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Suppositories, Inserts, and Sticks

SUPPOSITORIES

Urethral administration of suppositories has


become more acceptable with urethral
suppositories in the treatment of male erectile
dysfunction.
In US less than 1% of drugs are formulated as
suppositories
In Germany high as 5%
Progesterone vaginal inserts have become
much more widely used by post menopausal
women

Employed for 3 reasons:


1.
2.
3.

Promote defecation
Introduce drugs into the body
Treat anorectal diseases

Not often the first route of choice but a good


alternative when oral is inadvisable

SUPPOSITORY, INSERT, AND STICK SHAPES

The downside of rectal administration includes:


1.
2.
3.

Esthetics and stigma of violating the patients


dignity
Potential rectal irritation
Difficulty in titrating a correct dose due to
limited strengths of commercial suppositories
In treating hospice patients, rectally
administered medications are essential in
palliative medicine
An excellent dosage form for those patients to
whom one does not want to administer
numerous injections daily.
Can be administered to avoid nausea and
vomiting
Can often result in a fast onset of action

DEFINITIONS

A suppository is a solid dosage form in which


one or more APIs are dispersed in a suitable
base and molded or otherwise formed into a
suitable shape for insertion into the rectum to
provide local or systemic effect.
Are intended for insertion into body orifices
The derivation of the word suppository is from
the latin supponere to place under as
derived from sub (under) and ponere (to
place)
An insert Is a solid dosage form that is inserted
into a naturally occurring (non surgical) body
cavity other than mouth or rectum, including
the vagina and urethra.

Medication sticks are a convenient form for


administering topical drugs.

The shape and size of a suppository must be


such that:
1. It can be easily inserted into the intended
orifice without causing undue distension
2. Once inserted, it must be retained for the
appropriate period.
Rectal suppositories are inserted with the
fingers, but certain vaginal inserts may be
inserted high in the tract with the aid of an
appliance
Usually about 32 mm long, are cylindrical, and
have one or both ends tapered.
Some rectal suppositories are shaped like a
bullet, a torpedo or the little finger.
Adult rectal suppositories weigh about 2g when
cocoa butter is employed as the base.
Rectal suppositories for use by infants and
children are about half the weight and size of
the adult suppositories and assume a more
pencil-like shape
Vaginal inserts (suppositories or pessaries) are
usually globular, oviform, or cone-shaped and
weigh about 5 g when cocoa butter is the base.
Urethral inserts (bougies) are slender, pencilshaped suppositories intended for insertion
into the male or female urethra.
Male urethral suppositories may be 3 to 6 mm
in diameter and approximately 140 mm long.
When cocoa butter is employed as base, these
suppositories weigh about 4g.
Female urethral suppositories are about half
the length and weight of the male urethral
suppository, being about 70 mm long and
weighing about 2g when made of cocoa butter.
Medication sticks are cylindrical in shape and
generally range from 5 to 25 g. They are
generally packaged in an applicator tube for
topical administration.

USES AND APPLICATIONS


Suppositories containing drugs such as aspirin,
opiates for pain, ergotamine tartrate for
treating migraine headaches are commonly
used as suppositories.
These drugs are intended to be absorbed into
the general circulation to provide systemic
drug effects.
Examples of suppositories given for systemic
results:
-

Diazepam
Metronidazole
Progesterone

Aminophylline
Morphine
Prochlorperazine
Chlorpromazine
Thiethylperazine
Indomethacin
Diclofenac
Ketoprofen
Naproxen
Ondansetron

The advantages of rectal administration include the


following:
1.
2.

Avoiding, at least partially, the first pass effect


Avoiding the breakdown of certain drugs that
susceptible to gastric degradation
3. Ability to administer somewhat larger doses of
drugs
4. Ability to administer drugs that may have an
irritating effect on the oral or gastrointestinal
mucosa
5. Ability to administer unpleasant tasting or
smelling drugs
6. In children, the rectal route is especially useful.
7. In patients experiencing nausea and vomiting
or when the patient is unconscious
8. The presence of disease of the upper
gastrointestinal tract that may interfere with
drug absorption
9. Objectionable taste or odor of a drug
10. Achievement of a rapid drug effect
systematically

Provides for a rapid and in many cases,


extensive absorption of the active ingredient.
RAPIDITY, INTENSITY AND DURATION are
three parameters that must be considered
during formulation for rectal administration

The disadvantages of suppositories and the reasons


given for the infrequent use of suppositories include
the following:
1.
2.
3.
4.
5.

