Suppository Suppository Development and Development and

ProductionProduction• Marion GoldCenterchem, Inc., Stamford,

Connecticut.• Murti VePuriAble Labs, South Plainfield, New

Jersey• Lawrence H. Block Duquesne University of,

Pittsburgh, Pennsylvania

1

Oral route of administration is the most acceptable and common compared with other routs of administration.

Oral route is not without limitations. Some medication cause local stomach

irritation. Dose limitation. Certain patients, children, elderly, and

those with swallowing problems, are difficult to treat with oral tablets and capsules.

Target the medication to the affected area. Ophthalmic, Nasal, Otic, Dermal, Vaginal and Anorectal tissues.

Introduction

2

SuppositoriesSuppositories The suppositories are the neglected

dosage form. Although lots of research done on

this drug delivery system, there are continues to be a general rejection of the rectal delivery system.

There are important reasons to consider suppositories as a preferred route of administration in many situation.

3

Why the rectal route?Why the rectal route? When the patient is unable to use the

oral route Through, unconsuous, irritation in the

stomach When the drug is less suited to oral

administration

4

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

5

Definition

Typically consist of dispersion of the active ingredient in an inert matrix generally composed of a rigid or semi-rigid base.

This matrix should be inert not to interact with the active ingredients and the excipients.

The dispersed phase can be incorporated into the suppository as:

Solid (Powder).Liquid (either aqueous, alcoholic, or glycolic solutions, oils, extracts, etc.

6

The material for the base, are selected on The material for the base, are selected on the bases of its ability to the bases of its ability to soften, , melt, or , or dissolve at body temperature. at body temperature.

Finished suppositories are manufactured Finished suppositories are manufactured in a variety of shapes and sizes to best suit in a variety of shapes and sizes to best suit the treatment requirements (nature of the the treatment requirements (nature of the active ingredients, site of administration.active ingredients, site of administration.

Suppositories are available inSuppositories are available in

a range of physical forms a range of physical forms

(molded or compressed, (molded or compressed,

foil or plastic wrapped, or gelatin foil or plastic wrapped, or gelatin

encapsulated.encapsulated. 7

Rectal administration & Applications

1. For local2. Systemic drug delivery.

8

Drugs administered by Drugs administered by rectal routerectal route

Local Effect Astringents. Anti-septics. Local anaesthetics. Vasoconstrictors. Anti-inflammatory. Soothing agents. Protective agents. laxatives

Systemic Effect Analgesic &

antipyretic. Anti-inflammatory. Anti-asthmatic. Anti-convulsant. Anti-emetic. Nausea Narcotic analgesia

(Oxymorphone HCL)

9

Advantages

Reduce hepatic first-pass eliminationReduce hepatic first-pass elimination

Enhance drug bioavailability.Enhance drug bioavailability.

Alcoholic and aqueous solution can be Alcoholic and aqueous solution can be

rapidly absorbed, and this is used to rapidly absorbed, and this is used to

considerable advantage, for example, to considerable advantage, for example, to

administer diazepam in the treatment of administer diazepam in the treatment of

acute convulsive attacks.acute convulsive attacks.

10

Comparison with Oral Delivery Many studies have attempted to Many studies have attempted to

compare the oral dosage form with compare the oral dosage form with the rectal administration.the rectal administration.

The results are inadequate, because The results are inadequate, because of the different parameter used to of the different parameter used to make the studies, the experiment make the studies, the experiment conditions and choice of excipient.conditions and choice of excipient.

Certain active ingredients are just Certain active ingredients are just not well suited for suppository not well suited for suppository dosage.dosage.

11

Diazepam (as an alcoholic solution & Diazepam (as an alcoholic solution & propranolol have been shown to exhibit propranolol have been shown to exhibit greater bioavailability when administered greater bioavailability when administered rectally.rectally.

Theophylline suppositories was found Theophylline suppositories was found bioequivalence to oral administration bioequivalence to oral administration when microcrystalline drug was used.when microcrystalline drug was used.

Bioequivalence between pentobarbital Bioequivalence between pentobarbital despite its slower rectal absorption.despite its slower rectal absorption.

