SUPPOSITORIES

1

• SUPPOSITORIES

2
Dose character

• For rectal administration, one half to two or
  more times than the oral dose is given.
• - The correct dose of any drug depends on the
  rate of release from the suppository
• - Since the vehicle can change the rate of drug
  absorption , the amount of drug to be given in
  suppository dose depend on the vehicle, the
  chemical and physical from the drug.

3
Types

• 1- Rectal suppository 32 mm in length,
  cylindrical, have one or both end tapered.
• a) Adult rectal supp. Weight 2gm
• b) infant rectal supp.1gm
• 2- Vaginal suppository pessaries, 5gm, usually
  oviform or cone shaped, weight from 3-5 gm
• 3- Urethral suppository bougies 4gm and 10-15 cm
  long for male and 6-7.5cm long for female. ,
  pencil shaped.

4
Therapeutic uses

• Suppository can be used for local or systemic
  effect.
• The action depends on nature of drug ,
  concentration and rate of absorption
• Rectal suppository are intended for treatment of
  constipation and hemorrhoids.
• Suppositories are also administered for systemic
  action (analgesics, antispasmodics, sedatives
  tranquilizers).

5
Factor affecting drug absorption form rectal
suppository

• 1) Physiologic Factor
• The human rectum is approximately
• 15-20 cm in the length, when empty
• of fecal material it contains 2-3 ml of inert
  mucous fluid. In resting state, the rectum is non
  motile. There is no villa or microvillus on
  rectal mucosa. Physiological factors include

6

• A) Colonic Content
• When systemic effect are desired from
  suppository greater absorption may be expected
  from a rectum that is void than that with fecal
  matter. An evacuation enema maybe administered
  before insertion of a suppository.
• Diarrhea, colonic obstruction and tissue
  dehydration influence the rate degree of drug
  absorption from rectum.

7

• B) Circulation
• Drugs absorbed rectally partially by pass portal
  circulation, thereby enabling drug destroyed in
  liver to exert systemic effect. Depending on the
  height at which absorption occurs at rectum, the
  drug passes into inferior, middle or superior
  hemorrhoid veins. The inferior is nearest to the
  anus, the upper hemorrhoid vein gt portal
  circulation .thus it is advisable to keep supp in
  the lower part of rectum. 50 -70 of drug
  administered rectally, reported to go directly
  into general circulation.

8

• C) pH and lack of buffering capacity of the
  rectal fluid
• Rectal fluids are neutral (pH 7-8), have no
  effective buffer capacity. The barrier separating
  colon lumen from the blood is preferentially
  permeable to the unionized forms of drugs, thus
  absorption of drug would be enhanced by change in
  pH of the rectal mucosa to one that increase the
  proportion of unionized drugs.

9
2) Physiochemical characteristics of the drug

• A) Lipid water solubility of a drug (partition
  coefficient)
• The lipid water partition coefficient of a drug
  is important in selecting the suppository base
  and in anticipating drug release from that base
• lipophilic drug, in other word, distributed in a
  fatty suppository base has fewer tendencies to
  escape to the surrounding queues fluids
• .

10

• Thus water-soluble salt are preferred in fatty
  base suppository. water-soluble base e.g PEG,
  which dissolve in the rectal fluids, release both
  water-soluble and oil-soluble drugs.

11

• B) Degree of ionization
• The barrier separating colon lumen from the blood
  is preferentially permeable to the unionized
  forms of drugs, thus absorption of drug would be
  enhanced by increase the proportion of unionized
  drugs

12

• C) Concentration of a drug in a base
• - The more drugs in a base, the more drug will be
  available for absorption.
• - If the concentration of the drug in the
  intestinal lumen is above a particular amount,
  the rate of absorption is not change by further
  increase in concentration of drug.
• - In general, the rate limiting step in drug
  absorption from suppository is the partitioning
  of the dissolved drug from the melted base and
  not the rate of solution of drug in the body
  fluid.
• -

13

• - Scientists showed that the rate, at which the
  drug diffuses to the surface of the suppository,
  Particle size, and presence of surface-active
  agents are factors that affect drug release from
  suppositories.

14
3) Physiochemical Characteristics of the Base and
Adjuvant

• 1)- Nature of the Base
• - Suppository base capable of melting, softening
  or dissolving to release the drug for absorption.
• If the base irritating the colon, it will promote
  colonic response, lead to increase bowl movement
  and decrease absorption.

