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Suppositories and Pessaries

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Title: 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.

3
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

5
Definition
  • Solid or semisolid dosage forms used for rectal,
    vaginal, or urethral administration of
    therapeutic agents.

6
  • 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.

8
Rectal administration Applications
  1. For local
  2. Systemic drug delivery.

9
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.

11
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.

16
  • 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.

17
Factors affecting the absorption from Rectal
Suppositories
  1. Physiological factors.
  2. Physicochemical factors of the drug substance.
  3. Physicochemical factors of the base.

18
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.

19
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.

24
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.

25
  • 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.

26
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.

 
27
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.
  •  

28
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.

29
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
30
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.

31
  • 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
32
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.

33
  • 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
34
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.

35
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.

36
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.

37
  • 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
38
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.

39
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

40
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.

41
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.

42
  • 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.

43
  • 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.

44
  • 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.

45
  • 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.

46
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.

47
  • 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.

48
Advantages
  • The base is more flexible and not brittle.
  • More stable on oxidation and hydrolysis.
  • Less irritant compare with other bases.

49
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.

50
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.

51
  • 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.

52
  • 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.

53
  • 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)

54
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.

55
  • 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.

56
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.

57
  • 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.

58
Selection Criteria
  • Melting Temperature Range.
  • Iodine Value.
  • Hydroxyl Index.

59
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 .

60
  • 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
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