In case where there is no first pass In case where there is no first pass metabolism, it has been shown that rectal metabolism, it has been shown that rectal administration of drugs in solution can administration of drugs in solution can provide BE equivalent to that seen with provide BE equivalent to that seen with oral administration.oral administration.

12

Absorption of the materials is via passive Absorption of the materials is via passive diffusion; (diffusion; (no carrier-assisted means take no carrier-assisted means take part in the passage of drug through lipid part in the passage of drug through lipid membrane). membrane).

Thus, success or failure of therapeutic Thus, success or failure of therapeutic delivery is a function of lipo-solubility of the delivery is a function of lipo-solubility of the agent as well as its vehicle, because the agent as well as its vehicle, because the partition coefficient of the drug between partition coefficient of the drug between suppository base and the lumen contents suppository base and the lumen contents influences the latter's release into the bowel influences the latter's release into the bowel and eventually the actives passage through and eventually the actives passage through the wall of the intestine. the wall of the intestine.

13

Enhancement agents that affect the Enhancement agents that affect the mucous membrane similarly affect mucous membrane similarly affect absorption and are useful for boosting absorption and are useful for boosting delivery of poorly absorbed agents such delivery of poorly absorbed agents such as antibiotics and high M.W materials.as antibiotics and high M.W materials.

14

The use of suppositories in the world

Rectal as well as urethral and vaginal delivery of drugs via suppositories makes excellent therapeutic sense, and there use can be traced as far back as in the writings of Hippocrates.

In Japan, rectal dosage forms are more acceptable by the patient than other route of administration.

More than 7.5% of all prescriptions in France were formulation intended for rectal administration.

15

Anglo-Saxon countries, where social convention preclude greater use of rectal delivery (generally do not prescribe suppositories).

Latin American and Mediterranean Europeans use suppositories far more routinely.

In summary the use of rectal suppositories is limited and are vary between nations. 16

Factors affecting the absorption from Rectal

Suppositories1. Physiological factors.2. Physicochemical factors of the drug

substance.3. Physicochemical factors of the

base.

17

1. Physiological Factors

1. Colonic content.2. Circulation route.3. pH, and lack of buffering capacity of

the rectal fluids.

1. When systemic effects are desired, greater absorption may be expected from a rectum that is void then from one that is distended with fecal matter. An evacuant enema could be use before the administration of a suppository. 18

Diarrhea, which case tissue dehydration of the rectum can influence the absorption.

Colonic obstruction due to tumorous growths, influence the rate and the degree of drug absorption from the rectal site.

2. Circulation Route, drugs absorbed rectally, bypass the portal circulation during their first pass into the general circulation

19

Physiological Factors continued

3. pH and lack of buffering capacity of the rectal fluids.

The rectal fluids are neutral in pH (7-8), and have no effective buffering capacity.

The drug is administered will not generally be chemically changed by the rectal environment.

The suppository base used has major influence on the release of active constituents incorporated into it.

20

Physicochemical FactorsPhysicochemical FactorsIncludes:

1.Solubility of the drug in lipid and in water.

2.Particle size of dispersed drugs.3. Physicochemical factors of the base

include its ability to: Melt. Soften. Dissolve at body temperature. Release the drug substance, and its hydrophilic or hydrophobic

character. 21

Lipid-water solubility: The lipid-water partition coefficient of a drug

is an important factor in the selection of the suppository base and in drug release from that base.

A Lipophilic drug that is distributed in a fatty suppository base in low concentration has less of a tendency to escape to the surrounding aqueous fluids than the hydrophilic substance presents in a fatty base.

Water soluble base such as, PEG, which dissolve in the anorectal fluids, release for absorption both water soluble and oil soluble drugs.

22

Physicochemical Factors Continue…

Particle size: Particle size:

Particle size of drugs present in the Particle size of drugs present in the suppository in the undisclosed stat, the suppository in the undisclosed stat, the smaller the particle size the more readily smaller the particle size the more readily the dissolution of the particles and the the dissolution of the particles and the greater the chance for rapid absorption.greater the chance for rapid absorption.

