Rectal drug delivery systems with marketed products

1. Presented By:
Chiranjibi Adhikari
1st year M. Pharm. (Pharmaceutics)
MALLIGE COLLEGE OF PHARMACY
SEMINAR ON
RECTAL DRUG DELIVERY
SYSTEMS

2. INTRODUCTION
 Rectal drug delivery system is a type of Mucoadhesive
drug delivery systems. Such systems involves
mucoadhesion , i.e. the attachment of the drug along
with a suitable carrier to the mucous membrane.
 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.
 For a long period of time the rectal route was used only
for the administration of local anesthetics, anti-
hemorrhoidal, vermifugal, anti-bacterial and laxative

3. Advantages of Rectal drug delivery
system
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.

4. 6. Rectal drug delivery is useful in pediatric, geriatric and
unconscious patient specially having difficulty in
swallowing oral medicine.
7. When oral intake is restricted such as prior to x- ray
studies, before surgery or in patient having diseases
of upper GIT.
8. 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.
9. Drug which traditionally is only given parentally may
be
administered rectally. E.g. - Peptides and other

5. Applications of Rectal DDS
1. Rectal administration of the anti epileptic drugs
 First pass metabolism of anti epileptic drugs can be
partially avoided.
 Diazepam solution administered rectally result in rapid
and complete absorption with peak plasma
concentration attained within 5-15 min.
 The rectal formulation of carbamazepin, lamotrigine,
levetiracetam, phenobarbital, topiramate and valproate
have been found to be bioequivalent to oral tablets and
oral suspension.
2. Analgesics by rectal route
 Controlled release morphine suppositories are observed
to greater extent (larger AUC) than oral controlled
release tablets. The analgesia can be maintained

6. Disadvantages of Rectal dds
1. Many drugs are poorly or erratically absorbed
across the rectal mucosa.
2. Dissolution problems due to the small fluid content
of the rectum.
3. Drug metabolism by micro organisms and rectal
mucosa.
4. They are inconvenient and not preferred by
patients.
5. Frequently unpredictable because of leak or
expulsion after insertion.

7. Table 1: Category of Suppositories Indication and adverse effects

8. ANATOMY AND PHYSIOLOGY OF
RECTUM
 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.
 The surface area available for drug absorption in the
rectum is approximately 200- 400cm². Volume of fluid in
the rectum is about 1-3ml and is viscous. The rectal
milieu is constant as its pH is 7.5-8.
 The superior rectal vein which peruses the upper part
of the rectum drains into the portal vein and
subsequently into the liver where as the middle and
inferior rectal veins drains the lower part of the rectum

9. Fig: Vasculature of human rectum

10. ABSORPTION OF DRUGS IN
RECTUM
 Absorption of drugs from rectal epithelium involves two
transport routes:transcellular route & paracellular route.
An uptake mechanism in transcellular route depends on
lipophilicity where paracellular route is drug diffusion
through a space between epitelial cells.
 Aqueous and alcoholic solutions are absorbed quickly
where as suspensions and suppositories exhibit slow &
continuous absorption. Alkaline solutions are quickly
absorbed than acid solutions.
 Methods for improving rectal absorption of the drugs
include:-
i. Modification of the barrier functions of the mucosal
membrane.

11. Factors affecting the absorption of drug from
rectum
1. Physiological factors-
 Colonic content- Drug will have greater opportunity to
get absorbed when the rectum is empty.
 Circulation route- If the drug is absorbed from lower
hamorrhoidal veins it will directly take the drug to inferior
venacava.
 pH of rectal fluids- weaker acids and bases are more
readily absorbed than the stronger, highly ionized ones.
2. Physiochemical factors-
 Lipid-water partition coefficient- Water-soluble, oil-
insoluble salts are preferred in fat-based suppositories.
 Degree of ionization- unionized drugs are highly
absorbed.
 Particle size - The smaller the particle, greater the

