Semisolid dosage form

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Semisolid dosage form
Murat Kizaibek
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• Ointments
• Ophthalmic ointments
• Suppository

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ointments

• Concept
• Ointment base
• Adjuvants
• Preparation of ointments
• Quality control of ointments

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Concept

• Definition semisolid preparations intended for
  external application are termed ointments.
• Ingredient drug substance bases adjuvants

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• Classification

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• Quality requirement

• the product is required smooth and uniform with
  certain stickiness to skin
• the drug in bases even distributed
• stability of the ointment
• Skin infection preparations are designed to be
  sterile

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Ointment bases

• Ointment bases are classified into four general
  groups
• (1) Hydrocarbon bases
• (2) Absorption bases
• (3) Water-Removable Bases
• (4) Water-Soluble Bases

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(1) hydrocarbon bases

• Hydrocarbon bases (oleaginous bases) are
  water-free, and aqueous preparations may be
  incorporated into them only in small amounts and
  then with difficulty.
• Hydrocarbon bases are retained on the skin for
  prolonged periods, do not permit the escape of
  moisture from the skin to the atmosphere, and are
  difficult to wash off.
• As such they act as occlusive dressings. They do
  not "dry out" or change noticeably upon aging.

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• Petrolatum
• a mixture of semisolid hydrocarbons obtained from
  petroleum
• an unctuous mass, varying in color from yellow to
  white
• It may be used alone or in combination with other
  agents as an ointment base
• Commercial product is Vaseline

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• Paraffin
• A purified mixture of solid hydrocarbons obtained
  from petroleum.
• A colorless or white, more or less translucent
  mass that may be used to harden or stiffen
  oleaginous semisolid ointment bases.

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• Liquid paraffin
• a colorless, odorless oily liquid consisting of a
  mixture of hydrocarbons obtained from petroleum
• has the same character with paraffin
• be used in combination with paraffin to adjust
  viscosity

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• Hydrophilic Petrolatum

• is composed of cholesterol, stearyl alcohol,
  white wax, and white petrolatum
• has the ability to absorb water, with the
  formation of a water-in-oil emulsion.
• Aquaphor is a highly refined variation of
  Hydrophilic Petrolatum and because it can absorb
  up to 3 times its weight in water, it has proven
  useful to incorporate extemporaneously a
  water-soluble drug into an oleaginous base.

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Anhydrous Lanolin (refined wool fat)

• may contain no more than 0.25 of water.
• insoluble in water, but mixes without separation
  with about twice its weight of water
• The incorporation of water results in the
  formation of a water-in-oil emulsion.

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Lanolin (hydrous Wool Fat )

• a semisolid, fatlike substance obtained from the
  wool of sheep.
• a water-in-oil emulsion that contains between 25
  and 30 water.
• Additional water may be incorporated into lanolin
  by mixing.

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• Beeswax and spermaceti
• They are weak sufactants (W/O) and used as
  stabilization agents in O/W emulsive ointment.

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Mineral Oil

• a mixture of liquid hydrocarbons.
• It is useful as a levigating substance to wet and
  to incorporate solid substances into the
  preparation of ointments that consist of
  oleaginous bases as their vehicle.

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(2) Absorption bases

• Absorption bases may be of two types
• those that permit the incorporation of aqueous
  solutions, resulting in the formation of
  water-in-oil emulsions (e.g. Hydrophilic
  Petrolatum and Anhydrous lanolin) and those that
  are already water-in-oil emulsions (emulsion
  bases) that permit the incorporation of small,
  additional quantities of aqueous solutions (e.g.
  lanolin and Cold Cream).

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• These bases are useful as emollients although
  they do not provide the degree of occlusion
  afforded by the oleaginous bases.
• Absorption bases are not easily removed from the
  skin with water washing.
• They are also useful pharmaceutically to
  incorporate aqueous solutions of drugs, e g.,
  sodium sulfacetamide, into oleaginous bases.

