Suppositories 1

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SUPPOSITORIES


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Dose character:

For rectal administration, one half to two or moretimes than the oral dose is given.

- The correct dose of any drug depends on therate of release from the suppository

- Since the vehicle can change the rate of drugabsorption , the amount of drug to be given insuppository dose depend on the vehicle, thechemical and physical from the drug.


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Types:

1- Rectal suppository: 32 mm in length, cylindrical, haveone or both end tapered.

a) Adult rectal supp. Weight 2gm

b) infant rectal supp.1gm

2- Vaginal suppository: pessaries, 5gm, usually oviformor cone shaped, weight from 3-5 gm

3- Urethral suppository: bougies 4gm and 10-15 cm longfor male and 6-7.5cm long for female. , pencil shaped.


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Therapeutic uses

Suppository can be used for local or systemic effect.

The action depends on nature of drug , concentrationand rate of absorption

Rectal suppository are intended for treatment ofconstipation and hemorrhoids.

Suppositories are also administered for systemic action(analgesics, antispasmodics, sedatives & tranquilizers).


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Factor affecting drug absorption form

rectal suppository:

1) Physiologic Factor:

The human rectum is approximately

15-20 cm in the length, when empty

of fecal material; it contains 2-3 ml of inert mucous

fluid. In resting state, the rectum is non motile.

There is no villa or microvillus on rectal mucosa.

Physiological factors include:
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A) Colonic Content:

When systemic effect are desired fromsuppository greater absorption may beexpected from a rectum that is voidthan

that with fecal matter. An evacuationenema maybe administered beforeinsertion of a suppository.

Diarrhea, colonic obstruction and tissuedehydration influence the rate & degreeofdrug absorption from rectum.


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B) Circulation:

Drugs absorbed rectally partially by pass portalcirculation, thereby enabling drug destroyed inliver to exert systemic effect. Depending on theheight at which absorption occurs at rectum, the

drug passes into inferior, middle or superiorhemorrhoid veins. The inferior is nearest to theanus, the upper hemorrhoid vein > portalcirculation .thus it is advisable to keep supp inthe lower part of rectum. 50% -70% of drugadministered rectally, reported to go directly intogeneral circulation.


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2) Physiochemical characteristics ofthe drug:

A) Lipid water solubility of a drug (partitioncoefficient):

- The lipid water partition coefficient of a drug is

important in selecting the suppository base andin anticipating drug release from that base

- lipophilic drug, in other word, distributed in afatty suppository base has fewer tendencies toescape to the surrounding queues fluids

- .


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B) Degree of ionization:

The barrier separating colon lumen from theblood is preferentially permeable to theunionized forms of drugs, thus absorptionof drug would be enhanced by increasethe proportion of unionized drugs


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C) Concentration of a drug in a base:- The more drugs in a base, the more drug will be

available for absorption.

- If the concentration of the drug in the intestinallumen is above a particular amount, the rate ofabsorption is not change by further increase inconcentration of drug.

- In general, the rate limiting step in drugabsorption from suppository is the partitioning ofthe dissolved drug from the melted base and notthe rate of solution of drug in the body fluid.

-


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- Scientists showed that: the rate, at which thedrug diffuses to the surface of the suppository,

Particle size, and presence of surface-activeagents are factors that affect drug release fromsuppositories.


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3) Physiochemical Characteristics ofthe Base and Adjuvant:

1)- Nature of the Base:

- Suppository base capable of melting,softening or dissolving to release the drugfor absorption.

- If the base irritating the colon, it willpromote colonic response, lead toincrease bowl movement and decreaseabsorption.


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2) Presence of Adjuvant in Base :

Adjuvant in a formula may affect drugabsorption, change the rheologicalproperties of the base at bodytemperature, or affected the dissolution ofthe drug.


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Specifications for SuppositoryBases :

1- Origin & Chemical Composition:

A brief description of the composition of thebase reveals the sours of the origin

(natural or synthetic or modified naturalproducts). Physical or chemical in-compatibilities with other constituents maybe predicted if the exact formulacomposition is known includingpreservatives, antioxidants and emulsifiers


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2- Melting Range :

Suppository bases don't have a sharp meltingpoint, their melting characteristics are expressed

as ranges, indicating the temperature at whichthe fats start to melt and the temperature atwhich completely melted. Melting range isusually determination by " Wiley melting point",

"Capillary melting point", " Incipient melting (orthaw)point".


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3- Solid-Fat Index (SFI):One can determine the solidification and

melting ranges of fatty bases as well as

the molding character, surface feel andhardness of the bases. A base with sharpdrop in solids over a short temperature

span proves brittle if molded too quickly.


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The solid content at room temperaturecould determine suppository hardness.Since skin temperature is about 32 C,

one can predict that would be dry to touchfrom a solid content over 30% at thattemperature.