15

• 2) Presence of Adjuvant in Base
• Adjuvant in a formula may affect drug absorption,
  change the rheological properties of the base at
  body temperature, or affected the dissolution of
  the drug.

16
Specifications for Suppository Bases

• 1- Origin Chemical Composition
• A brief description of the composition of the
  base reveals the sours of the origin (natural or
  synthetic or modified natural products). Physical
  or chemical in- compatibilities with other
  constituents may be predicted if the exact
  formula composition is known including
  preservatives, antioxidants and emulsifiers

17

• 2- Melting Range
• Suppository bases don't have a sharp melting
  point, their melting characteristics are
  expressed as ranges, indicating the temperature
  at which the fats start to melt and the
  temperature at which completely melted. Melting
  range is usually determination by " Wiley melting
  point", "Capillary melting point", " Incipient
  melting (or thaw)point".

18

• 3- Solid-Fat Index (SFI)
• One can determine the solidification and melting
  ranges of fatty bases as well as the molding
  character, surface feel and hardness of the
  bases. A base with sharp drop in solids over a
  short temperature span proves brittle if molded
  too quickly.

.
19

• The solid content at room temperature could
  determine suppository hardness. Since skin
  temperature is about 32 C, one can predict that
  would be dry to touch from a solid content over
  30 at that temperature.

20
(No Transcript)
21

• 4- Solidification Point
• This test allow to determine the time required
  for solidifying the base, when it is chilled in
  the mold if the interval between the melting
  point and solidifying point is 10 C or more,
  time required for solidification may have to be
  shortened for amore efficient manufacturing
  procedure by refrigeration, if melting point 33
  C and solidifying point 20 C then it will be
  liquid for 13 C, then the drug will sediment and
  the apex of the suppository will contain all the
  drug.

22

• 5- Hydroxyl Value
• "It is the number of milligrams.of KOH (Potassium
  hydroxide) that would neutralize the acetic acid
  used to acetylate 1g of fat. It reflects the
  mono- and di-glyceride content of a fatty base.
• 6- Saponification Value
• The number of milligrams of KOH (Potassium
  hydroxide) required to neutralize the free fatty
  acids and saponify the ester contained in 1 g of
  a fat. From saponification value we can know the
  type of glyceride present (mono-, di- or tri-)
  and also amount present.

23

• 7- Iodine Value
• It is the number of grams of Iodine that reacts
  with l00 g of fat or other unsaturated material.
• The possibility of decomposition by moisture,
  acids, oxygen (which leads to rancidity of fats)
  increases with higher iodine value.
• 8- Water Number
• It is the amount of water in grams that can be
  incorporated in l00g of fat. The "water number"
  can be increased by the addition of surface-
  active agents.
• 9- Acid Value
• It is the number of milligrams of KOH (Potassium
  hydroxide) required neutralizing the free fatty
  acids in I g substance (fat). Low acid value or
  absence of acid value is important for good
  suppository bases.

24
Properties of an Ideal Suppository Base

• The ideal suppository base may be described as
  follows
• 1- Melts at rectal temperature 36 C, or dissolve
  in rectal fluid
• 2- Completely non toxic, and non irritating to
  sensitive and inflamed tissues.
• 3- Compatible with a broad variety of drugs.
• 4-No metastable forms.
• 5- Shrinks sufficiently on cooling to be released
  form the mold without the need for mold
  lubricants.
• 6- Non- sensitizing

25

• 7- Has a melting and emulsifying property.
• 8- Water number is high (a high percentage of
  water can incorporated in it)
• 9- It is stable on storage, dose not change odor,
  color, release pattern.
• 10- Can be manufactured by molding either by
  hand, compression, machine .
• 11- Acid value is below 0.2, saponification value
  ranges from 200 to 245, and Iodine value is less
  than 7.
• 12- SFI curve is sharp, in other word, the
  interval between melting point and solidification
  point is small

26
Type of Suppository Bases

• A- Fatty Bases.
• B- Hydrophilic Suppository Bases
• C-water dispersible Bases

27
A- Fatty Bases

• Cacao Butter (theobroma oil)
• It is the most widely used suppository base. It
  satisfy many requirement for ideal suppository
  base
• 1) Bland. 2) Non reactive. 3) Melt at body
  temperature.
• - Cacao Butter is a triglyceride, yellowish
  white, solid, brittle fat, smells and taste like
  chocolate. Its melting point between 30-35 C, it
  iodine value is between 34-38 and its acid
  value is no higher than 4, because cacao butter
  can melt and rancid. So it must be stored in cool
  dry place protected from light.