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(3)Water-Removable Bases

• oil-in-water emulsions that are capable of being
  washed from skin or clothing with water. For this
  reason, they are frequently referred to as
  "water-washable" ointment bases
• may be diluted with water or with aqueous
  solutions.
• have the ability to absorb serous discharges in
  dermatologic conditions.
• Certain medicinal agents may be better absorbed
  by the skin when present in a base of this type
  than in other types of bases.

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• Emulsifying agents

• sodium lauryl sulfate O/W emulsion
• stearyl alcohol and cetyl alcohol representing
  the oleaginous phase of the W/O emulsion to
  improve the stabilization and viscosity.
• sodium stearate and calcium stearate.
• Glyceryl monostearate weak W/O emulsifying
  agents and used as stabilization agents and
  emollient in the O/W emulsion.

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• Spans W/O emulsifying agents
• Tweens O /W emulsifying agents
• Peregal O and emulsive OP O/W

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• Stearic acid, beewax and paraffin are the main
  oleaginous bases.
• propylene glycol and water representing the
  aqueous phase
• Methylparaben and propylparaben are used to
  preserve the ointment against microbial growth

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(4) Water-Soluble Bases

• contain only water-soluble components.
• are water washable
• Because they soften greatly with the addition of
  water, aqueous solutions are not effectively
  incorporated into these bases. Rather, they are
  better used for the incorporation of nonaqueous
  or solid substances.

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• Polyethylene Glycol Ointment

• Polyethylene glycols are polymers of ethylene
  oxide and water
• The chain length may be varied to achieve
  polymers having desired viscosity and physical
  (liquid, semisolid, or solid) form.
• The general formula for this base calls for the
  combining of polyethylene glycol 3350(a solid)
  and polyethylene glycol 400 (a liquid) to prepare
  base.

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Adjuvants

• Antioxidants
• Antimicrobial preservatives

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• Antioxidants

preparations Antioxidants
aqueous Sodium sulfite(Na2SO3) sodium bisulfite(NaHSO3), hypophosphorous acid(H3PO2) ascobic acid( vitamin C)
oleaginous Alpha tocopherol(vitamin E) Butylhydroxyanisole(BHA) ascorbyl palmitate
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• Antimicrobial preservatives

• frequently require the addition of chemical
  antimicrobial preservatives to the formulation
  to inhibit the growth of contaminating
  microorganisms
• These preservatives include para-hydroxybenzoates
  (parabens), phenols, benzoic acid, sorbic acid,
  quaternary ammonium salts and other compounds.

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Selection of the Appropriate Base
The selection of the base to use in the
formulation of an ointment depends upon the
careful assessment of a number of factors,
including
(a) the desired release rate of the particular
drug substance from the ointment base (b) the
desirability for enhancement by the base of the
percutaneous absorption of the drug
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• (c) the advisability of occlusion of moisture
  from the skin by the base
• (d) the short-term and long-term stability of the
  drug in the ointment base
• (e) the influence, if any, of the drug on the
  consistency or other features of the ointment
  base.
• (f) patient factors also play an important role
  in a base's selection

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Preparation of Ointments

• Both on a large and a small scale, ointments are
  prepared by three general methods
• (1) incorporation method
• (2) fusion method
• (3) emulsification method
• The method for a particular preparation depends
  primarily upon the nature of the ingredients

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(1) incorporation

• the components of the ointment are mixed together
  by various means until a uniform preparation has
  been attained.
• On a small scale, the pharmacist may mix the
  components of an ointment in a mortar with a
  pestle, or a spatula and an ointment slab (a
  large glass or porcelain plate) may be used to
  rub the ingredients together.

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(2) fusion

• By the fusion method, all or some of the
  components of an ointment are combined by being
  melted together and cooled with constant stirring
  until congealed.
• Those components not melted are generally added
  to the congealing mixture as it is being cooled
  and stirred.
• Naturally, heat-labile substances and any
  volatile components are added last when the
  temperature of the mixture is low enough not to
  cause decomposition of volatilization of the
  components.

