GATE Preparation Material for Suppositories

Key Points for Suppositories

Smt. Dr. Jayanti Vijaya Ratna

1.    A suppository is a medicated solid
dosage form, intended for use in the rectum, vagina or the urethra.
2.    The suppository uses vehicles that
either melt at body temperature or dissolve or disintegrate in the
small amount of rectal body fluids.
3.    Suppository is mainly used in old
people, post operative people, bed ridden people or infants or in cases
where for some reason the oral route is ruled out, (cases of severe
nausea and vomiting or in paralytic ileus).
4.    For rectal administration, one half to
two or more times the oral dose is given for all but very potent drugs.
So much range is there because drug release differs widely from one
base to another.
5.    The suppository base and the amount of
drug must be considered together i.e. the dose of the drug changes with
the type of base.
6.    The amount of drug to be given in the
suppository depends on (a) the base used and on (b) the chemical
and  physical form of the drug.
7.    Rectal suppositories for adults
usually weigh 2g and are torpedo shaped.
8.    Children’s suppositories
weigh about 1g.
9.    Urethral suppositories for males weigh
4g each and for females they weigh 2g each.
10.    Suppositories can exert local or
systemic action.
11.    The action level depends on (1) the
nature of the drug (2) the concentration of the drug and (3) the rate
and site of absorption.
12.    Emollients, astringents,
antibacterial agents, hormones, steroids and local anesthetics are
given as suppositories.
13.    Suppositories are mainly used to
treat constipation or hemorrhoids.
14.    By giving a drug in the form of
suppositories, we can partly overcome the first pass effect.
15.    This is because; the lower
homorrhoidal vein surrounding the colon and the rectum enter into the
inferior vena cava and thus bypass the liver. The upper  
       homorhoidal vein connects
with the portal veins leading to the liver. So the drug absorbed from
the lower end of the rectum ( from a suppository placed  
      just in lower end of the
rectum)  is absorbed by the lower hemorrhoidal vein and it
bypasses the liver. The drug released from a suppository placed deep
        in the rectum is absorbed
by the upper hemorrhoidal vein and it does not bypass the liver, hence
it suffers from first pass effect. There are also many  
         
 ‘joinings’ between the two hemorrhoidal
veins. In spite of this fact, it was established that, the drug
released from the suppository, at least partially,
       
         overcomes the
first pass effect, especially if it is placed at the lower end of the
rectum.
       So if the suppository is
properly placed in the rectum (not too deep) then the drug is absorbed
(usually 50 to 70%) by the lower homorhoidal vein and it  
       bypasses the liver and
escapes the first pass effect.
16.    Ph of the rectal mucosa plays an
important role in rectal absorption.
17.    Rat colon has a pH of about 6.8.
18.    Rectal fluids have no buffer capacity.
19.    Weaker acids and bases are more
readily absorbed than the stronger highly ionized drugs.
20.    The barrier separating the colonic
lumen from the blood is preferentially permeable to the unionized forms
of drugs.
21.    Absorption of acidic drugs will be
increased in the rectum if we lower the pH.
22.    Absorption of salicylic acid rose
from 12% at a pH of about 7 to 42% at a pH of 4.
23.    For quinine, absorption decreased
from 20% at pH 7 to 9% at pH 4.
24.    Phenol is a weak acid; it is
completely unionized at pH 7 and at pH 4. So there is no change in its
absorption when we lower the pH.
25.    Drug absorption from suppositories is
influenced by
(a)    diffusion of the released drug to the
site of absorption
(b)    nature of the drug
(c)    presence of a surfactant
(d)    water-lipid partition coefficient of
the drug
(e)    physiological state of the colon
(amount and chemical nature of the fluids and solids present in it)
(f)    the state of anorectal membrance
(thickness of the mucous wall which can impede the absorption)
26.    A drug that can be absorbed from the
colon most likely would be completely absorbed in the small intestine
before reaching colon.
27.    Body temp. is 37OC on average, it may
vary from 36OC to 38OC.
28.    The affinity between the drug and the
base has a bearing on drug release
29.    If the drug is more soluble in the
base, it will be released very slowly from the base. If it is less
soluble in the base, it is released readily.
30.    Water soluble, oil insoluble salts
are preferred in fat-base suppositories
31.    But for water soluble bases, such as
glycero gelatin (the suppository dissolves and releases the drug) the
water soluble type salt is the one of choice for    
       quicker drug absorption.
32.    Ephedrine sulfate and quinine
hydrochloride and sodium barbital and sodium salicylate are preferred
to their respective bases and acids.
33.    The rate limiting step in drug
absorption from suppositories is the partitioning of the dissolved drug
from the melted base.
34.    The rate of release by drug from
suppository depends on
(a)    The rate of diffusion of the drug to
the surface of the suppository
(b)    particle size of the drug
(c)    Presence of surfactants
35.    Surfactants can both increase and
decrease drug absorption rate.
36.    Ex. Sodium iodide - for this drug the
surfactant may reduce the surface tension on the rectal membrane and
wash away the mucous blanket and hence      
     enhance the absorption.
37.    Ex. Phenol – type drugs. A
drug – surfactant complex may form and the absorption may be
reduced.
40.    In situations such as in retention
enema, the amount of drug absorbed into the body from the rectum
depends upon the initial saturation concentration    
         present in the
rectal mucous fluids. If beyond this saturation concentration, the
amount of drug is increased it has no effect on the amount of drug
       
