MODULE 2. SOFT AND ASEPTIC DOSAGE FORMS. PHARMACEUTICAL INCOMPATIBILITIES.
CONTENT MODULE 3. SOFT MEDICAL FORMS. SUPPOSITORIES.
LESSON 19. SUPPOSITORY METHOD OF POURING.
Suppositories – dosed medical forms, solid at room temperature and melted or dissolve at the temperature of body.
Depending on a place of introduction suppositories differentiated:
rectal (suppositoria rectalia), intended for introduction to the rectum;
vaginal (suppositoria vaginalia), intended for introduction in vagina;
sticks (bacilli), intended for introduction to motions of fistula, urethra, channel of neck of uterus, acoustic duct and others like that
For the method of preparation suppositories divided into:
Rolling (hand-pumping)
pouring.
For the localization procedure:
local action;
resorbtion action.
By type of suppositories basis:
suppositories in hydrophobic bases
suppositories in hydrophilic bases
Requirements to suppositories:
· Time of melting (for suppositories on hydrophobic bases) – 15 minutes
· Time of dissolution (for suppositories on hydrophilic bases) – 60 minutes
· Length of rectal suppositories must be from 2,5 to 4 centimeters
· A maximal diameter of rectal suppositories is 1,5 centimeters
· Mass of rectal suppositories is from 1,0 to a 4,0 g (middle 3,0)
· Mass of vaginal suppositories must be from 1.5 to a 6,0 gram (middle 4,0)
· Sticks must have a form of cylinder with a sharp end and diameter not more than 1 centimeters.
· Length of sticks must not exceed 10 centimeters, but mass must be from 0,5 to a 1,0 gram.
· Rejections in-bulk suppositories must not exceed ± 5 %. Medicinal matters which are contained in them are guilty to be exactly dosed.
· Suppositories must have correct and accordingly identical form, homogeneous mass, sufficient hardness (mechanical durability) and fuse at the temperature of body.
· Suppositional mass must be homogeneous, without inclusions, marbling, and sequins.
Disadvantages of suppositories:
· not hygienic of administration
· duration of preparing.
Requirements to the suppositories bases :
· sufficient hardness at a room temperature and ability to fuse (whether to dissolve) at a temperature not higher than 37 °C, that sharply to pass ability from the solid state to the liquid, passing the stage of softening influence – ointment stage; sufficient viscidity, absence of smell, providing of maximal contact between medicinal matters and mucus shell;
· chemical and pharmacological indifference, absence of irritating actions, firmness to the action of external factors (light, heat, moisture, oxygen of air, micro organisms);
· ability easily to acquire the proper form, mixed with the largest possible number of drugs, do not interact with them and be stable during storage;
· easily to free ability medicinal matters, instrumental in the display of them pharmacological action, which depends both on properties of bases and from the method of introduction of medicinal matters in basis;
· presence of the proper reological indexes and optimum structurally mechanical properties.
PRESCRIPTION OF SUPPOSITORIES
Suppositories prescribe in recipes by two methods:
· distributive
· separate.
GENERAL RULES OF PREPARATION SUPPOSITORIES
The main technological task in the preparation of suppositories is that most drugs dispersed evenly not only in suppository mass, but in every suppository, ball or stick, giving them the necessary geometry.
If mass of suppository in a recipe is not marked, prepare 3,0 grams suppository. In child’s practice mass of suppository is necessarily specified in a recipe is must be from 0,5 to 1,5 gram.
If mass of vaginal suppositories is not marked, 4,0 grams suppository. The size of sticks is guilty to be marked in a recipe.
For preparation of suppositories in the conditions of pharmacy utilize the method of deflation, and at presence of facilities of small mechanization are methods of outpouring and pressing.
The method of pouring consists of the followings stages:
· making and melting the proper base;
· mixing the prescribed medical substances with the molten base
· preparation of forms
· pouring the prepared precooled mass in forms;
· cooling;
· packing;
· registration.
Rules of introduction substances in suppository bases by the method of pouring :
In hydrophobic bases:
All substances, which are not soluble in basis, or a water-soluble enter only for type of suspension, if substances are soluble in basis, dissolve in a base (camphor, thymol, Menthol and other)
In hydrophilic bases:
All substances, which are not soluble in basis, or the oil-soluble enter only for type of suspension, if substances are a water-soluble, then they are dissolved in base , or her component parts (Glycerin, water, and others like that).
If substances more than 5 %, then take into account reverse coefficient substitution on fatty basis, if less than – does not take into account
Rp.: Osarsoli 0,25
Acidi borici
Glucosi ana 0,3
Butуroli q.s.
Misce, ut fiat suppositorium
Da tales doses N 6
Signa. 1 vaginal suppository at night
Technology
In porcelain cup melt Butуroli . In a mortar grind down a 1,8 glucose, mix with1,5 Osarsoli , got after a requirement and 1,8 boric acids to homogeneity. By rule Deryagin add » 2,4 melted Butуroli , mix up.
