Suppositories and Pessaries

1



Suppository Development and Production

• Marion Gold
• Centerchem, Inc., Stamford, Connecticut.
• Murti VePuri
• Able Labs, South Plainfield, New Jersey
• Lawrence H. Block
• Duquesne University of, Pittsburgh, Pennsylvania

2
Introduction

• Oral route of administration is the most
  acceptable and common compared with other routs
  of administration.
• Oral route is not without limitations.
• Some medication cause local stomach irritation.
• Dose limitation.
• Certain patients, children, elderly, and those
  with swallowing problems, are difficult to treat
  with oral tablets and capsules.
• Target the medication to the affected area.
• Ophthalmic, Nasal, Otic, Dermal, Vaginal and
  Anorectal tissues.

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Suppositories

• The suppositories are the neglected dosage form.
• Although lots of research done on this drug
  delivery system, there are continues to be a
  general rejection of the rectal delivery system.
• There are important reasons to consider
  suppositories as a preferred route of
  administration in many situation.

4
Why the rectal route?

• When the patient is unable to use the oral route
• Through, unconsuous, irritation in the stomach
• When the drug is less suited to oral
  administration

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Definition

• Solid or semisolid dosage forms used for rectal,
  vaginal, or urethral administration of
  therapeutic agents.

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• Typically consist of dispersion of the active
  ingredient in an inert matrix generally composed
  of a rigid or semi-rigid base.
• This matrix should be inert not to interact with
  the active ingredients and the excipients.
• The dispersed phase can be incorporated into the
  suppository as
• Solid (Powder).
• Liquid (either aqueous, alcoholic, or glycolic
  solutions, oils, extracts, etc.

7

• The material for the base, are selected on the
  bases of its ability to soften, melt, or dissolve
  at body temperature.
• Finished suppositories are manufactured in a
  variety of shapes and sizes to best suit the
  treatment requirements (nature of the active
  ingredients, site of administration.
• Suppositories are available in
• a range of physical forms
• (molded or compressed,
• foil or plastic wrapped, or gelatin
• encapsulated.

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Rectal administration Applications

1. For local
2. Systemic drug delivery.

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Drugs administered by rectal route

• Local Effect
• Astringents.
• Anti-septics.
• Local anaesthetics.
• Vasoconstrictors.
• Anti-inflammatory.
• Soothing agents.
• Protective agents.
• laxatives

• Systemic Effect
• Analgesic antipyretic.
• Anti-inflammatory.
• Anti-asthmatic.
• Anti-convulsant.
• Anti-emetic.
• Nausea
• Narcotic analgesia (Oxymorphone HCL)

10
Advantages

• Reduce hepatic first-pass elimination
• Enhance drug bioavailability.
• Alcoholic and aqueous solution can be rapidly
  absorbed, and this is used to considerable
  advantage, for example, to administer diazepam in
  the treatment of acute convulsive attacks.

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Comparison with Oral Delivery

• Many studies have attempted to compare the oral
  dosage form with the rectal administration.
• The results are inadequate, because of the
  different parameter used to make the studies, the
  experiment conditions and choice of excipient.
• Certain active ingredients are just not well
  suited for suppository dosage.

12

• Diazepam (as an alcoholic solution propranolol
  have been shown to exhibit greater
  bioavailability when administered rectally.
• Theophylline suppositories was found
  bioequivalence to oral administration when
  microcrystalline drug was used.
• Bioequivalence between pentobarbital despite its
  slower rectal absorption.
• In case where there is no first pass metabolism,
  it has been shown that rectal administration of
  drugs in solution can provide BE equivalent to
  that seen with oral administration.

13

• Absorption of the materials is via passive
  diffusion (no carrier-assisted means take part
  in the passage of drug through lipid membrane).
• Thus, success or failure of therapeutic delivery
  is a function of lipo-solubility of the agent as
  well as its vehicle, because the partition
  coefficient of the drug between suppository base
  and the lumen contents influences the latter's
  release into the bowel and eventually the actives
  passage through the wall of the intestine.

14

• Enhancement agents that affect the mucous
  membrane similarly affect absorption and are
  useful for boosting delivery of poorly absorbed
  agents such as antibiotics and high M.W
  materials.

15
The use of suppositories in the world

• Rectal as well as urethral and vaginal delivery
  of drugs via suppositories makes excellent
  therapeutic sense, and there use can be traced as
  far back as in the writings of Hippocrates.
• In Japan, rectal dosage forms are more acceptable
  by the patient than other route of
  administration.
• More than 7.5 of all prescriptions in France
  were formulation intended for rectal
  administration.