12. ABSORPTION ENHANCERS
 Enamine derivatives- Absorption of Amino acid in
aqueous solution with ethylacetoacetate increases with
an increase in the pH.
 Salicylates and its derivatives promots rectal
absorption of hydrophilic antibiotics and polypeptides.
 Fatty acids- Medium chain length fatty acids are
absorption promoting adjuvants for ampicillin and
hydrophilic antibiotics.
 Strong chelating agents- EDTA increases the transport
of both antipyrine (smaller mol. Wt.) and phenol red(
larger mol. Wt.).
 Protease inhibitors- e.g. aprotinin, trypsin, bacitracin,
puromycin, bestatin and bile salts such as Na-GC.
 Chemical modification- e.g. Acyl derivatives of insulin

13. Table 2: Uses of Cyclodextrins in rectal delivery of
drugs

14. 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 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 (eg. Zinc oxide), local
anaestheics (eg. Pramoxine HCL), protectants and
lubricants ( eg. Cocoa butter, lanolin) and antipruritis
and anti inflammatory agents ( eg. Hydrocortisone).

15.  The bases used in anorectal creams and ointments
includes combinations of polyethylene glycol 300 & 3350
, emulsion cream bases using cetyl alcohol & cetyl
esters wax , white petroleum and mineral oil.
 The preservatives like methylparaben, propylparaben,
benzlyacohol and butylated hydrocortisole (BHA) are
also used.
 Rectal ointments creams and gels are packed with
special perforated plastic tips for products to be
administered in to the anus.
Fig: rectal cream and ointment applicators

16.  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.
 Several commercial products includes Diastat Gel
(Diazepam), Analpram HC cream (hydrocortisone
acetate + pramoxine HCL) , ANUSOL ointment (starch),
Pilex Ointment, etc.

17. RECTAL SUPPOSITORIES
 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 2.5 g (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

18. •The ideal suppository base should be nontoxic, nonirritating,
inert, compatible with medicaments, and easily formed by
compression or molding. It should also dissolve or
disintegrate in the presence of mucous secretions or melt at
body temperature to allow for the release of the medication.
Table 3: Suppository bases

19.  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.
 The suppository may be useful as a sustained
release formulation for the treatment of chronic
diseases like essential hypertension, asthma,
diabetes, AIDS, anemia, etc.
 HPMC and Glyceryl Behenate polymer in higher
concentration are used to formulate sustained
release suppositories.

20. Methods of Preparation of
suppositories
I) Hand Rolling
 It is the oldest and simplest method of suppository
preparation and may be used when only a few
suppositories are to be prepared in a base. It has the
advantage of avoiding the necessity of heating the
cocoa butter.
 The base is first grated and then kneaded with active
ingredients by the use of mortar and pestle until the
mass is plastic. The mass is formed into a ball in the
palm of the hands, and then rolled into a uniform
cylinder with a large spatula or small flat board on a pill
tile.
 The cylinder is then cut into the appropriate number of
pieces which are rolled on one end to produce a conical

21. II) Compression Molding
 It is a method of preparing uniform and elegant
suppositories from a mixed mass of cold-grated
suppository base and medicaments.
 A hand turned wheel pushes a piston against the
suppository mass contained in a cylinder, so that the
mass is forced into compressed mold.
 This method avoids the possibilities of sedimentation of
the insoluble solids in the suppository base.
 The method requires that the capacity of the molds first
be determined by compressing a small amount of the
base into the dies and weighing the finished
suppositories. When active ingredients are added, it is
necessary to omit a portion of the suppository base
based on the density factors of the active ingredients.

22. III) Fusion/ Pour Molding
 It involves first melting the suppository base and then
emulsifying or suspending the drug in the melted base.
 The mixture is removed from the heat and poured into
cooled metal molds, which are usually chrome- or nickel-
plated. When the mixture has congealed, the
suppositories are removed from the mold.
 When they are mixed, melted and poured into
suppository mold cavities, they occupy a volume – the
volume of the mold cavity.
 Since the components are measured by weight but
compounded by volume, density calculations and mold
calibrations are required to provide accurate doses.
 The fusion method can be used with all types of
suppositories and must be used with most of them.

