Suppositories

Assist.lecturer Qasim Allawi Bader

Definition

• Are conical or ovoid, solid prep. For insertion into the body cavity where they melt,dissolve or disperse and exert a local or a systemic effect.

• Their basis is fat,a wax or glycerol-gelatin gelly.• They weight 1,2 or occasionally 4 g.• In the past ,small suppositories known as cones

were prescribed for ear infection and long, very narrow forms called bougies ,were used for nasal and urethral infections.

Purposes of suppositories

• To exert a direct action on the rectum especially to relieve the pain and irritation of haemorrhoids and they contain:

local anaesthetic e.g. benzocaineAstringent e.g. Bismuth subgallateAnti-inflammatory agents e.g. hydrocortisone

• To promot evacuation of the bowel e.g. laxatives.• To provide a systemic effect which is of particular value for: Patients who are unconscious,mentally disturbed or who cant

administer drugs orally e.g. vomiting Adminstering drugs that cause gastric irritation e.g. aminophylline Treating infants and children Drugs destroyed or inactivated by the pH or enzymatic activity of

the stomach or intestines need not be exposed to these destructive environments.

Drugs destroyed by portal circulation may bypass the liver after rectal absorption (drugs enter the portal circulation after oral administration and absorption).

Examples of drugs administered rectally in the form of suppositories for their systemic effects include (a) prochlorperazine and chlorpromazine for the relief of

nausea and vomiting and as a tranquilizer; (b) oxymorphone HCl for opioid analgesia;(c) ergotamine tartrate for the relief of migraine syndrome; (d) indomethacin, a nonsteroidal anti-inflamatory analgesic and antipyretic; and (e) ondansetron for the relief of nausea and vomiting.

SOME FACTORS OF DRUG ABSORPTION FROM RECTAL SUPPOSITORIES

1. PHYSIOLOGIC FACTORS Colonic Content• A drug will obviously have greater opportunity to make

contact with the absorbing surface of the rectum and colon in an empty rectum. Therefore an evacuant enema may be administered and allowed to act before the administration of a suppository of a drug to be absorbed.

• Other conditions, such as diarrhea, colonic obstruction due to

tumorous growths, and tissue dehydration can all influence the rate and degree of drug absorption from the rectum.

Circulation Route• Drugs absorbed rectally, unlike those absorbed after oral

administration, bypass the portal circulation during their first pass into the general circulation, thereby enabling drugs otherwise destroyed in the liver to exert systemic effects.

• The lower hemorrhoidal veins surrounding the colon receive the absorbed drug and initiate its circulation throughout the body, bypassing the liver. Lymphatic circulation also assists in the absorption of rectally administered drugs.

pH and Lack of Buffering Capacity of the Rectal Fluids

• Because rectal fluids are essentially neutral in pH and have no effective buffer capacity, the form in which the drug is administered will not generally be chemically changed by the environment.

• The suppository base has a marked influence on the release of active constituents. While cocoa butter melts rapidly at body temperature, because of its immiscibility with fluids, it fails to release fat-soluble drugs readily.

• .

• For systemic drug action using a cocoa butter base, it is preferable to incorporate the ionized (salt) form rather than the un-ionized (base) form of a drug to maximize bioavailability. Although un- ionized drugs more readily partition out of water-miscible bases such as glycerinated gelatin and polyethylene glycol, the bases themselves tend to dissolve slowly and thus retard release of the drug

2. PHYSICOCHEMICAL FACTORS OF THE DRUG AND SUPPOSITORY BASE

Lipid–Water Solubility• The lipid–water partition coefficient of a drug is an

important consideration in the selection of the suppository base and in anticipating drug release from that base.

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

• Water soluble bases—for example, polyethylene glycols—that dissolve in the anorectal fluids release for absorption water-soluble and oil-soluble drugs.

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

• However, if the concentration of a drug in the intestinal lumen is above a particular amount, which varies with the drug, the rate of absorption is not changed by a further increase in the concentration of the drug

Particle Size• For undissolved drugs in a suppository, the

size of the drug particle will influence its rate of dissolution and its availability for absorption.

• The smaller the particle, the greater the surface area, the more readily the dissolution of the particle and the greater the chance for rapid absorption.

