular
weight can be combined to achieve a suppository base of desired consistency and
that can achieve a specific drug release rate profile. The use of high melting
point solids as suppository bases permits convenient storage of the
suppositories without the need for refrigeration and without the danger of
excessive softening in warm climates. PEGs have inherently good solvent
properties that may result in the retention of a drug in the liquefied base, in
the rectum with the potential for a reduction in therapeutic activity. If the
drug is partly in solution and partly in suspension there is a high potential
for crystal formation, which may cause the formulation to become brittle and
prolong dissolution time. PEG bases are hygroscopic and therefore attract
water, resulting in a painful sensation for the patient. It is therefore
recommended that suppositories manufactured from these bases should be
moistened with water prior to introduction into rectum to minimize local
irritation. PEG bases have several advantages over synthetic and semi-synthetic
suppository bases, in particular with respect to stability against oxidation
and other degradation processes, their inert nature and a high water absorbing
capacity. Unlike glycerol-gelatin suppositories, PEG suppositories do not
adhere to moulds and contract sufficiently on cooling to make mould lubrication
unnecessary during manufacture. However, PEG suppositories may become brittle,
unless poured at the lowest temperature possible, but this may be overcome or
reduced by the addition of surfactants or plasticizing agents such as propylene
glycol to the formulation. Tarimici N et al., prepared witepsol H15 and PEG
mixture (PEG 400, PEG 1000, PEG 2000 and PEG 4000) based indomethacin sustained
release solid suppositories using cellulose acetate phthalate and Eudragit RL
and RS in 1:1 ratio and they found that formulations containing combinations of
PEG 400 and PEG 4000 as well as PEG 1000 and PEG 4000 and Eudragit mixture
exhibited sustained release effect27.
Surfactants
Surfactants can
increase and decrease drug absorption rate. For instance, in case of sodium
iodide, absorption is accelerated in the presence of surfactants and appears to
be proportional to the relative surface tension lowering of the vehicle.
Riegalman and Crowell showed that the rate at which drug diffuses to the
surface of suppository depends on the particle size of suspended drug and the
presence of surface active agents that affect drug release from suppositories28.
In addition, they suggested that the acceleration of sodium iodide absorption
might also be attributed to the mucus peptizing action of the vehicle. The
rectal membrane is covered by a continuous blanket, which may be more readily
washed away by colonic fluids that have reduced surface tension. The cleansing
action caused by the surfactant-containing vehicle may make additional pore
spaces available for drug absorption, thus facilitating drug movement across
the rectal membrane barrier. In case of phenol-type drugs, absorption rate is
decreased in the presence of surfactant, probably because of the formation of a
drug surfactant complex26.
Several
nonionic surface active agents, closely related chemically to the polyethylene
glycols, have been developed as suppository bases29. Many of these
bases can be used for formulating both water soluble and oil soluble drugs. The
most commonly used surfactants in suppository formulations are the
polyoxyethylene sorbitan fatty acid esters (tween), polyoxyethylene stearates
(Myrj), and the sorbitan fatty acid esters (Span and Arlacel). Caution should
be taken while using surfactants with drugs. It has been reported that
surfactants increased rate of drug absorption30, 31. Other reports
suggested interaction of surface active agents with drugs that may lead to
decrease in therapeutic activity32. Each formulation must be tested
in vivo to evaluate its medicinal effectiveness, as well as safety. Gross and
Becker recommended a water dispersible, high melting point (500 C)
suppository base consisting of polyoxyethylene 30 stearate (Myrj 51), water,
white wax and dioctyl sodium sulfosuccinate (Aerosol OT)33. The use
of aerosol OT in the formula was claimed to lend synergism to the surfactant
and thus aid in rapid disintegration of suppository. Drugs like phenobarbital,
quinine hydrochloride, tannic acid, and chloramphenicol were studied. Ward
designed suppositories using polyoxyethylene sorbitan derivatives (Tweens) to
melt at body temperature into liquids that disperse readily in the body fluids
34.