In a porcelain cup to melted Butуroli add the ready mixture from a mortar, carefully mix for even distribution of the suspended matters.
Mass is quickly poured out to the preliminary oil by soap alcohol the forms and place in a refrigerator. Prepared suppositories draw out from forms, wrap up in the paraffin paper, pack in a binary code, glue on the number of recipe, write the right side passport of writing control, design a signature and labels : to “Keep in a cool and protected from light place”, “Save from children”, “Handle with a care”, seal up.
WCP
(Front side)
Date № recipe
Glucosi 1,8
Osarsoli 1,5
Acidi borici 1,8
Butуroli 20,63
4,24 № 6
prepared
checked
OBJECTIVES:
AFTER THE END OF THIS TOPIC ,STUDENTS WILL BE ABLE TO :
· Define suppositories and pessaries.
· Differentiate between suppositories and pessaries.
· Classify suppositories
· Advantages & disadvantages of suppositories.
· Discuss different suppository bases used.
· Discuss the different method of preparation
Suppositories are solid dosage forms intended for insertion into body orifices where they melt, soften, or dissolve and exert localized or systemic effects.
Dosage form characteristics:
Rectal suppositories for adults weigh 2 gm and are torpedo shape.
Children’s suppositories weigh about 1 gm.
Vaginal suppositories or Pessaries weigh about 3-5gm and are molded in globular or oviform shape or compressed on a tablet press into conical shapes.
Urethral suppositories called bougies are pencil shape. Those intended for males weigh 4 gm each and are 100-150 mm long.
those for females are 2 gm each and 60-75 mm in length.
Nasal suppositories: called nasal bougies or buginaria meant for introduction in to nasal cavity.
They are prepared with glycerogelatin base.
They weigh about 1 gm and length 9-10 cm.
Ear cones:
Aurinaria and meant for introduction into ear.
Rarely used
Theobroma oil is used as base.
Prepared in urethral bougies mould and cut according to size.
SUPPOSITORIES & PESSARIES
ADVANTAGES:
_ Can exert local effect on rectal mucosa.
_ Used to promote evacuation of bowel.
_ Avoid any gastrointestinal irritation.
_ Can be used in unconscious patients (e.g. during fitting).
_ Can be used for systemic absorption of drugs and avoid first-pass metabolism.
Babies or old people who cannot swallow oral medication.
Post operative people who cannot be administered oral medication.
People suffering from severe nausea or vomiting.
DISADVANTAGES OF SUPPOSITORIES:
The problem of patient acceptability.
Suppositories are not suitable for patients suffering from diarrhea.
In some cases the total amount of the drug must be given will be either too irritating or in greater amount than reasonably can be placed into suppository.
Incomplete absorption may be obtained because suppository usually promotes evacuation of the bowel.
British Pharmacopoeia (BP) definition:
“Suppositories are solid, single-dose preparations. The shape, volume and consistency of suppositories are suitable for rectal administration.”
· Pessaries are a type of suppository intended for vaginal use.
· The larger size moulds are usually used in the preparation of pessaries such as 4 g and 8 g moulds.
· Pessaries are used almost exclusively for local medication, the exception being prostaglandin pessaries that do exert a systemic effect.
British Pharmacopoeia (BP) definition:
“ Pessaries are solid, single-dose preparations. They have various shapes, usually ovoid, with a volume and consistency suitable for insertion into the vagina. They contain one or more active substances dispersed or dissolved in a suitable bases that may be soluble or dispersible in water or may melt at body temperature. Excipients such as diluents, adsorbents, surface-active agents, lubricants, antimicrobial preservatives and colouring matter, authorised by the competent authority, may be added, if necessary.”
Pessaries
Common ingredients for inclusion in pessaries for local action include:
antiseptics
contraceptive agents
local anaesthetics
various therapeutic agents to treat trichomonal, bacterial and monilial infections.
IDEAL SUPPOSITORY BASE:
1. Melts at body temperature or dissolves in body fluids.
2. Non-toxic and non-irritant.
3. Compatible with any medicament.
4. Releases any medicament readily.
5. Easily moulded and removed from the mould.
6. Stable to heating above the melting point.
7. Easy to handle.
8. Stable on storage.
SUPPOSITORIES & PESSARIES
I FATTY BASES: designed to melt at body temperature.
Theobroma oil (Cocoa butter)
It is a yellowish-white solid with an odour of chocolate and is a mixture of glyceryl esters of different unsaturated fatty acids.
Advantages:
A melting range of 30 – 36°C (solid at room temperature but melts in the body).
Readily melted on warming, rapid setting on cooling.
Miscible with many ingredients.
Non-irritating.
Disadvantages:
a- Polymorphism:
When melted and cooled it solidifies in different crystalline forms, depending on the temperature of melting, rate of cooling and the size of the mass.
If melted at not more than 36°C and slowly cooled it forms stable beta crystals with normal melting point.
