Suppositories

Suppositories : SyllabusIdeal requirements Bases Manufacturing procedure, Packaging andEvaluation.

“suppositories are semi solid dosage form meant to be inserted into body cavity other than mouth like rectum, urethra, vagina where they melt, soften or dissolve to release the drugs and exert local or systemic effect.”

Definition :-

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.

Body orifices for using

Types of Suppositories

Rectal suppositoriesPessaries / Vaginal SuppositoriesUrethral Suppositories or bougies Nasal Suppositories or Nasal

bougies Ear cones or Aurinaria.

Rectal using

Vaginal

using

Shape of suppositories

Shapes available : conical, bullet, torpedo, oviform, pencil shaped, globular etc.

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RECTAL SUPPOSITORYIntended for local action to relieve constipation, irritation,

itching and inflammatory associated to hemorrhoids.To promote defecation.

Introduce drugs into the body.

Treat anorectal diseases.

Drugs employed: analgesics, antispasmodics, sedatives, tranquilizers, antibacterial agents.

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URETHRAL SUPPOSITORY Also called as BOUGIES .SHAPE – slender, pencil-shaped.Intended for anti-bacterial or as a local

anesthetic preparative for urethral examination.Occasionally used.

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VAGINAL SUPPOSITORY They are also called as PESSARIES.SHAPE : globular, oviform or cone-shaped.Used occasionally.Intended for local effects like contraceptives,

antiseptics in feminine hygiene

General Size: Rectal 2 gm (Adults) 1 gm (Children) Pessaries (Vaginal Suppositories) 3-5

gm Bougies (Urethral Suppositories) 4 gm and 100-150 mm long For

Males 2 gm and 60-75 mm long for females

Nasal suppositories: - called nasal bougies or buginaria meant for introduction in to nasal cavity.

They are prepared with glycero gelatin base.

They weigh about 1 gm and length 9-10 cm

Character of 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.Locally active drugs include astringents, antiseptics, local anesthetics,

vasoconstrictors, anti-inflammatory. soothing and protective agents and some laxatives.

1)Local Action

(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.

(e) Anti-asthmatics, anti rheumatics.

2)Systemic Action

administered rectally in the form of suppositories for systemic effects include:

Examples of drugs administered rectally in the form of suppositories for their systemic effects include

a) prochlorperazine b) chlorpromazinec) oxymorphone HCl d) ergotamine tartratee) indomethacinf) ondansetron

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);

Absorption of Drugs from Rectum

Proper Insertion of Suppository in Rectum

(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.

Advantages of Suppositories

Advantages

Avoid first-pass

metabolism

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ADVANTAGESEASILY ADMINSTERED to children, old

persons, to unconscious or sometimes to mentally unstable persons who cannot swallow the drug.

Convenient mode of administration for drugs which irritate the GIT, causing vomiting and destroyed in acidic ph of stomach and enzymes of GIT.

FASTER ONSET OF ACTION as compared to oral administration because absorption of drug through rectal mucosa directly reaches blood

Advantages ….1. Alternate dosage form for the drugs with

less bioavailability when taken orally.2. Drugs having bad odour & taste.3. For treating vomiting patients4. Site- specific action on rectal, urethra,

etc…5. Administration of drugs which are

destroyed by portal circulation.

Disadvantages of Suppositories

Disadvantages :-

1. Not much acceptable by patient.2. Manufacturing process is difficult.3. Drug which cause irritation to

mucous membrane can’t be administered

4. Leakage of suppository occurs upon insertion into the body cavity at elevated temperature.

Disadvantages…..

1. Slow and incomplete absorption.2. Inter and intra-subject variation.3. Development of proctitis.4. Problems with large scale production of

suppositories and of achievement of a suitable shelf life

5. Demanding stringent storage conditions as Maintenance of temperature is difficult as Most of the suppositories should be stored at low temperature10-20°c in a refrigerator , other wise the base gets liquefied.

Requirements to suppositories:

Rejections in-bulk suppositories must not exceed ± 5 %.

Medicinal matters which are contained in them are to be exactly dosed.

Suppositories must have correct and accordingly identical form, homogeneous mass, sufficient hardness (mechanical durability) and fuse at the temperature of body.

Suppositional mass must be homogeneous, without inclusions, marbling, and sequins.

Requirements to suppositories:Time of melting (for suppositories on hydrophobic

bases) – 15 minutesTime of dissolution (for suppositories on hydrophilic

bases) – 60 minutesLength of rectal suppositories must be from 2.5 to 4

centimeters.A maximal diameter of rectal suppositories is 1.5

centimeters.Mass of rectal suppositories is from 1.50 to a 4.0 g

(middle 3.0).Mass of vaginal suppositories must be from 1.5 to a

6.0 gram (middle 4.0).

Some factors of drug absorption from rectal

suppositories

1) Physiologic factors Colonic content- when deemed desirable, an

evacuant enema may be administered and allowed to act before the administration of a suppository of a drug to be absorbed.

