SUPPOSITORIES INSERTS AND STICKS

Suppositories

• solid dosage form in which one or more APIs are dispensed in a suitable base and molded into a suitable shape.

• Intended for insertion into the body orifices (rectal, vaginal, urethral) where they melt, soften, or dissolve.

• exert localized or systemic effects

• Promotes defecation.

• Introduce drugs into the body.

• Treat anorectal disease

Reasons in using suppositories are:

Rectal (adult)

• Cylindrical Bullet Torpedo Little finger

• Size & weight if cocoa butter is used as base:- 32mm -1.5in long - 2g

Rectal (infant & children)

• Pencil like

• Size & weight if cocoa butter is used as base: - 16mm - 0.75in - 1g

Vaginal (pessaries)

• Globular Oviform Cone shape

• Size & weight if cocoa butter is used as base: - sizes differ - 5g

Urethral bougies (male)

• Slender pencil shape

• Size & weight if cocoa butter is used as base: - 3-6mm in diameter -140mm long - 4g

Urethral (female)

• Slender pencil shape

• Size & weight if cocoa butter is used as base: -half of male 1.5-3mm in diameter - 70mm long - 2g

• Will not undergo first pass effect.

• Drug stability

• Administer larger doses of drugs than oral medication.

• Administer drugs that can cause irritation to gastrointestinal (GI) mucosa.

• Administer unpleasant tasting or smelling drugs.

• Useful in children, refuse oral medication and fear of injection.

• For patient experiencing nausea and vomiting when patient is unconscious.

• Presence of disease in upper gastrointestinal tract that may interfere drug absorption.

• Objectionable taste and odor of the drug x Rapid drug effect systematically

ADVANTAGES OF SUPPOSITORIES

• Lack of flexibility in dosage resulting to underuse and lack of availability.

• Made by demand, it is expensive.

• They are safe but effectiveness varies in different factors.

• Narrow therapeutic margin drugs cannot be interchanged without risk of toxicity.

• Bullet shape suppository after insertion can leave at anorectal site, should not be used at bedtime.

• Defecation may interrupt the absorption process of the drug; this may especially occur if the drug is irritating.

• Absorption surface area of rectum is much smaller than that of the small intestine.

• Fluid content of the rectum is much less than that of the small intestine which may affect dissolution rate.

• Possibility of degradation of some drugs by the microflora present in the rectum.

• Greater dose for rectal route than oral route.

DISADVANTAGES OF SUPPOSITORIES

LOCAL ACTION

• Once inserted, it will melt, soften, or dissolve, distributing its medicaments to the tissue of the region.

• ____ means its action/effect is only in that area.

RECTAL

- Constipation

-Relieve pain, irritation, itching, and inflammation associated w/ hemorrhoids & anorectal conditions

-Laxative (glycerin)

VAGINAL

- contraceptives (nonoxynol 9)

- antiseptic in feminine hygiene

-combat invading pathogen (trichomonacides, antifungal, antibiotics, antiinfectives)

URETHRAL

- antibacterial

- Local anesthetics for urethral examination

SYSTEMIC ACTION

• The action of effect of the product will enter the systemic circulation.

• Will elicit an effect that is used to treat or alleviate certain types of discomfort in the body.

Ondansetron

Nausea and vomiting

Prochlorperazine & chlorpromazine

Nausea, vomiting, tranquilizers

Oxymorphone & morphine

Opioid analgesic

Ergotamine tartrate

Migraine

Indomethacin

NSAID

Opigesic supp. (paracetamol)

Analgesic-antipyretic

Physiologic

• in body system

• Circulation route, pH of rectal fluids, Colonic content

Physicochemical

• product that are preparing

• Lipid-water solubility, Particle size, Nature of base

CIRCULATION ROUTE

• Under PHYSIOLOGICAL FACTOR

• Drugs absorbed in the rectum bypass the first pass effect in the liver instead of being absorbed into the general circulation.

• 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

• Under PHYSIOLOGICAL FACTOR

• Rectal fluids are essentially neutral in pH (7.2-7.4) and have no effective buffer capacity.

• the form in which the drug is administered will not generally be chemically changed by the rectal environment.

COLONIC CONTENT

• Under PHYSIOLOGICAL FACTOR

• It is more effective for a drug to absorbed systematically in an empty rectum than from one that is distended w/ fecal.

• Diarrhea, tissue dehydration can influence the rate and degree of absorption at the rectal site.

Colonic

It is in the colon.