If over-heated then cooled it produce unstable gamma crystals which melt at about 15°C or alpha crystals melting at 20°C.
Cocoa butter must be slowly melted over a warm water bath to avoid the formation of the unstable crystalline form.
b- Adherence to the mould:
c- Softening point too low for hot climates.
Melting point reduced by soluble ingredients: Phenol and chloral hydrate have a tendency to lower the melting point of cocoa butter.- So, solidifying agents like beeswax (4%) may be incorporated to compensate for the softening effect of the added substance.
Rancidity on storage:
Poor water-absorbing ability: Improved by the addition of emulsifying agents.
Leakage from the body:
Expensive
SYNTHETIC HARD FAT:
For example: Suppocire, witepsol.
Advantages:
Their solidifying points are unaffected by overheating.
They have good resistance to oxidation because of the lower content of unsaturated fatty acids.
The difference between melting and setting points is small. Hence they set quickly, the risk of sedimentation of suspended ingredients is low.
They are marketed in a series of grades with different melting point ranges, which can be chosen to suit particular products and climatic condition.
e-They contain a proportion of w/o emulsifying agents, and therefore, their water-absorbing capacities are good.
No mould lubricant is necessary because they contract significantly on cooling.
Disadvantages:
Brittle if cooled rapidly, avoid refrigeration during preparation.
The melted fats are less viscous than theobroma oil. As a result greater risk of drug particles to sediment during preparation lack of uniform drug distribution give localized irritancy.
II Water-soluble and water-miscible bases:
1- Glycero-gelatin:
The commonest is Glycerol Suppositories Base B.P., which has 14% w/w gelatin, and 70% w/w glycerol & water Q.S. to 100%. .
The glycerol-gelatin base U.S.P. consisted of 20% w/w gelatin, and 70% w/w glycerol & water Q.S. to 100%.
DISADVANTAGES:
A physiological effect: osmosis occurs during dissolving in the mucous secretions of the rectum, producing a laxative effect.
Can cause rectal irritation due to small amount of liquid present.
Unpredictable solution time.
Hygroscopic: So, they should be packaged in tight containers and also have dehydrating effects on the rectal and vaginal mucosa leading to irritation.
Microbial contamination likely.
Long preparation time.
Lubrication of the mould is essential.
Macrogols (polyethylene glycols):
Polyethylene glycols are polymers of ethylene oxide and water, prepared to various chain lengths, molecular weights, and physical states.
The numerical designations refer to the average molecular weights of each of the polymers.
Polyethylene glycols (PEGs) having average molecular weights of 300, 400, and 600 are clear, colorless liquids, while those with molecular weights of 600-1000 are semisolids.
Those having average molecular weights of greater than 1000 are wax-like, white solids with the hardness increasing with an increase in the molecular weight.
These polyethylene glycols can be blended together to
produce suppository bases with varying: melting points, dissolution rates and physical characteristics.
Drug release depends on the base dissolving rather than melting.
The melting point is often around 50°C.
Higher proportions of high molecular weight polymers
produce preparations which release the drug slowly and are also brittle.
Less brittle products which release the drug more readily can be prepared by mixing high polymers with medium and low polymers.
Preparation of suppositories:
Suppositories are prepared by four methods:
I Hand moulding:
-Hand molding is useful when we are preparing a small number of suppositories:
The drug is made into a fine powder.
It is incorporated into the suppository base by kneading with it or by trituration in a mortar.
The kneaded mass is rolled between fingers into rod shaped units.
The rods are cut into pieces and then one end is pointed.
II Compression molding:
1. The cold mass of the base containing the drug is compressed into suppositories using a hand operated machine.
**Advantages:
1.It is a simple method.
2. It gives suppositories that are more elegant than hand moulded suppositories.
3. In this method sedimentation of solids in the base is prevented.
Suitable for heat labile medicaments.
**Disadvantages:
1.Air entrapment may take place.
2.This air may cause weight variation.
3.The drug and/or the base may be oxidized by this air.
III Pour moulding:
Using a supp. mould which is made of metal or plastic. Traditional metal moulds are in two halves which are clamped together with a screw.
Steps:
The base is melted and precautions are takeot to overheat it.
The drug is incorporated in it.
The molten liquid mass is poured into chilled(lubricated if cocoa butter or glycrogelatin is the base)molds.
After solidification the cone shaped suppositories are
Lubricating the cavities of the mould is helpful in producing elegant suppositories and free from surface depression.
The lubricant must be different iature from the suppository base, otherwise it will be become absorbed and will fail to provide a buffer film between the mass &the metal.
The water soluble lubricant is useful for fatty bases while the oily lubricant is useful for water soluble bases.
The lubricant should be applied on a pledget of gauze or with fairly stiff brush.
LUBRICANTS FOR USE WITH SUPPOSITORY
BASES:
IV Automatic Moulding machine:
All the operations in pour moulding are done by automatic machines. Using this machine, up to about 10,000 suppositories per hour can be produced.
