SUPPOSITORIES AND PESSARIES Department of pharmaceutics CHALAPATHI INSTITUTE

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SUPPOSITORIES AND PESSARIES Department of pharmaceutics CHALAPATHI INSTITUTE OF PHARMACEUTICAL SCIENCES

SUPPOSITORIES AND PESSARIES Department of pharmaceutics CHALAPATHI INSTITUTE OF PHARMACEUTICAL SCIENCES

CONTENTS Ø Introduction Ø Classification of suppositories Ø Advantages & disadvantages Ø Ideal properties

CONTENTS Ø Introduction Ø Classification of suppositories Ø Advantages & disadvantages Ø Ideal properties of suppositories Ø Formulation of suppositories Ø Preparation of suppositories Ø Evaluation & packing of suppositories 2

Introduction • Suppositories are the solid dosage forms meant to be inserted into the

Introduction • Suppositories are the solid dosage forms meant to be inserted into the body cavities like rectum , urethra and vagina , where they melt or soften to release the drugs and exert local or systemic effects. 3

Anatomy and Physiology of Rectum • The rectum is about 15 to 20 cm

Anatomy and Physiology of Rectum • The rectum is about 15 to 20 cm long. • It hooks up with the sigmoid colon to the north and with the anal canal to the south. • It is a hollow organ with a relatively flat wall surface, without villi and with only three major folds, the rectal valves 4

Anatomy and Physiology of Rectum • The terminal 2 to 3 cm of the

Anatomy and Physiology of Rectum • The terminal 2 to 3 cm of the rectum is called the anal canal. • The opening of the anal canal to the exterior is called the anus. • The anus is controlled by an internal sphincter of smooth muscle and an external sphincter of skeletal muscle. 5

Anatomy and Physiology of Rectum • Under normal conditions, the rectum is empty and

Anatomy and Physiology of Rectum • Under normal conditions, the rectum is empty and filling provokes a defecation reflex which under voluntary control. • The transverse folds in rectum keep stool in place until the person is ready to go to the bathroom. Then, stool enters the lower rectum, moves into the anal canal, and then passes through the anus on its way out. • Rectum contains about 2 to 3 ml of mucous, which has a p. H of 7. 4 and little buffering capacity. 6

Absorption of drugs from the rectum • Medicaments absorbed in the lower part of

Absorption of drugs from the rectum • Medicaments absorbed in the lower part of the rectum are delivered directly into the systemic circulation, thus avoiding any first-pass metabolism. • However, it has been found that suppositories can settle high enough in the rectum to allow at least some drug absorption into the superior vein. • Thus keeping the drug in the lower part of the rectum would be advisable. 7

Absorption of drugs from the rectum • Insertion of a suppository into the rectum

Absorption of drugs from the rectum • Insertion of a suppository into the rectum results in a chain of effects leading to the bioavailability of the drug. • Depending on the character of the base, a suppository will either dissolve in the rectal fluid or melt on the mucous layer. • Since the volume of rectal fluid is so small, complete dissolution of the base require extra water. 8

Absorption of drugs from the rectum • Due to osmotic effects of the dissolved

Absorption of drugs from the rectum • Due to osmotic effects of the dissolved base, water is attracted with a painful sensation for the patient. • Independent on the base type, dissolved drugs in the suppository will diffuse out towards the rectal membrane. • The process of absorption will be passive diffusion. 9

Classification Of Suppositories • • • Rectal suppositories Vaginal suppositories ( PESSARIES ) Urethral

Classification Of Suppositories • • • Rectal suppositories Vaginal suppositories ( PESSARIES ) Urethral suppositories ( BOUGIES ) Nasal suppositories Ear suppositories 10

VAGINAL SUPPOSITORY • • They are also called as PESSARIES. SHAPE : globular, oviform

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 11

URETHRAL SUPPOSITORY • Also called as BOUGIES. • SHAPE – slender, pencil-shaped. • Intended

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. 12

RECTAL SUPPOSITORY • Intended for local action to relieve constipation, irritation, itching and inflammatory

RECTAL SUPPOSITORY • Intended for local action to relieve constipation, irritation, itching and inflammatory associated to hemorrhoids 13

Classification Of Suppositories Via Position Of Action LOCAL EFFECT : • In case of

Classification Of Suppositories Via Position Of Action LOCAL EFFECT : • In case of pain, itching and hemorrhoid. • Locally active drugs include astringents, antiseptics, local anesthetics, vasoconstrictors, anti-inflammatory, soothing and protective agents and some laxatives. SYSTEMIC EFFECT : • Anti-asthmatics, anti rheumatics, anti-pyretic and analgesics 14

ADVANTAGES • EASILY ADMINSTERED to children, old persons, to unconscious or sometimes to mentally