Poloxamer is
used as a base for liquid suppositories. Being non ionic surfactant, it is a
copolymer of poly (oxyethylene)-poly (oxypropylene)- poly(oxyethylene.
Poloxamer solutions are known to exhibit the phenomenon of reverse thermal
gelation thus remaining as solution at low temperature and gelling when
temperature increases. Furthermore, poloxamers were reported not to cause any
damage on mucosal membranes35, 36. Several attempts have been to
modulate the gelation temperature of poloxamer-based liquids. The gelation
temperature of poloxamer solutions was adjusted by modifying cross-linking
agents and monomers by mixing the different series of poloxamers, by changing
the weight of poloxamers, or by changing the pH and the ionic strength37, 38 . However, most previous studies
have been focused on modulating only the gelation temperatures of poloxamer
solutions. There has been a lack of knowledge on the strength and the
bioadhesive force of gelled poloxamers, although these two factors are crucial
in designing desirable liquid suppositories which do not leak out from the anus
and do not reach the end of the colon after administration. Kim CK et al.,
developed not only temperature-sensitive but also mucoadhesive liquid
suppositories containing acetaminophen using poloxamers and bioadhesive
polymers and investigated their effect on rectal mucous lining, gelation
temperature, gel strength and bioadhesive forces1.
Bioadhesive Polymers
Bioadhesive polymers are
generally hydrophilic macromolecules that contain anionic charges and strong
hydrogen bond forming groups (hydroxyl, oxide and carboxyl groups) with high
molecular weight, sufficient chain flexibility and surface energy properties
favoring spreading onto mucus39. It includes synthetic polymers such as poly (acrylic acid)
(PAA), hydroxypropyl methylcellulose and poly (methylacrylate) derivatives, as
well as naturally occurring polymers such as hyaluronic acid and chitosan40.
Poly (acrylic acid) is considered as a good mucoadhesive but due to a high
transition temperature and higher interfacial free energy, it cannot wet the
mucosal surface to the optimal level which may lose interpenetration and inter
diffusion of the polymer. These properties can be improved by copolymerizing
with polyethylene glycol (PEG) or poly (vinyl pyrrolidone) (PVP). El- Leithy at
al., prepared HPMC and carbopol 934 hydrogels containing diclofenac sodium
chitosan microspheres for rectal administration and they suggested microspheres
allowed adhesion to the rectal mucosa for subsequent controlled release
behavior with no burst41.
Evaluation of Suppositories
Solid suppositories
Appearance
For testing the
appearance, randomly selected suppositories cut longitudinally and examine the
surfaces with naked eye42.
Weight variation test
Weigh
individually twenty suppositories and determine the average weight. Compare the
individual weights with the average weight. No suppository should deviate from
average weight by more than 5% except two that may deviate by not more than 10%43.
Liquefaction / softening time
For
determination of liquefaction / softening time, a simple apparatus can be
fabricated in the laboratory44. Take a burette with broken stop-cock
and cut suitably so that it has a narrow opening on one side and broad opening
on another side. Dip the burette in hot water maintained at 370 C so
that narrow end faces towards hot water. Introduce the sample suppository from
the top of the burette through broad end and carefully push down its length
until it reaches narrow end. Insert a glass rod weighing 30 g and 45 cm in
length so that it rests over the suppository. Record the time at which glass
rod reaches the narrow end after complete melting of suppository represents the
liquefaction time.
Micro-melting range test
For
micro-melting range test, fill the formulation to about 1 cm height in
capillary tubes of 10 cm length and dip in a beaker containing water44.
Raise the temperature slowly and record temperature at which the mass liquefies
was recorded.
In vitro Dissolution
Studies
In vitro dissolution
studies of suppositories are carried out in USP XXIII tablet dissolution test
apparatus (Electrolab TDT – 06N) employing a basket stirrer45. A
specified volume of phosphate buffer pH 7.4 is used as a dissolution medium
maintained at 37±0.5º C.
