4 - Suppositories Theory Flashcards
Solid dispersions or Solid Solutions
Drug phase is uniformly dispersed in a
WAXY or RUBBERY
solid dispersion medium
Suppositories - can also use orally if in capsules
Solid dispersions- typically form a RIGID SOLID MASS
Dispersions in a Gel Matrix
Drugs may be admin. topically in the form of
Dispersions in a Gel Matrix
Ointments / Transdermal drug deliv systems
Gels typically form a FLEXIBLE SOLID MASS
but may be liquified prior to application by either heating or shaking vigorously (thixotropic)
Type of gel that is formed by polymers cross-linked to one another by COVALENT BONDS
maintain structural INTEGRITY after drying in order to REMOVE solvent
Type 1 Gels
Derivatives of methacrylic acid
Used to manufacture:
Implants / Opthalmic Inserts / Contact Lenses
Implants to Deliver Antibiotics
ex. treat infections of middle ear or other non-accessible sites
Type 1 Gel
cross linked variety of agents that form dry powders that swell & form a gel on contact with water
agents:
dimethacrylate / methylenebisacrylamide
Soft Contact Lenses
Opthalmic controlled release drug delivery systems
Type 1 Gels
cross linked poly methacrylate
Disintigrant for Tablet formulations
Type 1 Gels
Use Croscarmellose sodium, that SWELLS on contact with water
= cross-linked carboxymethylcellulose sodium
Type of gel that is formed by polymers linked by
REVERSIBLY FORMED intermolecular bonds
like hydrogen bonds
can be recovered through melting / diluting with solvent
Type 2 Gel
Classiified by apparent # of phases & nature of interstitial solvent
unstable to changes in temperature ,stability affected by additives (salt / cosolvents)
every OTHER semisolid or solid dispersion solid solution drug delivery system
The taking up of liquid
WITHOUT measurable change in VOLUME
IMBIBITION
The taking up of liquid with an INCREASE IN VOLUME
SWELLING
Particles of dispersed phase interact SO STRONGLY
that the dispersing medium is SQUEEZED OUT
and forms a Seperate liquid phase
THE GEL ITSELF SHRINKS IN VOLUME
SYNERSIS
Reversible gel-sol (semisolid -fluid) formation with
NO CHANGE in
VOLUME or TEMPERATURE
usually triggered by SHEER FORCES
THIXOTROPY
Desolvated gel in which the
Framework remains INTACT
both Type 1 & Type 2 gels can be desolvated to become this
XEROGELS
Type of Gel Classification
Consist of macromolecules forming twisted / matted strands with the liquid phase in interstitial spaces
Usually formed by organic polymers such as
methacrylic acid (carbopol) = NOT CROSS LINKED
tragacanth / cellulose derivatives
ONE-Phase System
not 2-phase
Type of Gel Classification
Consists of FLOCCULES of small particles with distinct interparticular phase boundaries
Usually formed by INORGANIC materials:
Aluinum hydroxide gel / Bentonite magma
Milk of Magnesia
TWO-Phase System
not 1phase
Type of Gel Classification
Formed by HIGH concentrations of HYDROPHILIC COLLOIDS:
very common in drug delivery systems:
Colloidal Silica / Bentonite / ragacanth
Gelatin / Pectin / Acacia
Methylcellulose / Sodium Alginate
HYDROGELS
hence HYDRO-PHILIC = water love
Alumina / METHACRYLIC ACID / Gums
Starches
Maltodextrin
Type of Gel Classification
formed by HIGH concentrations of LIPOPHYLIC materials or
HYDROPHILIC POLYMERS that self-associate
LESS common ingredients
ORGANOGELS
Ex: Petrolatum / Plastibase
FATS - lard / cocoa butter
Aluminum Stearate
PEG / PVP / Cellulose derivatives
Most wildley used NATURAL polymer in pharmaceutical products
HYDROPHILIC Colloid = HYDROGEL
Used as:
Soft/hard ____ capsules
Tab granulations / coatings
Emulsions / Suppositories
GELATIN
Compounding with Gelatin
Hydrogel + Onephase (organic)
similars: Gums agar / irish moss (carrageenan) / pectin
tragcanth
Cold Water –> powder gelatin = gel on surface of particle
Hot Water –> DISSOLVE gelatin
colloidal dispersion will readily form with stirring
Cooling –> semi-rigid gel forms
Gelatin
Gel or Solid Dispersion?