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• Anglo-Saxon countries, where social convention
  preclude greater use of rectal delivery
  (generally do not prescribe suppositories).
• Latin American and Mediterranean Europeans use
  suppositories far more routinely.
• In summary the use of rectal suppositories is
  limited and are vary between nations.

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Factors affecting the absorption from Rectal
Suppositories

1. Physiological factors.
2. Physicochemical factors of the drug substance.
3. Physicochemical factors of the base.

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1. Physiological Factors

• Colonic content.
• Circulation route.
• pH, and lack of buffering capacity of the rectal
  fluids.
• 1. When systemic effects are desired, greater
  absorption may be expected from a rectum that is
  void then from one that is distended with fecal
  matter. An evacuant enema could be use before the
  administration of a suppository.

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Physiological Factors continued

• Diarrhea, which case tissue dehydration of the
  rectum can influence the absorption.
• Colonic obstruction due to tumorous growths,
  influence the rate and the degree of drug
  absorption from the rectal site.
• 2. Circulation Route, drugs absorbed rectally,
  bypass the portal circulation during their first
  pass into the general circulation

20

• 3. pH and lack of buffering capacity of the
  rectal fluids.
• The rectal fluids are neutral in pH (7-8), and
  have no effective buffering capacity.
• The drug is administered will not generally be
  chemically changed by the rectal environment.
• The suppository base used has major influence on
  the release of active constituents incorporated
  into it.

21
Physicochemical Factors

• Includes
• Solubility of the drug in lipid and in water.
• Particle size of dispersed drugs.
• Physicochemical factors of the base include its
  ability to
• Melt.
• Soften.
• Dissolve at body temperature.
• Release the drug substance,
• and its hydrophilic or hydrophobic character.

22

• Lipid-water solubility
• The lipid-water partition coefficient of a drug
  is an important factor in the selection of the
  suppository base and in drug release from that
  base.
• A Lipophilic drug that is distributed in a fatty
  suppository base in low concentration has less of
  a tendency to escape to the surrounding aqueous
  fluids than the hydrophilic substance presents
  in a fatty base.
• Water soluble base such as, PEG, which dissolve
  in the anorectal fluids, release for absorption
  both water soluble and oil soluble drugs.

23
Physicochemical Factors Continue

• Particle size
• Particle size of drugs present in the
  suppository in the undisclosed stat, the smaller
  the particle size the more readily the
  dissolution of the particles and the greater the
  chance for rapid absorption.
• Nature of the base
• Melting point, softening, or dissolving to
  release its drug components for absorption,
  interacting with the drugs substance.

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Ratio of Components

• Once the correct excipient has been selected, the
  proper proportion of the components needs to be
  established.
• One important aspect to consider in suppository
  formulation is that of displacement.
• Suppositories generally weigh between 1 to 4 g,
  and displacement of the excipient by the active
  ingredient must be calculated when the product is
  formulated.

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• Simply, this step takes into account the volume
  of suppository base that will be displaced by an
  insoluble drug dispersed into it.
• This is necessitated by the practice of placing
  weighed quantities of suppository ingredients
  into molds whose contents are measured
  volumetrically.

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M F - (f S)

• M the quantity (weight) of suppository base
  needed.
• F the total capacity of the suppository mold.
• f the displacement factor of the active
  ingredients.
• S the quantity of the active ingredient per
  suppository.

 
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Calculation of Displacement Value
M the quantity (weight) of suppository base
needed. F the total capacity of the suppository
mold. f the displacement factor of the active
ingredients. S the quantity of the active
ingredient per suppository.

•  

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Displacement Value

• The volume of a suppository from a particular
  mould is uniform.
• The weight is vary according to the density of
  the medicaments.
• The displacement value of a drug is the number
  of parts by weight of drug which displaces one
  part by weight of the base.
• Could be calculated and could be found in the
  literature.

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Displacement Factors of Selected Materials Displacement Factors of Selected Materials
Acetylmorphine Hydrochloride 0.71
Acetylsalicylic acid 0.63
Beeswax 1.0
Benzocaine 0.68
Bismuth subgallate 0.37
Bismuth sbnitrate 0.33 0.33
Codeine phosphate 0.8
Glycerin 0.78
Phenacetin 0.6
Phenobarbital 0.84
Phenobarbital sodium 0.62
Procaine 0.8
Quinine chlorohdrate 0.83
Sulfamide 0.6
Theophylline 0.63
Zinc oxide 0.2
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Formulation
OK

• Choice of drug
• What makes a particular drug a candidate for
• administration in the form of a
  suppository?
• It must be sufficiently absorbed through the
  rectal mucosa to permit therapeutic blood levels.
• Drug that are poorly absorbed after oral dosage.
• Drugs that cause irritation to the
  gastrointestinal mucosa.
• Certain antibiotics cause major changes to the
  balance of intestinal flora, and there would be
  better given as suppositories.