         absorbed.
41.    Colonic absorption of drugs depends
on simple diffusion across the colonic membrane.
42.    But the rate of release of the drug
from the suppository is dependent on the concentration of drug.
43.    So the steps in drug absorption from
suppositories are like this :
1)    The drug should be released from the
suppository.
2)    It should diffuse through the mucous
fluids to the site of absorption on the lumen wall.
3)    It should be absorbed. The lipid
soluble, undissociated drug is most readily absorbed.
4)    Completely ionized drugs such as
quaternary ammonium compounds and sulfonic acid derivatives are poorly
absorbed.
44.    Unionized drugs that are lipid
insoluble are also poorly absorbed.
45.    So for absorption through the colon
two conditions are necessary and essential
1)    The drug should be unionized
2)    It should be lipid soluble
46.    Absorption through the colon :
1)    Weak acids with a  
pka below 4.3 and weak bases with a pka below 8.5 are readily absorbed.
2)    Acids having pka values below 3.0 and
bases having pka values above 10 show poor absorption.
47.  One way of increasing absorption through the colorectal
wall is to employ a buffer and change the pH of the fluids such that
the concentration of the    
       unionized drug increases.
48.    Factors affecting absorption from
anorectal area are
(a) Colonic contents (b) Circulation (c) pH (d) lack of buffering
capacity (e) physiological state (f) thickness of mucous blanket on the
lumen wall
     Physico chemical characters :
(a)    lipid – water partition
coefficient
(b)    degree of ionization
(c)    particle size of drug.
49.    Research showed that
1)    Drug absorption is faster from
suppository bases (oily bases) which have lower melting range than from
bases with higher melting range.
2)    Absorption increased with increasing
hydroxyl values.
3)    For the Polyethylene Glycol (PEG
bases) as the molecular mass of the PEG increased there was a decrease
in absorption time.
4)    Excipients added to the base may
affect absorption either through changing the rheological behaviour of
the suppository or by affecting its dissolution.
5)    In emulsion type bases,
a.    Amount of water soluble drug released
increased with the water content of the base.
b.    Rate of the drug released may be
prolonged by the addition of an aqueous polymer.
c.    When hydrophobic colloidal silicon
oxide was added to fatty base suppositories, their rhelogical behaviour
changed, affecting drug release.
d.    Salicylates improved the rectal
absorption of water-soluble antibiotics in lipophilic bases.
e.    When cylindric suppositories were made
from hydrogels of hydroxyethyl methacrylate, using a cross linking
agent (ethylene glycol dimethacrylate) → rate  
     of drug release decreased with
increasing percentages of cross – linking agent.