ADVANTAGES • EASILY 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 15

DISADVANTAGES • They are not acceptable by the patients. • The manufacturing process is

DISADVANTAGES • They are not acceptable by the patients. • The manufacturing process is difficult. • The drugs which cause irritation to the mucous membrane cannot be administered as suppositories. • Most of the suppositories should be stored at low temperature 10 -20°c in a refrigerator , other wise the base gets liquified. 16

IDEAL PROPERTIES OF SUPPOSITORY BASES • It should melt at body temperature or dissolve

IDEAL PROPERTIES OF SUPPOSITORY BASES • It should melt at body temperature or dissolve or disperse in body fluids. • It should release any medicament easily. • It should keep its shape when being handled. • It should be non-toxic and non-irritant to the mucous membrane. • It should be stable on storage and also stable if heated above its M. P. 17

IDEAL PROPERTIES OF SUPPOSITORY BASES • It should be easily molded and should not

IDEAL PROPERTIES OF SUPPOSITORY BASES • It should be easily molded and should not adhere to the mold. • It should possess good wetting and emulsifying properties. • It should be able to incorporate a high percentage of water. • It should be chemically and physically stable 18

IDEAL PROPERTIES OF SUPPOSITORY BASES • • If the base is fatty, it has

IDEAL PROPERTIES OF SUPPOSITORY BASES • • 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.

Specifications of suppository bases 1 - Origin and chemical composition v. The source of

Specifications of suppository bases 1 - Origin and chemical composition v. The source of origin (i. e. entirely natural or synthetic or modified natural). v. Physical and chemical incompatibilities with additives (i. e. preservatives, antioxidants and emulsifiers) 20

Specifications of suppository bases 2 - Melting range v. Since fats do not have

Specifications of suppository bases 2 - Melting range v. Since fats 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. 21

Specifications of suppository bases 3 - Solidification point v. This value indicates the time

Specifications of suppository bases 3 - Solidification point v. This value indicates the time required for base solidification when it is chilled in the mold. v. If the interval between the melting range and solidification point is 10ºC or more, the time required for solidification may have to be shortened for a more efficient manufacturing procedure by augmenting refrigeration. 22

Specifications of suppository bases 4 - Saponification value v. The number of milligrams of

Specifications of suppository bases 4 - Saponification value v. The number of milligrams of potassium hydroxide required to neutralize the free acids and to saponify the esters contained in 1 gm of fat is an indication of the type of glyceride (mono- or tri-) as well as the amount of glyceride present. 23

Specifications of suppository bases 5 - Iodine value v. This value express the number

Specifications of suppository bases 5 - Iodine value v. This value express the number of grams of iodine that react with 100 gm of fat or other unsaturated material. v. The possibility of decomposition by moisture, acids, and oxygen (leads to rancidity in fats) increases with high iodine values. 24

Specifications of suppository bases 6 - Water number v. The amount of water in

Specifications of suppository bases 6 - Water number v. The amount of water in grams, which can be incorporated in 100 gm of fat is expressed by this value. v. The water number can be increased by addition of surface active agents. 25

Specifications of suppository bases 7 - Acid value v The number of milligrams of

Specifications of suppository bases 7 - Acid value v The number of milligrams of potassium hydroxide required to neutralize the free acid in 1 gm of substance is expressed by this value. v Low acid values or complete absence of acid are important for good suppository bases. v Free acids complicate formulation work, because they react with other ingredients and can also cause irritation when in contact with mucous membranes. 26

Formulation of suppositories 1. 2. 3. 4. 5. 6. 7. Bases Anti- oxidants Emulsifying

Formulation of suppositories 1. 2. 3. 4. 5. 6. 7. Bases Anti- oxidants Emulsifying agents Hardening agents Preservatives Thickening agents Plasticizers 27

SUPPOSITORY BASES 1. Bases : They are of two types a. Hydrophilic bases i.

SUPPOSITORY BASES 1. Bases : They are of two types a. Hydrophilic bases i. water-dispersible bases: Ø properties: These are mixtures of non-ionic surfactants which are chemically related to polyethylene glycols. Ø These are used alone or in combination with other types of bases Ø Cellulose derivatives like methylcellulose sodium carboxy methylcellulose also come under this class. Eg; polyoxyethylene sorbitan fatty acid (tween) 28

ii)Water soluble bases: 1. Glycero-gelatin Ø This occurs as a gel. It is a

ii)Water soluble bases: 1. Glycero-gelatin Ø This occurs as a gel. It is a mixture of gelatin, glycerol and water. Ø According to B. P the composition of the base is gelatin-14%w/w , glycerol-70%w/w Ø To get a stiff mass, the quantity of gelatin should be increased to 32%w/w and that of glycerol reduced to 40%w/w. 29

b) Lipophilic bases 1. Coca butter: Ø Properties: It is a natural triglyceride Ø

b) Lipophilic bases 1. Coca butter: Ø Properties: It is a natural triglyceride Ø It can exist in more than one crystalline form i. e. , it exhibits polymorphism Ø It consists of mixture of oleic acid , palmitic acid , stearic acid. 30