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• Small polypeptides-normally subject to the
  enzymatic activity of the upper GIT, can often be
  better administered via the rectum.
• The pH of the upper GIT causes inadequate or
  otherwise undesirable uptake.
• For local conditions achieved using a suitable
  suppository formulation.

OK
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NO

• Nature of the active.
• Three principal factors that define
  formulation
• requirements
• The actives physical state under ambient
  conditions.
• The solubility characteristics of the active.
• The physicochemical activity with regards to
  potential excipients.

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• Physical State.
• The active can be either liquid, pasty, or solid
  in nature.
• Bulk Density. the big difference in the density
  between the active and the base cause problem
  during filling and homogeneity of the
  suppositories.
• Solubility

NO
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B. Choice of the Base
NO

1. They enable a selected active to be fabricated in
   a manner appropriate to both its physicochemical
   characteristics and the requirements of the
   manufacturer.
2. They are used to control delivery of the
   medication at its site of absorption.
3. For this reason the bases manufacturers offer a
   wide selection of raw materials in order to
   anticipate a correspondingly broad range of
   product needs.

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Selection criteria of the base
NO

1. Nature of the active ingredient.
2. Manufacturing capabilities.
3. Desired release characteristics.
4. Chemical no-reactivity with the active.
5. Nontoxic and nonirritant, and stable when
   formulated.

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Selection of the appropriate Base
NO

• During Production
• Slight contraction upon cooling in order to
  facilitate removal from the mold.
• Inertness no chemical interaction between the
  base and the active ingredients.
• Solidification (should be optimum).
• Viscosity to be viscose to prevent sedimentation
  during filling until cooling.

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• During Storage
• Impurity.
• Bacterial/Fungal contamination should be
  minimized by selecting a non-nutritive base
  with minimal water content.
• Softening.
• The suppositories should be formulated so that
  it does not soften or melt under transportation
  and storage conditions.
• Stability.
• The selected materials can not oxidize when
  exposed to air, humidity, Or light.

NO
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NO

• During Use
• Release.
• Choice of the proper base provides optimal
  delivery of the dispersed active into the
  target site.
• Tolerance.
• The finished suppository should have minimal
  toxicity and not be irritating to sensitive
  rectal mucosal tissue.

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Suppository Basis

• Suppository bases plays an important role in the
  release of the drug they hold and therefore in
  the availability of the drug for absorption for
  systemic effects or for local action.
• And because of the possibility of chemical and or
  physical interactions between the drug and the
  base, which could affect the stability and or
  bioavailability of the drug, the absence of any
  drug interaction between the two agents should be
  ascertained before formulation

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Suppository Bases

• From the point of view of composition,
  suppository bases can be described as falling
  into one of the three categories
• Naturally derived.
• Synthetic.
• Semisynthetic.

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I. Natural Bases

• All naturally derived suppository bases used
  today are produces from Cocoa Butter, its a
  fatty material composed of a mixture of C16 to
  C18 saturated and unsaturated fatty acid
  triglycerides obtained from the roasted seed of
  Theobroma cacao.
• Fatty bases are the most frequently used
  suppository bases.
• These bases melt at body temperature.

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• In addition to cocoa butter, other natural
  materials such as
• Gelatin, Agar, and Waxes have been employed as
  suppository bases.
• Their uses are limited and often relegated to
  special applications because special problems are
  encountered with their use.

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• Advantages
• It is readily liquefies on heating but sets
  rapidly when cooled down.
• Melt at body temperature.
• It is miscible with many ingredients.
• It is bland, therefore no irritation occurs.

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• Disadvantages
• Despite Theobroma oil been used for over 200
  years, however it is not without limitations.
• And those limitations are
• Theobroma oil is polymorphic i.e. when it is
  heated and cooled it solidifies in a different
  crystalline form.
• Theobroma oil shrinks slightly on cooling,
• adherence to the walls of suppository mold.
  
• The relatively low melting point makes it
  unsuitable for use in hot climates.

