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Suppository Bases

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24
Suppository Bases
Melgardt de Villiers, PhD

Definitions
CHAPTER
OUTLINE Desirable Properties of Suppository Bases
Classification and Characteristics of Suppository Bases

I. DEFINITIONS
A. Suppositories: “Suppositories are solid bodies of various weights and shapes, adapted for introduc-
tion into the rectal, vaginal, or urethral orifice of the human body. They usually melt, soften, or
dissolve at body temperature. A suppository may act as a protectant or palliative to the local tis-
sues at the point of introduction or as a carrier of therapeutic agents for systemic or local action”
(1). —USP
(See the section on definitions and nomenclature in Chapter 31, Suppositories, for a discussion of
proposed nomenclature changes for suppository dosage forms.)
B. According to the USP, there are six general classes of suppository bases (1):
1. Cocoa butter
2. Cocoa butter substitutes
3. Glycerinated gelatin
4. Polyethylene glycol base
5. Surfactant base
6. Tableted suppositories or inserts
C. According to Allen (2), four classifications of suppository bases are usually described, based on
their melting or dissolution properties:
1. The first is the fat- or oil-type base, which must melt at body temperature to release its med-
ication.
2. The second is the glycerin-gelatin base suppository, which absorbs water and dissolves to
release its medication.
3. The third is the water-soluble or water-miscible polymers and surface-active agents.
4. The fourth is a group of bases containing disintegrating agents, natural gums, effervescent
agents, collagen, fibrin, hydrogels, etc.

II. DESIRABLE PROPERTIES OF SUPPOSITORY BASES

A. Chemically and physically stable under normal conditions of use and storage
B. Nonreactive and compatible with a wide variety of drugs and auxiliary agents
C. Free from objectionable odor

291
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292 Part 4 Pharmaceutical Excipients

D. An aesthetically appealing appearance

E. Nontoxic, nonsensitizing, and nonirritating to sensitive tissues
F. Expansion–contraction characteristics such that it shrinks just enough on cooling so that it
releases easily from suppository molds
G. Melts or dissolves in the intended body orifice to release the drug
H. Nonbinding of drugs
I. Mixes with or absorbs some water
J. Viscosity low enough when melted to pour easily but high enough to suspend particles of solid
drug
K. Some wetting and/or emulsifying properties so that it will spread, disperse in, and release the
active ingredient(s) at the administration site

III. CLASSIFICATION AND CHARACTERISTICS OF SUPPOSITORY BASES

The six general classes of suppository bases identified by the USP (1) are described here.The descrip-
tions and solubilities for bases or base ingredient are a composite of information from Remington’s The
Science and Practice of Pharmacy (3), the Handbook of Pharmaceutical Excipients (4), official monographs in
the USP–NF (5,6), and other references as cited.Additional information on each agent, including ref-
erences to original research journal articles, can be found in the Handbook of Pharmaceutical Excipients.
A. Cocoa Butter NF
1. Description
a. Cocoa butter is the fat from the seeds of Theobroma cacao (chocolate beans). It may be
obtained either by expressing the oil from the seeds or by solvent extraction. Chemically, it
is a mixture of triglycerides of saturated and unsaturated fatty acids, primarily stearic,
palmitic, oleic, lauric, and linoleic.
b. It is a mellow, yellowish solid with a mild odor and bland taste. It is a solid at room tem-
perature but melts at body temperature with a melting point of 31° to 34°C. The specific
gravity of the melt is 0.858 to 0.864. It is available as bars or grated.
c. Cocoa butter does not contain emulsifiers, so it does not absorb significant amounts of
water.Tween 61, a tan, waxy, solid, nonionic surfactant, can be added (5% to 10%) to increase
the water absorption properties of cocoa butter (7), although addition of nonionic surfac-
tants reportedly gives suppositories with poor stability on storage (8).
2. Solubility: It is insoluble in water, slightly soluble in alcohol, and soluble in boiling absolute alcohol.
3. Incompatibilities: The most notable compatibility problem of cocoa butter is the lowering of
its melting point with drugs such as chloral hydrate, phenol, and thymol.This can be overcome
by the addition of 4% to 6% white wax or 18% to 28% cetyl esters wax, but determining the
exact amount that will give an appropriate melting temperature can be difficult and time con-
suming (9). A group of successful formulas for chloral hydrate suppositories, including some
made with cocoa butter, has been published (10).
4. Advantages
a. Cocoa butter is bland and nonirritating to sensitive membrane tissues. It is also an excellent
emollient and is used alone or in topical skin products for this property.
b. Because cocoa butter has a variety of uses besides suppository making, it is readily available
in many pharmacies. It is also one base that can be used for hand-molding suppositories; no
special molds or equipment are needed.These two properties make this base useful when a
custom suppository is needed on an emergency basis.
c. Cocoa butter has a solidification temperature 12° to 13° below its melting point.This makes
it easy to pour suppositories before the base solidifies (7).
d. Cocoa butter is available in grated form. This eliminates one time-consuming aspect of
compounding suppositories.
5. Disadvantages
a. Because of its relatively low melting point, cocoa butter and its suppositories must be stored
either at controlled room temperature or in the refrigerator. It is recommended that storage
temperature not exceed 25°C.
b. Cocoa butter has the further disadvantage of existing in several polymorphic forms that have
even lower melting points: 18°, 24°, and 28°C to 31°C (7). Cocoa butter suppositories are
therefore somewhat difficult to make by fusion.
(1) Cocoa butter can very easily be overheated and, when it is, it may solidify as one of the
lower melting polymorphs.This means that the suppositories do not set up properly, and
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Chapter 24 Suppository Bases 293

