vaginal and rectal drug delivery systems

1. VAGINAL and
RECTAL DRUG
DELIVERY SYSTEM
1

2. 2

3. Contents
 Introduction
 Advantages
 Disadvantages
 Factors affecting absorption of drugs
 Approaches towards vaginal drug delivery
 Bioadhesive delivery system
 Advantages of Bioadhesive systems
 Mucoadhesive vaginal drug delivery system
categorization
 Recent developments
 Applications
3

4. Introduction
 Vagina is route for administration for
contraceptives , antifungal and antimicrobials.
 It is used for the achievement of local or for
systemic absorption.
 The vaginal wall is very well suited for the
absorption of drugs for systemic use.
As it contains a vast network of blood vessels
4

5. Advantages
 Large surface area.
 Rich blood supply.
 Prolonged release.
 Minimal systemic side effects.
 An increase in bioavailability.
 Use of less total drug than an oral dose.
 First-pass metabolism can be avoided.
 Self medication is possible.
5

6. Disadvantages
 Patient incompliance.
 Only a few drugs are administered by
this route.
 Variability in drug absorption.
like related with pregnancy, can also
limit vaginal drug delivery route usage.
 Gender specificity.
6

7. Factors affecting absorption of
drugs
 Physicochemical properties of the drug
as lipophilicity, ionization, chemical
structure and interaction with vaginal
secretions and tissues.
 The thickness of vaginal wall.
 The ovarian cycle or by pregnancy.
 Changes in the vaginal epithelium and
pH with menopause.
7

8. Improvement of vaginal
absorption
 Use of penetration enhancers e.g. PEG.
 By increasing the contact time between
the dosage form and the vaginal
membrane by using mucoadhesive
polymers e.g. Carbopol.
 By increasing vaginal blood flow, thereby
raising the concentration gradient across
the vaginal mucosa.
 By the use of pro-drugs enhances drug
permeability through modification of the
hydrophilicity or lipophilicity of the 8

9. Ideality of intra-vaginal drug
delivery system
 Component should melt at vaginal
temperature i.e. at 36 °C.
 Intra-vaginal drug delivery device should
be non-toxic and non irritating.
 The preparation should have high water
number.
 The preparation should have wetting
and emulsifying properties.
9

10.  The preparation should be non-sensitized
on vaginal pH (i.e. 3.5-4.9).
 It should be stable on storage.
 The preparation should have small
interval between melting and solidification
point.
 The preparation should have proper
viscosity, so avoid the leakage of
preparation from vagina (in case of
semisolid dosage form).
 The preparation should have proper
bio-adhesive / mucoadhesive
properties, so increase the contact time
between the membrane and Preparation. 10

11. Approaches towards vaginal drug
delivery
 The traditional commercial preparations,
such as creams, foams, gels, irrigations
and tablets, are known to reside in the
vaginal cavity for a relatively short period
of time owing to the self-cleaning action of
the vaginal tract, and often require
multiple daily doses to ensure the desired
therapeutic effect.
 The vaginal route appears to be highly
appropriate for Bioadhesive drug delivery
systems in order to retain drugs for
treating largely local conditions, or for use
in contraception. 11

12.  To prolong the residence time in the
vaginal cavity, Bioadhesive therapeutic
systems have been developed in the
form of semi-solid and solid dosage
forms.
 The most commonly used mucoadhesive
polymers that are capable of forming
hydrogels are synthetic polyacrylates,
hyaluronic acid derivatives
chitosan, tragacanth, carrageenan,
pectin , sodium alginate,
cellulose derivatives
(hydroxyethycellulose,
hydroxypropylcellulose and
hydroxypropylmethylcellulose),
. 12

13. Bioadhesive delivery systems
13
 Bioadhesion may be defined as the state
in which two materials, at least one of
which is biologic in nature, are held
together for extended periods of time by
interfacial forces.
 If this attachment is due to a mucus
coating, the phenomenon is sometimes
referred to as mucoadhesion.
 Mucoadhesion is the interaction between
a synthetic or natural polymer and a
mucin surface, leading to a net attraction.