- Diarrhea, colonic obstruction, and tissue dehydration

Circulation route- The lower hemorrhoidal veins

surrounding the colon receive the absorbed drug and initiate its circulation throughout the body, bypass the liver.

- Lymphatic circulation also assists in the absorption of rectally administered drugs.

pH of the rectal mucosa- pH of rectal mucosa is 6.8.- Rectal fluids have no buffer

capacity.- Dissolved drugs determine the

pH of the anorectal area. - Weaker acids and bases are more

readily absorbed than the stronger , highly ionozed ones.

- Lower pH influence increased absorption of acidic drugs but decreased absorption of basic drugs.

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2) Physicochemical factors of the drug and suppository base

Lipid-water solubility- 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.

- Water soluble bases, for example, PEG, which dissolve in the anorectal fluids, release for absorption both water-soluble and oil-soluble drugs.

- Naturally, the more drug a base contains, the more drug will be available for potential absorption.

Particle size- For drugs present in a

suppository in the undissolved state, the size of the drug particle will influence its rate of dissolution and its availability for absorption.

- The smaller the particle size, the more readily the dissolution of the particle and the greater the chance for rapid absorption.

Nature of the base- The possiblity of chemical and/or

physical interactions between the medicinal agent and the suppository base, which could affect the stability and/or bioavailability of the drug.

- If the base is irritating to the mucous membranes of the rectum, it may initiate a colonic response and prompt a bowel movement, negating the prospect of complete drug release and absorption.

3. Suppository bases and Adjuvants

One of the first requisites for a suppository base is that

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.

Adjuvants… Adjuvants in the formula can affect

drug absorption through changes in the rheologic properties of the base at body temperatures.

Emulsion type bases: Prolonged drug release by the addition of an aqueous polymer.

Liophobic bases: salicylates improve rectal absorption of water-soluble antibiotics.

Hydrophobic colloidal silicon dioxide dramatically changes the rheologic behavior of the mass.

Formulation :-Formulation includes ;1. Suppository bases.2. Active ingredients.3. Additives. Anti- oxidants Emulsifying agents Hardening agents Preservatives Thickening agents Plasticizers

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1. SUPPOSITORY BASES• As with the ointment bases,

suppository base composition plays an important role in both the rate and extent of release of medications.

• Suppository bases may be classified according to their composition and physical properties: 1- Oleaginous (fatty) bases2- Water soluble or miscible

bases 3- Miscellaneous Bases

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Specifications of suppository bases

1- Origin and chemical compositionThe source of origin (i.e. entirely natural

or synthetic or modified natural).Physical and chemical incompatibilities

with additives (i.e. preservatives, antioxidants and emulsifiers) from its chemical make up.

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2- Melting rangeSince fats (complex mixtures of triglycerides) do not

have sharp melting point, their melting characteristics are expressed as a range indicating the temperature at which the fat start to melt and the temperature at which it is completely melted.

Method: USP Method, Wiley melting point, capillary melting point, softening point, incipient melting/Thaw point.

Example : Cocoa Butter 30-350C, Massuppol 34-370C.

Specifications of suppository bases3- Solid Fat Index

Solid fat index (SFI) is a measure of the percentage of fat in crystalline (solid) phase to total fat (the remainder being in liquid phase) across a temperature gradient.

The SFI of a fat is measured using a dilatometer that measures the expansion of a fat as it is heated; density measurements are taken at a series of standardized temperature check points.

The resulting SFI/temperature curve is related to melting qualities and flavor.

For example, butter has a sharp SFI curve, indicating that it melts quickly and that it releases flavor quickly.

• butter from camel milk contains a significantly higher portion of solid fat over the entire melting range relative to butter from cow milk

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4- Solidification pointThis value indicates the time required for base

solidification when it is chilled in the mold.If the interval between the melting range and

solidification point is 100C or more, the time required for solidification may have to be shortened for a more efficient manufacturing procedure by augmenting refrigeration.

Example: Massuppol 29.5-31.50C

Specifications of suppository bases5- Hydroxyl Value

• This is a measure of unesterified portion positions on glyceride molecules and reflects the monoglyceride and diglyceride content of a fat base.

• The number represents the mg of KOH that would neutralize the acetic acid used to acetylate 1 gm of fat containing free hydroxyl groups.

• The analytical method used to determine hydroxyl value traditionally involves acetylation of the free hydroxyl groups of the substance with acetic anhydride in pyridine solvent.

• After completion of the reaction, water is added, and the remaining unreacted acetic anhydride is converted to acetic acid and measured by titration with potassium hydroxide.

• Example: Massupol <3 (mixture of di and tri glycerides of saturated fatty acids)

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6- Saponification value The number of milligrams of potassium hydroxide required to

neutralize the free acids and to saponify the esters contained in 1 gm of fat.