What does adding/removing water do?
HydroGEL
with enough HOT water –> can be formed into shapes by molding or film casting then DEHYDRATING until you reach the desired rigidity
MORE WATER –> MORE FLEXIBLE
Less water = less rigid
EVEN LESS WATER = Brittle Plastic
Gelling agents that
REQUIRE HEAT
during compounding
Gelatin
Natural Gums
Gelling agents that are
ADVERSELY AFFECTED
by OVERHEATING
COCOA BUTTER
Define
Dispersions or Solutions of a drug substance prepared by HEATING a SOLID dispersing medium (organogel) above its melting point
Then dispersing the DRUG particles in the molten medium
sometimes with aid of a surfactant or emulsifier
SOLID DISPERSIONS
typically a organogel (fat / high MW polymer)
Result AFTER COOLING is a coarse/fine dispersion of the drug in a solid matrix
Define
Formed by dissolving a drug substance in a
MOLTEN solid solvent
have a VARIABLE MELTING POINT, based on composition
Solid SOLUTION
(molecular dispersion = solution)
Result after cooling is microcrystals of the drug substance in a SOLID matrix
may or may NOT be crystalline
Define
Mixture of 2 Solids that have a SHARP MELTING POINT
EUTECTICS
E = Eutectic Point
When the 2 compositions (drug in molten medium) reach this point, the remaining liquid crystallizes as a
MIXED CRYSTAL MASS
containing both A + B microcrystals
altered solubility properties!
Eutectics might have a
MORE RAPID DISSOLUTION
due to:
Increased DRUG Solubility
Solubilization by carrier
Prevention of Aggregation of drug particles
Altered Wettability
production of Metastable solid forms
TRUE Solid Solutions
Variable Melting Point, based on composition
NO eutectic is observed
Commonly observed for METAL ALLOYS
molecule of B is replaced by molecule of A in the crystal lattice of the solid
CONTINUOUS Solid Solutions
Variable Melting Point, based on composition
uncommon in pharmaceutical applications
2 components are MISCIBLE WITH EACH OTHER
in all proportions in the liquid/molten state
AMORPHOUS Solid Solution
Common with Gel-Forming Polymers as the SOLVENT component for the drug
PEG / PVP / Cellulose Derivatives
Solute molecules are DISPERSED MOLECULARLY
BUT IRREGULARLY within the Amorphous solvent
drug loading may be a problem,
Solubility in PEG for poorly water soluble drugs can be <10%
PEG
Amorphous Solid Solution
Polymer that contain BOTH
Microcrystalline + Amorphous Regions
Drug may dissolve in the Amorphous PEG which
PREVENTS Crystallization of the drug
Rectal Suppositories used for?