28

• Cacao butter exhibited polymorphism (exist in
  different crystalline forms). Cacao butter is
  thought to exist in 4 crystalline states
• 1) a - crystal ?? melt at 22oC ?? unstable
• 2) ? - crystal ?? melt at 18oC ?? unstable
• 3) ß - crystal ?? melt at 27oC ?? unstable
• 4) ß stable crystal ?? melt at 34-36oC ??
  stable

29

• Various forms of cacao butter depend on
• 1- Degree of heating.
• 2- Cooling process.
• 3- Conditions during this process.
• The re-conversion to the stable B- form takes
  form one to four days depending on the storage
  temperature, the higher the temperature the
  faster the change.

30
Disadvantages of Cacao Butter

• 1- Rancidity and slow deterioration during
  storage.
• 2- Melt in warm weather.
• 3- Liquefy when incorporated with certain drug
  such as volatile oils, creosote, phenol and
  chloral hydrate.
• 4- Over heating lead to isomerizes to metastable
  form. So this will decrease melting point.
• 5- Low contractility during solidification,
  suppository will adhere to the mold and will be
  necessitates uses of lubricant.
• 6- Quality of cacao butter varies with origin and
  treatment.
• 7- Water number is low (20-30), this could be
  improved by addition of 5-10tween61.
• 8- Leakage from the body.

31
Advantages of Cacao Butter

• 1- Non reactive.
• 2- Melt at body temp.
• 3- Solidification point lies 12-13 C below
  melting point, during formulation the mass can be
  stirring and maintain cacao butter liquid below
  its solidification point.
• 4- Emulsion can be added in Conc 5-10 to keep
  insoluble drug suspended.

32

• 5-Increase conc. of water soluble drugs, lead to
  decrease melting point until eutectic point is
  obtained
• 6- Melted cocoa butter is viscous (semisolid)
  which help in corporation of drug. The difference
  in melting point solidification point is large
  to give chance for incorporation with drugs.

33
B- Hydrophilic Suppository Bases

• 1-Glycerine Suppositories
• Glycerine 91 g
  
• Sod. Stearate 4g
• Purified water 5g
• To make approximately l00g
• 2- Glycerated gelatin suppositories
• Drug purified water 10g
• Gelatin 20g
• Glycerin 70g
• - Because glycerin is hygroscopic, there
  suppositories are packed in materials that
  protect them from environmental moisture.
• - This base do not melt at body temp., but
  dissolve in the secretions of the body cavity in
  which they are inserted.

34

• 3-Polyethylen glycol (PEG)
• Marketed as carbowax or polyethylenglycol, exist
  as liquid or wax like solid depending on
  molecular weight. Their water soluble,
  hygroscopic and vapor pressure decrease with
  increasing average molecular weights. The wide
  range of melting point and solubility makes
  possible the formulation of suppository with
  various degrees of heat stability and with
  different dissolution rates. They do not
  hydrolyze or deteriorate, are physiologically
  inert and do not support mold growth. Base
  usually dipped in water before insertion, so that
  possible irritation maybe eliminated

35
3-WATER - DISPERSIBLE BASE

• Several non-ionic surface active materials,
  closely related chemically to PEG as suppository
  bases. The bases can be used for formulation both
  water-soluble and oil-soluble drugs (e.g. Tween
  Span). These surface active agents may be used
  alone, blended or used in combination with other
  suppository vehicle. Another type of water
  dispersible suppository vehicle is based on the
  use of water soluble cellulose derivatives (e.g.
  methylcellulose sodium carboxymethylcellulose
  ).
• Advantages of Water Dispersible Bases
• 1. Stable on storage at elevated temperature.
• 2. Compatible with many drugs.
• 3. Non support of microbial growth, non toxic and
  non sensitive.

36
Method Of Manufacture Of Suppositories

• 1- Hand Molding
• It is the oldest and simplest method, by rolling
  the suppository into the desired shape. The mass
  is then rolled into a cylindrical rod of desire
  length and diameter.
• 2- Compression Molding
• Elegant suppository can be made b compression the
  cold-grated mass into the desired shape .
• It is simple and more elegant appearance than
  hand molding.
• It avoids the possibility of sedimentation of the
  insoluble solids in the suppository base.