Anti-oxidants • They protect the drug and the base from getting degraded due to

Anti-oxidants • They protect the drug and the base from getting degraded due to oxidation. • Examples : i. Ethyl or propyl gallate ii. Ascorbic acid and its esters iii. Hydroquinone iv. Tocopherols 31

Emulsifying agents: § They increase the water-absorbing capacity of fatty bases. This makes it

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 Hardening agents: Ø These are included in those formulations where the melting point of the base is decreased by the drug. 32

ØThese agents bring the melting point to normal. ØExamples : macrogols with high molecular

ØThese agents bring the melting point to normal. ØExamples : macrogols with high molecular weight. Preservatives : They should be included in suppositories which contain water soluble bases to prevent microbial growth. ØExamples : methyl paraben , propyl paraben Thickening Agents: They increase the viscosity of molten base and prevent sedimentation of suspended insoluble solids. ØExamples: Aluminium monostearate , collodial silica , magnesium stearate. 33

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

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 34

Preparation of suppositories

Preparation of suppositories

PREPARATION METHODS • Suppositories are prepared by four methods: - 1. 2. 3. 4.

PREPARATION METHODS • Suppositories are prepared by four methods: - 1. 2. 3. 4. HAND MOLDING METHOD COMPRESSION MOLDING METHOD POUR MOLDING METHOD AUTOMATIC MOLDING METHOD.

HAND MOLD SUPPOSITORIES Mix measured quantity of medicinal substances with sufficient theobroma oil Triturate

HAND MOLD SUPPOSITORIES Mix measured quantity of medicinal substances with sufficient theobroma oil Triturate soften with diluted alcohol and rub until smooth paste is formed Add remaining qty of theobroma oil and add wool fat for consistency Remove the mass from the mortar and pestle Transfer to a piece of filter paper and keep in hands during the kneading and rolling procedure Roll the mass by quick rotating movements of the hands and place on a pill tile Rolling the mass on the tile with a flat board forms a cylindrical suppository Cut into pieces by spatula Give the shape by rolling one end on the tile with spatula Pack in butter paper or in a proper container and store in a cool place

HAND MOLD SUPPOSITORIES v Advantages: Ø Suitable for thermo labile ingredients. Ø Economical for

HAND MOLD SUPPOSITORIES v Advantages: Ø Suitable for thermo labile ingredients. Ø Economical for the manufacture of small number of suppositories. v Disadvantages: Ø No uniformity in shape & size of suppository.

COMPRESSION MOLD SUPPOSITORIES [ COLD COMPRESSION] Mix theobroma oil and drug Mixture is forced

COMPRESSION MOLD SUPPOSITORIES [ COLD COMPRESSION] Mix theobroma oil and drug Mixture is forced into a mold under pressure , using a wheel operated press Mold is removed , opened , replaced On large scale , cold compression machines are hydraulically operated by water – jacketed cooling and screw fed

COMPRESSION MOLD SUPPOSITORIES [ COLD COMPRESSION] v. Advantages: ØSuitable for thermo labile drugs. ØNo

COMPRESSION MOLD SUPPOSITORIES [ COLD COMPRESSION] v. Advantages: ØSuitable for thermo labile drugs. ØNo possibility of settling of the insoluble solids in base. v. Disadvantages: ØRate of production is low so not suitable for large scale. ØAir get entrapped in the mass which leads to oxidation of ingredients.

FUSION OR MELT OR POUR MOLD SUPPOSITORIES Drug is dispersed or dissolved in a

FUSION OR MELT OR POUR MOLD SUPPOSITORIES Drug is dispersed or dissolved in a melted suppository base Pour the mixture into a suppository molds and allow cooling in ice bath Finished suppositories are removed by opening the mold Various types and sizes of molds are available for preparation of suppositories. Molds are made of aluminium alloys , brass or plastic and are available in 6 to several hundred cavities

FUSION OR MELT OR POUR MOLD SUPPOSITORIES v Incorporation of drug: Ø Solid: -drug

FUSION OR MELT OR POUR MOLD SUPPOSITORIES v Incorporation of drug: Ø Solid: -drug and additive powder mixed on warm tile Ø Semisolid: -triturate the ingredients on warm tile with water. this decrease the viscosity and give homogenous liquid. Ø Liquid: § § Volatile liquid: -they can be added to the molten base directly. Nonvolatile liquid: - same as semisolid.