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• The melting point is reduced if the active
  ingredients are soluble in the base.
• Theobroma oil deteriorates on storage and is
  prone to oxidation.
• The quality of Theobroma oil may vary from batch
  to batch, and it can be expensive.
• For these reasons, the use of cocoa butter as a
  suppository base is becoming increasingly less
  attractive, particularly in the of the
  availability of more modern alternatives.

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II. Synthetic Semi-synthetic Bases

• Chemically they are usually derivatives of fatty
  acids that undergo chemical alteration
  (transesterification) to enhance their use for
  this application
• Such chemical reactions yield a range of products
  with controllable characteristics making them
  suitable to be used as suppository bases.

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• For example
• Hydrogenation is typically carried out to
  improve stability (enhance stability to
  oxidation and to increase chemical inertness).
• Hydrogenating suitable vegetable oils such as
• (Palm kernel oil and cottonseed oil) are
  used.
• Melting point ranges can be more precisely
  tailored to specific requirements.
• Examples of semisynthetic suppository bases
  Novata, Suppocire, Wecobee and Witepsol types.

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Advantages

• The base is more flexible and not brittle.
• More stable on oxidation and hydrolysis.
• Less irritant compare with other bases.

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Disadvantages

• The viscosity of the synthetic fats, when melted,
  is lower than that of Theobroma oil. this may
  lead to.
• Sedimentation risk of the active ingredients
  during the preparation process.
• Lack of uniformity of the active ingredients.
• These bases become very brittle if cooled too
  rapidly, so should not be refrigerated during the
  preparation period.
• There is more than one grade of synthetic fatty
  basis.

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Water soluble water miscible bases

• Glycerol-gelatin bases
• These bases is a mixture of glycerol and water,
  which is stiffened with gelatin.
• Mass of Glycerol suppositories BP has 14 w/w
  gelatin and 70 w/w glycerol.
• In hot climates gelatin content can be increased
  to 18.
• Gelatin is purified protein produces by the
  hydrolysis of the caliginous tissue of animals
  such as skins and bones.
• There is two types of gelatin Type A and
  Type B.

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• This type of base is less frequently used than
  the fatty bases for a variety of reasons.
• Disadvantages of this type of bases
• Glycerol-gelatin base have a physiological
  effect.
• This is useful if a laxative effect is required
  but otherwise is undesirable.
• Difficulties in preparation and handling.
• The dissolution time depends on the content and
  quality of the gelatin and also the age of the
  suppository.

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• They are hygroscopic and therefore require
  careful storage and may cause rectal irritation.
• Possibility of microbial contamination is more
  likely than with the fatty bases.

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• Macrogols
• These are different types of polyethylene
  glycols which are blended together to produce
  suppository bases which vary in
• Melting point.
• Dissolution rates.
• Physicochemical characteristics.
• High polymer produce preparation which release
  the drug slowly (they are brittle).
• A combination of different polymer release the
  drug more readily can be prepared by mixing high
  polymers with medium and low polymers. (Less
  brittle)

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Drug is release as the base dissolves in the
rectal contents.

• Advantages
• They have no physiological effect, e.g. do not
  produce a laxative effect.
• They are not prone to microbial contamination.
• Some polymers have a high melting point.
• They have a high water-absorbing capacity.
• In solution, viscosity is high, which means there
  is less likelihood of leakage from body.

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• Disadvantages
• They are hygroscopic which means they must be
  carefully stored.
• They are incompatible with several drugs and
  materials, e.g. bnzocaine, penicillin and
  plastic.
• They become brittle if cooled too quickly and
  also may become brittle on storage.
• Crystal growth occurs with some active
  ingredients.

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Hydrogels

• Currently, an alternative vehicle for rectal
  delivery is being actively investigated.
• Hydrogels are among them, and it defined as
  macromolecular networks that swell, but do not
  dissolve, in water.
• The swelling of hydrogels, i.e., the absorption
  of water, is a consequence of the presence of
  hydrophilic functional groups attached to the
  polymeric network.
• The aqueous insolubility of hydrogels results
  from the cross-links between adjacent
  macromolecules.

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• The use of hydrogel matrix for drug delivery
  involves the dispersal of the drug in the matrix,
  followed by drying of the system and simultaneous
  immobilization of the drug.
• When the hydrogel delivery system is placed in an
  aqueous environment, e.g., the rectum, the
  hydrogel swells, and drug is then able to diffuse
  out of the macromolecular network.

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Selection Criteria

• Melting Temperature Range.
• Iodine Value.
• Hydroxyl Index.

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Suppository Production Methods

• Melting.
• Compression.
• Injection.
• Injection molding production process involving
  PEGs as the base might proceed as follows
• The PEGs are first melted and mixed in a vessel
  equipped with a stirrer and a heating device at
  about 60C to 80C .