14.  Bioadhesive vaginal formulations are
capable of delivering the active agent
for an extended period at a predictable
rate.
 Bioadhesive formulations have been
found to reduce the conventional
treatment time of fungal infections by at
least 25%.
 A Bioadhesive formulation might not
necessarily contain a therapeutic agent
and can be used as a moisturizer for
14

15.  The vaginal route appears to be highly
appropriate for Bioadhesive drug
delivery systems in order to retain
drugs for treating largely local
conditions, or for use in contraception.
 Particularly, protection against sexually
transmitted diseases(STDs), such as
HIV is critical.
15

16. The main advantages of the
Bioadhesive systems over the
existing solid and semi-solid
preparations
 Low production costs,
 Avoidance of aqueous or organic
solvents,
 Ease of self-administration with no need
to use applicators,
 Gel-like consistency in the activated
state,
 Avoidance of local irritation phenomena,
 Rapid bioadhesion , prolonged residence
time , extended dosing interval, improved16

17. Mucoadhesive vaginal drug
delivery system categorized as
follows:
 1) Mucoadhesive gels.
 2) Mucoadhesive tablets.
 3) Mucoadhesive films.
 4) Emulsion type mucoadhesive
systems.
 5) Pessaries or suppositories
17

18. Mucoadhesive Vaginal Gels
 The most widely used mucoadhesive
vaginal drug delivery systems are gels.
 In particular, for drugs designed for
gynaecological use, a Bioadhesive gel
able to ensure prolonged contact
between the active ingredient and the
vaginal mucosa.
 Gradual release of that ingredient
overtime, provides the ideal solution in
terms of efficacy and compliance by
patients. 18

19. 19
 Among vaginal formulations, gels are
easy to manufacture , comfortable,
and have the ability to spread onto the
surface of mucous and to achieve an
intimate contact with vaginal mucosa.
 Because of their high water content
and their rheological properties, they
present the further advantage of a
hydrating and lubricating action, which is
particularly useful in pathological
situations characterized by dryness of
the vaginal mucosa.
 The employment of mucoadhesive
polymers can improve the time of
contact with the mucosa, delaying the
loss of the formulation and prolonging
the effect.

20. Some of the Marketed
Mucoadhesive Vaginal Gels
20

21. Mucoadhesive Vaginal Tablets
 Mucoadhesive polymers such as polycarbophil,
cellulose ethers, chitosan and
polyvinylpyrrolidine were used for the
preparation of tablet formulations.
 The manufacturing process of vaginal
Bioadhesive
controlled release matrix tablets consists of the
preparation of a matrix mixture comprising the
pharmaceutically acceptable excipients.
 The release mechanism is based on drug
diffusion through the swollen polymers and
progressive
erosion /dissolution of the gel matrix. 21

22. 22
 The tablet contains a microbicide
such as cellulose acetate 1, 2
benzenedicarboxylate (CAP) as the
vaginal medication is vaginally
administered before coitus in
methods for preventing the sexual
transmission of HIV-1, HIV-2, herpes
virus or an infection caused by
Neisseria gonorrhoea , Chlamydia
trachomatis , Trichomonas vaginalis,
or Treponema palladium.

23. Mucoadhesive Vaginal
Films
 Described a Bioadhesive hot-melt extruded
film for
topical and mucosal adhesion applications.
 The film is made from a precursor composition
containing a water-soluble or water- swellable
thermoplastic polymer, preferably HPC and/or
PEO and a Bioadhesive polymer.
 The film can also contain a therapeutic agent,
preservative, buffering agent, antioxidant, super-
disintegrant or absorbent, flavorant, colorant,
water-insoluble polymer, organic acid,
surfactant, film modifier and/or cross-linking
agent.
23

24. 24
 The film has a controllable rate of gelling, swelling
and degradation and is preformed into a device or
is applied as a coating to the surface of a more
complex drug delivery system.
 The pH-responsive film of the present invention
comprises a laminated composition of
a) a Bioadhesive layer that serves to affix the
film to a mucosal
surface within the vagina.
b) at least one reservoir layer comprising one
beneficial agent and a biocompatible hydrophilic
polymer.
 This film formulation can be used for
contraception, treatment and/or prevention of viral
infections, treatment of vaginal infections, relief of
vaginal itch, vaginal cleansing and enhancement
of vaginal lubrication.