Lack of flexibility
Expensive
They exhibit variable effectiveness
Cannot be interchanged without risk of toxicity
Can leave the anorectal site and ascend to the
rectosigmoid and descending colon
6. Defecation may interrupt the absorption
process of the drug
7. Absorbing surface area of the rectum is much
smaller
8. The fluid content of the rectum is much less
which may affect the dissolution rate
9. Possibility of degradation of some drugs
10. The dose of a drug required for rectal
administration may be greater than or less
than the dose of the same drug given orally
11. Anatomic and physiological factors and
physicochemical factors of the drug and base

LOCAL ACTION

These medicaments may be intended for


retention within the cavity for local effects
They may be intended to be absorbed for
systemic effects
Rectal suppositories intended for local action
are most frequently used to relive constipation
Antihemorrhoidal suppositories frequent
contain a number of components, including
local anesthetics, vasoconstrictors, astringents,
analgesics, soothing emollients and protective
agents.
Glycerin suppositories promote laxation by
local irritation of the mucous membranes
Vaginal suppositories or inserts intended for
local effects are employed mainly as
contraceptives, as antiseptics, and as specific
agents to combat invading pathogen

Most commonly drugs used:

Nonoxynol 9 for contraception


Trichomonacides to combat vaginitis
Antifungals, anti-infectives/antibiotics

Urethal suppositories may be antibacterial or a


local anesthetic preparative for a urethral
examination
Sticks are commonly used for local effect;
includes hydration/emollient, antibacterial,
sunscreen, antipruritic

SYSTEMIC ACTION

For systemic effects, the mucous membranes


of the rectum and vagina permit the absorption
of many soluble drugs
Rectum is used frequently as the site for the
systemic absorption of drugs

Examples of drugs administered rectally in the


form of suppositories for their systemic effects
include:

Prochlorperazine & Chlorpromazine for the


relief of nausea and vomiting and as a
tranquilizer
Morphine and oxymorphone for opioid
analgesia
Ergotamine tartrate for the relief of migraine
syndrome
Indomethacin a nonsteroidal antiinflammatory analgesic and antipyretic
Ondansetron for the relief of nausea and
vomiting

PHYSIOLOGICAL FACTORS AND DRUG EFFECT

The physiologic factors that affect drug absorption


from the rectum are:
1.
2.
3.
4.

Circulation route
Colonic contents
pH
Lack of buffering capacity

Urethra- there are stratified columnar cells, then


stratified squamous cells

CIRCULATION ROUTE

The lower hemorrhoidal veins surrounding the


colon receive the absorbed drug and initiate its
circulation
Lymphatic circulation also assists in the
absorption of rectally administered drugs

pH AND LACK OF BUFFERING C APACITY OF THE


RECTAL FLUIDS
The pH of the rectal fluid is generally in the
range of 7.2 to 7.4 and it has negligible buffer
capacity.
Rectal- the last few inches of the large intestine
constitute the rectum , terminating at the anus

COLONIC CONTENT

Superior hemorrhoidal vein


Middle hemorrhoidal vein
Inferior hemorrhoidal vein

Acts by transporting the active principle


absorbed in the rectum to the blood system
The three hemorrhoidal veins are linked by an
anastomosis network
At least 50% to 70% of the active ingredients
administered rectally take the direct pathway

Vaginal is a specialized organ whose primary


function is reproduction. A highly elastic muscular tube,
located between the urethra and rectum.
3 tissue layers:
Epithelial tissue
Loose connective tissue
Muscle tissue
.
Branches of the uterine arteries supply blood
to the upper vagina
The inferior vesicle arteries supply blood to the
middle portion of the vagina
The hemorrhoidal and internal pudendal
arteries feed into the lower vagina
The pH of the vagina is in the range about 4 to
4.5
Normal vaginal discharge consists of about 1.5
g of vaginal fluid daily

Physicochemical factors include such


properties as the relative solubility of the drug
in lipid and in water and the particle size of
dispersed drug.
Physicochemical of the base include its ability
to melt, soften, or dissolve at body
temperature, its ability to release the drug
substance and its hydrophilic or hydrophobic
character.

LIPID-WATER SOLUBILITY

A drug will obviously have greater opportunity


to make contact with the absorbing surface of
the rectum and colon in the absence of fecal
matter.
An evacuant enema may be administered and
allowed to act before the administration of a
suppository of a drug to be absorbed.