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• Additional viscosity -plasticity adjusting
  ingredient, auxiliary ingredients, and actives
  are added while stirring.
• Once blending is complete, the melt is extruded
  into precision-machined multi-cavity molds.
• Rapid solidification of the melt is followed by
  ejection of the molded units from the mold
  cavities.
• Very fast,
• Precise metering and molding.
• Range of shapes and sizes

61
In-Process Control

• Proper monitoring of product physical
  characteristics is necessary to ensure that the
  production process remains under control
  throughout filling.
• Visual Examination Examination of physical
  defects of finished suppositories provides
  valuable information for process monitoring.
  Color variations, chips, cracks, depressions, and
  surface irregularities are evidence of problems
  that require attention.

62

1. Weight checks periodic weighing of individual
   suppositories will reveal problem in the filling
   operation. (in each filling needle).
2. Leak Test
3. The quality of the seal is a parameter that can
   affect the stability of the product (vacuum test).

63
Quality Control

• A. Physical Analysis
• Visual Evaluation, surface appearance and color
  can be verified visually to assess
• Absence of fissuring, pitting, fat blooming,
  exudation, and migration of the active
  ingredients.
• The last test accomplished by taking a
  longitudinal section of the suppository to verify
  the homogeneity of the active ingredients within
  the mass.

64

• 2. Melting Point.
• The melting point is a critical factor in the
  determination of the release rate of the active
  ingredients from the suppository.
• The melting point of the finished suppository
  should generally not be greater than 37C.

65

• 3. Liquefaction Time.
• This is an important element indicates the
  physical behavior of a suppository subjected to
  its maximum functional temperature 37C.
• It measures the time necessary for a suppository
  to liquefy under pressures similar to those found
  in the rectum (30g) in the presence of water at
  body temperature.
• A rule of thumb is that liquefaction time should
  be no longer than 30 minutes.

66

• 4. Mechanical strength
• This is the determination of the mechanical
  force necessary to break a suppository, and it
  indicates whether a suppository is brittle or
  elastic.
• The mechanical strength should in no case be less
  than 1.8 to 2 kg.

67

• 5. Melting and Solidification
• The most commonly used methods are
• Open capillary tube.
• U-Tube.
• Drop Point.
• These methods are similar in principle, differ
  somewhat in their methodologies. all require the
  introduction of a sample into a specified place
  in the apparatus, after which heat is applied in
  a controlled manner.
• Means are provided for the determination of the
  point at which the test material undergoes a
  change in physical state, (i.e., melts).

68

• An ideal suppository base must
• Melt at or just below body temperature or
  dissolve in body temperature.
• Solidify quickly after melting.
• Be miscible with many ingredients.
• Be bland, i.e. non-toxic and non-irritant.
• Be stable on storage.
• Be resistant to handling.
• Be stable to heating above its melting point.
• Release the active ingredients readily.
• Be easily molded and removed from the mold.

69
Release Process of drug from suspension
suppository

• Suppository
• Melting and Spreading
• Sedimentation
• Wetting
• Dissolution

70
Factors affecting drug release process

• Temperature
• Contact area
• Release medium
• Movements
• Membranes

71
Formulation of suppositories

• Different types rectal, vaginal, and urethral.
• Different shapes and sizes
• Usually between 1-4g
• Drug content varies widely 0.1 to 40
• Vehicle (base) in which drug is incorporated
  sometimes contain other additives

72
Mould Calibration

• The capacity of the mould is determined by
  filling the mould by the chosen base.
• The total weight of the perfect product is taken
  and a mean weight calculated.
• This value is the calibration value of the mould
  for the particular base.

73

• Melt 2/3 of the base and then remove form the
  heat, the residual heat will melt the rest of the
  base.
• Reduce the particle size of the active
  ingredients.
• Weigh the correct amount of medicament and place
  on a glass tile.
• Add half of the molten base to the powdered drug
  and rub together with a spatula.
• Scrape this mixture off the tile, using the
  spatula and place back into the porcelain basin.
• Quickly pour into the mould, slightly overfilling
  each cavity.
• Leave the mould and its contents to cool for 5
  min.
• Allow to cool for further 10-15 min.
• Unscrew the mould and remove the suppositories.

74
Packaging and Storage

• Plastic (PVC) or aluminium foil pack
• Protection against moisture and oxygen
• Store in cool place
• High humidity absorb moisture spongy
• Low humidity lose moisture - brittle