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4- Solidification Point:

This test allow to determine the time required for

solidifying the base, when it is chilled in the moldif the interval between the melting point andsolidifying point is 10 C or more, time requiredfor solidification may have to be shortened foramore efficient manufacturing procedure byrefrigeration, if melting point 33 C andsolidifying point 20 C then it will be liquid for 13

C, then the drug will sediment and the apex ofthe suppository will contain all the drug.


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5- Hydroxyl Value:

"It is the number of milligrams.of KOH (Potassium

hydroxide) that would neutralize the acetic acidused to acetylate 1g of fat. It reflects the mono-and di-glyceride content of a fatty base.

6- Saponification Value:The number of milligrams of KOH (Potassium

hydroxide) required to neutralize the free fattyacids and saponify the ester contained in 1 g of

a fat. From saponification value we can knowthe type of glyceride present (mono-, di- or tri-)and also amount present.


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7- Iodine Value:It is the number of grams of Iodine that reacts with l00 g of fat or other

unsaturated material.The possibility of decomposition by moisture, acids, oxygen (which

leads to rancidity of fats) increases with higher iodine value.

8- Water Number:It is the amount of water in grams that can be incorporated in l00g of

fat. The "water number" can be increased by the addition of surface-active agents.

9- Acid Value:It is the number of milligrams of KOH (Potassium hydroxide) required

neutralizing the free fatty acids in I g substance (fat). Low acid valueor absence of acid value is important for good suppository bases.


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Properties of an Ideal SuppositoryBase:

The ideal suppository base may be described as follows :

1- Melts at rectal temperature 36 C, or dissolve in rectalfluid

2- Completely non toxic, and non irritating to sensitive and

inflamed tissues.3- Compatible with a broad variety of drugs.

4-No metastable forms.

5- Shrinks sufficiently on cooling to be released form the

mold without the need for mold lubricants.6- Non- sensitizing


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7- Has a melting and emulsifying property.

8- Water number is high (a high percentage of

water can incorporated in it)9- It is stable on storage, dose not change odor,

color, release pattern.

10- Can be manufactured by molding either by

hand, compression, machine .11- Acid value is below 0.2, saponification value

ranges from 200 to 245, and Iodine value is lessthan 7.

12- SFI curve is sharp, in other word, the intervalbetween melting point and solidification point issmall


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Type of Suppository Bases:

A- Fatty Bases.

B- Hydrophilic Suppository Bases

C-water dispersible Bases


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A- Fatty Bases:

Cacao Butter (theobroma oil)

It is the most widely used suppository base. It satisfy manyrequirement for ideal suppository base :

1) Bland. 2) Non reactive. 3) Melt at body

temperature.- Cacao Butter is a triglyceride, yellowish white, solid, brittle

fat, smells and taste like chocolate. Its melting pointbetween 30-35C, it iodine value is between 34-38 andits acid value is no higher than 4, because cacao buttercan melt and rancid. So it must be stored in cool dryplace protected from light.


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Cacao butter exhibited polymorphism (existin different crystalline forms). Cacao butteris thought to exist in 4 crystalline states:

1) - crystal

melt at 22oC

unstable

2) - crystal melt at 18oC unstable

3) - crystal melt at 27oC unstable

4) stable crystal melt at 34-36oC stable


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Various forms of cacao butter depend on:

1- Degree of heating.2- Cooling process.

3- Conditions during this process.

The re-conversion to the stable B- formtakes form one to four days depending onthe storage temperature, the higher thetemperature the faster the change.


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Disadvantages of Cacao Butter

1- Rancidity and slow deterioration during storage.2- Melt in warm weather.3- Liquefy when incorporated with certain drug such as:

volatile oils, creosote, phenol and chloral hydrate.

4- Over heating lead to isomerizes to metastable form. Sothis will decrease melting point.5- Low contractility during solidification, suppository will

adhere to the mold and will be necessitates uses oflubricant.

6- Quality of cacao butter varies with origin and treatment.7- Water number is low (20-30), this could be improved byaddition of 5-10%tween61.

8- Leakage from the body.


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Advantages of Cacao Butter:

1- Non reactive.

2- Melt at body temp.

3- Solidification point lies 12-13 C belowmelting point, during formulation the masscan be stirring and maintain cacao butterliquid below its solidification point.

4- Emulsion can be added in Conc 5-10 %to keep insoluble drug suspended.


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5-Increase conc. of water soluble drugs, leadto decrease melting point until eutectic

point is obtained6- Melted cocoa butter is viscous (semisolid)

which help in corporation of drug. The

difference in melting point &solidificationpoint is large to give chance forincorporation with drugs.