37

• 3- Pour Molding
• Most commonly used method for production of
  suppository on both small large scale.
• First, the base is melted on water bath, and then
  the drugs are either emulsified or suspended in
  it. Then, the mass is pour into cooled metal
  molds, which are usually chrome or nickel plated.
• 4- Automatic Molding Machine
• The molding operation (pouring, cooling
  removal) can be performed by machine .
• The output of a typical rotary machine, range
  from 3500 to 6000 suppositories per hour.

38
(No Transcript)
39
SPECIFIC PROBLEMS IN FORMULATING SUPPOSITORIES

• 1- Water in suppositories
• Use of water as a solvent for drug should be
  avoided for the following
• Reasons
• a- Water accelerates oxidation of fats.
• b- If water evaporates, the dissolved substance
  crystallizes out.
• c- Unless H2O is present at level than that
  requires for dissolving the drug, the water has
  little value in facilitating drug absorption.
  Absorption from water containing suppository
  enhance only if an oil in water emulsion exist
  with more than 50 of the water in the external
  phase .
• d- Reaction between ingredients (in suppository)
  are more likely to occur in the presence of
  water.
• e- The incorporation of water or other substances
  that might be contaminate with bacteria or fungi
  necessitates the addition of bacteriostatic
  agents (as parabens)

40

• 2- Hygroscopicity
• a- Glycerinated gelatin suppositories lost
  moisture by evaporation in dry climates and
  absorbed moisture under conditions of high
  humidity
• b- PEG bases are also hygroscopic.

41

• 3- Incompatibilities
• a- PEG bases are incompatible with silver salt,
  tannic acid, aminopyrine , quinine , icthammol,
  asprine , benzoc.aine sulphonamides .
• b- Many chemicals have a tendency to crystallize
  out of PEG, e.g. sodium sarbital, salicylic acid
  camphor.
• c- Higher concentration of salicylic acid softens
  PEG to an ointment-like consistency, d- Aspirin
  complexes with PEG.
• e- Penicillin G , although stable in cocoa butter
  and other fatty bases , was found to decompose in
  PEG bases .
• f- Fatty bases with significant hydroxyl values
  may react with acidic ingredients.

42

• 4- Viscosity
• The viscosity of the melted suppository base is
  important in the manufacture of the suppository
  and to its behavior in the rectum after melting.
• Melted cocoa butter have low viscosity than
  glycerinated gelatin and PEG type base in low
  viscosity bases, extra
• Care must be exercised to avoid sedimentation of
  suspended particles.
• To overcome the problems caused by use of low
  viscosity bases
• a- Use base with a more narrow melting rang that
  is closer to body temperature.
• b- The inclusion of approximately 2 aluminum
  monostearate not only increase the viscosity of
  the fat base but to maintain homogenous
  suspension of insoluble material.
• c- Cetyl , stearyl or myristyl alcohols or
  stearic acid are added to improve the consistency
  of suppositories .

43

• 5- Brittleness
• Suppositories made from cocoa butter are elastic
  and don't fracture readily.
• Synthetic fat base with high degree of
  hydrogenation and high stearate content and a
  higher solids content at room temperature are
  usually more brittle.
• To overcome, 1) the temperature difference
  between the melted base the mold should be
  minimal.
• 2) Addition of small
  amount of Tween 80, castor oil, glycerin imparts
  plasticity to a fat

44

• 6- Volume contraction
• Occurs in many melted suppository base after
  cooling the mold, result in
• a- Good mold release (contraction facilitate the
  removal of the suppository from the mold ,
  eliminating the need for mold release agents).
• b- Contraction hole formation at the open end of
  the mold, this will lowered suppository . The
  contraction can be eliminated by pouring a mass
  slightly above its congealing temperature into a
  mold warmed at about the same temperature or the
  mold is overfilled so that the excess mass
  containing the contraction hole can be scraped
  off.

45

• Lubricant or mold releasing agent
• Cocoa butter adhere to suppository molds because
  of its low volume contraction. A various mold
  lubricants or release agents must be used to
  overcome this difficulty (mineral oil , aqueous
  solution of sodium lauryl sulfate , alcohol ,
  silicones , soap). The release of suppository
  from damaged mold was improved by coating the
  cavities with polytetrofluoroethylene (Teflone).