Packaging and storage:
-Suppositories are usually packed in tin or aluminium, paper or plastic.
-Poorly packed suppositories may give rise to staining, breakage or deformation by melting.
-Both cocoa butter and glycerinated gelatin suppositories stored preferably in a refrigerator.
– Polyethylene glycol suppositories stored at usual room temperature without the requirement of refrigeration.
SUPPOSITORIES
1-Introduction:
Suppositories are medicated, solid bodies of various sizes and shapes suitable for introduction into body cavities. The medicament is incorporated into a base such as cocoa butter which melts at body temperature, or into one such as glycerinated gelatin or PEG which slowly dissolves in the mucous secretions. Suppositories are suited particularly for producing local action, but may also be used to produce a systemic effect or to exert a mechanical effect to facilitate emptying the lower bowel.
The ideal suppository base should be nontoxic, nonirritating, inert, compatible with medicaments, and easily formed by compression or molding. It should also dissolve or disintegrate in the presence of mucous secretions or melt at body temperature to allow for the release of the medication. As with the ointment bases, suppository base composition plays an important role in both the rate and extent of release of medications.
2- Methods of preparation :
Suppositories can be extemporaneously prepared by one of three methods.
qHand Rolling is the oldest and simplest method of suppository preparation and may be used when only a few suppositories are to be prepared in a cocoa butter base. It has the advantage of avoiding the necessity of heating the cocoa butter. A plastic-like mass is prepared by triturating grated cocoa butter and active ingredients in a mortar. The mass is formed into a ball in the palm of the hands, then rolled into a uniform cylinder with a large spatula or small flat board on a pill tile. The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape.
Effective hand rolling requires considerable practice and skill. The suppository “pipe” or cylinder tends to crack or hollow in the center, especially when the mass is insufficiently kneaded and softened.
qCompression Molding is a method of preparing suppositories from a mixed mass of grated suppository base and medicaments which is forced into a special compression mold. The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories. When active ingredients are added, it is necessary to omit a portion of the suppository base, based on the density factors of the active ingredients.
qFusion Molding involves first melting the suppository base, and then dispersing or dissolving the drug in the melted base. The mixture is removed from the heat and poured into a suppository mold. When the mixture has congealed, the suppositories are removed from the mold. The fusion method can be used with all types of suppositories and must be used with most of them.
3- Suppository bases :
Suppository bases may be conveniently classified as according to their composition and physical properties:
· Oleaginous (fatty) bases
· Water soluble or miscible bases (hydrophyllic)
a) Oleaginous Bases include Theobroma Oil and synthetic triglyceride mixtures.
Theobroma Oil or cocoa butter is used as a suppository base because, in large measure, it fulfills the requirements of an ideal base. At ordinary room temperatures of 15° to 25°C (59° to 77°F), it is a hard, amorphous solid, but at 30° to 35°C (86° to 95°F), i.e., at body temperature, it melts to a bland, nonirritating oil. Thus in warm climates, theobroma oil suppositories should be refrigerated.
Particular attention must be given to two factors when preparing suppositories with cocoa butter base. First, this base must not be heated above 35°C (95°F) because cocoa butter is a polymorphic compound and if overheated will convert to a metastable structure that melts in the 25° to 30°C (77° to 86°F) range. Thus, the finished suppositories would melt at room temperature and not be usable.
The second factor is the change in melting point caused by adding certain drugs to cocoa butter suppositories. For example, chloral hydrate and phenol tend to lower the melting point. It may be necessary to add spermaceti or beeswax to raise the melting point of finished suppositories back to the desired range.
The newer synthetic triglycerides consist of hydrogenated vegetable oils. Their advantage over cocoa butter is that they do not exhibit polymorphism. They are, however, more expensive. Some of the bases are single entity formulations. Some of the names may denote a series of bases. In a series, the bases are varied to give a range of melting points. For example, Fattibase® is a single entity base that consists of triglycerides from palm, palm kernel, and coconut oils. Wecobee® is a series of bases. Wecobee FS, M, R, and S are all made from triglycerides of coconut oil.
b) Water Soluble/Water Miscible Bases are those containing glycerinated gelatin or the polyethylene glycol (PEG) polymers.
Glycerinated Gelatin is a useful suppository base, particularly for vaginal suppositories. It is suitable for use with a wide range of medicaments including alkaloids, boric acid, and zinc oxide. Glycerinated gelatin suppositories are translucent, resilient, gelatinous solids that tend to dissolve or disperse slowly in mucous secretions to provide prolonged release of active ingredients.
Suppositories made with glycerinated gelatin must be kept in well-closed containers in a cool place since they will absorb and dissolve in atmospheric moisture. In addition, those intended for extended shelf-life should have a preservative added, such as methylparaben or propylparaben, or a suitable combination of the two. To facilitate administration, glycerinated gelatin suppositories should be dipped in water just before use.