Nature of the base:Nature of the base:

Melting point, softening, or dissolving to Melting point, softening, or dissolving to release its drug components for release its drug components for absorption, interacting with the drugs absorption, interacting with the drugs substance.substance.

23

Ratio of ComponentsRatio of Components

Once the correct excipient has been Once the correct excipient has been selected, the proper proportion of the selected, the proper proportion of the components needs to be established. components needs to be established.

One important aspect to consider in One important aspect to consider in suppository formulation is that of suppository formulation is that of displacement.displacement.

Suppositories generally weigh between 1 Suppositories generally weigh between 1 to 4 g, and displacement of the excipient to 4 g, and displacement of the excipient by the active ingredient must be by the active ingredient must be calculated when the product is formulated. calculated when the product is formulated.

24

Simply, this step takes into account the Simply, this step takes into account the volume of suppository base that will be volume of suppository base that will be displaced by an insoluble drug dispersed displaced by an insoluble drug dispersed into it.into it.

This is necessitated by the practice of This is necessitated by the practice of placing weighed quantities of placing weighed quantities of suppository ingredients into molds suppository ingredients into molds whose contents are measured whose contents are measured volumetrically.volumetrically.

25

M = F - (f * S)M = = the quantity (weight) of suppository the quantity (weight) of suppository base needed.base needed.

F = the total capacity of the suppository = the total capacity of the suppository mold.mold.f = the displacement factor of the = the displacement factor of the active ingredients.active ingredients.S = the quantity of the active ingredient = the quantity of the active ingredient per suppository.per suppository.

26

Calculation of Calculation of Displacement ValueDisplacement Value

27

M = the quantity (weight) of suppository base needed.F = the total capacity of the suppository mold.f = the displacement factor of the active ingredients.S = the quantity of the active ingredient per suppository.

Displacement ValueDisplacement Value

The volume of a suppository from a The volume of a suppository from a particular mould is uniform.particular mould is uniform.

The weight is vary according to the The weight is vary according to the density of the medicaments.density of the medicaments.

The displacement value of a drug is the The displacement value of a drug is the number of parts by weight of drug which number of parts by weight of drug which displaces one part by weight of the base.displaces one part by weight of the base.

Could be calculated and could be found in Could be calculated and could be found in the literature.the literature.

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Displacement Factors of Selected Materials

Acetylmorphine Hydrochloride 0.71

Acetylsalicylic acid 0.63

Beeswax 1.0

Benzocaine 0.68

Bismuth subgallate 0.37

Bismuth sbnitrate 0.33 0.33

Codeine phosphate 0.8

Glycerin 0.78

Phenacetin 0.6

Phenobarbital 0.84

Phenobarbital sodium 0.62

Procaine 0.8

Quinine chlorohdrate 0.83

Sulfamide 0.6

Theophylline 0.63

Zinc oxide 0.2

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FormulationFormulationA.A. Choice of drug:Choice of drug:

What makes a particular drug a candidate for administration in the form of a suppository?

1)1) It must be sufficiently absorbed through the It must be sufficiently absorbed through the rectal mucosa to permit therapeutic blood rectal mucosa to permit therapeutic blood levels.levels.

2)2) Drug that are poorly absorbed after oral Drug that are poorly absorbed after oral dosage.dosage.

3)3) Drugs that cause irritation to the Drugs that cause irritation to the gastrointestinal mucosa.gastrointestinal mucosa.

4)4) Certain antibiotics cause major changes to Certain antibiotics cause major changes to the balance of intestinal flora, and there the balance of intestinal flora, and there would be better given as suppositories.would be better given as suppositories.

30

OK

5)5)Small polypeptides-normally subject Small polypeptides-normally subject to the enzymatic activity of the upper to the enzymatic activity of the upper GIT, can often be better administered GIT, can often be better administered via the rectum.via the rectum.

6)6)The pH of the upper GIT causes The pH of the upper GIT causes inadequate or otherwise undesirable inadequate or otherwise undesirable uptake.uptake.

7)7)For local conditions achieved using a For local conditions achieved using a suitable suppository formulation.suitable suppository formulation.