Nature of the Base• The base must be capable of melting, softening, or

dissolving to release its drug for absorption. If the base interacts with the drug to inhibit its release, drug absorption will be impaired or even prevented. Also, if the base irritates the mucous membranes of the rectum, it may initiate a colonic response and prompt a bowel movement, eliminating the prospect of complete drug release and absorption.

• In a study of the bioavailability of aspirin from five brands of commercial suppositories product, only about 40% of the dose was absorbed when the retention time in the bowel was limited to 2 hours. Thus, the absorption rates were considered exceedingly low, especially when compared with orally administered aspirin.

• Because of the possibility of chemical and/or physical

interactions between the medicinal agent and the suppository base, which may affect the stability and/or bioavailability of the drug, the absence of any drug interaction between the two agents should be ascertained before or during formulation.

Properties of an ideal suppository base

1. Should be melt at body temp.or dissolved or dispersed in body fluids.

2. Release any medication readily.3. Keep its shape during handling.4. Non toxic and non irritant to the mucous membrane.5. Stable on storage.6. Compatible with any added medication7. Stable when heated above its melting point8. Easily moulded and not adhere to the mould.9. Mouldable by pouring or cold compression.

Types of suppository bases

Fatty or oleaginous bases, Water-soluble or water-miscible bases,and Miscellaneous bases, generally combinations

of lipophilic and hydrophilic substances

Fatty or Oleaginous Bases

• Theobroma oil (cocoa butter)Advantages• Has a melting point range of 30-36 °C.• Readily liquefy on warming and rapid setting

on cooling.• Miscible with many ingredient.• Blandness, which is a valuable feature when

suppository is intended to allay irritation

Disadvantages Polymorphism:• When melted and cooled it solidifies in different crystalline

forms, depending on the temp. of the melting, rate of the cooling and size of the mass.

• If melted at not more than 36 °C and slowly cooled it will form stable beta form with normal melting point.

• If overheated it may produce, on cooling unstable gamma crystal which melt at 15 °C ,or alpha crystals, melting at 20 °C.

• This lowering in solidification point lead to sedimentation of suspended solids.

Adherence to the mouldBecause theobroma oil doesn’t contract enough on cooling to loosen the supp. In the mould, sticking may occur .this is preventing by lubricating the mould before use.

Softening point too low for hot climateTo rise the softening point ,white bees wax may be added to theobroma oil supp. Intended for use in tropical and subtropical countries.

melting point reduced by soluble ing.• Substances such as chloral hydrate ,that dissolve in

theobroma oil , may lower its melting point to such extent that the supp. Is too soft for use .

slow deterioration during storageThis is due to oxidation of unsaturated glycerides.

poor water absorbing capacityThis fault can be improved by the addition of emulsifying agent . leakage from the body Relatively high cost.

• Synthetic fats It is used as substitute free from disadvantages of theobroma oil .It was produced by hydrolyzing the vegetable oil then hydrogenating the free fatty acids and finally re-esterifying the acids by heating with glycerol.

• They are superior to theobroma oil because1. Their solidifying points are unaffected by overheating.2. Have good resistance to oxidation 3. Small difference bet. Melting and setting points (1.5-2)hencei. They set quicklyii. The risk of sedimentation is lowiii. Easier to administer. When the setting point of a base is well

below the melting point, the supp. Soften quickly when handled and become too slippery to administer.

4. Its availability in a series of grades with slightly difference in M.P. ranges and degree of hardness.5. Has good water absorbing capacity because they usually contain a proportion of glycerides some of which are w/o E.A. 6. They contact significantly on cooling 7. They produce supp. That is white and almost odoureless and has very attractive, clean and polished appearance .

• Disadvantages of synthetic fatty bases1. They become brittle if cooled quickly, 0.05 %

of polysorbate 80 help to correct this fault.2. They are more fluid than theobroma oil when

melted and at this stage sedimentation may occur. Thickinners such as Mg stearate ,bentonite and colloidal silicon dioxide may be added to reduce this.