Calibration of Suppository Molds with Glycerinated Gelatin Base
Glycerinated Gelatin Suppositories have the following proportions of glycerin, gelatin, and water. Use 75 g of the suppository base for this calibration exercise.
|
Ingredients |
Percentage |
Weight Basis |
Amt./Vol. to measure |
|
Glycerin |
70% |
__________ g |
_________ ml |
|
Gelatin |
20% |
__________ g |
_________ g |
|
Purified Water |
10% |
__________ g |
_________ ml |
To calibrate the mold with glycerinated gelatin suppository base:
· Clean mold with soap and water.
· Dry the mold.
· Have the mold at room temperature.
· Lubricate the mold with light mineral oil.
· Mix the glycerin and water together and heat on a steam bath or hot plate for 5 minutes. Gently stir in the gelatin to avoid incorporating air in the mixture. After the gelatin has been added, continue heating for another 40 – 50 minutes. Do not allow the temperature to get above 90 – 95°C, as the color will darken.
· Remove from the heat and allow the mixture to cool near the melting point before pouring into the mold.
· Overfill the cavities in the mold, cool at room temperature for 30 minutes, and then place in a refrigerator 15-20 minutes if the suppositories have not completely congealed.
· Carefully remove excess with a hot spatula or knife. Remove suppositories from mold.
· Using only perfect specimens, weigh the suppositories and record the total weight. Calculate the average suppository weight.
|
Mold # |
__________ |
|
Total weight for ____ suppositories = |
_________ g |
|
Average weight for one suppository = |
_________ g |
|
Mold lubricant used |
_____________________ |
|
Inspection of Final Product |
_____________________ |
N.B.
– Gelatin base is incompatible with many of the substances prescribed in supp. E.g. Tannic acid , Ferric chloride , Gallic acid , and for this another reasons this base is less frequently use than coca butter .
– Glycerin supp. Containing Ichthammol became insoluble on storage
– Gelatoglycerin bases used mainly for preparing supp. Containing boric acid , chloral hydrate , ichthamol , iodine (dissolved by the aid of KI )
Standardization of suppositorise :
The Standardization of any supp. Involves the following determinations:
a- Determination of DISPLACEMENT VALUE of the active ingredients
b- Determination of FRACTURE POINT of the prepared supp. ( the weight under which the supp. Sample collapses under given conditions is taken as a measure of the strength of the supp. Tested .
c- determination of MELTING TIME of the prepared suppository .
d- determination of UNIFORMITY OF WEIGHT of the prepared suppository .
4Preparation of the glycerogelatin bases :
– In a prcelin dish soak the gelatin powder with amount of H2O present in the formula for about 5 – 10 min. till it completely wetted and swelled
– add the amount of glycerin to the soaked gelatin.
– Put the dish on boiling water bath .
– Stirr gently till complete solubility of gelatin and the formulation of a translucent mass, avoid air bubbles formation during stirring
– Pour the translucent mass into mould (previusly lubricated with liquid paraffin or any other oil ) after adding the medicament (if the formula containing medicament ) and – Take care that preferably JUST FILL the cavities because the mass does not contract upon cooling .
4Preparation of Boroglycerin Suppository
Rx
Boric acid 7.5 g
Gelatin 15.0 g
Glycerin 62.5 g
Water 15.0 g
Fiat supp. Mitte III
Calculation :-
– The formula gives 100 g of suppository mass.
– To prepare 3 supp. Calculate for 5 .
– If we use mould of 1 g capacity the amounts are as follows :
Boric acid = (1 x 5 x 7.5 ) / 100 = 0.375 g
Gelatin = ( 1 x 5 x 15 ) / 100 = 0.750 g
Glycerin = ( 1 x 5 x 62.5 ) / 100 = 3.125 g
Water = ( 1 x 5 x 15 ) / 100 = 0.750 g
-If we use mould of 2 g capacity the amounts given above multiplied by (2) and so on.
Prepartaion :
– In a porcelin dush soak gelatin in water , then transfer to dish over a water bath
– Dissolve boric acid in glycerin by the aid of gentle heat .
– Add the dissolved boric acid the gelatin solution and continue heating over a water bath until a clear solution produced and constant wt is attained .
N.B.
– Boric acid reacts with glycerin on heating giving glyceryl borate which has an antiseptic action .
Upon completion of this exercise, you should be able to:
· List and describe a variety of suppository bases.
· Describe the proper formulation, packaging, and administration of suppository bases.
· Describe three (3) methods of suppository preparation.
· Prepare suppositories by the fusion (molding) technique.
· Determine the density factor of a drug in polyethylene glycol suppositories.
· Suppositories are medicated, solid bodies of various sizes and shapes suitable for introduction into body cavities. The medicament is incorporated into a base such as cocoa butter which melts at body temperature, or into one such as glycerinated gelatin or PEG which slowly dissolves in the mucous secretions. Suppositories are suited particularly for producing local action, but may also be used to produce a systemic effect or to exert a mechanical effect to facilitate emptying the lower bowel.