It is an indication of the type of glyceride (mono- or tri-) as well as the amount of glyceride present.

It is a measure of the average molecular weight (or chain length) of all the fatty acids present.

As most of the mass of a fat/tri-ester is in the 3 fatty acids, it allows for comparison of the average fatty acid chain length.

The long chain fatty acids found in fats have a low saponification value because they have a relatively fewer number of carboxylic functional groups per unit mass of the fat as compared to short chain fatty acids.

If more moles of base are required to saponify N grams of fat then there are more moles of the fat and the chain lengths are relatively small.

Example: Massuppol 230-240, Cocoa butter 192-196.

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7- Acid valueThe number of milligrams of potassium hydroxide

required to neutralize the free acid in 1 gm of substance is expressed by this value.

Low acid values or complete absence of acid are important for good suppository bases.

Free acids complicate formulation work, because they react with other ingredients and can also cause irritation when in contact with mucous membranes.

Example : Cocoa Butter 1.68 (Not Higher than 4)

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8- Iodine valueThis value express the number of grams of

iodine that react with 100 gm of fat or other unsaturated material.

The possibility of decomposition by moisture, acids, and oxygen (leads to rancidity in fats) increases with high iodine values.

Example: Massuppol <3, Cocoa Butter 32.11–35.12.

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9- Water numberThe amount of water in grams, which can be

incorporated in 100 gm of fat is expressed by this value.

The water number can be increased by addition of surface active agents.

Example: Massuppol 50-100.

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1. Suppository basesThe ideal suppository base should be• Nontoxic and nonirritating to sensitive and inflamed

tissues.• Inert and compatible with a broad variety of

medicaments.• No meta-stable forms.• Can be easily manufactured by compression or molding. • Dissolve or disintegrate in the presence of mucous

secretions or melt at body temperature to allow for the release of the medication.

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• Remain molten for a sufficient period of time to allow pouring into moulds.

• Solidify sufficiently rapidly to minimize sedimentation of dispersed solids.

• Contract on cooling to allow easy withdrawal of the suppository from the mould.

• Has wetting and emulsifying properties. • High water number.• Stable on storage, does not change color, odor and

drug release pattern.

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If the base is fatty, it has the following additional requirements:

• Acid value is below 0.2.• Saponification value ranges from 200 to 245.• Iodine value is less than 7. • The interval between melting point and

solidification point is small.

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1. Oleaginous Bases

Include:• Theobroma Oil • Synthetic

triglyceride mixtures.

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A- Theobroma Oil or cocoa butter

Theobroma Oil or cocoa butter is used as a suppository base because, in large measure, it fulfills the requirements of an ideal base.

Cocoa butter is primarily a tri-glyceride (Oleopalmitostearin and oleodistearin chains).

It is yellowish- white, solid, brittle fat, which smells and tastes like chocolate.

At ordinary room temperatures of 15° to 25°C it is a hard, amorphous solid, but at 30° to 35°C i.e., at body temperature, it melts to a bland, nonirritating oil.

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A- Theobroma Oil or cocoa butter

Thus in warm climates, theobroma oil suppositories should be refrigerated.

Cocoa butter has iodine value between 34 and 38.

Its acid value not higher than 4.

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Disadvantages of theobroma oil

Shrinks only slightly on solidification; a mould lubricant is therefore required.

Exists in four polymorphic forms with different melting points (24.0, 28.0-31.0, 34.0-35.0ºC and 18.0 ).

Theobroma oil should only be heated for a short time and at temperatures below 36 ºC in order to minimize the formation of the unstable low melting point forms.

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The change (reduction) in melting point caused by addition of certain drugs such as volatile oils, phenol or chloral hydrate to cocoa butter suppositories. The solution is to raise the melting point back to the desired range by addition of 3% to 5% of beeswax or spermaceti.

Theobroma oil has a low absorptive capacity for water, but this can be increased by adding surfactants such as cholesterol 2%, emulsifying wax up to 10%, polysorbates 5 to 10%, or wool fat 5 to 10%. However, the addition of surfactants may lead to a drug- base interaction or affect the release of drug from suppository.

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Theobroma oil is prone to oxidation (due to high iodine value); this can be partly overcome by storage in a cool, dark place.

Theobroma oil may vary in consistency, odor, and color depending on its source like other natural products.

The low melting point of theobroma oil may pose storage problems in hot climates.

• Emulsified Theobroma Oil: to incorporate large quantity of aqueous solutions.

5% Glyceryl monostearate, 10% lanette wax, 2-3% cetyl alcohol, 4% bees wax and 12% spermaceti is recommended to prepare emulsified Theobroma oil suppository.

• Hydrogenated Oil: Hydrogenation of various vegetable oils like coconut oil, cotton seed oil, palm oil etc used as substitute for theobroma oil.

