cocoa butter based suppository formulation

Suppository Formulation Suppository Formulation and Manufactureand ManufactureJim McElroy

What Is A Suppository?What Is A Suppository?

A suppository is a medicated solid dosage form used in the rectum, vagina and urethra.Suppositories often contain vehicles that melt or soften at body temperature. Vaginal suppositories, called pessaries, can be made as compressed tablets. Urethra suppositories are called bougies.

Shapes and Weights of Shapes and Weights of SuppositoriesSuppositories

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 SuppositoriesTypical Suppositories

Types of Suppository Types of Suppository BasesBases

Oleaginous (i.e. triglycerides)Lipid based suppositories are typically used for hemorrhoidal

preparations but can be used for vaginal and urethral dosing. Glycerinated Gelatin

Used particularly for vaginal suppositories. They are a translucent gelatinous solid that tend to disperse slowly in mucous secretions to provide prolonged release of active ingredients.

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

minimal manufacturing issues. Surfactants

Surfactant based suppositories offer rapid delivery but cannot be used for an extended period of time because of irritation.

Tablets Used particularly for vaginal suppositories.

TriglyceridesTriglycerides

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) and most suppository bases intended for hemorrhoid therapy are triglycerides.

Crystallization and Melting Crystallization and Melting Ranges of Cocoa ButterRanges of Cocoa Butter

Cocoa butter is a polymorphic substance. There are four to six forms of crystals in cocoa butter.

Different researchers have used different nomenclatures over the years.

Different researchers disagree over the number of crystal forms.

Crystal Melting Ranges of Cocoa Crystal Melting Ranges of Cocoa ButterButter

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

Tempering Cocoa ButterTempering 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.

The Tempering ProcessThe 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 BasesSynthetic 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 BloomFat BloomFat 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 BloomCauses of Fat BloomPoor temperingBloom can form if cocoa butter is

mixed with incompatible fatsHigh moisture

Surfactant Use Inhibits Fat Surfactant Use Inhibits Fat BloomBloom

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 RatiosSurfactant RatiosSpan 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 Surfactants as Bioavailability EnhancersEnhancers

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.

DrawbacksDrawbacksof Surfactant Use in of Surfactant Use in SuppositoriesSuppositories

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.

Insoluble APIsInsoluble APIsIt is difficult to suspend insoluble

APIs while forming suppositories.Content uniformity is a challenge.

Some commonly used APIs (i.e. phenylephrine HCl) are present at 0.15%.

Possible formulation strategies include solubilizing the API and spraying it onto starch (or other carrier)

Soluble APIsSoluble APIsWater soluble, oil insoluble 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.

Water Soluble BasesWater Soluble BasesIdeally, water soluble bases

should be used whenever possible.

Typical water soluble bases are glycerinated gelatin and PEG

Suppository TabletsSuppository Tablets

Typically used for vaginal dosingIngredients include API, lactose

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

Vaginal tablet suppositories are used for topical therapy.

Drug Absorption From Oral Drug Absorption From Oral AdministrationAdministration

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 Drug Absorption From Rectal SuppositoriesSuppositories

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.

ConclusionsConclusions

Suppository formulations using cocoa butter (or synthetics) requires detailed knowledge of the raw materials used to manufacture suppositories.

Suppository formulation using water soluble bases are the ideal and are preferred.

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