· The ideal suppository base should be nontoxic, nonirritating, inert, compatible with medicaments, and easily formed by compression or molding. It should also dissolve or disintegrate in the presence of mucous secretions or melt at body temperature to allow for the release of the medication. As with the ointment bases, suppository base composition plays an important role in both the rate and extent of release of medications.
Routes of Administration That Utilize Suppositories
Routes of Administration That Utilize Suppositories
Suppositories are medicated solid formulations that are inserted into body cavities. They are made in a variety of shapes and sizes because they are used in many different routes of administration (body cavities).
Rectal
Drugs administered via the rectum are given for a local effect or to achieve a systemic effect. Local effects may include the soothing of inflamed hemorrhoidal tissues, promoting laxation, and enemas. Using rectal administration to achieve systemic activity is preferred when the drug is destroyed in the GI tract, if oral administration is not possible because of vomiting, or the patient is unconscious or incapable of swallowing oral formulations. Rectal administration has been used to treat a variety conditions such as asthma, nausea, motion sickness, anxiety, and bacterial infections.
The most common rectal formulations are suppositories, solutions, and ointments. Suppositories are solid dosage forms that dissolve or melt when inserted into the rectum. Suppositories are manufactured in a variety of shapes. Rectal suppositories for adults are tapered at one end and usually weigh about 2 grams. Infant rectal suppositories usually weight about 1 gram or about half that of adult suppositories.
The major disadvantages of rectal suppositories:
1. They are not preferred by patients; they are inconvenient.
2. Rectal absorption of most drugs is frequently erratic and unpredictable.
3. Some suppositories “leak” or are expelled after insertion.
Vaginal
Vaginal administration has many advantages.
1. Generally there is less drug degradation via this route of administration compared to oral administration
2. The dose can be retrieved if necessary
3. There is the potential of long term drug absorption with various intrauterine devices (IUDs).
Vaginal administration does lead to variable absorption since the vagina is a physiologically and anatomically dynamic organ that causes pH and membrane permeability to change over time. There is also a tendency of some dosage forms to be expelled after insertion into the vagina.
Vaginal formulations include solutions, powders for solutions, ointments, creams, aerosol foams, suppositories, and tablets. Vaginal suppositories are employed as contraceptives, feminine hygiene antiseptics, bacterial antibiotics, or to restore the vaginal mucosa. Vaginal suppositories are inserted high in the vaginal tract with the aid of a special applicator. The suppositories are usually globular, oviform, or cone-shaped and weigh between 3 – 5 grams. Patients should be instructed to quickly dip the suppository in water before insertion. Because suppositories are generally used at bedtime and can be messy if the formulation is an oleaginous base, patients should wear a sanitary napkin to protect nightwear and bed linens.
Urethral
Urethral suppositories are not specifically described in the USP 24/NF19 either by weight or dimension. Traditionally, they are cylindrical in shape (3 – 6 mm in diameter) and vary in length according to gender. Female urethral suppositories can be 25 – 70 mm in length while male urethral suppositories can be about 50 – 125 mm in length. The one commercially available urethral suppository is actually marketed as a “pellet,” and is 1.4 mm in diameter and 3 or 6 mm in length depending on strength. Urethral suppositories are unusual and may not be encountered in a compounding practice.
Inserting Suppositories
Inserting Rectal Suppositories
1. If possible, go to the toilet and empty bowels.
2. Wash hands carefully with soap and warm water.
3. Remove any foil or plastic wrapping from the suppository.
4. Lubricate the tapered end of the suppository with a small amount of K-Y® Jelly. If the jelly is not available, moisten the suppository with a small amount of water.
5. Either stand with one leg on a chair, or lay on one side with one leg straight and the other leg bent toward your stomach.
|
|
|
6. Separate buttocks to expose the rectal area.
7. Gently but firmly push the suppository into the rectum until it passes the sphincter (about 1/2 to 1 inch in infants, and 1 inch in adults.
8. Close your legs and sit (or lay) still for about 15 minutes. Avoid emptying bowels for at least one hour (unless the suppository is a laxative). Avoid excessive movement or exercise for at least one hour.
9. Wash hands again with soap and warm water immediately after inserting the suppository.
Inserting Vaginal Suppositories
1. Wash your hands carefully with soap and warm water.
2. Remove any foil or plastic wrapping from suppository.
3. Place suppository in applicator.
4. Hold the applicator by the opposite end from where the suppository is.
5. Either lay on your back with your knees bent, or stand with your feet spread a few inches apart and your knees bent.
6. Gently insert the applicator into the vagina as far as it will go comfortably. Once you are ready, push the inside of the applicator in and place the suppository as far back in the vagina as possible.