25. Emulsion Type Mucoadhesive
Vaginal Systems
 Mucoadhesive semisolid dosage forms
(emulgels o/w) containing mucoadhesive
polymers (HEC and NaCMC) for vaginal
delivery of benzydamine.
 For this purpose simple gels (HEC 5 % and
NaCMC 3 % and 4 %)were formulated and
then added as outer water phase of an oil-
in-water emulsion named “cetomacragol-
based cream”.
 The most suitable emulgels for vaginal
application were those containing NaCMC
(3 %).
25

26. Vaginal Suppositories
 Suppositories can be easily applied to
the vagina.
 Hydrated Bioadhesive vaginal
suppository formulations are formed of
one or more hydrophilic polymers,
such as sodium carboxymethyl
cellulose, polyacrylic acids or
polyacrylates , pessary or suppository
base, water (30 % by weight of the
formulation) and an active ingredient.
26

27. Recent developments
 Recently, effervescent vaginal tablets of
nystatin were formulated, their antifungal
and therapeutic effect was found higher than
that of conventional one.
 Also , the antifungal activity of effervescent
vaginal tablets containing clotrimazole was
improved as compared to the conventional
one.
 Moreover, Bioadhesive effervescent
ketoconazole tablets for vaginal delivery
was studied.
 Therefore, effervescent vaginal tablets can
consider as one of vaginal medication
dosage forms. 27

28. List of vaginal preparations
recently developed or under
development
Preparation Active ingredient Company Status
Acidform (gel) --- TOPCAD (IL,
USA)
Phase I/II clinical trials
Cleocin (cream) Clindamycin phosphate Pharmacia &
Upjohn (MI,
USA)
Approved (USA)
Crinone® (gel) Progesterone Wyeth–Ayerst
Laboratories (PA,
USA)
Approved (1997)
Efamast Evening primrose oil Scotia Holdings
(Surrey, UK)
Phase II clinical trials
(Europe)
Estradiol 17-β-estradiol Watson
Pharmaceuticals
(CA, USA)
Phase II/III trials (USA)
Invisible
condom
Thermoreversible gel Laval University
(Canada)
Phase I clinical trials
Pro 2000 (gel) Napthalene 2-sulfonate Procept (MA, Phase II NIAID trial 28

29. Applications of intra-vaginal
drug delivery system
 This route of drug administration is
useful for vaginal immunization.
 Multi-cycle administration of vaginal
contraceptive rings.
 Effective route for the treatment of HIV
infection.
 Effective route for the treatment of
local fungal infection.
 Effective for the delivery of hormones.
29

30. RECTAL DRUG DELIVERY

31. Contents
 Introduction
 Advantages
 Factors affecting absorption
 Formulations
 Marketed Drugs
31

32. INTRODUCTION
 Rectal drug delivery
system is used both
for the local and
systemic drug
delivery.
 Effectively utilized to
treat local disease of
the anorectal area as
well as to deliver drugs
systemically as an
alternative to oral

33. ADVANTAGES OF RECTAL
DRUG DELIVERY
WHY WE USE RECTAL
ADMINISTRATION?
 In case of Nausea and vomiting.
 Irritation in the stomach and intestine
associated with drugs.
 Contact with digestive fluids is avoided.
 When oral intake is restricted.
 In pediatric , geriatric and unconscious
patients.

34. FACTORS AFFECTING
ABSORPTION
 Physiological factors.
 Limited rectal fluid volume.
 Chemical composition of fluid.
 pH and viscosity.
 Surface retention.
 Pressure exerted on the rectal wall.
 Chemical composition and additives
present in the vehicles may also
promote or retard the absorption.

35. FORMUALTIONS
THE VARIOUS FORMULATIONS WHICH
ARE AVAILABLE IN THE MARKET ARE:
1.Solid suppositories
2. Solutions
3. Gel/Foams/Ointments
4. Controlled release formulations
a. Controlled release suppositories
b. Sustained release rectal gels
c. Osmotic rectal drug delivery
d. Controlled release rectal capsules
e. Controlled release rectal enemas.

36. SOLID SUPPOSITORIES
 Solid suppositories are the most
common dosage form used for rectal
drug administration and represent
greater than 98% of all rectal dosage
forms. Typically, these are torpedo-
shaped dosage forms composed of
fatty bases (low-melting) or water-
soluble bases (dissolving) which vary
in weight from 1g (children) to 2.5 g
(adult).
 The composition is largely dictated
by the physicochemical properties of
the drug and the desired drug release
profile. Lipophilic drugs are usually
incorporated into water-soluble bases
while hydrophilic drugs are formulated
into the fatty base suppositories

37. Vehicles used in the preparation
of the suppositories
FATTY BASES MELTING RANGE SOLIDIFICATION
POINT
WITEPSOL 32-44 27-38
COCOA BUTTER 30-35 24
HARD BUTTER 36-45 32-40
WATER SOLUBLE
BASES
MELTING RANGE SOLIDIFICATION
POINT
PEG 38-49 39
TWEEN 51 35-49

38. SOLUTIONS
 Solutions, suspensions, or
retention enemas represent
rectal dosage forms with very
limited application.
 largely due to inconvenience
of use and poor patient
compliance.
 Although drug absorption
from solutions has been
shown to exceed that from
solid suppositories in some
cases, this particular
administration route is only
infrequently employed.