they may melt at room temperature, or the suppositories may liquefy when handled by
the patient during insertion.
(2) When melting cocoa butter, a warm-water bath should be used and the temperature
should be controlled closely. When melted, the base should have a slightly opalescent
appearance. Once the molten cocoa butter has completely turned to a clear, straw-col-
ored liquid, the desired melting point has been exceeded; all the stable -crystals have
been destroyed, and the suppositories will melt at a temperature below the desired 34°C
to 35°C.A sample procedure with appropriate temperatures for the warm-water bath and
the cocoa butter melt is given with example 31.1 in Chapter 31, Suppositories.
c. As with all fatty bases, cocoa butter suppositories may give poor and somewhat erratic
release of some drugs.The release of a drug from a fatty suppository base, like cocoa butter,
to the aqueous medium in the body cavity depends on the water/base partition coefficient
of the drug. Because many organic drug molecules are water-insoluble and lipophilic unless
present in an ionized salt form, this can be a problem.
(1) For this reason, from a bioavailability point of view, water-soluble ionized (salt) forms of
drugs (these have high water/base partition coefficients) should be used when possible
with cocoa butter, particularly when a systemic effect is desired. For example, if a drug
such as phenobarbital is being incorporated into a cocoa butter suppository base, the
sodium salt of phenobarbital is the preferred form of the drug to use. This principle is
illustrated with Sample Prescription 31.2 in Chapter 31.
(2) For drugs, such as acetaminophen, that do not have a water-soluble form, cocoa butter
is not a good choice for the suppository base (11).
B. Cocoa butter substitutes
1. Description
a. The USP has the following description of cocoa butter substitutes:
Fat-type suppository bases can be produced from a variety of vegetable oils, such as coconut or
palm kernel, which are modified by esterification, hydrogenation, and fractionation to obtain
products of varying composition and melting temperatures (e.g., Hydrogenated Vegetable Oil and
Hard Fat). These products can be so designed as to reduce rancidity. At the same time, desired
characteristics such as narrow intervals between melting and solidification temperatures, and
melting ranges to accommodate various formulation and climatic conditions, can be built in (1).
b. Chemically, this type of base is composed primarily of mixtures of triglyceride esters of sat-
urated fatty acids in the C-12 to C-18 range, with lesser amounts of mono- and diglyc-
erides. Other additives include beeswax, lecithin, polysorbates, ethoxylated fatty alcohols,
and ethoxylated partial fatty glycerides (4). As can be seen later in the descriptions of some
commercially available synthetic fatty bases, some also contain surfactants, self-emulsifying
agents, and suspending agents.
c. Substitutes for cocoa butter were first developed in Europe during the Second World War
because of the limited availability of natural cocoa butter. In recent years, suppliers of com-
pounding materials in the United States have developed additional products of this type (8).
Several of these are described here.
d. Witepsol
(1) Witepsol is a whitish, waxy, brittle solid that melts to a clear to yellowish liquid; it is
nearly odorless and has a density of 0.95 to 0.98 at 20C. It contains emulsifying agents
and will absorb a small amount of water (4,8).
(2) Although the Handbook of Pharmaceutical Excipients lists 20 different grades of Witepsol, the
H15 grade is the most readily available to pharmacists. It has a melting point range of
33.5°C to 35.5°C (4), which is quite close to its congealing range of 32°C to 34°C (8).
(3) Although some pharmacists speak highly of Witepsol bases, others report poor or uneven
results. Although suppositories made with this base solidify rapidly and should contract
to release easily from the mold, there are reports of problems with suppositories break-
ing into pieces when being removed from the suppository mold.
e. Fattibase (Paddock Laboratories)
(1) Fattibase is an opaque, white, waxy solid; it is odorless and has a bland taste. Its specific
gravity at 37°C is 0.89. It is a mixture of triglycerides from palm, palm kernel, and
coconut oils, together with self-emulsifying glyceryl monostearate and polyoxyl stearate,
which serve as emulsifiers and suspending agents (12).
(2) It has a melting point range of 32°C to 36.5°C, but instructions from its manufacturer,
Paddock Labs, state that the base should be heated slowly and evenly to 49°C to 54°C
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294 Part 4 Pharmaceutical Excipients