31

OK

1. Nature of the active. Three principal factors that define

formulation requirements:

1. The actives physical state under ambient conditions.

2. The solubility characteristics of the active.

3. The physicochemical activity with regards to potential excipients.

32

NO

1. Physical State. The active can be either liquid, The active can be either liquid,

pasty, or solid in nature.pasty, or solid in nature. Bulk Density. the big difference in Bulk Density. the big difference in

the density between the active and the density between the active and the base cause problem during the base cause problem during filling and homogeneity of the filling and homogeneity of the suppositories. suppositories.

Solubility:Solubility:

33

NO

B. Choice of the Base1)1) They enable a selected active to be They enable a selected active to be

fabricated in a manner appropriate to fabricated in a manner appropriate to both its physicochemical characteristics both its physicochemical characteristics and the requirements of the and the requirements of the manufacturer.manufacturer.

2)2) They are used to control delivery of the They are used to control delivery of the medication at its site of absorption.medication at its site of absorption.

3)3) For this reason the bases manufacturers For this reason the bases manufacturers offer a wide selection of raw materials offer a wide selection of raw materials in order to anticipate a correspondingly in order to anticipate a correspondingly broad range of product needs.broad range of product needs.

34

NO

Selection criteria of the Selection criteria of the basebase

A.A. Nature of the active ingredient.Nature of the active ingredient.

B.B. Manufacturing capabilities.Manufacturing capabilities.

C.C. Desired release characteristics.Desired release characteristics.

D.D. Chemical no-reactivity with the active.Chemical no-reactivity with the active.

E.E. Nontoxic and nonirritant, and stable Nontoxic and nonirritant, and stable

when formulated.when formulated.

35

NO

Selection of the appropriate Base

I. During Production: Slight contraction upon cooling in order Slight contraction upon cooling in order

to facilitate removal from the mold.to facilitate removal from the mold. Inertness no chemical interaction Inertness no chemical interaction

between the base and the active between the base and the active ingredients.ingredients.

Solidification (should be optimum).Solidification (should be optimum). Viscosity: to be viscose to prevent Viscosity: to be viscose to prevent

sedimentation during filling until cooling.sedimentation during filling until cooling.

36

NO

II. During Storage: Impurity. Impurity.

Bacterial/Fungal contamination should Bacterial/Fungal contamination should be be minimized by selecting a non-minimized by selecting a non-nutritive nutritive base base with minimal with minimal water content.water content.

Softening. Softening.

The suppositories should be formulated The suppositories should be formulated so so that it does not soften or melt that it does not soften or melt under under transportation and storage transportation and storage conditions.conditions.

Stability. Stability.

The selected materials can not oxidize The selected materials can not oxidize when exposed to air, humidity, Or light.when exposed to air, humidity, Or light.

37

NO

III. During Use: Release. Release.

Choice of the proper base provides Choice of the proper base provides optimal optimal delivery of the dispersed delivery of the dispersed active into the active into the target site.target site.

Tolerance. Tolerance.

The finished suppository should The finished suppository should have have minimal toxicity and not minimal toxicity and not be irritating to be irritating to sensitive rectal sensitive rectal mucosal tissue.mucosal tissue.

38

NO

Suppository Basis Suppository Basis Suppository bases plays an important role

in the release of the drug they hold and therefore in the availability of the drug for absorption for systemic effects or for local action.

And because of the possibility of chemical and or physical interactions between the drug and the base, which could affect the stability and or bioavailability of the drug, the absence of any drug interaction between the two agents should be ascertained before formulation

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Suppository Bases

From the point of view of From the point of view of composition, suppository bases can composition, suppository bases can be described as falling into one of be described as falling into one of the three categories:the three categories:

1. Naturally derived.

2. Synthetic.

3. Semisynthetic.

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I. Natural BasesI. Natural Bases

All naturally derived suppository bases used today are produces from Cocoa Butter, it’s a fatty material composed of a mixture of C16 to C18 saturated and unsaturated fatty acid triglycerides obtained from the roasted seed of Theobroma cacao.

Fatty bases are the most frequently used suppository bases.

These bases melt at body temperature.

41

In addition to cocoa butter, other natural materials such as:

Gelatin, Agar, and Waxes have been employed as suppository bases.

