Suppository Formulation and

ManufactureJim McElroy

What Is A Suppository?

A suppository is a medicated solid dosage form used in the rectum, vagina and urethra.

One differentiates suppositories between water-soluble and fat-containing preparations.

Vaginal suppositories, called pessaries, can be made as compressed tablets.

Urethra suppositories are called bougies.

Shapes and Weights of Suppositories

Rectal suppositories weigh about 2 grams for adults and 1 gram for children. They are bullet shaped.

Vaginal suppositories weigh about 3 to 5 grams and are oval or globular shaped.

Urethral suppositories for males weigh about 4 grams & are 100-150 mm long. Female urethral suppositories weigh about 2 grams and are 60-75mm in length. They are pencil shaped and pointed on one end.

Typical Suppositories

Types of Suppository Bases

Water InsolubleOleaginous Lipid based suppositories are typically used for hemorrhoid preparations but can be used for vaginal and much rarer urethral dosing.

Water SolubleGlycerinated Gelatin Used particularly for vaginal suppositories.

Polyethylene Glycol (PEG) polymers PEG based suppositories offer rapid delivery of the

API with minimal manufacturing issues.

Tablets Used particularly for vaginal suppositories. Easy to

manufacture on standard tablet press

Oleaginous (specifically triglycerides)

A triglyceride is a lipid with a glycerin backbone with three fatty acid groups

A molecule of glycerin can be pictured as a capital E. It becomes a glyceride when one of the “forks” becomes attached to a fatty acid. If all the forks contain fatty acid groups, the result is a triglyceride.

Cocoa butter (theobroma oil) is an example of a naturally occurring triglyceride that is typically used for hemorrhoid therapy.

Most naturally occurring lipids are triglycerides!

Cocoa Butter is an ideal base for many reasons that will be discussed.

Crystallization and Melting Ranges of Cocoa Butter

Cocoa butter is a polymorphic substance.

Different researchers have used different nomenclatures over the years.

Different researchers disagree over the number of crystal forms. There are four to six (possibly more) forms of crystals in cocoa butter.

Despite the confusion the manufacturing process is well understood.

Crystal Melting Ranges of Cocoa Butter

VAECK(1960)

DUCK(1964)

WILLIE & LOVEGREN(1966)

LOVEGREN ET. AL

(1976)

DAVIS & DIMICK(1986)

Form Temperature Form Temperature Form Temperature Form Temperature Form Temperature

γ 17 γ 18 I 17.3 VI 13.0 I 13.1/17.6

ά 21-24 ά 23.5 II 23.3 V 20.0 II 17.7/19.9

III 25.5 IV 23.0 III 22.4/24.5

β' 28 β'’ 28.0 IV 27.3 III 25.0 IV 26.4/27.9

β' 33.0 V 33.8 II 30.0 V 30.7/34.4

β 34-35 β 34.4 VI 36.3 I 33.5 VI 33.8/34.1

Processing Cocoa Butter

Tempering is a process that puts desired crystal structure in cocoa butter.

Tempering improves product stability.

Poor tempering results in a poor product with marginal overall aesthetics.

Failure to control crystal structure is the main reason for post hardening effects and quality attribute failures.

The Tempering Process

• Melt the cocoa butter completely at 50-52ºC (eliminates crystal memory)

• Cool the cocoa butter with mixing to 25ºC. (mitigates the formation of Form I, II and III crystals).

• Continue to mix at this temperature product until the viscosity is at a maximum (maximum crystal growth of Form IV, V and VI).

• Heat the product to 33-35ºC with continued mixing (Form V predominates).

• Form into suppositories

Synthetic Fatty Bases

Most if not all triglycerides (including synthetic triglycerides) go through a phase transition. Typically, it is the form V to VI. Some manufacturers insist that Span 65 be used to stabilize the formulation. Regardless, post hardening of the suppository is an issue and must be addressed during formulation.

Fat Bloom

• Fat bloom is recognized as a grayish white film on the surface.

• Fat bloom is occurs because fat migrates to the surface through micro-fissures and crystallizes as “bloom.”

• Fat bloom is an aesthetic issue and does not have an impact on product quality.

Causes of Fat Bloom

• Poor tempering

• Bloom can form if cocoa butter is mixed with incompatible fats

• High moisture

Surfactant Use Inhibits Fat Bloom

• The mechanism is as follows:

• The IV to V transition is facilitated because this transition occurs in the liquid phase only.

• The V to VI transition is hindered because there is less solid fraction in the butter and this transition occurs only in the solid phase.

Surfactant Ratios

• Span 60 + Tween 60 (75:25)

• Span 65 + Tween 65 (50:50)

• Span 60 + Tween 65 (75:25)

• Span 65 + Tween 60 (50:50)

• Span 65 + Tween 65 (50:50)

• Span 65 + Tween 65 (75:25)

• Span 65 (100)

• All surfactants to be used at 1 to 10%

Surfactants as Bioavailability Enhancers

• Cleansing action caused by the surfactant-containing vehicle may make additional pore spaces available for drug absorption.

• Drug movement across the rectal membrane is facilitated.

Drawbacksof Surfactant Use in

Suppositories

• Absorption is decreased for phenol type drugs, likely due to drug surfactant complex

• Surfactants can disrupt mucosal membrane and produce a marked histological change to the mucosa after prolonged administration.

API and Suppository Base Solubility

It is difficult to suspend APIs that are insoluble in the base vehicle while forming suppositories.Content uniformity is a challenge. Must devise formulation strategies include solubilizing the API and spraying it onto carrier substrates.Remember:Ideally water soluble, oil insoluble API salts are preferred in fat based suppositories.If the drug has a lipid-water coefficient favoring fat solubility, the drug will be released slowly if at all.

Glycerinated Gelatin

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.

Polyethylene Glycol (PEG) polymers

They are chemically stable, nonirritating, miscible with water and mucous secretions, and can be formulated in a wide range of hardness and melting points

They do not melt at body temperature, but dissolve to provide a more prolonged release than cocoa butter.

They are not completely inert and may pose formulation issues particularly wit narcotics.

Suppository Tablets

Typically used for vaginal dosing

Ingredients include API, lactose and /or dextrose, boric and/or phosphoric acid to adjust acidity of the vagina to pH 5.

Technology investment is small since standard tablet press can be used.

Drug Absorption From Oral Administration

Drug is absorbed from the small intestine and is carried to by the hepatic portal vein to the liver.

Therapeutic activity may be modified by the liver.

Systemic effectiveness may be affected because the liver chemically modifies many drugs after absorption.

Drug Absorption From Rectal Suppositories

Drug absorption by the hemorrhoidal veins surrounding the colon and rectum enter into the inferior vena cava and by-pass the liver.

The upper hemorrhoidal vein does connect with portal veins leading to the liver.

The rate limiting step is the diffusion of the drug to the site of the drug to the site of the rectal mucosa at which absorption occurs.

Conclusions

Suppository formulation using water soluble bases are the ideal and are preferred for vaginal preparations

Suppository formulations using lipid bases are preferred for hemorrhoid preparations but requires detailed knowledge of the raw materials used to manufacture suppositories.

Drug absorption is dependent on many factors such as pH , drug solubility and suppository vehicle.