Advantages: Resistant to oxidation. Mold lubrication not required. solidification point not affected by overheating. produce colourless, odourless and elegant suppositories. good emulsifying and water absorbing capacities.Disadvantages• Become brittle on rapid cooling.• More fluid than theobroma oil which is overcome by bentonite or

magnessium stearate.

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B- Synthetic Tri-glycerides (hard fat) The newer synthetic tri-glycerides consist of

esterified, hydrogenated or fractionated vegetable oils.

Their advantages over cocoa butter are:1- Do not exhibit polymorphism. 2- Contain mainly saturated acids (Iodine number <3),

while cocoa butter contains considerable amount of the unsaturated fatty acids (Iodine number 34-38).

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B- Synthetic Tri-glycerides (hard fat)

3- The melting range of the synthetic bases is usually about 3ºC higher than that of cocoa butter

4- The acid content is lower (mostly <0.5)5- hard fat is a mixture of mono, di and tri-

glycerides of saturated fatty acids (C10 to C18). The hydroxyl value of a base is determined by the proportions of mono and di-glycerides contained in it.

A higher hydroxyl value indicates that the base can absorb water more readily and less suitable to easily hydrolyzed drugs.

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6- The solidification temperatures of hard fats are unaffected by over heating.

7- There is only a small temperature difference between melting and solidification, thus the sedimentation of suspended drugs is minimized.

8- Mold lubrication is unnecessary since these bases show marked contraction on cooling.

9- The water absorbing capacity of hard fats can be improved (to about 25% or 30% w/w) by inclusion of glyceryl monostearate.

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They are, however, more expensive. A tendency to fracture upon pouring into chilled

moulds can be overcome by including very small quantities of polysorbate 80.

On prolonged storage, synthetic suppository bases have been shown to be subjected to crystallization, which causes hardening and increases the melting time. This can be reduced by storage in a cold place.

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The hard-fat alternatives to theobroma oil are available in various grades with different melting ranges, hydroxyl values and other physicochemical characteristics.

Some of the bases are single entity formulations. Some of the names may denote a series of bases. In a series, the bases are varied to give a range of

melting points.

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For example, Fattibase® is a single entity base that consists of triglycerides from palm, palm kernel, and coconut oils.

Wecobee® is a series of bases. Wecobee FS, M, R, and S are all made from triglycerides of coconut oil. But FS has a melting point range of 39.4 to 40.5°C, M has a range of 33.3 to 36.0°C, R has a range of 33.9 to 35.0°C, and S has a range of 38.0 to 40.5°C.

Other triglyceride type bases include Dehydag®, Hydrokote®, Suppocire®, and Witepsol®, Massuppol.

Selection of a Suppository Base

• Narrow interval between melting range and solidification point.

• High melting ranges (37-41 0C) for incorporation of drugs that lower melting points of bases. Ex: Chloral Hydrate.

• Low melting ranges (30-34 0C) when the substances added or large amount of total solids increase the viscosity of the molded suppository.

• Low acid values (<3) and iodine values (<7) essential for long intended shelf-life.

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2. Water Soluble/Water Miscible Bases

• Water Soluble/Water Miscible Bases are those containing:

A. Glycerinated gelatinB. Polyethylene glycol

(PEG) polymers.

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A- Glycerinated Gelatin Glycerinated Gelatin is a useful suppository base,

particularly for vaginal suppositories, where the prolonged localized action is usually desired.

Glycerinated gelatin suppositories are translucent, resilient, gelatinous solids that tend to dissolve or disperse slowly in mucous secretions to provide prolonged release of active ingredients.

It is suitable for use with a wide range of medicaments including alkaloids, boric acid, and zinc oxide.

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Suppositories made with glycerinated gelatin must be kept in well-closed containers in a cool place since they will absorb and dissolve in atmospheric moisture.

Suppositories may have a dehydrating effect and be irritating to the tissues upon insertion. The water present in the formula of suppositories minimizes this action and the suppositories may be moistened with water prior to insertion to reduce the tendency of the base to draw water from mucous.

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In addition, those suppositories intended for extended shelf-life should have a preservative added, such as methylparaben or propylparaben, or a suitable combination of the two.

To facilitate administration, glycerinated gelatin suppositories should be dipped in water just before use.

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Preparation of glycerinated gelatin rectal suppositories

• Mix or dissolve the medicaments in water to make a total of 10 g.

• Add 70 g of glycerin and mix.• Add 20 g of granular gelatin, mix carefully to avoid

incorporation of air.• Heat on a steam bath until the gelatin is dissolved.• Pour the melted mixture into molds and allow to

congeal.

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Preparation of glycerinated gelatin urethral suppositories

• The gelatin constitutes about 60% of the weight of the formula, the glycerin about 20%, and the medicated aqueous portion about 20%.

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B- Polyethylene Glycol Polymers

Polyethylene Glycol Polymers have received much attention as suppository bases in recent years because they possess many desirable properties.