Their uses are limited and often relegated to special applications because special problems are encountered with their use.

42

Advantages:

1.1.It is readily liquefies on heating but It is readily liquefies on heating but sets rapidly when cooled down.sets rapidly when cooled down.2.Melt at body temperature.3.It is miscible with many ingredients.4.It is bland, therefore no irritation occurs.

43

Disadvantages: Despite Theobroma oil been used for

over 200 years, however it is not without limitations.And those limitations are:

1. Theobroma oil is polymorphic i.e. when it is heated and cooled it solidifies in a different crystalline form.

2. Theobroma oil shrinks slightly on cooling, adherence to the walls of suppository

mold. n The relatively low melting point makes it

unsuitable for use in hot climates.44

4. The melting point is reduced if the active ingredients are soluble in the base.

5. Theobroma oil deteriorates on storage and is prone to oxidation.

6. The quality of Theobroma oil may vary from batch to batch, and it can be expensive.

For these reasons, the use of cocoa butter as a suppository base is becoming

increasingly less attractive, particularly in the of the availability of

more modern alternatives. 45

II. Synthetic & Semi-II. Synthetic & Semi-synthetic Basessynthetic Bases

Chemically they are usually derivatives of fatty acids that undergo chemical alteration (transesterification) to enhance their use for this application

Such chemical reactions yield a range of products with controllable characteristics making them suitable to be used as suppository bases.

46

For example:For example:Hydrogenation is typically carried out to improve stability (enhance stability to oxidation and to increase chemical inertness). HHydrogenating suitable vegetable oils such as (Palm kernel oil and cottonseed oil) are used.Melting point ranges can be more precisely tailored to specific requirements. Examples of semisynthetic suppository Examples of semisynthetic suppository bases: bases: NovataNovata, , SuppocireSuppocire, , WecobeeWecobee and and WitepsolWitepsol types. types.

47

Advantages:

The base is more flexible and not The base is more flexible and not

brittle.brittle.

More stable on oxidation and More stable on oxidation and

hydrolysis.hydrolysis.

Less irritant compare with other Less irritant compare with other

bases.bases.48

DisadvantagesDisadvantages1. The viscosity of the synthetic fats, when

melted, is lower than that of Theobroma oil. this may lead to.

2. Sedimentation risk of the active ingredients during the preparation process.

3. Lack of uniformity of the active ingredients.

4. These bases become very brittle if cooled too rapidly, so should not be refrigerated during the preparation period.

5. There is more than one grade of synthetic fatty basis. 49

Water soluble & water miscible Water soluble & water miscible basesbases

1. Glycerol-gelatin bases: These bases is a mixture of glycerol and

water, which is stiffened with gelatin. Mass of Glycerol suppositories BP has 14%

w/w gelatin and 70% w/w glycerol. In hot climates gelatin content can be

increased to 18%. Gelatin is purified protein produces by the

hydrolysis of the caliginous tissue of animals such as skins and bones.

There is two types of gelatin: Type A and Type B.

50

This type of base is less frequently used than the fatty bases for a variety of reasons.

Disadvantages of this type of bases:1. Glycerol-gelatin base have a physiological

effect. This is useful if a laxative effect is required but otherwise is undesirable.

2. Difficulties in preparation and handling.

3. The dissolution time depends on the content and quality of the gelatin and also the age of the suppository.

51

4. They are hygroscopic and therefore require careful storage and may cause rectal irritation.

5. Possibility of microbial contamination is more likely than with the fatty bases.

52

2.Macrogols These are different types of polyethylene

glycols which are blended together to produce suppository bases which vary in:

Melting point. Dissolution rates. Physicochemical characteristics.

High polymer produce preparation which release the drug slowly (they are brittle).

A combination of different polymer release the drug more readily can be prepared by mixing high polymers with medium and low polymers. (Less brittle)

53

Advantages:1. They have no physiological effect, e.g. do not

produce a laxative effect.2. They are not prone to microbial contamination.3. Some polymers have a high melting point.4. They have a high water-absorbing capacity.5. In solution, viscosity is high, which means

there is less likelihood of leakage from body.