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(3) emulsification

• In the preparation of ointments having an
  emulsion type of formula, the general method of
  manufacture involves a melting process as well
  as an emulsification process.

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• the water-immiscible components such as the oil
  and waxes are melted together in a steam bath to
  about 70 to 75C
• Meantime, an aqueous solution of all of the
  heat-stable, water-soluble components is being
  prepared in the amount of purified water
  specified in the formula and heated to the same
  temperature as the oleaginous components.

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• Then the aqueous solution is slowly added, with
  constant stirring (usually with a mechanical
  stirrer), to the melted oleaginous mixture, the
  temperature is maintained for 5 to 10 minutes to
  prevent crystallization of waxes
• the mixture is slowly cooled with the stirring
  continued until the mixture is congealed.

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Notice

• If the aqueous solution were not the same
  temperature as the oleaginous melt, there would
  be solidification of some of the waxes upon the
  addition of the colder aqueous solution to the
  melted mixture.

Emulsification
ointments
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?ophthalmic ointments

• Concept
• semisolid preparations intended for application
  to the eye are specially prepared and are termed
  ophthalmic ointments.

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Preparation of ophthalmic ointments

• The methods of preparation just like
  ointments,but under the aseptic condition for
  prevent eye infection.

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• The bases

• must be non-irritating to the eye and must permit
  the diffusion of the medicinal substance
  throughout the secretions bathing the eye.
• Ointment bases utilized for ophthalmics have a
  melting or softening point close to body
  temperature.
• In most instances, mixtures of petrolatum and
  liquid petrolatum (mineral oil) are utilized as
  the ointment base.
• Sometimes a water-miscible agent as lanolin is
  added. This permits water and water-insoluble
  drugs to be retained within the delivery system.

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• The advantage and disadvantage

• The primary advantage of an ophthalmic ointment
  over an ophthalmic solution is the increased
  ocular contact time of the drug.
• One disadvantage to ophthalmic ointment use is
  the blurred vision which occurs as the ointment
  base melts and is spread across the lens.

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Suppositories
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1.Definition

• Suppositories are semisolid dosage forms
  intended for insertion into body orifices where
  they melt, soften, or dissolve and exert
  localized or systemic effects.

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2. Body orifices for using

• Suppositories are commonly employed rectally,
  vaginally and occasionally urethrally.
• They have various shapes and weights depending
  upon the density of the base and the medicaments
  present in it, and the individual manufacturer's
  product.

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3.character of action
1)Local Action

• Rectal suppositories are most frequently employed
  to relieve constipation or the pain, irritation,
  itching, and inflammation associated with
  hemorrhoids or other anorectal conditions.
• Vaginal suppositories or inserts are employed
  mainly as contraceptives, antiseptics in feminine
  hygiene, and as specific agents to combat an
  invading pathogen.
• Urethral suppositories may be used as
  antibacterial and as a local anesthetic
  preparative to urethral examination.

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2)Systemic Action
administered rectally in the form of
suppositories for systemic effects include

• (a) for the relief of nausea and vomiting and as
  a tranquilizer
• (b) for narcotic analgesia
• (c) for the relief of migraine syndrome
• (d) anti-inflammatory analgesic and antipyretic.

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3) advantages over oral therapy(rectal route for
achieving systemic effects )

• (a) drugs destroyed or inactivated by the pH or
  enzymatic activity of the stomach or intestines
  need not be exposed to these destructive
  environments
• (b) drugs irritating to the stomach may be given
  without causing such irritation
• (c) drugs destroyed by portal circulation may
  bypass the liver after rectal absorption (drugs
  enter the portal circulation after oral
  administration and absorption)

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• (d) the route is convenient for administration of
  drugs to adult or pediatric patients who may be
  unable or unwilling to swallow medication
• (e) it is an effective route in the treatment of
  patients with vomiting episodes.