They are chemically stable, nonirritating, miscible with water and mucous secretions, and can be formulated, either by molding or compression, in a wide range of hardness and melting point.

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Like glycerinated gelatin, they do not melt at body temperature, but dissolve to provide a more prolonged release than theobroma oil.

Certain polyethylene glycol polymers may be used singly as suppository bases but, more commonly, formulas call for compounds of two or more molecular weights mixed in various proportions as needed to yield a finished product of satisfactory hardness and dissolution time.

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PEGs having average molecular weights of 200, 400 and 600 are clear, colorless liquids.

Those having molecular weights of greater than 1000 are wax-like, white solids with hardness increasing with an increase in the molecular weight.

Since the water miscible suppositories dissolve in body fluids and need not be formulated to melt at body temperature, they can be formulated with much higher melting points.

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This property permits a slower release of medicaments from the base, safe storage at room temperature without need for refrigeration, and ease and slow insertion.

To prevent irritation of the mucous membranes after insertion of PEGs suppositories, they should contain at least 20% of water or dipped in water just prior to use.

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Examples of various PEGs used in suppository bases

14508000

3008000

30%70%

60%40%

3006000

10003350

10003350

48%52%

95%5%

75%25%

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3. Miscellaneous Bases

• Chemical or physical Mixtures of oleaginous and water soluble or water miscible materials.

• Emulsions, generally of w/o type (i.e. mixing of cocoa butter with emulsifying agents).

• Polyoxyl 40 stearate is a mixture of the mono-stearate and di-stearate esters of mixed poly-oxyethylene diols and the free glycols.

• Soap may be used as a base (i.e. Glycerin suppositories, USP, with soap as the base).

Special Characteristics of Different Bases

Cocoa butter remains solid at room temperature but melts in the body.

Synthetic hard fat has good water absorbing capacity due to presence of w/o emulsifying agent .

Glycero-gelatin produce laxative effect.

Polyethylene glycols are present in different physical state. (solid, semisolid, liquid )

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2.Anti-oxidants

• They protect the drug and the base from getting degraded due to oxidation.

• Examples :i. Ethyl or propyl gallateii. Ascorbic acid and its estersiii. Hydroquinone iv. Tocopherols

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3.Emulsifying agents:

They increase the water-absorbing capacity of fatty bases. This makes it possible to include aqueous solutions in the formulation.

Examples : polysorbates (tween 61) Wool alcohol ,wool fat

4. Hardening agents: These are included in those formulations where the

melting point of the base is decreased by the drug (Volatile oil, phenol, chloral hydrate.)

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These agents bring the melting point to normal.Examples : macrogols with high molecular weight.

5.Preservatives : They should be included in suppositories which contain water soluble bases to prevent microbial growth.Examples :methyl paraben , propyl paraben

6.Thickening Agents: They increase the viscosity of molten base and prevent sedimentation of suspended insoluble solids.Examples: Aluminium monostearate ,collodial silica ,magnesium stearate.

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7.Plasticizers :

• They impart plasticity to the fatty base and makes it less brittle.

• Examples :

i. Castor oil

ii. Glycerine or propylene glycol

iii. Glycol

iv. Tween 80

v. Tween 85

Preparation of Suppository

Hand Rolling

Compression Molding

Pour/ Fussion Molding

Automatic Molding

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METHODS OF PREPARATION

• Suppositories can be extemporaneously prepared by one of three methods.

1. Hand Rolling • It is the oldest and simplest method of

suppository preparation and may be used when only a few suppositories are to be prepared in a cocoa butter base.

• It has the advantage of avoiding the necessity of heating the cocoa butter.

• A plastic-like mass is prepared by triturating grated cocoa butter and active ingredients in a mortar.

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Follow; 1. Hand Rolling

• The mass is formed into a ball in the palm of the hands, then rolled into a uniform cylinder with a large spatula or small flat board on a pill tile.

• The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape.

• Effective hand rolling requires considerable practice and skill. The suppository "pipe" or cylinder tends to crack or hollow in the center, especially when the mass is insufficiently kneaded and softened.

Hand Rolling

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1. MOLDING BY HAND

STEP 3

Trituration in pestle and

mortar

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MOLDING BY HAND

STEP 4

Mass

Rolled

Long rods

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1. MOLDING BY HAND

STEP 5

Rods

cut into pieces

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2. Compression Molding• Compression molding is a method of preparing

suppositories from a mixed mass of grated suppository base and medicaments which is forced into a special compression mold using suppository making machines.

• The suppository base and the other ingredients are combined by thorough mixing.

• The friction of the process causing the base to soften into a past-like consistency.

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2.COMPRESSION MOLDING

• The cold mass of the base containingthe drug is compressed into suppositories using a hand operated machine.

STEP 1

drug

fine powder

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COMPRESSION MOLDING

STEP 2

Drug (fine powder)

Base

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COMPRESSION MOLDING

STEP 3

Trituration in pestle and

mortar

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COMPRESSION MOLDING

STEP 4

Compress the mixture in the

compression mold

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• On a small scale, a mortar and pestle may be used (preheated mortar facilitate softening of the base).