54

Drug is release as the base dissolves in the rectal contents.

Disadvantages:

1.1. They are hygroscopic which means They are hygroscopic which means they must be carefully stored.they must be carefully stored.

2.2. They are incompatible with several They are incompatible with several drugs and materials, e.g. bnzocaine, drugs and materials, e.g. bnzocaine, penicillin and plastic.penicillin and plastic.

3.3. They become brittle if cooled too They become brittle if cooled too quickly and also may become brittle on quickly and also may become brittle on storage.storage.

4.4. Crystal growth occurs with some Crystal growth occurs with some active ingredients.active ingredients.

55

Hydrogels Currently, an alternative vehicle for rectal

delivery is being actively investigated. Hydrogels are among them, and it defined

as macromolecular networks that swell, but do not dissolve, in water.

The swelling of hydrogels, i.e., the absorption of water, is a consequence of the presence of hydrophilic functional groups attached to the polymeric network.

The aqueous insolubility of hydrogels results from the cross-links between adjacent macromolecules.

56

The use of hydrogel matrix for drug delivery The use of hydrogel matrix for drug delivery involves the dispersal of the drug in the involves the dispersal of the drug in the matrix, followed by drying of the system and matrix, followed by drying of the system and simultaneous immobilization of the drug.simultaneous immobilization of the drug.

When the hydrogel delivery system is When the hydrogel delivery system is placed in an aqueous environment, e.g., the placed in an aqueous environment, e.g., the rectum, the hydrogel swells, and drug is rectum, the hydrogel swells, and drug is then able to diffuse out of the then able to diffuse out of the macromolecular network.macromolecular network.

57

Selection CriteriaSelection Criteria

Melting Temperature Range.Melting Temperature Range.

Iodine Value.Iodine Value. Hydroxyl Index.Hydroxyl Index.

58

Suppository Production Suppository Production MethodsMethods

1.1. Melting.Melting.

2.2. Compression.Compression.

3.3. Injection.Injection. Injection molding production process Injection molding production process

involving PEGs as the base might involving PEGs as the base might proceed as follows:proceed as follows:

The PEGs are first melted and mixed in The PEGs are first melted and mixed in a vessel equipped with a stirrer and a a vessel equipped with a stirrer and a heating device at about 60°C to 80°C . heating device at about 60°C to 80°C .

59

Additional viscosity -plasticity –adjusting Additional viscosity -plasticity –adjusting ingredient, auxiliary ingredients, and ingredient, auxiliary ingredients, and actives are added while stirring. actives are added while stirring.

Once blending is complete, the melt is Once blending is complete, the melt is extruded into precision-machined multi-extruded into precision-machined multi-cavity molds. cavity molds.

Rapid solidification of the melt is Rapid solidification of the melt is followed by ejection of the molded units followed by ejection of the molded units from the mold cavities. from the mold cavities.

Very fast, Precise metering and molding. Range of shapes and sizes

60

In-Process ControlIn-Process Control Proper monitoring of product physical

characteristics is necessary to ensure that the production process remains under control throughout filling.

Visual Examination: Examination of physical defects of finished suppositories provides valuable information for process monitoring. Color variations, chips, cracks, depressions, and surface irregularities are evidence of problems that require attention.

61

1) Weight checks: periodic weighing of

individual suppositories will reveal problem in

the filling operation. (in each filling needle).

2) Leak Test

3) The quality of the seal is a parameter that can

affect the stability of the product (vacuum

test).

62

Quality ControlA. Physical Analysis: 1.Visual Evaluation, surface appearance and color can be verified visually to assess:

Absence of fissuring, pitting, fat blooming, exudation, and migration of the active ingredients.

The last test accomplished by taking a longitudinal section of the suppository to verify the homogeneity of the active ingredients within the mass.

63

2. Melting Point. The melting point is a critical

factor in the determination of the release rate of the active ingredients from the suppository. The melting point of the finished suppository should generally; not be greater than 37°C.

64

3. Liquefaction Time.This is an important element indicates the physical behavior of a suppository subjected to its maximum functional temperature 37°C. It measures the time necessary for a suppository to liquefy under pressures similar to those found in the rectum (30g) in the presence of water at body temperature. A rule of thumb is that liquefaction time should be no longer than 30 minutes.