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B- Hydrophilic Suppository Bases:

1-Glycerine Suppositories:Glycerine 91 gSod. Stearate 4gPurified water 5gTo make approximately l00g

2- Glycerated gelatin suppositories:Drug & purified water 10gGelatin 20gGlycerin 70g

- Because glycerin is hygroscopic, there suppositories are packed inmaterials that protect them from environmental moisture.- This base do not melt at body temp., but dissolve in the secretions of

the body cavity in which they are inserted.


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3-Polyethylen glycol (PEG):

Marketed as carbowax or polyethylenglycol, exist as liquidor wax like solid depending on molecular weight. Theirwater soluble, hygroscopic and vapor pressure decrease

with increasing average molecular weights. The widerange of melting point and solubility makes possible theformulation of suppository with various degrees of heatstability and with different dissolution rates. They do nothydrolyze or deteriorate, are physiologically inert and do

not support mold growth. Base usually dipped in waterbefore insertion, so that possible irritation maybeeliminated


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3-WATER - DISPERSIBLE BASE

Several non-ionic surface active materials, closely related chemically toPEG as suppository bases. The bases can be used for formulationboth water-soluble and oil-soluble drugs (e.g.; Tween & Span).These surface active agents may be used alone, blended or used incombination with other suppository vehicle. Another type of waterdispersible suppository vehicle is based on the use of water soluble

cellulose derivatives (e.g. methylcellulose & sodiumcarboxymethylcellulose ).

Advantages of Water Dispersible Bases:1. Stable on storage at elevated temperature.2. Compatible with many drugs.

3. Non support of microbial growth, non toxic and non sensitive.


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Method Of Manufacture Of

Suppositories:

1- Hand Molding:

It is the oldest and simplest method, by rolling thesuppository into the desired shape. The mass is thenrolled into a cylindrical rod of desire length and diameter.

2- Compression Molding:

Elegant suppository can be made b compression the cold-grated mass into the desired shape .

It is simple and more elegant appearance than handmolding.

It avoids the possibility of sedimentation of the insolublesolids in the suppository base.


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3- Pour Molding:

Most commonly used method for production of

suppository on both small & large scale.First, the base is melted on water bath, and then

the drugs are either emulsified or suspended init. Then, the mass is pour into cooled metal

molds, which are usually chrome or nickelplated.

4- Automatic Molding Machine:

The molding operation (pouring, cooling &removal) can be performed by machine .

The output of a typical rotary machine, range from3500 to 6000 suppositories per hour.


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SPECIFIC PROBLEMS IN FORMULATINGSUPPOSITORIES :

1- Water in suppositories:Use of water as a solvent for drug should be avoided for the

followingReasons:a- Water accelerates oxidation of fats.

b- If water evaporates, the dissolved substance crystallizes out.c- Unless H2O is present at level than that requires for dissolving the

drug, the water has little value in facilitating drug absorption.Absorption from water containing suppository enhance only if an oilin water emulsion exist with more than 50% of the water in theexternal phase .

d- Reaction between ingredients (in suppository) are more likely tooccur in the presence of water.e- The incorporation of water or other substances that might be

contaminate with bacteria or fungi necessitates the addition ofbacteriostatic agents (as parabens)


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2- Hygroscopicity:

a- Glycerinated gelatin suppositories lostmoisture by evaporation in dry climatesand absorbed moisture under conditions ofhigh humidity

b- PEG bases are also hygroscopic.


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3- Incompatibilities:a- PEG bases are incompatible with silver salt,

tannic acid, aminopyrine , quinine , icthammol,asprine , benzoc.aine & sulphonamides .

b- Many chemicals have a tendency to crystallizeout of PEG, e.g.: sodium sarbital, salicylic acid &camphor.

c- Higher concentration of salicylic acid softensPEG to an ointment-like consistency, d- Aspirincomplexes with PEG.

e- Penicillin G , although stable in cocoa butter and

other fatty bases , was found to decompose inPEG bases .f- Fatty bases with significant hydroxyl values may

react with acidic ingredients.


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4- Viscosity:The viscosity of the melted suppository base is important in the

manufacture of the suppository and to its behavior in the rectumafter melting.

Melted cocoa butter have low viscosity than glycerinated gelatin andPEG type base in low viscosity bases, extra

Care must be exercised to avoid sedimentation of suspended particles.

To overcome the problems caused by use of low viscosity bases:

a- Use base with a more narrow melting rang that is closer to bodytemperature.b- The inclusion of approximately 2% aluminum monostearate not only

increase the viscosity of the fat base but to maintain homogenoussuspension of insoluble material.

c- Cetyl , stearyl or myristyl alcohols or stearic acid are added to

improve the consistency of suppositories .