before adding the active ingredients.The suppositories should be poured when the mix-
ture is 43°C to 49°C.The base should not be heated above 60°C, and use of microwave
ovens for heating the base is not recommended (12,13).
(3) Fattibase has the advantages of cocoa butter without the difficulties caused by the sen-
sitive melting point range and polymorphism of cocoa butter. Suppositories made from
this base release well from molds; a light spraying of the molds with vegetable oil can be
used if needed.
f. Fattyblend (Gallipot Inc.) (14)
(1) The suppository base Fattyblend exhibits the body-temperature melting characteristic
inherent in cocoa butter without the polymorphism. It offers uniformity, bland odor, and
low irritation characteristics as well as excellent mold release properties as compared
with cocoa butter.
(2) It contains triglycerides from palm, palm kernel, and coconut oils, as well as emulsifying
and suspending agents.
(3) It has also been used in lip balms and lipsticks because of its bland taste.
g. Supposiblend (Gallipot Inc.) (14)
(1) This is a pellet form of a triglyceride (fatty-acid blend type) suppository base made from
vegetable oils, predominantly palm kernel oil that resists oxidation, and does not exhibit
the polymorphism of cocoa butter.
(2) It has a melting point range of 34°C to 37°C. It contracts slightly while cooling, which
imparts excellent mold release characteristics.
(3) It contains emulsifiers to allow absorption of small amounts of aqueous solutions.
h. Supposibase-F (Hawkins) (15)
(1) Like Supposiblend, Supposibase-F is a pellet-form suppository base that is made from
refined, hydrogenated, deodorized vegetable oils, primarily palm kernel oil. It is reported
to have good chemical stability, little tendency for oxidation, and physical stability with
minimal polymorphism.
(2) It has a melting point range of 34°C to 37°C.
2. Solubility: Cocoa butter substitutes are practically insoluble in water and slightly soluble in
warm alcohol.
3. Incompatibilities:The cocoa butter substitutes may have some of the same temperature-lower-
ing difficulties as are seen with cocoa butter.
4. Advantages
a. Fatty bases are favored because they are bland and nonirritating to sensitive membrane tissues.
b. Some of the commercially available synthetic versions of cocoa butter are easier to work
with than cocoa butter because they are not as sensitive to minor melting temperature
fluctuations and, unlike cocoa butter, they exhibit minimal problems with polymorphic
forms.
c. Some of the specially formulated synthetic fatty bases include surfactants and self-emulsify-
ing agents that improve drug release and bioavailability (16).
5. Disadvantages
a. Because of their relatively low melting points, these synthetic cocoa butter bases and
their suppositories must be stored either at controlled room temperature or in the refrig-
erator.
b. As discussed earlier in the section on cocoa butter (see section III.A), fatty bases tend to give
poor and somewhat erratic release of water-insoluble drugs, although those bases formu-
lated with surfactants and emulsifiers are reported to be superior in this regard (16). Still,
water-soluble ionized (salt) forms of drugs should be used when possible with fatty bases,
particularly when a systemic effect is desired. For drugs that do not have water-soluble
forms, therapeutic results should be monitored for assurance of adequate drug release from
the dosage form.This is illustrated with an indomethacin suppository formulated in Sample
Prescription 31.1 in Chapter 31.
C. Glycerinated gelatin bases
1. Description:This base consists of 70 parts of glycerin, 20 parts of gelatin, and 10 parts of water
(1).The method of preparation is like that for glycerinated gummy gel base, which is described
in Table 26.3 in Chapter 26.
2. These bases are used infrequently because they are more difficult to make and offer few advan-
tages.
3. The base material has a soft, rubbery consistency (rather like the candy, gummy worms), which
makes them suitable for vaginal administration but not firm enough for rectal use.
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Chapter 24 Suppository Bases 295