65

4. Mechanical strength:

This is the determination of the This is the determination of the mechanical force necessary to break a mechanical force necessary to break a suppository, and it indicates whether suppository, and it indicates whether a suppository is brittle or elastic. a suppository is brittle or elastic. The mechanical strength should in no The mechanical strength should in no case be less than 1.8 to 2 kg.case be less than 1.8 to 2 kg.

66

5. Melting and Solidification:5. Melting and Solidification:The most commonly used methods are:The most commonly used methods are:Open capillary tube.U-Tube.Drop Point.These methods are similar in principle, differ somewhat in their methodologies. all require the introduction of a sample into a specified place in the apparatus, after which heat is applied in a controlled manner.Means are provided for the determination of the point at which the test material undergoes a change in physical state, (i.e., melts).

67

An ideal suppository base must:An ideal suppository base must:1. Melt at or just below body temperature

or dissolve in body temperature.2. Solidify quickly after melting.3. Be miscible with many ingredients.4. Be bland, i.e. non-toxic and non-irritant.5. Be stable on storage.6. Be resistant to handling.7. Be stable to heating above its melting

point.8. Release the active ingredients readily.9. Be easily molded and removed from the

mold.68

Release Process of drug Release Process of drug from suspension from suspension

suppositorysuppository SuppositorySuppository

Melting and Melting and SpreadingSpreading

SedimentationSedimentation

WettingWetting

DissolutionDissolution

69

Factors affecting drug Factors affecting drug release processrelease process

TemperatureTemperature

Contact areaContact area

Release mediumRelease medium

MovementsMovements

MembranesMembranes

70

Formulation of Formulation of suppositoriessuppositories

Different types – rectal, vaginal, and Different types – rectal, vaginal, and urethral.urethral.

Different shapes and sizesDifferent shapes and sizes Usually between 1-4gUsually between 1-4g Drug content varies widely – 0.1% to Drug content varies widely – 0.1% to

40%40% Vehicle (base) in which drug is Vehicle (base) in which drug is

incorporated – sometimes contain incorporated – sometimes contain other additivesother additives

71

Mould CalibrationMould Calibration

The capacity of the mould is The capacity of the mould is determined by filling the mould by determined by filling the mould by the chosen base.the chosen base.

The total weight of the perfect The total weight of the perfect product is taken and a mean weight product is taken and a mean weight calculated.calculated.

This value is the calibration value of This value is the calibration value of the mould for the particular base.the mould for the particular base.

72

7.7. Melt 2/3 of the base and then remove form the Melt 2/3 of the base and then remove form the heat, the residual heat will melt the rest of the heat, the residual heat will melt the rest of the base.base.

8.8. Reduce the particle size of the active Reduce the particle size of the active ingredients.ingredients.

9.9. Weigh the correct amount of medicament and Weigh the correct amount of medicament and place on a glass tile.place on a glass tile.

10.10. Add half of the molten base to the powdered Add half of the molten base to the powdered drug and rub together with a spatula.drug and rub together with a spatula.

11.11. Scrape this mixture off the tile, using the Scrape this mixture off the tile, using the spatula and place back into the porcelain basin.spatula and place back into the porcelain basin.

12.12. Quickly pour into the mould, slightly overfilling Quickly pour into the mould, slightly overfilling each cavity.each cavity.

13.13. Leave the mould and its contents to cool for 5 Leave the mould and its contents to cool for 5 min.min.

14.14. Allow to cool for further 10-15 min.Allow to cool for further 10-15 min.15.15. Unscrew the mould and remove the Unscrew the mould and remove the

suppositories.suppositories.73

Packaging and StoragePackaging and Storage

Plastic (PVC) or aluminium foil packPlastic (PVC) or aluminium foil pack Protection against moisture and Protection against moisture and

oxygenoxygen Store in cool placeStore in cool place High humidity – absorb moisture – High humidity – absorb moisture –

spongyspongy Low humidity – lose moisture - Low humidity – lose moisture -

brittlebrittle

74