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4.Quality control of suppository
The shape and size of a suppository must be such
that

• the medicaments and base mixed uniformly with
  certain hardness under condition of shipment and
  storage
• capable of being easily inserted into the
  intended body orifice without causing undue
  distension.
• once inserted, the base melts, softens, or
  dissolves, distributing the medicaments it
  carries to the tissues of the region. It must be
  retained for the appropriate period of time for
  local effects or quickly absorbed for systemic
  effects .

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? Ingredients of suppositories

• contains drug,base and other adjuvant ,which the
  affecting factors for preparation are the
  physicochemical nature of the drug, the nature of
  the suppository vehicle and its capacity to
  release the drug and clinical desired effects
  from administration ?
• Drug
• properties as the relative solubility of the drug
  in lipid and in water , the particle size of a
  dispersed drug.

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• Base

• 1.requisites for a suppository base is that
• 1)it remains solid at room temperature but
  softens, melts, or dissolves readily at body
  temperature so that the drug it contains may be
  made fully available soon after insertion
• 2)with certain hydrophilic or hydrophobic
  character
• 3)melting point near to solidifying point
• 4) easily ejectable from mold
• 5) dont irritate to the mucous membranes

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2.Classification of Suppository Bases

• According to bases physical characteristics the
  bases can be classified into
• (1) fatty or oleaginous bases
• (2)water-soluble or water-miscible bases

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(1) fatty or oleaginous bases

• Fatty bases are perhaps the most frequently
  employed suppository bases . 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
  would a hydrophilic substance present in a fatty
  base to an extent approaching its saturation.
• fatty bases contains
• (a) Cocoa Butter and (b) compounds of glycerin

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(a) Cocoa Butter

• the fat obtained from the roasted seed of
  theobroma cacao.
• At room temperature it is a yellowish, white
  solid having a faint, agreeable chocolate-like
  odor.

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• Chemically, it is a triglyceride (combination of
  glycerin and one or different fatty acids)
  primarily of oleopalmitostearin and
  oleodistearin.
• It melts between 30? to 36 ?, an ideal
  suppository base, melting just below body
  temperature and yet maintaining its solidity at
  usual room temperatures.

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• because of its triglyceride content, cocoa butter
  exhibits marked polymorphism, or different
  crystalline forms a, ß,ß,?.
• Because of this, when cocoa butter is hastily or
  carelessly melted at a temperature greatly
  exceeding the minimum required temperature and
  then quickly chilled, As a result a metastable
  crystalline form (a crystals) with a melting
  point much lower than the original cocoa butter
  that the cocoa butter will not solidify at room
  temperature.

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• Since the form represents a metastable condition,
  there is a slow transition to the more stable ß
  form of crystals having the greater stability and
  the higher melting point.
• Cocoa butter must be slowly and evenly melted.
  Preferably over a water bath of warm water, to
  avoid the formation of the unstable crystalline
  form and ensure the retention in the liquid of
  the more stable ß crystals that will constitute
  nuclei upon which the congealing may occur during
  chilling of the liquid.

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• Substances such as phenol and chloral hydrate
  have a tendency to lower the melting point of
  cocoa butter when incorporated with it.
• If the mp is lowered to such an extent that it is
  not feasible to prepare a solid suppository using
  cocoa butler alone as the base, solidifying
  agents like cetyl esters wax (about 20) or
  beeswax (about 4) may be melted with the cocoa
  butter to compensate for the softening effect of
  the added substance.

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• However, the additions of hardening agents must
• not be so excessive as to prevent the melting of
  the base after the suppository has been inserted
  into the body,
• nor must the wax material interfere with the
  therapeutic agent in any way so as to alter the
  efficacy of the product.