46

• 7- Rancidity and Antioxidant
• Rancidity results from the autoxidation and
  subsequent decomposition of unsaturated fats into
  low medium molecular weight saturated
  unsaturated aldehydes , ketones and acids , which
  have strong unpleasant odor. Example of effective
  antioxidant are phenols such as " hydroquinone or
  B-naphtholquinone.

47
DOSAGE REPLACEMENT FACTOR

• The amount of base that is replaced by active
  ingredient in suppository formulation can be
  calculated. The replacement factor (f) is derived
  from the following equation
• F100(E-G)1
• Where
• E weight of pure suppository base.
• G weigh of suppositories with x active
  ingredient.

48
WEIGHT AND VOLUME CONTROLE

• The amount of active ingredient in each
  suppository depends on
• 1 . Its concentration in the mass.
• 2. The volume of the mold cavity.
• 3. The specific gravity of the base.
• 4. The volume variation between molds (within 2
  of the desired value).
• 5. Weight variations between suppositories due to
  inconsistencies in the manufacturing process.
  e.g. incomplete closing of molds, uneven
  scrapings (variations in weight should be within
  5)

49
Quality Control of Suppository

• Surface appearance and shape
• to evaluate absence of fissuring absence of
  migration of active ingredient, absence of
  pitting, absence of fat blooming (dullness of
  surface)

50

• 2) MELTING RANGE TEST
• Macromelting range measures the time it takes
  for the entire suppository to melt when immersed
  in a constant temperature (370C) water bath.
• Micromelting range is the melting range
  measured in capillary tubes for the fat base
  only.
• The apparatus used for measuring the melting
  range of the entire suppository is a USP tablet
  disintegration apparatus. The suppository is
  completely immersed in the constant temperature
  water bath, and the time for the entire
  suppository to melt or dispense in the
  surrounding water is measured. The in-vitro drug
  release pattern is measured by using the same
  melting range apparatus.

51

• 3) LIQUIFACTION OR SOFTENING TIME TESTS OF RECTAL
  SUPPOSITORIES
• The "softening test" measures the liquefaction
  time of rectal suppositories are an apparatus
  that simulate
• in-vitro conditions (at 37oC).

52
(No Transcript)
53

• 4) BREAKING TEST
• It is designed as a method for measuring the
  fragility or brittleness of suppositories.
• The apparatus consists of double-wall chamber in
  which the test suppository is placed. Water at
  37C is pumped
• through the double walls of the chamber, and the
  suppository, contained in the drug inner chamber,
  
• supports a disk to which a rod is attached. The
  outer end of the rod consists of another disc
• to which weights are applied.

54
(No Transcript)
55

• 5) Mechanical strength It is a force necessary
  to break a supp. And indicate whether supp is
  brittle or elastic. ( not less than 1.8-2 Kg) by
  Erweka method
• 6) Melting solidification
• Solidification can be determine by using
  evacuated flask into which the melt is placed,
  the temp of cooling is noted to determine the
  solidification point.

56

• 7) DISSOLUTION TESTING
• The patterned is measured by using the same
  melting range apparatus. If the volume of water
  surrounding the suppository is known, then by
  measuring aliquots of the water for drug content
  at various intervals within the melting period. A
  (time versus drug release) curve could be
  established and can be plotted.

57
PACKAGING OF SUPPOSITORY

• Suppository must be placed in a container in such
  a manner that they do not touch each other.
• Staining, breakage or deformation by melting
  caused by adhesion can result from poorly wrapped
  packaged suppository. Suppository is foiled in
  tin or Al paper and plastic.
• Over wrapping is done by hand or machine.
  Many suppositories are not individually, wrapped.
  In such cases, they are placed into cardboard
  boxes or plastic containers that have been molded
  to provide compartment for 6 or 12 suppositories.

58

• IN- PACKAGE MOLDING
• A significant advance in suppository
  manufacturing was the development of automated
  method for molding suppository, directly in their
  wrapping materials. This is currently
  accomplished with either plastic or Al-foil.
• ADVANTAGE OF INPACKAGE MOLDING
• 1. high production rate.
• 2. no generation of scraping.
• 3. no bulk handling.
• 4. maintenance of strict temperature control

59
STORAGE

• Suppository should be protected from heat,
  preferably stored in the refrigerator.
  Glycerinated gelatin suppositories should be
  protected from heat, moisture, and dry air by
  packaging in well-sealed containers and storing
  in a cool place.