{mospagebreak title=More info 50 to 65}

50.    Research :
      Comparision of oral, rectal and i.v.
administration of theophylline derivatives :
a)    i.v. administrered drug is immediately
available in blood.
b)    It takes about 30 minutes for the drug
that is released into the rectum to be absorbed into the blood.
c)    After making allowance for this 30
minutes lag time, the two routes were found to be equally effective.
51.    Research :
a)    That there is effective absorption
from suppositories, and that it can give therapeutically effective
levels is a debatable issue. All scientists do not agree on  
     it.
b)    To maintain the therapeutic
effectiveness of a drug from the suppository, two conditions are
necessary :
(i)    proper choice of drug salt
(ii)    proper choice of base.
52.    Specifications for suppository bases
include
1)    Origin and chemical composition
2)    Melting range
       Fatty bases are complex
mixtures of triglycerides and they do not have a sharp melting point.
Some methods used to find the melting range are
(i)    Wiley melting point
(ii)    Capillary melting point
(iii)    Softening point
(iv)    Incipient melting or thaw point
(v)    Solid – fat index :
(i)    SFI is determined by dilatometry
(ii)    Dilatometry necessitates melting the
base
(iii)    SFI is a graph of percentage of
solids versus temperature.
(iv)    From this graph we can determine
(a)    the solidification and melting range
of fatty bases
(b)    molding character of base
(c)    surface feel of base
(d)    hardness of base
(v)    If a base has a sharp drop in solids
over a sharp temperature span it may be brittle if molded too quickly.
When we are using this base we should keep a    
    high difference between mold temperature and the
temperature of fatty mass.
(vi)    If we know the SFI at room
temperature, we can determine the suppository hardness.
(vii)    Skin temp. is 32OC.
(viii)    If a base has an SFI above 30% at
32O then the suppository made with it would be dry to touch.
(d)    Hydroxyl value :
a.    The hydroxyl value measures the
unesterified positions on glyceride molecules.
b.    It reflects the monoglyceride and
diglyceride content of the fatty base.
c.    It is a number which is equal to the
mg of KOH, that is required to neutr alize the acetic acid which is
used to acetylate 1g of fat.
(e)    Solidification Point :
       Determination of this
solidification temperature is necessary to determine the time required
for solidifying the base when it is chilled in the mold. If there is
       more than 10OC difference
between solifidication point and melting range, it is better to give
refrigeration to the molds to reduce time taken for  
   
       solidification.
(f)    Saponifaction value :
      This is the amount of potassium
hydroxide in mg required to neutralize the free acids and saponify the
esters contained in 1g of a fat. It indicates the type  
      of glyceride (is it mono or di or tri
?) and it also tells the amount of glyceride present in the fat.
(g)    Iodine Value :
       The iodine value indicates
the amount of iodine in grams that reacts with 100 grams of fat or
other unsaturated material. As the iodine value increases the
 
       possibility of decomposition
by moisture, acids and oxygen increases.
(h)    Water Number :
       Water number indicates the
amount of water, in grams, that can be incorporated in 100g of fat. By
adding surface active agents, monoglycerides and    
       other emulsifying agents to
the fatty base, we can increase its water number.
(i)    Acid Value :
     Acid value indicates the number of mg.
of potassium hydroxide that are required to neutralize the free acid in
1g of a substance. Ideal suppository bases    
     have low acid values or show complete
absence of acids. If acids are present in the base, they may react with
other excipients and they may also irritate    
     the mucous membranes on coming into
contact with them.
53.    The Ideal suppository base must have
the following characteristics :
1)    It should melt at rectal temperature
of 36OC. But if we are dealing with eutectic mixtures or if we are
incorporating oils or balsams we can employ bases    
   having higher melting ranges.
2)    If the suppositories are intended to
be used in tropical climates, bases with higher melting ranges may be
used.
3)    It should be nontoxic. It should not
irritate sensitive or inflamed tissues.
4)    It should be compatible with a large
number of drugs.
5)    It should not have metastable forms.
6)    It should not be necessary to
lubricate the mold to release the formed suppository, i.e., the formed
suppository should shrink in size after cooling.
7)    It should be nonsensitizing.
8)    It should have good melting and
emulsifying properties.
9)    It should be capable of imbibing a
large percentage of water, i.e, its water number should be high.
10)    On storage, it should be stable, i.e,
it should not change in color or odour or in drug release pattern.
11)    It should be suitable to be molded
into suppositories, either by hand or by machine or by compression or
by extrusion.
        An ideal fatty suppository
base should have the following qualities, in addition to the qualities
described above :
1.    Its “acid value”
should be below 0.2
2.    Its saponification value should range
form 200 to 245.
3.    Its iodine value should be less than 7.
4.    Its SFI curve should be sharp.
       The interval between its
melting point and solidification point should be small.
54.    Often the addition of drugs changes
the desirable characteristics of the base.
55.    Cocoa butter :
       
1)    Cocoa butter is the most widely used
suppository base.
       
2)    It is innocuous, bland, and
nonreactive and melts at body temperature.
       
3)    It has some disadvantages, like :
       
        a.It can
become rancid
       
        b.It may
melt in warm weather.
       
        c.When
mixed with certain drugs, it may liquefy.
       