39. Gels/Foams/Ointments
 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 with semisolid
dosage forms is usually limited
to local indications such as
haemorrhoids and lower bowel
inflammation.
 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.

40. Controlled release formulations
1. Controlled release formulations are designed to release
the active agent in sustained or controlled fashion.
2. Controlled release dosage forms ensure safety,
improved efficacy of drugs as well as better patient
compliance. This is achieved by better control of plasma
drug levels and less frequent dosing.
3. Controlled drug delivery system that provide optimum
drug effects by controlling the absorption rate and
duration in the systemic circulation are widely accepted
4. These drug delivery systems require minimal medical
supervision and provide localized drug action in the
diseased tissue or organ.
5. For the design of the controlled release rectal drug
delivery systems, suppositories, gels and newer concept
of hydrogels and xerogels have also been investigated.
There are also reports of osmotic pumps, capsules and
enemas being designed as rectal drug delivery for
controlled release.

41. Controlled release suppositories
1. Suppositories are
defined as the solid
products of various
weights and shapes
intended for introduction
into the body cavities
such as rectum, vagina
and urethra.
2. fatty acids and
Polyethylene glycols
bases have been used
to design controlled
release suppositories.

42. Controlled release rectal gels
1.Rectal gels have been
primarily used for local
action, either externally or
for internal application.
2.Currently, rectal gels are
being investigated as
suitable dosage forms for
systemic controlled drug
delivery various polymers
like poloxamer ABA block
copolymer, polyacrylic acid,
polyvinyl alcohols,
eudragits have been used
for the preparation of the
gels.
eg. Polyacrylic acid gels,

43. Osmotic rectal drug delivery
system
1. Osmotic pumps have been used
for oral and subcutaneous drug
delivery. These devices are
investigated for rectal drug
delivery.
2. This device is slightly larger than
the normal adult suppository and
has drug reservoir surrounded by
an osmotic driving agent
encapsulated in a semi permeable
membrane; the membrane serves
as a rigid housing and contains an
orifice for delivery of drug solution
or suspension.
3. The drug is released in solution
form at a controlled, constant rate
under an osmotic pressure
gradient.

44. Controlled release rectal
capsules
1.Both hard and soft gelatin
capsules have been used
as rectal dosage forms.
2.Hard gelatin capsules
have been formulated
using different diluents
such as dicalcium
Phosphate and
hydroxypropyl
methylcellulose(HPMC).
3.Capsules containing
lactose behave like
immediate release
formulation while those
containing HPMC
behaves like prolonged

45. Controlled release rectal enemas
1. Rectal enema have been
primarily used as
cleansing enemas for
evacuation of the
bowels.
2. The volume
administered as a
cleansing enema is in
the range of 500-1000
ml, retention enema
comprise of the smaller
volume and not more
than 180ml.

46. Marketed drugs and therapeutic
classes Rectal dosage forms marketed in the United
States for systemic indications
Therapeutic category and drug Drug load, solida (mg)
Antihistamine
Promethazine
12.5–50
Antimigraine
Ergotamine 2
NSAID
Aspirin 50
Analgesic
Hydromorphone 3
Morphine 5–30
Opium 30–60
Oxymorphone 5
Acetaminophen 120–650

47. CONT.
Insomnia
Pentobarbital 30–200
Chloral hydrate 325–650
Promethazine 12.5–50
Tranquilizer
Chlorpromazine 25–100
Prochlorperazine 2.5–25
Bronchodilator
Aminophylline 105
Antiemetic
Thiethylperazine 10
Trimethobenzamide 100–200
Hyperkalemia
Polystyrene sulfonate 1250b
Portal-systemic encephalopathy
Lactulose Variable

48. 48

49.  Robinson JR, Bologna WJ. Vaginal and
reproductive system treatments using a
Bioadhesive polymer. J Control Release
1994;28: 87-94.
 Brannon-Peppas L. Novel vaginal drug
release applications.
Drug Deliv Rev 1993; 11: 169-177.
 das Neves J, Bahia MF. Gels as vaginal drug
delivery systems. Int J Pharm 2006; 318: 1-
14.
 Acartürk F, Robinson JR. Vaginal
permeability and enzymatic activity studies in
normal and ovariectomized rabbits. Pharm
Res 1996; 13: 779-783.
49

50. 50