Water-Soluble and Water-Miscible Bases

1. Glycero-gelatin • Is a mix. Of glycerol and water made into stiff jelly by adding

gelatin.• Contain about 14% w/w gelatin( 18% in hot climates) and

70% w/w glycerol .• Glycero-gelatin dissolves in body secretions and therefore is

preferable over the fatty base for administering antiseptics.• Since solution is slow,drug release is more prolonged than

from fatty bases.• At present the B.P allows a maximum disintegration time of 1

hr for glycerol supp.

• Glycero-gelatin bases are less often used than fatty bases because:

1. They have a physiological action (laxatives)

2. More difficult to prepare and handled.

3. Their solution time depends on the content and quality of the gelatin and the age of the base

4. They are hygroscopic leading to dehydration of the rectal mucosa.

5. Gelatin is incompatible with protein precipitant like tannic acid.

• Tow types of gelatin found :1. Type A , made by acid hydrolysis, isoelectric point

between 7 and 9 on the acid side of this range behaves as cationic agent most effective at about pH 3.2

2. Type B, made by liming, isoelectric point between 4 and 5 on the alkaline side of this range behaves as anionic agent ,most effective at pH 7-8

Cationic and anionic antibacterial agents should not be formulated with gelatin of opposite charge.

Macrogols

• Are a mixture of polycondensation products of ethylene oxide and water and they are described by numbers representing their average molecular weight. They vary in consistency from viscous liq. To waxy solids

Macrogols 200-400 viscous liq. 1500 greasy ,semisolid 1540-6000 waxy solids

• Avantages :1. They used in mixture of grades has a M.P. above 42 °C so,

cool storage is not req.and they are satisfactory for use in hot climates

2. They are gradually dissolved and dispersed freeing their medication slowly providing longer action than fatty bases

3. Their physical properties can be varied by suitable admixture of high and low polymer

High polymers give hard products that disintegrate and release their drugs slowly.

5. Don’t stick to the mould so, no lubricant is req.6. No leakage from the body due to the high viscosity of their solution after melt.7. Have good water absorbing capacity 8. Have clean smooth appearance.

• Disadvantages 1. They are hygroscopic2. Retention of the drug in the liquefied base in the body

(bec. Of its good solvent properties ) with conseq.reduction in therapeutic activity

3. Products sometimes fracture on storage, particularely if they contain water bec. Of high solubility of macrogols which can lead to supersaturated solution in the water and subsequent crystallization. Leading to brittleness.

4. Crystall growth.which in addition to making the product brittle , the crystals may be irritating and take longer time to dissolve.

5. They are incompatible with bismuth salts,tannins and phenols leading to liquification of the supp.

Miscellaneous Bases

• In the miscellaneous group of bases are mixtures of oleaginous and water-soluble or water- miscible materials. These materials may be chemical or physical mixtures. Some are preformed emulsions, generally of the water-in-oil type, or they may be capable of dispersing in aqueous fluids.

• Mixtures of many fatty bases (including cocoa butter) with emulsifying agents capable of forming water-in-oil emulsions have been prepared. These bases hold water or aqueous solutions and are said to be hydrophilic.

PREPARATIONOF SUPPOSITORIES

• Suppositories are prepared by three methods:1. Molding from a melt,2. Compression, and3. Hand rolling and shaping. The method most frequently employed both on a small scale and on an industrial scale is molding.

PREPARATION BY MOLDING

• The steps in molding include (a) melting the base,(b) incorporating any required medicaments,(c) pouring the melt into molds,(d) allowing the melt to cool and congeal into suppositories, (e) removing the formed suppositories from the mold. • Cocoa butter, glycerinated gelatin, polyethylene glycol,

and most other bases are suitable for preparation by molding.

• Calibration of the MoldEach individual mold is capable of holding a specific volume of material in each of its openings.Because of the difference in the densities of the materials, if the base is cocoa butter, the weight of the suppositories will differ from the weight of suppositories prepared in the same mold with a base of polyethylene glycols. Similarly, any added medicinal agent alters the density of the base, and the weight of the resulting suppository differs from that of those prepared with basematerial alone.

• The first step in calibration of a mold is to prepare molded suppositories from base material alone. After removal from the mold, the suppositories are weighed and the total weight and average weight of each suppository are recorded (for the particular base used).