7. Remove the applicator for the vagina.
8. Wash your hands again with soap and warm water.
Suppository Bases
Suppository bases may be conveniently classified as according to their composition and physical properties:
|
· Oleaginous (fatty) bases · Water soluble or miscible bases |
|
Oleaginous Bases
Oleaginous bases include Theobroma Oil and synthetic triglyceride mixtures.
A.
Particular attention must be given to two factors when preparing suppositories with cocoa butter base. First, this base must not be heated above 35°C (95°F) because cocoa butter is a polymorphic compound and if overheated will convert to a metastable structure that melts in the 25° to 30°C (77° to 86°F) range. Thus, the finished suppositories would melt at room temperature and not be usable.
The second factor is the change in melting point caused by adding certain drugs to cocoa butter suppositories. For example, chloral hydrate and phenol tend to lower the melting point. It may be necessary to add spermaceti or beeswax to raise the melting point of finished suppositories back to the desired range.
B. The newer synthetic triglycerides consist of hydrogenated vegetable oils. Their advantage over cocoa butter is that they do not exhibit polymorphism. They are, however, more expensive. Some of the bases are single entity formulations. Some of the names may denote a series of bases. In a series, the bases are varied to give a range of melting points. For example, Fattibase® is a single entity base that consists of triglycerides from palm, palm kernel, and coconut oils. Wecobee® is a series of bases. Wecobee FS, M, R, and S are all made from triglycerides of coconut oil. But FS has a melting point range of 39.4 to 40.5°C, M has a range of 33.3 to 36.0°C, R has a range of 33.9 to 35.0°C, and S has a range of 38.0 to 40.5°C. Other triglyceride type bases include Dehydag®, Hydrokote®, Suppocire®, and Witepsol®.
Water Soluble/Water Miscible Bases
Water soluble/water miscible bases are those containing glycerinated gelatin or the polyethylene glycol (PEG) polymers.
A.
Suppositories made with glycerinated gelatin must be kept in well-closed containers in a cool place since they will absorb and dissolve in atmospheric moisture. In addition, those intended for extended shelf-life should have a preservative added, such as methylparaben or propylparaben, or a suitable combination of the two. To facilitate administration, glycerinated gelatin suppositories should be dipped in water just before use.
B.
Certain polyethylene glycol polymers may be used singly as suppository bases but, more commonly, formulas call for compounds of two or more molecular weights mixed in various proportions as needed to yield a finished product of satisfactory hardness and dissolution time.
Since the water miscible suppositories dissolve in body fluids and need not be formulated to melt at body temperature, they can be formulated with much higher melting points and thus may be safely stored at room temperature.
Examples of various PEGs used in suppository bases are:
|
|
|
|
||||||||||||||||||
|
|
|
|
Methods of Preparation
Suppositories can be extemporaneously prepared by one of three methods.
1. Hand Rolling is the oldest and simplest method of suppository preparation and may be used when only a few suppositories are to be prepared in a cocoa butter base. It has the advantage of avoiding the necessity of heating the cocoa butter. A plastic-like mass is prepared by triturating grated cocoa butter and active ingredients in a mortar. The mass is formed into a ball in the palm of the hands, then rolled into a uniform cylinder with a large spatula or small flat board on a pill tile. The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape.
Effective hand rolling requires considerable practice and skill. The suppository “pipe” or cylinder tends to crack or hollow in the center, especially when the mass is insufficiently kneaded and softened.
2. Compression Molding is a method of preparing suppositories from a mixed mass of grated suppository base and medicaments which is forced into a special compression mold. The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories. When active ingredients are added, it is necessary to omit a portion of the suppository base, based on the density factors of the active ingredients.
3. Fusion Molding involves first melting the suppository base, and then dispersing or dissolving the drug in the melted base. The mixture is removed from the heat and poured into a suppository mold. When the mixture has congealed, the suppositories are removed from the mold. The fusion method can be used with all types of suppositories and must be used with most of them.
Suppositories are generally made from solid ingredients and drugs which are measured by weight. When they are mixed, melted, and poured into suppository mold cavities, they occupy a volume – the volume of the mold cavity. Since the components are measured by weight but compounded by volume, density calculations and mold calibrations are required to provide accurate doses.
When a drug is placed in a suppository base, it will displace an amount of base as a function of its density. If the drug has the same density as the base, it will displace an equivalent weight of the base. If the density of the drug is greater than that of the base, it will displace a proportionally smaller weight of the base. Density factors for common drugs in cocoa butter are available in standard reference texts. The density factor is used to determine how much of a base will be displaced by a drug. The relationship is:
For example, aspirin has a density factor in cocoa butter of 1.3 (see Remington’s). If a suppository is to contain 0.3 g of aspirin, it will replace 0.3 g ÷ 1.3 or 0.23 g of cocoa butter. If the blank suppository (suppository without the drug) weighed 2 g, then 2 g – 0.23 g or 1.77 g of cocoa butter will be needed for each suppository, and the suppository will weigh 1.77 g + 0.3 g = 2.07 g. So if a pharmacist was making 12 aspirin suppositories using cocoa butter as the base, he would weigh 1.77 g × 12 or 21.24 g of cocoa butter and 0.3 g × 12 or 3.6 g of aspirin.