PHYSICOCHEMICAL FACTORS AND DRUG EFFECT

Three types of hemorrhoidal veins:

There are small mucus-secreting urethral


glands that help protect the epithelium from
the corrosive urine,
The female urethra is supplied by blood vessels
called the internal pudendal and vaginal
arteries
The male urethra is supplied by inferior vesical
and middle rectal arteries
The nerve supply is via the pudendal nerve

The lipid-water partition coefficient of a drug is


an important consideration in the selection of
the suppository base and in anticipating drug
release from the base
A lipophilic drug that is distributed in a fatty
suppository base in low concentration has less
tendency to escape to the surrounding
aqueous fluids than a hydrophilic substance in
a fatty base.

Example of water-soluble bases:

Polyethylene glycols- that dissolve In


anorectal fluids

PARTICLE SIZE

The smaller the particle, the greater the


surface area and the greater the chance for
rapid absorption.

The rate of absorption is influenced by the


solubilization rate
It is preferable to avoid a too fine particle size
because of the high increase of the viscosity of
the melted excepient that can result from the
use of excessively small particles

FATTY OR OLEAGINOUS BASES

SUPPOSITORY BASES

Suppository bases play an important role in


the release of the medication they hold and
therefore, in the availability of the drug.
It should remain solid at room temperature but
soften, melt, or dissolve readily at body
temperature
Cocoa butter melts quickly at body
temperature
Glycerinated gelatin or polyethylene glycol,
both of which dissolve slowly in body fluids.
Treatment of anorectal disorders, cocoa butter
appears to be the superior base

The absence of any drug interaction between


the two agents should be ascertained before or
during formulation.
Morphine sulfate in slow-release suppositories
is prepare in a base that includes a material
such as alginic acid, which will prolong the
release of the drug over several hours

CLASSIFICATION OF BASES
1.
2.
3.

Fatty or oleaginous bases


Water-soluble or water miscible bases
Miscellaneous bases- generally combination of
lipophilic and hydrophilic substances

A suppository base should be physically and


chemically stable, non-irritating, non-toxic ,
non-sensitizing, chemically and physiologically
inert, compatible with a variety of drugs, stable
during storage, and esthetically acceptable
Has wetting and emulsifying properties
Has high water number
Can be manufactures by molding by hand,
machine, compression or extrusion.
Should melt or dissolve in rectal fluids
Should not bind or otherwise interfere with the
release of absorption of drug substances

Drugs that lower the melting point of the base:

Camphor
Chloral hydrate
Mentol
Phenool
Thymol

Fatty bases are perhaps the most frequently


employed suppository bases, principally
because cocoa butter is a member of this
substances.

Among the other fatty or oleaginous materials used in


suppository bases:

NATURE OF THE BASE

Volatile oils

Hydrogenated fatty acids of vegetable oils


such as palm kernel oil, and cottonseed oil
Fat-based compounds containing
compounds of glycerin such as palmitic
and stearic acid (glyceryl monostearate
and glyceryl monopalmitate)

Some bases are prepared with the fatty


materials emulsified or with an emulsifying
agent present to prompt emulsification when
the suppository makes contact with the
aqueous body fluids.
Cocoa Butter, NF, is the fat obtained from the
roasted seed of Theobroma cacao. It is a
yellowish-white solid. It is a triglyceride
Cocoa butter melts @ 30*C to 36*C. It is an
ideal suppository base
Cocoa butter exhibits marked polumorphism or
existence in several crystalline forms
Substances such as phenol and chloralhydrate
have a tendency to lower the melting point of
cocoa butter.
Solidifying agents like cetyl esters was or
beeswax may be melted with the cocoa butter
to compensate for the softening effect of the
added substance

Other bases:
1.
2.

Fattibase triglycerides from palm, palm


kernel, and coconut oils
Wecobee bases triglycerides of saturated
fatty acids

WATER-SOLUBLE AND WATER-MISCIBLE BASES

The main members of this group are:


glycerinated gelatin and polyethylene glycols
A glycerinated gelatin base is most frequently
used in the preparation of vaginal suppositories
The glycerinated gelatin base is slower to
soften and mix with the physiologic fluids than
is cocoa butter and therefore provides a slower
release
Glycerinated gelatin base suppositories have a
tendency to absorb moisture