AUTOMATIC MOLD MACHINE • All filling , ejection and mold cleaning operations are fully

AUTOMATIC MOLD MACHINE • All filling , ejection and mold cleaning operations are fully automatic • Output – 3500 to 6000 suppositories per hour • Suppository mold is lubricated with brushing or spraying and then filled to a slight excess • Excess material is removed after the mass gets solidified and collected for re – use

PACK AND LABEL Packing of suppositories: - ØIt can be foiled in aluminum ,

PACK AND LABEL Packing of suppositories: - ØIt can be foiled in aluminum , plastic, paper, tin strip. ØModern packing machine: nearly 8000 suppositories can be wrapped per hour. ØIn packing molding : In this , the suppository mass is directly move into the series of molds which are made up of plastic. After cooling , excess mass is trimmed of. By this technique 12, 000 to 15, 000 suppositories can be produce per hour. ØDisposable molds: - They are suitable for tropical climate. They are made up of plastic or aluminum. Labeling: - “store in a cool place. ” “Not to be taken orally. ”

DISPLACEMENT VALUE Ø The volume of suppository from particular mold is uniform but its

DISPLACEMENT VALUE Ø The volume of suppository from particular mold is uniform but its weight will vary because the density of medicament usually differ from the density of base. Ø To prepare product accurately , allowance must be made for the change in density of mass due to added medicament Ø The most convenient way of making this allowance is to use the displacement value-“ THE NUMBER OF PART BY THE WEIGHT OF MEDICAMENT THAT DISPLACE THE ONE PART BY WEIGHT OF BASE”

Recent development(new trend in suppository) ØCapsule suppositories ØCoated suppositories ØLayer suppositories ØTablet suppositories; §

Recent development(new trend in suppository) ØCapsule suppositories ØCoated suppositories ØLayer suppositories ØTablet suppositories; § Compressed tablet § Effervescent base tablet

EVALUATION OF SUPPOSITORIES ØAppearance ØUniformity of weight ØDisintegration ØTest for uniformity of drug content

EVALUATION OF SUPPOSITORIES ØAppearance ØUniformity of weight ØDisintegration ØTest for uniformity of drug content ØBreaking test ØSoftening time ØTest of melting rang Ø Test for Dissolution rate

APPEARANCE • • • Odor Color Surface condition Shape They may contain several layers

APPEARANCE • • • Odor Color Surface condition Shape They may contain several layers Instabilities are identified based on changes in surface texture , color, odor

WEIGHT VARIATION • • Weigh individually 20 suppositories Weigh 20 at a time Calculate

WEIGHT VARIATION • • Weigh individually 20 suppositories Weigh 20 at a time Calculate average weight Limit: not more than 2 suppository differ from the average weight by more than 5% and no suppository differs from average weight by more than 10%

HARDNESS or BREAKING TEST 1. PLACE THE SUPPOSITORY IN THE INSTRUMENT 2. ADD 600

HARDNESS or BREAKING TEST 1. PLACE THE SUPPOSITORY IN THE INSTRUMENT 2. ADD 600 g, leave it for 1 min 3. If not broken add 200 gm every 1 minute untill suppository is broken

MELTING RANGE TEST • Macro-melting range is a measure of the time it takes

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 • THE SUPPOSITORY IS CONSIDERED DISINTERGRATED if: • It is completely dissolved • Become soft “change in shape” with formation of core which is not resistant to pressure with glass rod

Disintegration • For each 3 suppositories examine the state of the sample 1. After

Disintegration • For each 3 suppositories examine the state of the sample 1. After 30 minutes – fat-based suppository 2. After 60 min – water –based suppository

Uniformity of mass • Not more than 2 of the individual masses should deviate

Uniformity of mass • Not more than 2 of the individual masses should deviate from the average mass by more than 5 % , and none by more than 10%

Softening time test • u tube is partially immersed in a constant bath and

Softening time test • u tube is partially immersed in a constant bath and is maintained at a temperature between 35 to 37 c • There is a constriction in the tube in which the suppository is kept and above is a glass rod is kept • Time taken for a glass rod to go through the suppository and reach the constriction is known as liquefaction time or softening time

Dissolution test • Wire mesh basket or dialysis tubing is used for invitro release

Dissolution test • Wire mesh basket or dialysis tubing is used for invitro release from suppositories

Stability testing • Cocoa butter suppositories on storage , BLOOM i. e they form

Stability testing • Cocoa butter suppositories on storage , BLOOM i. e they form a white powdery deposit on the surface • This can be avoided by storing them at uniform cool temperatures and by wrapping them in foils • Fat based suppositories harden on storage [ shift in melting range to become more stable polymorphic form of base ] • Softening time test and DC can be used to test stability