Some example density factors of drugs in cocoa butter are shown in the table below (see Remington’s):
|
Aspirin |
1.3 |
|
Barbital |
1.2 |
|
Bismuth salicylate |
4.5 |
|
Chloral hydrate |
1.3 |
|
Cocaine hydrochloride |
1.3 |
|
Codeine phosphate |
1.1 |
|
Diphenhydramine hydrochloride |
1.3 |
|
Morphine hydrochloride |
1.6 |
|
Phenobarbital |
1.2 |
|
Zinc Oxide |
4.0 |
All About Suppository Molds and Packaging
Pouring and Opening Suppository Molds
Molds should be filled only when they are at room temperature. A cold or frozen mold should never be used because it can cause fractures and fissures throughout the suppository. Each cavity should be filled slowly and carefully ensuring that no air bubbles are entrapped in the cavity. To prevent layering in the suppositories, the pouring process should not be stopped until all the cavities have been filled. Molds should be allowed to set at room temperature. Refrigeration should only be used if the suppository has not congealed after 30 to 40 minutes.
Aluminum molds usually require lubrication before use. Hard rubber molds may require lubrication. One way is to use a vegetable oil spray. Other lubricants include light mineral oil when water soluble bases are being used and glycerin or propylene glycol when oleaginous bases are being used. Whatever lubricant is used, only a light coating is needed. If too much lubricant is used, the excess will pool in the tip of the suppository cavity. Any excess lubricant should be wiped off with an absorbant tissue such as a Kimwipe.
When suppository mixtures and bases cool, they contract. Some mixtures and bases have very pronounced contractions (e.g., cocoa butter, PEG) while others have much smaller ones (e.g., glycerinated gelatin, MBK®). This contraction will produce a hole in the open end of the suppository. Such a hole is undesirable. If the suppository mixture is poured just immediately before it reaches its congealing temperature, the contraction will be minimized. It is also helpful to pour a small excess of the suppository mixture on top of the open end of the mold.
When filling a suppository mold, start pouring the melt at one end and pour continuously without stopping. Don’t go to the next cavity until the previous cavity is filled and a slight excess has been poured to overfill the cavity. Excess base can be removed once the suppositories have congealed by trimming the top of the mold with a warm stainless steel spatula.
Suppositories shells are generally poured using a back light to help visualize the mark on the shell. Some molds (depending on the size or type of the suppository) cannot be poured, but the mixture is added using a syringe.
Examples of each of these pouring (or filling techniques) are given.
When the suppository mixture has congealed, the excess mass is removed from the top surface of the mold and the mold is separated into the two halves. An efficient way to separate the mold is to remove the wing nuts or loosen the centered screw and place the mold so that the posts rest on the table top. Then apply a downward pressure only on the bottom half of the mold. A knife or spatula should not be used to pry the two halves apart. This will damage the matching mold faces which have been accurately machined to give a tight seal. (See Opening a Mold)
Suppository shells can be opened by peeling the halves apart if this type of shell is used. There are suppository shells that do not peel apart at the bottom but must be torned along its edge. These are very difficult to open, and should not be used.
Suppositories that are not in a plastic shell mold or flexible rubber mold should be wrapped before they are dispensed. This will provide protection for the suppository and limit any oil staining that might occur from the materials contained in the suppository base.
Plastic shell molds must be heat-sealed. Heat sealing is generally a two step process. First the open end of the shell is “shrunk” with the aid of heat. A hair dryer (at highest hot setting) is capable of providing enough heat to shrink the plastic. There are labatory type hot air “guns” that also can be used. The heat will cause the two sides of the opening to collapse together and begin to seal the opening. The second step is to use an electric sealer to completely seal the opening.
Opening A Suppository Mold
|
The suppository mixture is poured into the cavities of a closed mold. When the suppository mixture has congealed, the excess mass is removed from the top surface of the mold and the mold is separated into the two halves. |
|
|
An efficient way to separate the mold is to remove the wing nuts or loosen the centered screw and place the mold so that the posts rest on the table top. |
|
|
Then apply a downward pressure only on the bottom half of the mold. |
|
|
A knife or spatula should not be used to pry the two halves apart. This will damage the matching mold faces which have been accurately machined to give a tight seal. |
Suppository shells can be opened by peeling apart the two tabs at the bottom of the shell.
When the Density Factor is Not Known
When bases other than cocoa butter are used, or when the density factor for a drug in cocoa butter is not known, then the density factor can be estimated by calculation or experimentally determined by the double casting technique.
The weight of the blank suppository is easily determined. A portion of the suppository base is melted, poured into the suppository mold and allowed to congeal. The suppositories are removed from the mold, and the total weight of the suppositories is determined. The average weight of the blank suppository is determined by dividing the total weight by the number of suppositories.