23. New Approach- Double Casting
Technique

24.  Packaging of suppository is done after lubrication with
proper lubricant in aluminum foil or in other suitable
material and with indication [STORE IN A COOL
PLACE].
 Several commercial suppository products include-
ANUSOL HC ( Hydrocortisone ), DULCOLAX (
Bisacodyl ) , CANASA (Mesalamine ) , NUMORPHAN (
Oxymorphane ),
PANADOL ( Paracetamol ), etc.
Acetaminophen Glycero-Gelatin Laxative Eucalyptol Anucort-HC
Fig: Different types of suppositories

25. 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.
 In many cases, these formulations are utilized to
administer contrast media and imaging agents for lower
GI roentgenography. 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

26. Fig: Rectal liquid inserts (Bubble insert)
Fig: Liquid applicator (squeeze inse

27. 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.
 Several marketed rectal aerosols are like
PROCTOFOAM HC (Pramoxine), CORTIFOAM
(Hydrocortisone), etc.

28. Evaluation of Suppositories
1. Weight Variation
 All the suppositories are weighed and average weight is
calculated.
 No suppositories should deviate from average weight by
> 5% except two, which may deviate not > 7.5 %.
2. Disintegration Test
 The disintegration test is performed on six suppositories
using tablet disintegration test apparatus.
 160ml of distilled water is used as medium at 37°C.
 The time required for complete disintegration of
suppository is determined.

29. 3. Breaking Test-
 It is designed as a method for measuring the fragility or
brittleness.
 Water at 37°C is pumped through the double wall
chamber of the apparatus. The test suppository is
placed in the dry inner chamber, which supports a disc
to which a rod is attached. The other end of the rod
consists of another disc to which weights are applied.
 The test is conducted by placing 600 g on the platform.
At 1 min intervals, 200 g weights are added, and the
weight at which the suppository collapses is the
breaking point.
 The desired breakpoints of various shaped suppositories
are established as the level that withstands the break

30. 4. Macro Melting Range Test
 For macro melting range test, the formulation is filled to
about 1cm height in capillary tubes of 10 cm length and
dipped in a beaker containing water.
 The temperature is raised slowly and the temperature at
which the mass liquefies is recorded.
5. Drug Content
 For determination of drug content the suppositories are
dissolved in suitable solvent.
 After the solution is filtered; and the filtrate is diluted
suitably, the absorbance is measured against blank at
particular nm using UV Spectrophotometer.

31. 6. Liquefaction Time & Temperature
 Liquefaction/ softening time and temperature can be
estimated using fabricated instrument.
 A big pipette is taken having a narrow opening on one
side and broad opening on another side. The pipette is
dipped in hot water maintained at 37 °C so that narrow
end faces toward hot water.
 The sample suppository is introduced from the top of the
pipette through broad end and carefully pushed down its
length until it reaches narrow end. A glass rod is then
inserted so that it rests over the suppository.
 The temperature at which the glass rods just come down
is noted that represents the liquefaction temperature.
The time at which glass rod reaches to narrow end after
complete melting of suppositories represents the

32. 7. Dissolution Test
 In vitro dissolution studies of suppositories are carried
out in tablet dissolution test apparatus employing a wire
mess basket, or a membrane to separate the sample
chamber from the reservoir.
 One suppository is used in each test at specified rpm
using buffer at 37±0.5°C as dissolution medium.
 At predetermined time intervals 5 ml sample are
withdrawn by means of syringe fitted with a pre filter
then filtered through watman filter paper. The volume
withdrawn at each interval is replaced with same
quantity of fresh dissolution medium and maintained at
37±0.5°C.
 The sample is analyzed for drug release by measuring
the absorbance at particular nm using UV visible

33. 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
metabolism.
 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.

34. REFERENCES
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delivery: A promising route for enhancing drug absorption.
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