They must be protected from atmospheric


moisture
The suppository may have a dehydrating effect
and irritate tissues upon insertion
Urethral suppositories may be prepared from a
glycerinated gelatin base
Urethral suppositories of glycerinated gelatin
are much more easily inserted
Polyethylene glycols are polymers of ethylene
oxide and water prepared to various chain
lengths, molecular weights and physical states
The numeric designations refer to the average
molecular weight of each of the polymers.
Polyethylene glycols having average molecular
weights of greater than 1,000 are wax-like
white solids whose hardness increases
Progesterone vaginal suppositories are used in
pre-menstrual syndrome. They are commonly
molded with either a polyethylene glycol base
or a fatty acid base
Polyethylene glycol suppositories do not melt
at body temperature but rather dissolve slowly
in the bodys fluids
Polyethylene glycol-based suppositories do not
leak from the orifice
Poloxamers are water-soluble block copolymers
with a wide range of uses
Oluronics L44, L62, L64 amd F68 are potential
suppository bases
The poloxamers have practically no odor or
taste

FORMULATION VARIABLES
Formulation variables that are generally considered
include:

The nature and form of the active principle


The physical state, particle dimensions and
the specific surface of product
The solubility of the drug in various bases
The presence or absence of adjuvants
The nature and type of dosage form in
which the active principle is incorporated
Pharmaceutical procedures used in the
preparation of the dosage form

PHYSICAL STATE

An active drug can be a solid, liquid, or semisolid in nature


For solids, the drugs particle size may be very
important
The increase in surface area resulting from
decreased particle size can serve to enhance
its activity

It is necessary to take up the liquid into the


suppository base using one of several
techiniques such as forming emulsion,etc
For the semisolids or paste-type drugs, it can
be either mixed with a solid that will serve to
thicken the drug.

PARTICLE SIZE

If a drug is readily soluble, the influence of


particle size may be minimal.

SOLUBILITY

Increased solubility of the active in the base


can improve product homogeneity
It may also delay the release of the active if
there is too great an affinity f the drug for the
suppository vehicle.

VISCOSITY

If the viscosity of a base is low, it may be


necessary to add suspending agent such as
silica gel

BRITTLENESS

Cocoa butter suppositories are usually not


brittle unless the percentage of solids present
is high
Synthetic fat bases with high stearate
concentrations or those that are highly
hydrogenated are typically more brittle

VOLUME CONTRACTION

Bases, excepients and active ingredients


generally occupy less space at lower
temperatures than at higher temperatures

SPECIAL PROBLEMS

Hard, crystalline materials can be incorporated


either by pulverizing them to a fine state or by
dissolving them in a small quantity of solvent
An aqueous solvent and PEG base are
appropriate for water soluble and an oily base
must be used, wool fat could be used to take
up the solution for incorporation into the
suppository base

A number of ingredients are incompatible with PEG


bases including:

Benzocaine
Iodochlorhydroxyquin
Sulfonamides
Ichthammol

Aspirin
Silver salts
Tannic acid

Other materials reported to have a tendency to


crystallize out of PEG:

Sodium barbital
Salicylic acvid
Camphor

Polyethylene glycol-based suppositories may


be irritating to some patients
Triglyceride-type bases can sometimes accept
up to about 50% glycerin without much
difficulty

PREPARATION OF SUPPOSITORIES
Suppositories are prepared by two methods:
A. Molding from a melt
B. Hand rolling and shaping
SUPPOSITORY MOLDS

Molds in common use today are made from


stainless steel, aluminum, brass or plastic

LUBRICATION OF THE MOLD

Lubrication is seldom necessary when the base


is cocoa butter or polyethylene glycol
Lubrication is usually necessary with
glycerinated gelatin

PACKAGING AND STORAGE

In filling each suppository cavity, the pouring


must be continuous to prevent layering

Hand rolling and shaping is a historic part of


the art of the pharmacist

MANUFACTURING SUPPOSITORIES

Manufactured suppositories are generally


prepared by the melt fusion method
The process starts with two main components:
the packaging shell material and the molten
bulk product

QUALITY CONTROL

Physical observation can generally detect


physical stability problems including softening,
hardening, drying, cracking, separation,
polymorphs

CHEMICAL STABILIY

HAND ROLLING AND SHAPING

Glycerin suppositories and glycerinated gelatin


suppositories are packaged in tightly closed
glass containers to prevent a change in
moisture content
Suppositories prepared form cocoa butter base
are usually individually wrapped or otherwise
separated in compartmented boxes to prevent
contact and adhesion
Suppositories containing light-sensitive drugs
are individually wrapped in an opaque material
such as metallic foil
Most commercial suppositories are individually
wrapped in either foil or plastic
Some are packaged in a continuous strip
Suppositories are commonly packaged in slide
boxes or in plastic boxes
It is necessary to maintain them in a cool palce
Suppositories made from a base of
polyethylene glycol may be stored at usual
room temperatures
Suppositories stored in high humidity mas
absorb moisture