LIPID-WATER SOLUBILITY

• under PHYSICOCHEMICAL FACTORS

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

  o API (fats) + base (fats) -> rectum w/ aqueous fluid = bad absorption

  o API (aqueous) + base (fats) -> rectum w/ aqueous fluid = good absorption

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

PARTICLE SIZE

• under PHYSICOCHEMICAL FACTORS

• Smaller particles size the more readily the dissolution of the particle and the greater chance for rapid absorption.

• It is preferable to avoid a too fine particle size because of the high increase of the viscosity of the melted excipient that can result from the use of excessively small particles and possible difficulties in flow during production.

NATURE OF THE BASE

• under PHYSICOCHEMICAL FACTORS

• Base must be capable of melting, softening, or dissolving to release its absorption.

• If the base interacts w/ the drug to inhibit its release, drug reaction will be impaired or prevented.

• 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.

• Physically and chemically stable

• Nonirritating

• Nontoxic

• Nonsensitizing

• Chemically and physically inert

• Compatible w/ a variety of drug

• Stable during storage

• Esthetically acceptable (odor and appearance)

IDEAL SUPPOSITORY BASES

FATTY OR OLEAGINOUS

• -most frequently used

• - Cocoa butter

• -Hydrogenated fatty acids of vegetable oil (palm kernel oil & cottonseed oil)

• Fat based w/ glycerin & high MW fatty acids (palmitic & stearic acids; glyceryl monosterate & glyceryl monopalmitate)

WATER SOLUBLE OR WATER MISCIBLE

• -glycerinated gelatin

• -Polyethylene glycol

MISCELLANEOUS

• -mixture of oleaginous and water soluble and water miscible -

• ex. polyoxyl 40 stearate

COCOA BUTTER

• Most commonly used base

• Fats from roasted seed of Theobroma cacao

• Has high melting point, Melts at 30-36 degrees Celsius

• Ideal rectal suppository base

• Disadvantage: because of triglyceride it will exhibit polymorphism -> crystals

• Must be slowly and evenly melted in water bath to avoid crystallization.

Phenol and chloral hydrate

• lowers melting point. (to COCOA BUTTER)

• Problem: if we add these it will not solidify the preparation that is why we need to add the solidifying agents.

Cetyl esters wax

• 20%

• or beeswax (4%)

• solidifying agent

Witepsol bases

• triglycerides of saturated fatty acids (lauric acid)

• Triglycerites of saturated fatty acids C12-C18 w/ varied portion of corresponding partial glycerides.

Wecobee bases

triglycerides derived from coconut oil

Fattibase

• triglycerides from palm, palm kernel, and coconut oils w/ self-emulsifying glyceryl monostreate and polyoxyl stearate.

• This drug is registered and patented, and available in market.

Glycerinated gelatin

• most frequently used in the preparation of vaginal suppositories.

• Gelatin (20%) glycerin (70%) medication - API (10%)

• Tends to absorb moisture, has dehydrating effect and irritates tissue upon insertion (moist prior to insertion).

  -To avoid dehydrating effects, dip the glycerinated gelatin w/ water before insertion.

urethral type %

ƒ Gelatin (60%) ƒ Glycerin (20%) ƒ Medication - API (20%)

MACROGOLS (POLYETHYLENE GLYCOLS)

• Polyethylene glycols are polymers of ethylene oxide and water, prepared to various chain lengths, molecular weights, and physical states.

• white solids w/ the hardness increasing w/ an increase in the molecular weight.

• Do not melt at body temperature but rather dissolved slowly

• Do not leak from orifices, PEG less than 20% water should be dipped in water prior to use

clear, colorless liquids

average molecular weight of 300, 400, and 600

semisolids

molecular weight of 600-1000

wax-like

average molecular weight of greater than 1000

above 20% water

no need to dip in water.

20% water or less

it is necessary to dip in water before insertion.

FORMULATION CONSIDERATION

• nature and form of the active ingredients

• physical state, particle dimension and specific surface of the product.

• Solubility of the drug in various bases.

• Presence or absence of adjuvants added to the active principles.

• Nature and type of dosage form in which the active principles are incorporated.

• Pharmaceutical procedures used in the preparation of the dosage forms.

PHYSICAL STATE

an active drug can be solid, liquid, or semisolid in nature.

solids

especially if the drug is not very water soluble; the increase in surface area resulting from decreased particle size can serve to enhance its activity.

liquids

it is necessary to take up the liquid into the suppository base using one of several techniques such as forming an emulsion, adding a drying powder, or adding a suitable thickening agent when the liquid is mixed w/ the suppository base

semisolids or paste-type drugs

it can be either mixed w/ a solid that will serve to thicken the drug prior to mixing w/ the base or mixed with the base to which a thicker is added.