Used to administer drugs for systemic effects for patients
unable to take medication by mouth
or
for LOCAL action in the PERIANAL Area
ex. cathartic suppositories - produce peristalsis
hemorrhoid suppositories
Rectal Absorption of Drugs
Suppositories
Mucosa of the rectum/anus are LIPOID BARRIERS
Solid dosage forms typically soften / melt @ body temp
Partitioning effects control bioavailbility
Formulation of a Suppository
Coarse Dispersion of drug particles in a BASE of:
low-melting AMORPHOUS solid matrix
(cocoa butter / similar fats)
or
semi-CRYSTALLINE solid matrix
slowly-dissolving water-soluble polymers
(PEG / Glycerinated Gelatin)
Formulation of VAGINAL Suppositories
have a local dehydrating Effect;
MOISTEN with WATER before use & STORE DRY
MOST use HYDROPHILIC BASES
(PEG +/- Surfactants / Glycerinated Gelatin)
Hygroscopic (absorb moisture from the AIR) & require protection from moisture
Uses for Vaginal Suppositories
ANTIBIOTICS
clindamycin = bacterial infections
Miconazole nitrate = antifungal / yeast infections
CONTRACEPTRION
nonoxynol-9
Urethral Suppositories
UNCOMMON
OG made from cocoa butter, but need SMALL DIAMETER
so PEG-Based are now PREFFERED, have resistance to breaking
Type of Suppository Base
Mixture of Crystalline Polymorphs that MELT in the range of 30-36*C
Suppositories need to be SOLID @ room temp,
but readily dissolved @ body temp
COCOA BUTTER
(Theobroma Oil)
MELT @ 30-36*
melting point can be CONTROLLED using additives
Type of Suppository Base (dispersing medium) that
DISSOLVES,
rather than MELT
Suppositories need to be SOLID @ room temp,
but readily dissolved @ body temp
PEG (Carbowax)
PEG 1000 = 37-40*C
PEG 3350 = 54-58*C
PEG 4600 / 6000 = 60+
Hygroscopic / releases much slower
Type of Suppository Base (dispersing medium) that
Softens & Dissolves SLOWLY,
rather than MELT
Suppositories need to be SOLID @ room temp,
but readily dissolved @ body temp
GLYCERINATED GELATIN
softens / dissolves slowly
mainly for Vaginal Inserts
MORE HYGROSCOPIC
may irritate tho if NOT pre-moistened
Cocoa Butter Formulation
From a Mixture of Triglycerides from Theobroma Cacoa
major component of CHOCOLATE
Adding Fat-Soluble Drugs–> can lower melting point
SO we can HIGHER the MP by adding:
waxes / spermaceti to adjust the MP to reach 36*C
- HydroPHILIC drugs are INSOLUBLE in cocoa butter*
- they form solid dispersions*
Fattibase
(TG’s from PALM + COCONUT oils w/ glycerol…)
Wecobee Bases
(Coconut oil TGs)
Witopsol Bases
COMPETING PRODUCTS
of cocoa butter
Cocoa butter is from a mixture of TG’s from Theobroma cacao, which forms Multiple Crystalline Polymorphs, which has a
_Melting point of ~36*C?_
Beta - Polymorph
PREFERRED POLYMORPH
Alpha polymorphs will slowly convert into Beta over several days
Cocoa butter is from a mixture of TG’s from Theobroma cacao, which forms Multiple Crystalline Polymorphs, which has a
_Melting point of <30*C?_
Metastable
Alpha-Polymorph
Formed if heated ABOVE 60* and is RAPIDLY CHILLED
UNUSABLE as a suppository
will convert to Beta over several days
In order to PREVENT formation of the Alpha-Polymorph (instead of the Beta-Polymorph) what must you do?
Cocoa Butter Suppository Base
heat/melt BELOW <50*C
use slow cooling of melt
PEG = Carbowax
Formulation / Composition
Base for Suppositories
DISSOLVE in body fluids rather than melt
May form Solid Solutions / Dispersions
hygroscopic (absorb moisture)
Partitioning Effect =
Hydrophilic drugs may release MORE SLOWLY
use cocoa butter for rapid onset of action
Glycerinated Gelatin
Formulation / Composition
Base for Suppositories
20 parts gelatin + 70 parts glycerol + 10 parts water/drug
Used mostly for Vaginal Inserts
Softens SLOWLY, provides a DELAYED RELEASE
Hygroscopic
(more than PEG, may IRRITATE if not premoistened)
Method of Compounding Suppositories
Like making BREAD!
-
Titurate drug into fine powder
- add grated cocoabutter/base
- Incorporate drug into base using pestle
- Place between sheets of filtered paper
- kneed + roll into CYLINDER
- cut to length
COLD ROLLED
Traditional method
w/ mortar & Pestle
Method of Compounding Suppositories
Similar to Cold-Rolled but
Place initial compact mass in a
PRESS & FORCE INTO MOLD
COMPRESSION MOLDED
Method of Compounding Suppositories
-
Melt the base
- use SLOW heating w/ cocoa butter
- avoid completing melting to preserve Beta polymorph seed crystals
- use SLOW heating w/ cocoa butter
- Add Drug & dissolve or disperse in molten base
-
Pour into mold
- allow to cool,
- use SLOW COOLING to force crystallization as Beta polymorph
- allow to cool,
Fusion
or
Hot Melt Molding