Table 24.1 PHYSICAL PROPERTIES OF POLYETHYLENE GLYCOLS

DENSITY MELTING SOLUBILITY

GRADE MW PHYSICAL AT 20°C* RANGE IN WATER pH OF 5%
(AVG. MW) RANGE FORM OR 60°C** (°C) (WT % 20°C) SOLUTION

300 285–315 liquid 1.1250* –15 to –8 Complete 4.5 to 7.5

400 380–420 liquid 1.1254* 4 to 8 Complete 4.5 to 7.5
600 570–630 liquid 1.1257* 20 to 25 Complete 4.5 to 7.5
1,000 950–1,050 soft solid 1.0926** 37 to 40 80 4.5 to 7.5
1,450 1,300–1,600 soft solid or flake 1.0919** 43 to 46 72 4.5 to 7.5
3,350 3,000–3,700 flake or powder 1.0926** 54 to 58 67 4.5 to 7.5
4,600 4,400–4,800 flake or powder 1.0926** 57 to 61 65 4.5 to 7.5
8,000 7,000–9,000 flake or powder 1.0845** 60 to 63 63 4.5 to 7.5
Source: The Dow Chemical Company, Carbowax and Carbowax Sentry Product Data Sheets (http://www.dow.com/polyglycols/
carbowax/index.htm).
*Density measurements done at 20° for those grades that are liquid at that temperature (300, 400, 600).
**Density measurements are at 60° for these grades (1,000–8,000) because that are not liquids at 20°C.

4. They do not melt but dissolve slowly in the mucous secretions of the vagina; they have been
recommended for sustained release of local antimicrobial agents (7). Glycerinated gelatin sup-
positories should be moistened before insertion.
5. Glycerinated gelatin suppositories are hygroscopic, so they must be dispensed in tight containers.
6. They are reported to support mold or bacterial growth, so they should be stored in the refrig-
erator and should contain a preservative (e.g., methylparaben 0.18%, propylparaben 0.02%) (8).
D. Polyethylene glycol bases
1. Description: Polyethylene glycol (PEG) suppository bases are composed of blends of polyeth-
ylene glycol polymers of various molecular weights. Polyethylene Glycol is described in Chap-
ter 23, Ointment Bases, and properties of some PEG polymers that are used often for phar-
maceutical applications are given in Table 24.1. Formulas for some PEG suppository bases are
given in Table 24.2.
2. Some commercial polyethylene glycol suppository bases also contain additional components,
such as surfactants.Two widely used bases are Polybase (Paddock Labs) and PEGblend (Gallipot
Inc.): Both contain a mixture of polyethylene glycols plus the emulsifier polysorbate 80. Poly-
base is a white solid with an average molecular weight of 3,440 and a specific gravity of 1.177
at 24° C (13,17).
3. PEG suppository bases are formulated so they do not melt at body temperature but rather dis-
solve in body fluids. Suppositories made from these bases should be moistened with water
before insertion.
4. Advantages
a. PEG suppositories are easily made by fusion.
b. When formulated with an appropriate PEG blend, they dissolve in body cavity fluids and
release the active ingredient(s), both hydrophilic and hydrophobic drugs. Provided there are
sufficient aqueous secretions in the body cavity, they provide more reliable release of drug
from the dosage form than do fatty bases.
c. Because their melting points are easily controlled by appropriate blending, these bases and
their suppositories do not require carefully monitored storage temperatures.
5. Disadvantages
a. PEG suppositories are irritating to body cavity tissues, so they have less patient acceptance
than do fatty-base suppositories.
b. They are incompatible with a long list of drugs, especially those prone to oxidation. Spe-
cific examples are given in the description of polyethylene glycol in Chapter 23.
c. They interact with polystyrene, the plastic often used for prescription vials, so they should
not be dispensed in these containers unless the suppositories are first wrapped with foil.
E. Surfactant or water-dispersible bases
1. Several nonionic surfactants, such as polyoxyethylene sorbitan fatty-acid esters and the poly-
oxyethylene stearates, are used alone or in combination with other suppository vehicle mate-
rials to make suppository bases (1).
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296 Part 4 Pharmaceutical Excipients

Table 24.2 POLYETHYLENE GLYCOL (PEG) BASES

BASE 1

PEG 8,000 50%

PEG 1,540 30%
PEG 400 20%
Base 1 is a good general-purpose, water-soluble suppository base.