Liquid suppositories
Gelation temperature
Gelation
temperature is determined by using the tube tilting method46.
Transfer 2 ml aliquot of gel to test tubes immersed in a water bath at 4°C and
seal with aluminum foil. Increase the temperature of water bath in increments
of 1°C and allow to equilibrate for 5 min at each new setting. Examine samples
for gelation, which is said to have occurred when the meniscus would no longer
move upon tilting through 90°C.
Measurement
of gel strength
The gel
strength is determined according to the method adopted by Kim et al. Put 50 g
of liquid suppository in a 100 ml graduated cylinder and gel in a thermostat at
37°C. Place the apparatus for measuring the gel strength (weight 35 g) into the
liquid suppository. Determine gel strength by the time in seconds that
apparatus take to penetrate 5 cm down through the gel.
Determination
of the mucoadhesive force
The
mucoadhesive force, the detachment stress of the liquid suppositories is
determined using a modification of the mucoadhesive force-measuring device used
by Choi et al. Cut a section from the fundus of rabbit rectum and secure
instantly with the mucosal side out into each glass vial. Store the vials at
36.5°C for 10 min. connect one vial to the balance and fix other with the
poloxamer gel added and adjust the height so that the gel is placed between the
mucosal sides of both vials. Allow water from a burette to fall in a beaker at
a constant rate of 10 mg/sec. Add increasing weight of water gradually that
will detach the two vials. Determine mucoadhesive force, the detachment stress
(dyne/cm²), from the minimal weights of water that detach 2 vials.
In-vivo tests
experiments
Male
Sprague–Dawley rats are used for in vivo studies having a weight of 250 ± 20 g. those rats are fasted for 24–36 h prior to the experiments
but allow free access to water9 . Divide fifteen rats into two
groups. Use one group as control and administer 1.5 g liquid suppositories
containing drug/kg into the rectum 4 cm above the anus through a stomach sonde
needle. Block the entrance of the anus with a cyanoacrylate adhesive to prevent
leakage of preparations from the anus during the pharmacokinetic experiment as
it may lead to inaccuracy in pharmacokinetic data. Collect half milliliter of
blood from the right femoral artery at various intervals and centrifuge at 3000
rpm for 10 min.
Mix plasma
(0.05 ml) with 0.4 ml of acetonitrile solution containing flufenamic acid (0.5_g/ml),
as an internal standard47. Centrifuge at 3000 rpm for 10 min to
precipitate the proteins. Evaporate the supernatant layer (0.4 ml) under N2 (g).
Reconstitute the residue in 50µl of mobile phase and then analyze, the
resulting solution by HPLC equipped with an Inertsil ODS-3 C18 column (GL
science, 0.5 µm, 15 cm × 0.46 cm
i.d.) and UV detector. The mobile phase should be acetoniltrile and phosphate
buffer (pH 3.5) (4:6, volume ratio). Monitor the eluent with a flow rate of 1.2
ml/min at a specified wavelength.
Kosior A
prepared rectal suppositories with chorpropamide alone and chlorpropamide in
the dispersion system with urea using a mixture of witepsol H15 and H19 and
polyoxyethylene glycol as bases. The developed formulations were tested on the
rabbits and compared with the commercial tablets of chlorpropamide48.
Finally, he concluded that the suppositories prepared with witepsol H15 along
with the dispersed chlorpropamide caused much higher decrease of blood glucose
levels than the commercial tablets.
CONCLUSION:
Rectal route is
an effective alternative for oral drug administration. Suppositories formulated
by using mucoadhsive polymers play a vital role in enhancing the
bioavailability of drugs. An exhaustive study of solid and liquid suppository
as a novel alternative for oral administration reveals that suppositories are
able to avoid the first pass effect and improve enzymatic drug stability as
well as patient compliance. Narrowing the research on mucoadhesive polymers and
suppository bases would benefit the pharmaceutical science for exploring the
alternative route of administration to oral administration of drugs.
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