        d.On
overheating, it may change into a crystal from that melts at a lower
temperature.
4)    Cocoa butter is a triglyceride
     The predominant glyceride chains in
cocoa butter are oleopalmitostearin and oleopalmitostearin. It is a
yellowish-white, solid, brittle fat. It smells and tastes like
chocolate.
Its melting point lies between 30^OC and 36^OC
Its iodine value lies between 34 and 38.
Its acid value is less than 4.
It can easily melt and become rancid, so it must be stored in a cool,
dry place and must be protected from light. Cocoa butter exhibits
polymorphism, that means, it exists in different crystalline forms.
This property may be due to a high proportion of unsaturated
triglycerides. Different polymorphs have different melting points and
they release the drugs at different rates.
If cocoa butter is overheated (to above its melting point of 36^OC)
and then chilled to its solidification point (below 15^OC),
immediately after returning to room temperature its melting point would
be 24^OC.
56.    Cocoa butter exists in four
crystalline states.
1)    Α form – melting
point is 24^OC.
2)    ß΄ form – melting
point is in between 28 and 31^OC.
3)    ß  form –
melts between 34 and 35^OC. Most stable form
The ß΄ form slowly changes to ß form and is
accompanied by volume contraction.
4)    r form – melting
point  is 18^OC. This is obtained by
melting cocoa butter, cooling it to 20^OC, and
pouring it into a container and then cooling the container in a deep
freezer.
57.    If cocoa butter gets changed to one
of the unstable polymorphic forms, its reconversion to the stable
ß form takes one to four days. The time taken for
reconversion depends on the storage temperature – the higher
the temperature, the faster the change.
The following steps may be taken to avoid the formation of unstable
forms.
1)    Overheating must be avoided.
2)    The mass should not be melted
completely. A little unmolten mass must be there; this will prevent the
formation of unstable crystal formation.
3)    If the unstable form has already
formed, then if a small amount of crystals of stable form are added to
the mass, it will quickly return to the stable state. This procedure is
called “seeding”.
4)    The solidified melt should be tempered
at temperatures between 28 and 32^OC for hours or
days. Then it will quickly change from the unstable to the stable
        form.
58.   Cocoa butter suppositories do not
easily slip out of the mold, because cocoa butter has low
contractility; so we have to lubricate the mold with liquid
       
        paraffin.
59.    Cocoa butter’s water
absorption capacity is low; 100 g of cocoa butter can take a maximum of
30g of water. If an emulsifier is added, water absorption
        
increases considerably.
60.    When materials are suspended in cocoa
butter, aluminium monostearate and silica are used as suspending agents
to give suspension stability. But    
          suppositories
containing these agents will harden on storage.
61.    Drugs such as volatile oils,
creosote, phenol and chloral hydrate lower the melting point of cocoa
butter.
62.    To counteract the lowering of the
melting point wax and spermaceti are added.
63.    Vegetable oils such as coconut oil
and palm kernel oil may be modified by esterification, hydrogenation
and fractionation into fatty bases. These processes  
       may be so carried out as to
obtain the product with the desired melting range.
64.    Hard butter is obtained by the
following procedure :
       
  Corn
oil   

1. hydrogenation   to
    reduce  unsaturation and  increase the %
   of    solid triglycerides
2.  Solvent Extraction   
   hard butter   or pressing to remove triglycerides of
   low in.p.

65.    Methods of producing fats for
suppository bases.
1)    Coconut oil, palm kernal oil or palm
oil taken, (chosen because of their high content of lauric acid
moieties)
2)    Refined to remove free fatty acids,
3)    Deodorized to remove volatiles
4)    Hydrogenated
5)    Interesterified – this step
is catalyzed by sodium methoxide. This step distributes the fatty acids
among the glycerin molecules, and products with more  
 
       common triglycerides and a
narrow melting range are obtained.

{mospagebreak title=Synthesising Suppository Bases}

1.Method of synthesising suppository bases:

    Method of re-esterification:
1)    Oil is treated by high pressure steam
and is split into fatty acids and glycerin.
2)    Glycerin is removed.
3)    Free fatty acids, with carbon chain
lengths of C6-C18 remain in the mixture.
4)    Caproic, caprylic and capric acid get
readily rancid and they also irritate the mucous membranes. So they are
removed by fractional vacuum distillation.
5)    Lauric acid is the main ingredient in
the remaining mixture. The remaining mixture is hydrogenated to harden
it and lower its iodine value.
6)    Catalyst used in hydrogenation is
removed.
7)    The mixture is re-esterified with an
excess of glycerin.
8)    A mixture of triglycerides,
diglycerides and monoglycerides is obtained.
9)    Mixture is deodorized and purified by
filtration.

By controlling the re-esterification process, a base with good
properties is obtained. The properties controlled are melting range,
good mold release, smoothness and viscosity.

2. We follow certain guidelines when choosing a suppository
base:

1)    We look for a suppository with a
narrow interval between the melting point and the solidification point,
especially when we are working on a small scale (say, in a pharmacy).
2)    When we are incorporating a drug that
can lower the melting point, we look for a base with a high melting
range (say 37 to 41OC). Examples for such drugs are camphor, chloral
hydrate, menthol, phenol, thymol, and volatile oils.
3)    When we have to add large amounts of
total solids, that can increase the viscosity of the melted
suppository, we use bases with low melting ranges, such as (30 to 34OC).
4)    Bases with low acid values (below 3)
and iodine values (below 7) give suppositories with long shelf life.