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(b) compounds of glycerin

• The higher molecular weight fatty acids, such as
  palmitic and stearic acids, may be found in fatty
  suppository bases.
• Such compounds as glyceryl monostearate and
  glyceryl monopalmitate are examples of this type
  of agent.

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(2) water-soluble or water-miscible bases
(a) Glycerinated gelatin

• This base is slower to soften and mix with the
  physiologic fluids , therefore provides a more
  prolonged release
• Because it have a tendency to absorb moisture due
  to the hygroscopic nature of glycerin, the
  suppository must be protected from atmospheric
  moisture in order for them to maintain their
  shape and consistency
• Due also to the hygroscopicity of the glycerin,
  the suppository may have a dehydrating effect and
  be irritating to the tissues upon insertion.

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The water present in the formula for the
suppositories minimizes this action however, if
necessary, the suppositories may be moistened
with water prior to their insertion to reduce the
initial tendency of the base to draw water from
the mucous membranes and irritate the tissues.
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• A glycerinated gelatin base is most frequently
  used in the preparation of vaginal suppositories,
  where the prolonged localized action of the
  medicinal agent is usually desired.
• vaginal suppositories are much more easily
  inserted than suppositories with a cocoa butter
  base, owing to the brittleness of cocoa butter
  and its rapid softening at body temperature.

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They are available in a number of molecular
weight ranges, the more commonly used being
polyethylene glycol 200,400, 600,1000,1500,1540,
3350, 4000,6000, and 8000. The numerical
designations refer to the average molecular
weights of each of the polymers.
(b) Polyethylene glycols

• Various combinations of these polyethylene
  glycols may be combined by fusion, using two or
  more of the various types to achieve a
  suppository base of the desired consistency and
  characteristics.

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Polyethylene glycol suppositories do not melt at
body temperature but rather dissolve slowly in
the body's fluids.

• If the polyethylene glycol suppositories do not
  contain at least 20of water to avoid the
  irritation of the mucous membranes after
  insertion, they should be dipped in water just
  prior to use.

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(c) polyoxyl 40 stearate

• a surface-active agent with the average polymer
  length being equivalent to about 40 oxyethylene
  units.
• The substance is a waxy, white to light tan solid
  that is water-soluble. Its melting point is
  generally between 39? and 45 ?.

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? Preparation of Suppositories
Suppositories are prepared by two methods (1)
Preparation by compression (2) Fusion or
preparation by mold
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(1) Preparation by Compression

• Suppositories may be prepared by forcing the
  mixed mass of the suppository base and the
  medicaments into special molds using suppository
  making machines.
• In preparation for compression into the molds,
  the suppository base and the other formulative
  ingredients are combined by thorough mixing, the
  friction of the process causing the base to
  soften into a paste-like consistency.

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(a)cold Compression The process of compression
is especially suited for the making of
suppositories containing medicinal substances
that are heat labile and for suppositories
containing a great deal of substances insoluble
in the base.
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• (b) hand rolling and shaping
• With the ready availability of suppository molds
  of accommodating shapes and sizes, there is
  little requirement for today's pharmacist to
  shape suppositories by hand.
• Hand rolling and shaping is a historic part of
  the art of the pharmacist.

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(2) Fusion or preparation by mold

• The method is most frequently employed in the
  preparation of suppositories both on a small
  scale and on an industrial scale.

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Mold shape

• Molds in common use today are made from stainless
  steel.
• The molds, which separate into sections,
  generally longitudinally, are opened for cleaning
  before and after the preparation of a batch of
  suppositories.
• Care must be exercised in cleaning the mold for
  the desired smoothness of the resulting
  suppositories.

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LUBRICATION OF THE MOLD

• Depending upon the formulation, suppository molds
  may require lubrication before the melt is poured
  to facilitate the clean and easy removal of the
  molded suppositories.
• Lubrication is seldom necessary when the
  suppository base is cocoa butter or polyethylene
  glycol.
• Lubrication is usually necessary when
  glycerinated gelatin suppositories are prepared.
• Any materials which might cause irritation to the
  mucous membranes should not be employed as a mold
  lubricant.