BASE 2

PEG 3,350 60%

PEG 1,000 30%
PEG 400 10%
Base 2 is a good general-purpose base that is slightly softer than base 1 and dissolves more
readily.

BASE 3

PEG 8,000 30%

PEG 1,540 70%
Base 3 has a higher melting point, which is usually sufficient to compensate for the melting point
lowering of drugs such as chloral hydrate.

BASE 4

PEG 8,000 40%

PEG 400 60%

BASE 5

PEG 8,000 20%

PEG 400 80%
Bases 4 and 5 have been used for progesterone suppositories. Personal communication to the
author from practitioners report base 5 to be superior for this purpose.

BASE 6

PEG 8,000 60%

PEG 1,540 25%
Cetyl Alcohol 5%
Water 10%
Base 6 can be used for water-soluble drugs.
Bases 1, 2, 3, 4, and 6 are found in Plaxco JM, Suppositories. In: King RE, ed. Dispensing of medications, 9th
ed. Easton, PA: Mack Publishing Co., 1984; 93–94.

2. Bases of this type are not used as frequently for compounding because they are more compli-
cated to formulate.
3. If formulated correctly, these bases have desirable melting points and consistencies. Because
they contain surfactants, there are readily dispersed in body cavity fluids.
4. One blend that could be easily made in the pharmacy contains 60% Tween 61 and 40% Tween
60 (7). Both of these compounds are solids at room temperature. They are available through
vendors of compounding drugs and chemicals.
F. Tableted suppositories or inserts
1. Vaginal suppositories (now usually referred to as vaginal inserts) are occasionally prepared by the
compression of powdered materials into a suitable shape.They are prepared also by encapsula-
tion in soft gelatin (1).
2. The compression method is suited for suppositories that contain heat-labile drugs or contain a
large proportion of insoluble ingredients.
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Chapter 24 Suppository Bases 297

3. This method offers the possibility to make suppositories of many shapes and sizes.
4. The filler used in these suppositories is usually lactose combined with a disintegrating agent, a
dispensing agent, and a lubricant.
G. Release of drug from suppository bases is a complicated and unpredictable process.The rate-lim-
iting step in drug release is not only the speed at which fatty bases melt or PEG bases dissolve but
also the time required for the drug to partition and diffuse out of the base into the rectal or vagi-
nal lumen. In practice, because bioavailability studies are usually impracticable, it is important to
monitor the effectiveness of the drug delivery system by frequent monitoring of therapeutic
results.

REFERENCES
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2. Allen LV. Compounding rectal dosage forms. Part II. Secundum
Artem, 14(4) (http://www.paddocklabs.com/forms/secundum/
volume_14.4.pdf).
3. Block LH. Medicated topicals. In: University of the Sciences in
Philadelphia, ed. Remington: The science and practice of phar-
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2005; 883–886.
4. Rowe R, Sheskey P, Weller P, eds. Handbook of pharmaceutical
excipients, 5th ed.Washington, DC: APhA Publications, 2005.
5. The United States Pharmacopeial Convention, Inc. NF mono-
graphs. 2007 USP 30/NF 25. Rockville, MD: Author, 2006.
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7. Coben LJ, Lieberman HA. Suppositories. In: Lieberman HA,
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13. Paddock Laboratories Customer Service Department. Personal
correspondence. Minneapolis, MN: Paddock Laboratories, Inc.
14. Gallipot Inc. Brochure. 2400 Pilot Knob Road, St. Paul, MN
55120, E-mail: info//www.gallipot.com/).
15. Hawkins Inc. 2008 Hawkins Pharmacy Compounding Catalog.
3000 East Hennepin Avenue, Minneapolis, MN 55413, E-mail:
pharmcs//www.hawkinsinc.com/pharmaceutical).
16. Yamazaki M, Soichi I, Sasaki N, et al. Comparison of three test
methods for suppositories. Pharmacopeial forum. Rockville,
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Sept–Oct; 2427–2437.
17. The Dow Chemical Company. Carbowax and Carbowax Sen-
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