5)    Formula in USP XX for
Glycerin Suppositories :
        Glycerin
–    
    91g
        Sodium
Stearate –       9g
        Purified
water –       5g
       
       
    _______
        To make
    -     100g
       
       
    _______

Preparation:

1.    Heat the glycerin to about 120OC.
2.    Dissolve sodium stearate in the heated
glycerin with gentle stirring.
3.    Add the purified water and mix.
4.    Pour the hot mixture into a mold.
5.    Unofficial formula for glycerinated
gelatin suppositories :
Drug and purified water    - 10g
Gelatin       
        - 20g
Glycerin       
    - 70g
    This formula is usually used in vaginal
suppositories, for administering  antimicrobial agents locally.
    As this suppository is susceptible to
spoilage by water, packing material should be such that it can protect
the suppository from the environment.
6.    Glycerinated Gelatin suppositories
melt in the fluids in the body cavity in which they are inserted.
Properties
of this suppository:

1. Time taken to dissolve depends on the percentage of
   glycerin, gelatin and that of water.
2. Time taken to dissolve also depends on nature of the
   gelatin used and on the chemical reaction of the drug with gelatin.
3. These suppositories are vulnerable to microbial growth, so
   preservatives are added to them and they are stored in a cool place.

7.    Properties of Polyethylene Glycols :

1. Known as carbowax and polyglycols.
2. Used as suppository bases.
3. Chemically, they are long-chain polymers of ethylene oxide,
   their general formula is HOCH2 (CH2OCH2) x CH2OH
4. They exist as liquids when their average molecular weights
   range form 200-600.
5. They exist as wax-like solids when their average molecular
   weights are above 1000.
6. Their water solubility, hygroscopicity, and vapor pressure
   decrease with increasing average molecular weights.
7. They do not hydrolyze.
8. They do not decompose.
9. They are physiologically inert.
10. They are not susceptible to microbial decomposition.

8.    Examples of formulas using
polyethylene glycols :
1.    Polyethylene glycol 1000 –
96%
Polyethylene glycol 4000 – 4%
(a)    This is a low melting point base.
(b)    Used when rapid disintegration is
needed.
(c)    Must be stored in refrigerator in
summer months.
2.    Polyethylene glycol 1000 –
75%
Polyethylene glycol 4000 – 25%
(a)    This is more heat stable than the
first base.
(b)    May be stored at higher temperature
than the first one.
(c)    Useful when a slow release of active
ingredients is preferred.
9.    Polyethylene glycol suppositories are
dipped in water before insertion, to avoid  
irritation to mucous membranes.
10.    When these are placed in the body
cavity, they draw water from the mucosa, hence the irritation or
“sting”.
11.    Some scientists suggest the addition
of 10% water to facilitate solution of the suppository after insertion.

12.    Points regarding manufacture :
(a)    They may be prepared by both molding
as well as cold compression methods.
(b)    A mixture consisting of
6% hexanetriol – 1,2,6,polyethylene glycol –
1540,12% of polyethylene oxide and Polymer – 4000, is
suitable for cold compression technique.
(c)    Drug is dissolved or dispersed in the
base.
(d)    The base is soluble in water, so the
mold must be dry.
(e)    The melted mass must be allowed to
cool almost to the congealing point before pouring into mold, otherwise
the resultant suppository will develop fissures, due to the
crystallization and contraction of the polymer.
These cannot be prepared by hand rolling.
They do not require a mold lubricant.

13.    When disintegration and dissolution
studies were done in vitro on suppositories, and in vivo
bioavailability studies were done, employing X ray studies with barium
sulfate – there is no correlation between the two.
So in vitro studies can only be used to test for product uniformity
form one production lot to another. To select an appropriate
polyethylene glycol base we must rely on clinical studies only.

14.    Water – dispersible bases :
1.    Non ionic surface active materials,
related chemically to polyethylene glycols can be used for formulating
both water soluble and oil soluble drugs.
2.    These can be handled and stored at
elevated temperatures.
3.    They have broad drug compatibility
4.    They are not vulnerable to microbial
growth.
5.    They are nontoxic
15.    Surfactants used in suppository
formulations :
(a)    polyoxyethylene sorbitan fatty acid
esters (Tweens)
(b)    polyoxyethylene stearates (Myrj)
(c)    Sorbitan fatty acid esters (Span and
Arlacel)
They may be used alone or in combination.