PHYSICAL STABILITY

PREPARING AND POURING THE MELT

Quality control procedures listed in the USP 36NF 31 for manufactured suppositories and
inserts include identification, assay, and in
some cases, loss on drying, disintegration and
dissolution

In working with suppositories, the majority will


be anhydrous
Water may be present to help incorporate the
drug into base
It may be present as part of the hydrated form
of the drug components crystalline structure
If emulsions or suspensions are incorporated
into suppositories, water may be present

BEYYOND-USE DATING FOR COMPUNDED


SUPPOSITORIES

The completed compounded suppositories are


generally considered dry or non-aqueous

EXPIRATION DATING FOR MANUFACTURED


SUPPOSITORIES
Exempt from this requirement are:

Homeopathic drug products


Allergenic extracts
Investigational new drugs

Excessive softening is the major indication of


instability in suppositories
As a general rule, suppositories should be
stored in a refrigerator
INFORMING AND EDUCATING THE PATIENT
The pharmacist is obligated to inform the
patient about the proper storage conditions for
both prescription and non prescription products
and to suggest a reasonable estimate of the
time after which the medication should be
discarded.
Patients should be encouraged to clean out
their drug storage cabinets periodically
RECTAL SUPPOSITORIES
Intended to be absorbed into the general curcylation to
provide systemic effects:

Aspirin given for pain


Ergotamine tartrate for treating migraine
headaches
Theophylline as a smooth muscle relaxant
in treating asthma
Chlorptomazine and prochlorperazine
which act as antiemetics and tranquilizers

Suppositories are also intended to provide local


action within the perianal area
Local anesthetic suppositories are commonly
employed to relieve pruritus ani
Cathartic suppositories are contact-type agents
that act directly on the colonic mucosa to
produce normal peristalsis
Cathartic suppositories are more rapid acting
than orally administered medication
Glycerin, a hygroscopic material, contributes to
the laxative effect of the suppository

COMPOUNDING URETHRAL SUPPOSITORIES

These preparations are employed principally to


combat infections in the female genitor urinary
tract, to restore the vaginal mucosa to its
normal state, and for contraception.
Among the anti-infective agents in commercial vaginal
preparations are:

Nystatin
Clotrimazole
Butoconazole nitrate
Terconazole
Miconazole

Anti-fungals:

Triple sulfas
Sulfanilamide
Povidone Iodine
Clindamycin phosphate
Metronidazole
Oxytetracyline

VAGINAL INSERTS (TABLETS)

URETHRAL SUPPOSITORIES
Suppositories for urethra administration tend to
be thinner and tapered, often about 5mm in
diameter
They have been used for the treatment of local
infections

A straw or thin glass tube can be used as the


mold when preparing urethral suppositories
The MUSE (aprostadil) urethral microsuppository (Vivus inc.) is a single-used
medicated transurethral system for the
delivery of alprostadil in the male urethra

VAGINAL INSERTS

A much smaller urethral suppository has been


introduced for the administration of alprostadil
in the treatment of erectile dysfunction

Vaginal inserts (tablets( are widely used today


as they are easy to manufacture, more stable
and less messy
Accompanied in their packaging with a plastic
inserter, a device for easy placement of the
tablet within the vagina
They are prepared by tablet compression and
are commonly formulated to contain lactose as
the base or filler, a disintegrating agent such
as starch, a dispersing agent such as
polyvinylpyrrolidone, and a table lubricant such
a magnesium stearate

MEDICATION STICKS

The medication stick, a fairly recent


preparation, is used for both cosmetic and
medical purposes

Medication sticks are prepared similar to


suppositories except that the melt Is poured
into the administering device or tube

Melting bases:

Cocoa butter
Petrolatum waxes
Polyethylene glycols (PEGS)

Penetration enhancers:
Glycerin
Propylene glycol
Alcohol
Surfactants
.
Using waxes, oils, or plain polymers suchs as
PEGs alone achieves a topical effect

CLINICAL CONSIDERATIONS:

Rub cocoa butter suppositories gently with


fingers to melt the surface to provide
lubrication for insertion
Glycerinated gelatin or polyethylene glycol
suppositories should be moistened with water
to enhance lubrication
The shape of the suppository determines how it
will be inserted.
Bullet-shaped rectal suppositories should be
inserted point-end first