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5- Brittleness :Suppositories made from cocoa butter are elastic

and don't fracture readily.Synthetic fat base with high degree of

hydrogenation and high stearate content and ahigher solids content at room temperature are

usually more brittle.To overcome, 1) the temperature difference

between the melted base & the mold should beminimal.

2) Addition of small amount ofTween 80, castor oil, glycerin imparts plasticityto a fat


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6- Volume contraction:Occurs in many melted suppository base after cooling the

mold, result in:a- Good mold release (contraction facilitate the removal of

the suppository from the mold , eliminating the need formold release agents).

b- Contraction hole formation at the open end of the mold,this will lowered suppository . The contraction can beeliminated by pouring a mass slightly above itscongealing temperature into a mold warmed at about the

same temperature or the mold is overfilled so that theexcess mass containing the contraction hole can bescraped off.


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Lubricant or mold releasing agent:

Cocoa butter adhere to suppository moldsbecause of its low volume contraction. A various

mold lubricants or release agents must be usedto overcome this difficulty (mineral oil , aqueoussolution of sodium lauryl sulfate , alcohol ,silicones , soap). The release of suppository

from damaged mold was improved by coatingthe cavities with polytetrofluoroethylene(Teflone).


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7- Rancidity and Antioxidant:

Rancidity results from the autoxidation andsubsequent decomposition of unsaturatedfats into low & medium molecular weight

saturated & unsaturated aldehydes ,ketones and acids , which have strongunpleasant odor. Example of effectiveantioxidant arephenols such as "hydroquinone or B-naphtholquinone.


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DOSAGE REPLACEMENT FACTOR

The amount of base that is replaced byactive ingredient in suppository formulationcan be calculated. The replacement factor

(f) is derived from the following equation:F=100(E-G)+1

Where:

E= weight of pure suppository base.G= weigh of suppositories with x% active

ingredient.


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Quality Control of Suppository

1) Surface appearance and shape:

to evaluate: absence of fissuring absenceof migration of active ingredient, absenceof pitting, absence of fat blooming(dullness of surface)


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2) MELTING RANGE TEST:

Macromelting range: measures the time it takes for the

entire suppository to melt when immersed in a constanttemperature (370C) water bath.Micromelting range: is the melting range measured in

capillary tubes for the fat base only.

The apparatus used for measuring the melting range of theentire suppository is a USP tablet disintegrationapparatus. The suppository is completely immersed inthe constant temperature water bath, and the time for the

entire suppository to melt or dispense in the surroundingwater is measured. The in-vitro drug release pattern ismeasured by using the same melting range apparatus.


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3) LIQUIFACTION OR SOFTENING TIMETESTS OF RECTAL SUPPOSITORIES:

The "softening test" measures the

liquefaction time of rectal suppositories arean apparatus that simulate

in-vitro conditions (at 37oC).


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4) BREAKING TEST:

It is designed as a method for measuring the

fragility or brittleness of suppositories.The apparatus consists of double-wall chamber in

which the test suppository is placed. Water at37C is pumped

through the double walls of the chamber, and thesuppository, contained in the drug innerchamber,

supports a disk to which a rod is attached. Theouter end of the rod consists of another disc

to which weights are applied.


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5) Mechanical strength: It is a force necessary tobreak a supp. And indicate whether supp isbrittle or elastic. ( not less than 1.8-2 Kg) byErweka method

6) Melting & solidification

Solidification can be determine by using

evacuated flask into which the melt is placed,the temp of cooling is noted to determine thesolidification point.


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7) DISSOLUTION TESTING:

The patterned is measured by using thesame melting range apparatus. If thevolume of water surrounding thesuppository is known, then by measuring

aliquots of the water for drug content atvarious intervals within the melting period.A (time versus drug release) curve could

be established and can be plotted.


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PACKAGING OF SUPPOSITORY

Suppository must be placed in a container in sucha manner that they do not touch each other.

Staining, breakage or deformation by meltingcaused by adhesion can result from poorly

wrapped packaged suppository. Suppository isfoiled in tin or Al paper and plastic. Over wrapping is done by hand or machine.

Many suppositories are not individually,wrapped. In such cases, they are placed intocardboard boxes or plastic containers that havebeen molded to provide compartment for 6 or 12suppositories.


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IN- PACKAGE MOLDING:A significant advance in suppository manufacturing was the

development of automated method for moldingsuppository, directly in their wrapping materials. This is

currently accomplished with either plastic or Al-foil.

*ADVANTAGE OF INPACKAGE MOLDING:

1. high production rate.

2. no generation of scraping.3. no bulk handling.

4. maintenance of strict temperature control


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STORAGE

Suppository should be protected from heat,preferably stored in the refrigerator.Glycerinated gelatin suppositories should

be protected from heat, moisture, and dryair by packaging in well-sealed containersand storing in a cool place.

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Suppositories 1