PARTICLE SIZE

• the smaller the particle sizes the better

• If a drug is readily soluble minimal effect on particle size

highly soluble drugs

it will be dissolved and migrate to the rectal barrier.

poorly water-soluble drugs

the dissolution rate will be slower, and a reduction in particle size may increase the rate of dissolution by exposing a greater surface area.

SOLUBILITY

• Increased solubility of the active in the base can improve product homogenicity.

• If there is greater affinity of the drug for the suppository vehicle it will delay the release of the drug.

• Homogenicity of the mixture can be obtained by constant agitation of the mixture during processing and filling.

• Select a temperature just above the melting point of the suppository mixture where the mixture is thick but still pourable.

VISCOSITY

• If the ___of a base is low, it may be necessary to add suspending agent such as silica gel to ensure that the drug is uniformly dispersed until solidification occurs.

• When preparing the suppository, stir the melt constantly and keep it at the lowest possible temperature to maintain a high viscosity.

• After the suppository has been administered, the release rate of the drug may be slowed if the viscosity of the base id very high, this is because the ____causes the drug to diffuse more slowly through the base to reach the mucosal membrane for absorption.

BRITTLENESS

• ___ suppositories can be difficult to handle, wrap, and use.

• Cocoa butter suppositories are usually not brittle unless the percentage of solid present is high.

• ____results when the percentage of non-base materials exceed about 30%

• Synthetic fat bases w/ high stearate concentrations or those that are highly hydrogenated are typically more brittle.

Shock cooling

• also causes fat and cocoa butter suppositories to crack.

  - Can be prevented by ensuring that the temperature of the molds is as close to the temperature of the melted base as possible.

  - Suppositories should also not be placed in a freezer, which also causes ___

VOLUME CONTACTION

Bases, excipients, and active ingredients generally occupy less-space at lower temperature than at higher temperatures

Oil-soluble drug: oily base

Slow release; poor escaping tendency

Water-soluble drug: oily base

• best combination

• Rapid release

Oil-soluble drug: water miscible base

Moderate release

water miscible drug: water miscible base

Moderate release; based on diffusion; all water soluble

Molding from a melt

most frequently used.

fusion method

w/ aid of heat.

1. Melting of the base

2. Incorporation of any required medicament

3. Pouring the melt in the molds

4. Allowing the melt to cool and congeal to suppositories.

5. Removing the formed suppositories from the mold

6. The molds may be made up of stainless steel, aluminum, brass, plastic.

fusion method steps

Lubricant

necessary w/ glycerinated gelatin (mineral oil - commonly used) to facilitate easy removal of the product into the molder

Hand rolling and shaping

• oldest and simplest method, by rolling the suppository into the desired shape.

• the mass is then rolled into a cylindrical rod of desire length and diameter.

• Not commonly use anymore.

Compression

cold mass of the base containing the drug is compressed into suppositories by using compression into desired shape.

Cocoa Butter

• Individually wrapped w/ separate compartmentalized box.

• ‘Stored below 30C refrigerated

Glycerinated gelatin

• Tightly closed container

• Controlled room temperature

PEG

• Tightly closed container

• Usual room temperature

Light sensitive drugs

individually wrapped, opaque material like metallic foil or plastic.

Stored in high humidity

• Never store suppositories in

• absorb moisture tends to become spongy.

Stored in extreme dryness

• Never store suppositories in

• may lose moisture and become brittle.

Muse (ALPROSTADIL)

• urethral microsuppository.

• This is the only popular product for urethral supp.

• A single use medicated transurethral system for the delivery of alprostadil to the male urethra.

• Treatment of erectile dysfunction.

VAGINAL INSERT

• Other term is vaginal tablet.

• Advantage: easy to manufacture; more stable; less messy.

• Usually ovoid packed w/ inserted.

• Prepared by tablet compression

VAGINAL INSERT Ingredients

o Lactose - filler/diluent

o Starch - disintegrants

o Polyvinylpyrrolidone - dispersing agent

o Magnesium stearate - lubricant

Capsules of gelatin coating

innovation that now can be inserted into the vagina and rectum.

MEDICATION STICKS

• Administering topical drugs (outer surface area of skin)

• Packaging 5g tube 1-2oz for local anesthetics

• Packed in an applicator tube for topical administration and the applicator can be adjusted to continually exposed new fresh sticks

• Local anesthetics, sunscreens, oncology products, antiviral and antibiotics.

Penetration enhancers

can increase the amount of transdermal drug delivery.

Melting base

can be further divided into opaque and clear

• Opaque bases include waxes, oils, PEGs.

• Clear bases include sodium stearate/glycerin mixtures.