• On large scale, mechanically operated kneading mixers and a warmed mixing vessel may be applied.

• In the compression machine, the suppository mass is placed into a cylinder which is then closed.

• Pressure is applied from one end to release the mass from the other end into the suppository mold or die.

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• When the die is filled with the mass, a movable end plate at the back of the die is removed and when additional pressure is applied to the mass in the cylinder, the formed suppositories are ejected.

• The end plate is returned, and the process is repeated until all of the suppository mass has been used.

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• The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories.

• When active ingredients are added, it is necessary to omit a portion of the suppository base, based on the density factors of the active ingredients.

Advantages: It is a simple method. It gives suppositories that are more elegant than hand

moulded suppositories. In this method sedimentation of solids in the base is

prevented.Suitable for heat labile medicaments.Disadvantages:Air entrapment may take place.This air may cause weight variation.The drug and/or the base may be oxidized by this

air.

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3. Fusion Molding• Fusion Molding involves:

1- Melting the suppository base2- Dispersing or dissolving the drug in the melted base. 3- The mixture is removed from the heat and poured into a suppository mold.4- Allowing the melt to congeal 5- Removing the formed suppositories from the mold.

• The fusion method can be used with all types of suppositories and must be used with most of them.

Fusion Molding

Using a supp. mould which is made of metal or plastic. Traditional metal moulds are in two halves which are clamped together with a screw.

Suppository molds

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Suppository molds

• Small scale molds are capable of producing 6 or 12 suppositories in a single operation.

• Industrial molds produce hundreds of suppositories from a single molding.

3.Automatic Molding Machine

The molding operations(pouring, cooling, and removal) can be performed by machine. All filling, ejecting, and mold-operations are fully automated. The output of a typical rotary machine ranges from 3500 to 6000 suppositories.

The machine usually made up of chrome-plated brass molds are installed radially in the cooling turn able.

3.Automatic Molding Machine

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Lubrication of the mold

• Depending on the formulation, suppository molds may require lubrication before the melt is poured to facilitate the clean and easy removal of the molded suppository.

• Lubrication is seldom necessary when the suppository base is contracting sufficiently on cooling.

• Lubrication is usually necessary when glycerinated gelatin suppositories are prepared.

Base•Theobroma oil•Glycerol-gelatin base

Lubricant

•Soap spirit•liquid paraffin

No lubricant required

•Synthetic fats•Macrogols

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Lubricants for use with Suppository bases

Problems in Formulation of Suppositories

• Water in suppositories.• Hygroscopicity.• Incompatibilities.• Viscosity.• Brittleness.• Density.• Volume correction.• Lubricants or mold release agents.• Dosage Replacement factor.• Weight and volume control.• Rancidity and antioxidants.• Packaging.

Water in suppositories• Water as a solvent to incorporate substances in suppositories

should be avoided for the following reasons:

• Water accelerates the oxidation of fat.• If water evaporates dissolved substances crystallize out.• Water in suppositories has little effect on drug absorption

unless in significantly higher quantity to dissolve the drug or present as O/W emulsion.

• More chances of a reaction between suppository ingredients compared to use of anhydrous ingredients.

• Incorporation of water or other possibly microbe contaminated substances necessitates the use of bacteriostatics such as parabens.

HygroscopicityGlycerinated Suppositories

• Loose moisture in dry climates and absorbs in high humid conditions.

Polyethylene Glycol Bases

• Rate of moisture change depends upon humidity and temperature.

• Molecular weight/Chain length increases, Hygroscopicity decreases ( significant drop in 4000 and 6000 series)

Incompatibilities

• Polyethylene glycol bases incompatible with silver salts, quinine, aspirin etc.

• Many chemicals crystallize out of PEG. Ex: salicylic acid, sodium barbital.

• Salicylic acid soften PEG to an ointment like consistency and aspirin complexes with it.

• Penicillin G stable in cocoa butter or other fatty bases decomposes in PEG.

• High hydroxyl value fatty bases may react with acidic ingredients.

Viscosity

• Glycero-gelatins and PEGs have more viscosity than Cocoa butter and some of its substitutes after melting.

• Low viscosity bases have problems like sedimentation of suspended particles, nonuniform distribution of active ingredients.

• For low viscosity bases:• Handling of well mixed molten mass at lowest possible

temperature in melting range to maintain fluidity but prevent segregation of particles.

• Constant stirring without entrapping air and quick solidification in the mold.

• Use of base with narrow melting range close to body temperature.• Use of viscosity enhancers like 2% aluminum monostearate.

Brittleness• Cocoa butter produces elastic suppositories that do not

fracture readily.• Synthetic fat bases for having high degree of hydrogenation

and high stearate content, have higher solid content in room temperature and thus brittle.