16.    Research :
Some research suggests increased absorption in the presence of
surfactants and some research suggests reduced absorption.
17.    A water dispersible, high melting
point (50OC) suppository base consists of polyoxyethylene 30 stearate
(Myrj 51), water, white wax and dioctyl sodium sulfosuccinate. This is
called (Aerosol OT).
When Aerosol OT is placed in the base, the suppository disintegrates
rapidly.
18.    Research :
19 different formulas for suppository bases were studied. They
contained hydrogenated cottonseed oil as the main constituent and
varying amounts of surfactant. The bases containing 35 to 40% of the
surfactants studied gave best release.
19.    Research :
A 2.5g suppository consisting of Tween 61 (60%) and Tween 60 (40%) and
one of Tween 61 (90%) and glyceryl laurate (10%) melted at 37.5OC in
about 16 minutes.
20.    Rectal suppositories are usually
molded; compressed tablets cannot be used as rectal suppositories
because the amount of liquid in the rectal cavity is not sufficient to
allow disintegration of the tablet in the rectum.
21.    Compressed tablets (3g) can be used
as vaginal suppositories. The amount of fluid in the vagina is
sufficient for the disintegration and dissolution of the tablet
– suppository.

22.    Effervescent tablet suppositories may
be used as laxative suppositories.
They may be made using the formula :
        Dried
soidum biphosphate
        Sodium
bicarbonate
        Starch or
finely divided cellulose (disintegrants)
They release carbon dioxide and disintegrate.

23.    If the compressed tablet –
suppositories are coated with a thin spray of water soluble
polyethylene glycol,
•    It will form an external coat
and protect the core.
•    It helps in smoothening the
insertion into the rectum.

24.    When fat based vaginal suppositories
are placed in the vagina, they are sometimes rejected. This is because
of the discomfort caused to the patient due to seepage from the fatty
suppository.
25.    Vaginal suppositories –
tablets are usually almond shaped – they offer maximum
surface area and they are easy to insert.

26.    A formula for vaginal suppository :
Drug
Lactose
Anhydrous dextrose
Boric acid
Phosphoric acid

27.    Vaginal suppositories are used for
treating vaginitis. Also used in birth control (they contain drugs
which are spermatocides).

28.    Layered suppositories are made
– outer shell has one drug; melts at 37OC to 38OC.
(a)    They separate incompatible drugs
(b)    By providing two different layers
with two different melting characteristics rate of drug release is
controlled.