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the steps in molding

• (a) the melting of the base
• (b) incorporating of any required medicaments
• (c) pouring the melt into molds
• (d) allowing the melt to cool and congeal into
  suppositories
• (e) removing the formed suppositories from the
  mold.
• NoticeSuppositories of cocoa butler,
  glycerinated gelatin, polyethylene glycol, and
  most other suppository bases are suitable for
  preparation by molding.

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pouring the melt into molds
removing the formed suppositories
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CALIBRATION OF THE MOLD

• Each individual mold is capable of holding a
  specific volume of material in each of its
  openings.
• If the material is changed, the weight of the
  resulting suppositories will differ from the
  weight of suppositories prepared in the same mold
  because of the difference in the densities of the
  materials.
• Similarly, any added medicinal agent would
  further alter the densities of the bases, and the
  weights of the resulting suppositories would be
  different from those prepared with base material
  alone.

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• It is important that the pharmacist calibrate
  each of his suppository molds for the suppository
  bases that he generally employs in order that he
  may prepare medicated suppositories each having
  the proper quantity of medicaments.
• First step to prepare molded suppositories from
  base material alone. After removal from the mold,
  the suppositories are weighed, and the total
  weight and the average weight of each suppository
  are recorded as G

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• Second step
• to prepare molded suppositories from base and
  drug. After removal from the mold, the
  suppositories are weighed, and the total weight
  and the average weight of each suppository are
  recorded as M

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• Third step to calculate the displacement value
  by the equation below

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• For example
• Prepare the suppositories using cocoa buffer. The
  average weight of each blank suppository is 3.5g.
  Then adding 1.5g drugs into cocoa buffer and
  preparing a medicated suppository. The weight of
  the medicated suppository is 4.2g.
• Please calculate the dosage of cocoa buffer if 10
  medicated suppositories, every medicated
  suppositories contain 1.0g drug, want to be
  prepared.

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? Packaging and Storage
Most commercially available suppositories are

• individually wrapped in either foil or a plastic
  material. Some are packaged in a continuous strip
  with suppositories being separated by tearing
  along perforations placed between suppositories
• Suppositories are also commonly packaged in slide
  boxes or in plastic boxes.
• maintain in a cool place.
• stored in environments of fitting humidity

flash1
flash2
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? Treating role and Clinical applying

• systemic action medicaments may be intended to
  be absorbed for the exertion of systemic effects
• local action medicaments may be intended for
  retention within the cavity for localized drug
  effects.

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Systemic Action

• For systemic effects, the mucous membranes of the
  rectum and vagina permit the absorption of many
  soluble drugs. Although the rectum is utilized
  quite frequently as the site for the systemic
  absorption of drugs, the vagina is not as
  frequently used for this purpose.

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• Absorption route
• According to the course of venous flow, a drug
  absorbed in the lower part of the rectum should
  enter the vena cava
• A drug placed in the upper part of the rectum
  should diffuse into blood vessels which lead to
  the liver.

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Affecting factors for absorption

• The factors affecting the rectal absorption of a
  drug administered in the form of a suppository
  may be divided into
• physiologic factors colonic contents,
  circulation route, and the pH and lack of
  buffering capacity of the rectal fluids
• (2) physicochemical factors of the drug and the
  base The lipid-water partition
  coefficientparticle size nature of the bases

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Glossary
Ointments bases oleaginous hydrocarbon bases
absorption bases water-removable
baseswater-soluble bases Petrolatum
Vaseline Paraffin Anhydrous lanolin
Hydrophilic Antioxidants incorporation method
fusion method emulsification method ophthalmic
ointments Suppositories Body orifices
Rectal Vaginal melting point Cocoa Butter
polymorphism hygroscopicity Glycerinated
gelatin Polyethylene glycols polyoxyl 40
stearate displacement value