• Shock cooling also results brittle suppositories.

• Brittle suppositories are difficult in manufacturing, handling wrapping and in use.

• Prevention: 1. heating of mold close to melted base. 2. use of plasticizers like Tween 60, castor oil,

glycerin, Propylene Glycol etc

Density

• The volume of mold cavity is fixed.• The weight of individual suppository depends upon the

density of the mass and volume of given mold.• The amount of drug in each molded suppository should be

carefully maintained the same.• Compensate for volume contraction.• Determination of suppository weight empirically by small

batch runs when volume contraction occurs.

Calibration of the mold

• Each individual mold is capable of holding a specific volume of material in each of its openings.

• The pharmacist should calibrate each suppository mold for the usual base so as to prepare medicated suppositories each having the proper quantity of medicaments.

volume contraction• Occurs in case of many suppository bases: • This may cause1. Good mold release without the need of mold

release agents.2. Formation of contraction hole at the open end of

the mold. This can be avoided by compensation or overfilling and scrapping of the congealed excess base at the top.

Lubricants or Mold Release Agents

• Bases with low volume contraction like cocoa butter are difficult to remove .

• Need of lubricants like: mineral oil, aqueous solution of SLS, silicones, alcohols etc.

• Method of application of lubricants: wiping, brushing or spraying.

• Teflon coating of damaged mold cavities improves suppository release from them.

Dosage Replacement factor• Using cocoa butter as base.

• Determination of the dosage replacement factor methodf={100(E-G)/GX}+1where E=the weight of the pure base suppositoriesG=the weight of suppositories with X% of the active ingredient

• Example: Boric Acid 0.67. castor oil 1. ZnO 0.15-0.25. Camphor 1.49.

Weight and volume control

• The amount of active ingredients in each suppository depends upon

1. Concentration in the mass.2. Volume of mold cavity.3. Specific cavity of the base.4. Volume variation between mold due to manufacturing of

molds (within 2%).5. Weight variation between suppositories due to inconsistent

manufacturing i.e., incomplete closing of the mold and uneven scrapping etc.

6. Variation of suppository weight should be within 5%.

Rancidity and anti-oxidants• Auto-oxidation and subsequent decomposition of

unsaturated fats into low/medium molecular weight saturated and unsaturated aldehydes, ketones and acids.

• Lower the unsaturated fatty acid content, greater the resistance towards rancidity.

• Rancidity is measured by formation of hydroperoxides and presence of strong, unpleasant odour.

• Iodine test with KI measures peroxide oxygen. • Anti-oxidants used are: tocopherols, BHA, BHT,propyl

gallate and tannic acid etc.

Stability of Suppositories

• Storage stability studies are conducted at 40C and at room temperature (25±30C) for suppository base and the active ingredient(s).

• Stability of suppositories intended for tropics are tested in their final packages under tropical conditions

• Important stability related problems includes-1. Bloom.2. Hardening of fat base suppositories upon storage.3. Pinholes in suppository overwrap foil of an acid containing

suppository.4. Maintaining physicochemical properties during storage in tropical

temperature (500C).5. Shipment and handling related problems.

Labeling And Packaging

“Should be Stored in a Cool Place”

Special polyethylene shell packages are employed.

Glycerinated gelatin and PEG suppositories should be protected from heat moisture and dry air by packaging them in well sealed container an storing them at a cool temperature.

Refrigeration.Protection from light for photosensitive ingredients

TEST/EVALUATION OF SUPPOSITORIES.

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Testing of suppositoriesFinished suppositories are routinely

inspected for: Appearance.Content uniformityMelting range testDrug release testFragility testDisintegration test

a) Melting Range test :-

Macro melting range tes The micro melting range test .

The apparatus commonly used for measuring the melting range of the entire suppository is a USP Tablet Disintegration Apparatus.

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Macro Melting range test Macro-melting range is a measure of the

time it takes for the entire suppository to melt when immersed in a constant-temperature (37ºC) water bath.

USP tablet disintegration apparatus is used

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Micro Melting range test

In contrast the micro melting range test is the melting range measured in capillary tubes for the fat base only.

The apparatus commonly used for measuring the melting range of the entire suppository is a USP Tablet Disintegration Apparatus.

This test consists of a U-tube partially submersed in a constant- temperature water bath. A constriction on one side holds the suppository in place in the tube. A glass rod is placed on top of the suppository, and the time for the rod to pass through the constriction is recorded as the “softening time”.

b) Liquefaction or Softening time test:-

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To measure the fragility or brittleness of suppository

Double wall chamber in which the test suppository is placed.

Water at 37ºC is pumped through the double wall.

The suppository supports a disc to which rod is attached.

The other end of the rod consist of another disc to which weights are applied.

c) Breaking Test:-

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Follow; HardnessThe test was conducted by placing the

suppository to support the axis of 600 g weight.