29.    Suppositories are coated to meet the
following objectives :
1.    Protect form fast disintegration to
give lubricant actionprevent  coalescing of adjacent
suppositories
30.    Suppositories are modified in several
ways.
    Polyethylene glycol, cetyl alcohol or
polyvinyl alcohol and Tween are used for modifying suppositories
– to protect them from fast disintegration, to lubricate them
and to prevent coalescing of adjacent suppositories.
31.    Soft gelatin capsules are also
sometimes used for rectal and vaginal use.
32.    Producing suppositories through
lyophilization or freeze drying is also known. The resultant
suppositories do not melt. They dissolve in body fluids.
33.    Four methods are used for manufacture
of suppositories :
i.    Molding by hand
ii.    Compression
iii.    Pour molding
iv.    Compression in a tabletting machine
34.    Hand molding is useful when we are
preparing a small number of suppositories:
Steps:
1.    The drug is made into a fine powder.
2.    It is incorporated into the
suppository base by kneading with it or by trituration in a mortar.
3.    The kneaded mass is rolled between
fingers into rod shaped units.
4.    The rods are cut into pieces and then
one end is pointed.
35.    Compression molding:
1.    The cold mass of the base containing
the drug is compressed into suppositories using a hand operated machine.
Advantages:
1.    It is a simple method.
2.    It gives suppositories that are more
elegant than hand molded suppositories.
3.    In this method sedimentation of solids
in the base is prevented.
Disadvantages:
1.    Air entrapment may take place.
2.    This air may cause weight variation.
3.    The drug and/or the base may be
oxidized by this air.
36.    Pour Molding:
1.    The base is melted and precautions are
taken not to overheat it.
2.    The drug is incorporated in it.
3.    The molten liquid mass is poured into
chilled (lubricated if cocoa butter is the base) molds.
4.    After solidification the cone shaped
suppositories are removed.
37.    Automatic Molding machine: All the
operations in pour molding are done by automatic machines. Using this
machine, up to about 10,000 suppositories per hour can be produced.
38.    When the suppositories are being
stored and shipped, they must be overwrapped so that no two
suppositories touch each other.
39.    Poorly packed suppositories may give
rise to staining, breakage or deformation by melting.
40.    Suppositories are usually packed in
tin or aluminium, paper or plastic.
41.    Overwrapping is done by hand or
machine.
42.    Machines can overwrap about 8000
suppositories per hour.
43.    If the material of the base or the
drug is hygroscopic or volatile, glass or plastic is used for packing.
44.    In package molding means the
suppositories are molded directly in their wrapping material; plastic
or aluminium foil is used for this.
45.    Steps in this:
a.       Machines emboss
two parallel strips of foil so that when they are sealed together,
molds are formed.
b.    The tops of the molds are left open,
so that filling nozzles can enter them.
c.       A small variable
throw piston pump fills the molds.
d.    The tops are sealed.
e.       The strips pass
through a cooling station.
f.       One machine can
make 12,000 to 20,000 suppositories per hour in this technique.
Advantages:
a.       High production
rate.
b.    No removal of scrapping is necessary.
c.       No bulk handling
d.    No storage of unwrapped suppositories.
e.       These are
suitable for tropical climates, as melted mass stays within the mold.
Disadvantages:
a.       The shape of the
suppository changes with mold shape.
b.    It depends on the completeness of the
sealing.
c.       Depression
formation in the rear of the suppository since no scraping takes place.
46.    The drug should be homogeneously
dispersible in the base. Then when the suppository is placed in the
body the drug should be released at the required rate.
47.    If the drug is soluble in water, a
fatty base with a low water number may be preferred.
48.    If the drug is oil-soluble, a water
type base (with an added surfactant to enhance solubility) should be
used.
49.    When suppositories are made, they
should be stored at room temperature for at least 48 hours before
testing them for in vitro drug release.
50.    If the drug is to be incorporated
into the base as it is, it should be made into a fine powder, such that
100% of it can pass through 100 – mesh.
51.    Some other physical tests on
suppositories are fragility, brittleness, and ease of handling.
52.    In vitro – In Vivo
correlation is not very good in testing of suppositories.
53.    When suppositories are kept for
stability testing, they are tested for (a) Change in appearance (b)
melting and softening range (c) drug stability (d) base stability and
(e) in vitro drug release pattern.
54.    Drugs intended for local action such
as drugs for hemorrhoids, local anaesthetics and antiseptics and the
bases used for those drugs are usually not absorbed into the body.
55.    Local effects start within 30 minutes
and last for 4 hours.
56.    Formulators do not like to use water
for dissolving drugs in suppositories for the following reasons :
a.    Water causes oxidation of fats
b.    If the suppositories are manufactured
at a high temperature, the water evaporates, the drugs crystallize out.
c.    Absorption of water soluble drugs is
enhanced only if the base is an oil – in – water
emulsion with more than 50% of the water in the external phase.
d.    Drug excipient interactions are more
likely to happen in the presence of water.
e.    Bacterial contamination may be a
problem, so we may be forced to add a preservative.
57.    Hygroscopicity of the base is another
problem. Glycerogelatin suppositories lose moisture in drug climates
and absorb moisture in humid conditions.
58.    The hygroscopicity of polyethylene
glycol bases depends on the chain length of the molecule. As the
molecular weight of these ethylene oxide polymers increases, the
hygroscopicity decreases, for the 4000 and the 6000 series, there is a
significant drop.
59.    Incompatibilities exist between
polyethylene glycol base and silver salts, tannic acid, aminopyrine,
quinine, icthammol, aspirin, benzocaine, iodochlorohydroxyquin and
sulfonauids.
60.    Sodium barbital, salicylic acid and
camphor crystallize out of polyethylene glycol.
61.    High concentrations of salicylic acid
soften polyethylene glycol to an ointment like consistency.
62.    Penicillin G is stable in cocoa
butter and other fatty bases. It decomposes in polyethylene glycol
bases.
63.    Fatty bases with high hydroxyl values
may react with acidic ingredients.
64.    When the base has low viscosity,
sedimentation of the drug is a problem.
65.    If we are using a low viscosity base;
a.    We must use a base with a more narrow
melting range that is closer to body temperature.
b.    2% aluminium monostearate may be added
to increase the viscosity of the base.
c.    Cetyl, stearyl or myristyl alcohols or
stearic acid are added to improve the consistency of suppositories.
66.    Cocoa butter suppositories are
elastic, not brittle.
67.    Synthetic fat bases are brittle.
68.    If we make suppositories with such
bases and then subject them to sudden cooling (shock cooling), they
tend to fracture. This problem can be overcome by keeping the
temperature difference between the melted base and the mold as small as
possible.
69.    Materials that impart plasticity to a
fat and make them less brittle are small amounts of Tween 80, Tween 85,
fatty acid monoglycerides, castor oil, glycerin or propylene glycol.
70.    Density: Density of the base, the
drug, the volume of the mold and whether the base is having the
property of volume contraction are all important. They all determine
the weight of the suppository.
71.    Volume contraction: On solidification
the volume of the suppository decreases. The mass of the suppository
pulls away from the sides of the mold. This contraction helps the
suppository to easily slip away from the mold, preventing the need for
a lubricating agent.
72.    Sometimes when the suppository mass
is contracting, a hole forms at the open end. This gives an inelegant
appearance to the suppository. Weight variation among suppositories is
also likely to occur.
73.    This contraction can be minimized by
pouring the suppository mass slightly above its congealing temperature
into a mold warmed to about the same temperature. Another way to
overcome this problem is to overfill the molds, and scrape off the
excess mass which contains the contraction hole.
74.    Lubricants: Cocoa butter has a very
low volume of contraction. So cocoa butter suppositories adhere to the
mold and it is difficult to remove them. So we lubricate the mold with
liquid paraffin while preparing the mold. Some widely used lubricating
agents are mineral oil, aqueous solution of SLS, silicones, alcohol and
tincture of green soap. These are applied by wiping, brushing or
spraying.
75.    By coating the mold cavities with
polytetrafluoroethylene (Teflon) we can easily remove the suppositories
from damaged molds.
76.    Displacement value or Dosage
Replacement Factor :
The amount of base that is replaced by one unit of the drug is the
displacement value, or the replacement factor F. It may be calculated
from the formula,
 