At one minute intervals 200 gm weights are added.

The weight at which the suppository collapses is the breaking point

When the breaking point reached in the first 20 sec, the added weight was not calculated

When the breaking point reached in the second 20 sec, half the added weight was calculated

When the breaking point reached in the third 20 sec, all the added weight was calculated

Testing for the rate of in vitro release of drug substances from suppositories has always posed a difficult problem, owing to melting, deformation, and dispersion in the dissolution medium. Early testing was carried out by simple placement in a beaker containing a medium.

In an effort to control the variation in mass/ medium interface, various means have been employed including a wire mesh basket, or a membrane, to separate the sample chamber from the reservoir. Samples sealed in dialysis tubing or natural membrane have also been studied. Flow cell apparatus have been used, holding the sample in place with cotton, wire screening, and most recently with glass beads.

d) Dissolution Test:-

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In-vitro drug release In-vitro drug release pattern is measured

by using the same melting rang apparatus.

Aliquots of the release medium were taken at different time intervals within the melting period.

The drug content in the aliquots was determined.

The drug release pattern was plotted (time versus-drug release curve)

Is the medication intended for local or systemic use.

Is the site of application rectal, vaginal or urethral.

Is the desired effect to be quick or slow and prolonged.

Formulation Considerations

Packaging and storage

In-Package Molding: Thermoformed Molds. Foil/Polypropylene/Lacquer laminated emboss two parallel strips. If the mass should melt at high storage temperature, ,old still retained the its proper shape upon cooling. Disadvantages: Shape of the formed mold and seal completeness.

Packaging and storage

Glycerin suppositories and glycerinated gelatin suppositories are packaged in tightly closed glass containers to prevent a moisture change in the content of the suppositories.

Suppositories prepared from a cocoa butter base are usually individually wrapped or otherwise separated in compartmentalized boxes to prevent contact and adhesion.

Suppositories containing light-sensitive drugs are individually wrapped in an opaque material such as metallic foil.

Suppositories are also commonly packaged in slide boxes or in plastic boxes.

It is necessary to maintain suppositories in a cool place.

Suppositories having cocoa butter as the base must be stored below 30-C, and preferably in a refrigerator (2-8-C).

Glycerinated gelatin suppositories are best stored at temperatures below 8-C and can routinely be stored at controlled room temperature (20-25-C).

Suppositories made from a base of polyethylene glycol may be stored at usual room temperature without the requirement of refrigeration.

Density (Dose Replacement)

Calculations for Suppositories

Dosage Factor Method.

Determination of Density Factor Method.

Determination of Occupied Volume Method.

Density calculations for suppositories

Determination of the dosage replacement factor methodf={100(E-G)/GX}+1where E=the weight of the pure base suppositoriesG=the weight of suppositories with X% of the active ingredient

Example 1Prepare a suppository containing 100 mg of phenobarbital (f=0.81) using cocoa butter as the base. The weight of the pure cocoa butter suppository is 2.0 g. What will be the total weight of each suppository?

Determination of density factor method

1) Determine the average blank weight, A, per mold using the suppository base of interest

2) Weigh the quantity of suppository base necessay for 10 suppositories.

3) Weigh 1.0 g of medication4) Melt the suppository base and

incorporate the medication, mix, pour into molds, cool, trim, and remove from the molds

5) Weigh the 10 suppositories and determine the average weight (C).

6） determine the density factor as followsDensity factor = B/(A-C+B)

where A=average weight of blankB=weight of medication per suppositoryC=average weight of medicated suppository

7) Take the weight of the medication required for each suppository and divide by the density factor of the medication to find the replacement value of the suppository base

8) Subtract this quantity from the blank suppository weight

9) Multiply by the number of suppositories required to obtain the quantity of suppository base required for the prescription.

10) Multiply the weight of drug per suppository by the number of suppositories required to obtain the quantity of active drug required for the prescription.

Example 2Prepare 12 acetaminophen 300 mg suppositories using cocoa butter, where the average weight of the cocoa butter blank is 2 g and the average weight of the medicated suppository is 1.8 g.

Determination of occupied volume method

1) Determine the average weight per mold (blank) using the suppository base of interest

2) Weigh the quantity of suppository base necessary for 10 suppositories

3) Divide the density of the active drug by the density of the suppository base to obtain a ratio

4) Divide the total weight of active drug required for the total number of suppositories by the ratio obtained in step 3 (this will give the amount of suppository base displaced by the active drug).

5) Substract the amount obtained in step 4 from the total weight of the prescription to obtain the weight of suppository base required

6) Multiply the weight of active drug per suppository times the number of suppositories to be prepared to obtain the quantity of active drug required

Example 3Prepare 10 suppositories, each containing 200 mg of a drug with a density of 3.0. The suppository base has a density of 0.9 and a prepared blank weighs 2.0 g. Using the “determination of occupied volume method,” prepare the required suppositories.

Suppositories

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