    Where E = weight of pure base
suppositories
                
G = weight of suppositories with X% active ingredient
77.    Various factors influence the weight
of the suppository, the volume of the suppository and the amount of
active ingredient in each suppository :
They are:
1.    Concentration of the drug in the mass
2.    Volume of the mold cavity
3.    The specific gravity of the base
4.    Volume variation between molds
5.    Weight variation between suppositories
due to the inconsistencies in the manufacturing process.
78.    The upper limit for the weight
variation in suppositories is 5%.
79.    Rancidity :
    The unsaturated fatty acids in the
suppository bases undergo auto oxidation and subsequently they
decompose into low and medium molecular weight (C3-C11) saturated and
unsaturated aldehydes, ketones and acids. These products have strong,
unpleasant odours. This is known as rancidity. The lower the content
of unsaturated fatty acids in a base, the higher is its resistance to
rancidity.
80.    The iodine liberated from an
acidified solution of potassium iodide by the “peroxide
oxygen” of the fats is its peroxide or active oxygen value.
This is a measure of the auto oxidation going on in the base.
81.    We test suppositories for appearance
and uniformity of mix, drug content, melting range and fragility tests.
82.    Melting range test determines the
time taken by an entire suppository to melt when it is immersed in a
constant temperature bath at 37OC. This is also known as the
macromelting range test.
83.    In the micromelting range test we
determine the melting range of the fatty base only when it is placed in
capillary tubes.
For determination of the macromelting range we make use of the USP
Tablet Disintegration Apparatus.
84.    Liquefaction Time or Softening Time
Test:
In this test a U tube is partially immersed in a constant temperature
bath and is maintained at a temperature between 35 to 37°C.
There is a constriction in the tube in which the suppository is kept
and above the suppository, a glass rod is kept. The time taken for the
glass rod to go through the suppository and reach the constriction is
known as the liquefaction time or softening time.
85.    Another apparatus is there for
finding “softening time”  which mimics in
vivo conditions. It uses a cellophane tube, and the temperature is
maintained by water circulation. Time taken for the suppository to melt
is noted.
86.    Breaking Test:
The breaking test is designed as a method for measuring the fragility
or brittleness of suppository.
87.    A double walled chamber consisting of
a glass rod with disc is used and weights are placed on the disc. The
weight at which the suppository collapses is the breaking point.
88.    Dissolution testing in different
types of apparatus such as wire mesh basket, or dialysis tubing is used
to test for in vitro release from suppositories.
89.    Cocoa butter suppositories on
storage, “bloom”; i.e., they form a white powdery
deposit on the surface. This can be avoided by storing the
suppositories at uniform cool temperatures and by wrapping them in
foils.
90.    Fat based suppositories harden on
storage, i.e., there is an upward shift in melting range due to slow
crystallization to the more stable polymorphic forms of the base.
91.    The softening time test and
differential scanning calorimetry can be used as stability indicating
test methods.
92.    If we store the suppositories at an
elevated temperature, just below its melting range, immediately after
manufacture, the aging process is speeded up.
93.    If the suppository contains an acid,
the foil wrapping may be attacked and it may develop pinholes.